Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:14]([NH:17][CH2:18][C:19](O)=[O:20])(=[O:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[O:10][C:19](=[O:20])[C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1O
Reactant: CC(=O)NCC(=O)O
Product: CC(=O)Nc1cc2cc(Br)cc([N+](=O)[O-])c2oc1=O

Procedure:
The second step was the Erlenmeyer condensation of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) with N-acetyl-glycine to yield N-(6-bromo-8-nitro-2-oxo-2H-1-benzopyran-3-yl)acetamide (3*).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([O:43]C)=[O:42])=[CH:37][C:36]=4[CH3:45])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O1CCOCC1>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([OH:43])=[O:42])=[CH:37][C:36]=4[CH3:45])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(Cl)cc(Cl)c2)[C@@H]1C
Temperature: 60 °C
Yield: 90.9 %

Procedure:
To methyl 3′-[2-(azetidin-1-yl)-4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (78 mg, 0.121 mmol) in dioxane (2.4 mL) was added LiOH (0.5 M, 1.2 mL, 0.605 mmol). The reaction was heated to 60° C. for 1 hour before cooling and acidifying with TFA. The volatiles were removed and the crude material was purified by reverse phase HPLC to yield 3′-[2-(azetidin-1-yl)-4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (70 mg, 0.110 mmol). LCMS calc.=633.2. found=−633.3. 1H NMR (CDCl3, 500 MHz) 8.19 (s, 1H), 7.98 (m, 2H), 7.33 (m, 3H), 7.15 (m, 3H), 7.04 (d, J=8.6 Hz, 1H), 5.42 (br s, 1H), 4.75 (br s, 1H), 4.23 (m, 5H), 4.01 (br s, 1H), 3.87 (s, 3H), 2.43 (m, 2H), 2.36 (s, 3H), 0.73 (s, 3H). RTA=4.43 nM
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][CH2:14][CH:15](O)[CH2:16][F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:15]([CH2:16][F:17])[CH2:14][F:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OC(CF)CF
Reactant: Oc1ccc2ncnc(Cl)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FCC(CF)Oc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
4-Chloro-6-hydroxy-quinazoline (500 mg; 2.78 mmol), 800 mg (8.33 mmol) of 1,3-difluoro-2-propanol and 2.18 g (8.33 mmol) of triphenyl phosphine were dissolved in 30 ml of THF and 3.62 g (8.33 mmol) was added thereto at room temperature. The reaction solution was stirred at room temperature for 3 hours more, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:2) to give 530 mg (yield: 74%) of 4-chloro-6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazoline as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH3:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][C:28](=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH3:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1cc2c(cc1N)N1C(=NNC(=O)C1C)CO2
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 32.2 %

Procedure:
A solution of 6-amino-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.1 g, 4.5 mmol) and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.53 g, 8.9 mmol) in methanol (45 mL) and acetic acid (5 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (0.563 g, 8.9 mmol) was added and the resulting dark solution was stirred at rt for 14 h. The solvent was removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluting with 33% EtOAc in petroleum ether) to give 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (racemate, 0.580 g, 1.45 mmol, 32%) as an off-white powder. The racemate was further separated by chiral SFC (Table 2, Method 3) to give two enantiomers: 3-(4(R),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 1, SFC (Table 1, Method 8), Rt=3.090 min, 0.250 g, 14%) and 3-(4(S),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, SFC (Table 1, Method 8), Rt=4.151 min, 0.240 g, 13%). LC/MS (Table 1, Method 2) Rt=1.065 min.; MS m/z: 424 [M+23]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N[C:14]1[NH:18][CH:17]=[N:16][C:15]=1[C:19]([NH2:21])=[O:20].C(O)(=O)C.C([BH3-])#[N:27].[Na+]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:27][C:15]2([C:19]([NH2:21])=[O:20])[CH2:14][NH:18][CH:17]=[N:16]2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1nc[nH]c1N
Reactant: O=Cc1ccnc2ccccc12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)C1(NCc2ccnc3ccccc23)CNC=N1
Temperature: 25 °C

Procedure:
The title compound was prepared in accordance with the general method described in Example 17(e) using quinoline-4-carbaldehyde (1.0 g, 6.4 mmol), 5-aminoimidazole-4-carboxamide (0.80 g, 6.4 mmol), acetic acid (0.44 mL, 7.6 mmol) and sodium cyanoborohydride (0.48 g, 7.6 mmol) with the exception that after stirring o.n., another portion of sodium cyanoborohydride (0.48 g, 7.6 mmol) was added and the mixture heated to reflux for 4 h. After cooling to r.t., the solution was concentrated in vacuo. A portion of the 2.9 g of crude material obtained was used in the next step without further purification. MS (ESI) m/z 268 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:8]([C:14]([CH3:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[H][H].I[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:20]([C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]1)([C:14]([CH3:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(C(C)=O)C1CCCC1
Reactant: [H][H]
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(C(C)=O)(C(=O)OCC)C1CCCC1
Yield: 70.9 %

Procedure:
A mechanically stirred suspension of sodium hydride (4.00 g of 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (DMF, 100 mL) was treated dropwise with a solution of ethyl 2-cyclopentyl-3-methyl-3-oxo-propionate (17.7 g) in DMF (50.0 mL) at room temperature under nitrogen atmosphere. Stirring of the reaction mixture was continued at this temperature until the formation of hydrogen ended and the reaction mixture became transparent. After that the mixture was treated dropwise with a solution of 1-iodobutane (19.9 g) in DMF (50 mL) and stirred at room temperature overnight. The reaction mixture was then quenched by pouring onto a mixture of ice and 10% aqueous hydrochloric acid. The formed organic phase was separated and the aqueous phase was extracted with hexane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and distilled in vacuum to give 16.1 g (70%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:19]([O:20][CH3:21])[CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)C1CCCN(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCCN(Cc2ccccc2)C1
Yield: 71.5 %

Procedure:
1-Benzylpiperidine-3-carboxylic acid (318 mg, 1.45 mmol) and N,O-dimethylhydroxylamine hydrochloride (287 mg, 2.94 mmol) in tetrahydrofuran (5 mL) was stirred with triethylamine (283 μL, 2.03 mmol), 1-hydroxybenzotriazole (101 mg, 0.747 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg, 2.92 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (272 mg, yield 71%).
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26]C)=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:30][CH:29]=1)(C)(=O)=O.Br.[CH2:40]([S:46]C(=N)N)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].B(Br)(Br)Br>CN(C)C=O>[CH2:40]([S:46][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[C:28]1[CH:29]=[CH:30][C:31]([C:32]([N:34]([CH3:35])[CH3:36])=[O:33])=[CH:37][CH:38]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COc1ccc2c(c1)CCC(c1ccc(C(=O)N(C)C)cc1)C2CCCCCCCCCCOS(C)(=O)=O
Reactant: CCCCCCSC(=N)N
Agent: Br
Agent: BrB(Br)Br
Solvent: CN(C)C=O
Product: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(C(=O)N(C)C)cc1
Reaction time: 2 h

Procedure:
Aqueous 1ON-sodium hydroxide solution (0.08 ml.) was added to a solution of p-[(1RS,2RS)-1-(10- mesyloxydecyl)-6-methoxy-1,2,3,4-tetrahydronaphth-2-yl]-N,N-dimethylbenzamide (0.107 g.) and S-n-hexylisothiourea hydrobromide (0.097 g.) in dimethylformamide (5 ml.) and the mixture was stirred at laboratory temperature for 2 hours and then evaporated to dryness. Water (5 ml.) was added to the residue and the mixture was extracted three times with diethyl ether (10 ml. each time). The combined extracts were dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using initially cyclohexane and then toluene as eluent. The product thus obtained was demethylated with boron tribromide by a similar process to that described in the second paragraph of Example 1, and the product was purified by chromatography on a silica gel column using a 4:4 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil p-[(1RS,2RS)-1-(10-hexylthiodecyl)-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-N,N-dimethylbenzamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][C@H:26]([CH3:28])[N:25]([CH3:29])[C@H:24]([CH3:30])[CH2:23]2)=[CH:18][CH:17]=1.BrC1C=C2C(=CC=1)[C:38](=[O:42])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:42][CH3:38].[CH3:30][CH:24]1[N:25]([CH3:29])[CH:26]([CH3:28])[CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH2:15])=[CH:21][CH:20]=2)[CH2:23]1
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C[C@H](C)N1C
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CC1CN(c2ccc(N)cc2)CC(C)N1C
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, after purified using silica gel chromatography (using 5% MeOH/CHCl3 as solvent), 0.68 g (91.0% yield) of light brown solid is obtained from 0.45 g (1.60 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 0.38 g (1.76 mmol) of 4-(3,4,5-trimethyl-piperazin-1-yl)-phenylamine: mp 213-214° C.; MS (ESI) m/z 469.1-471.1 (M+H)+1
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[S:26])[CH2:21][CH2:20]1)=[O:18])[CH3:15]>O1CCCC1.C(N(CC)CC)C.C(Cl)Cl>[NH:9]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[NH:1][C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH2:20][CH2:21]1)=[S:26]
Reactant: Nc1ccccc1Cc1ncc[nH]1
Reactant: CCOC(=O)N1CCN(C(=S)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1

Procedure:
To a suspension of 3.8 g of 2-(2-aminobenzyl)imidazole in 38 ml of tetrahydrofuran and 3.23 ml of triethylamine is added dropwise a solution of 5.5 g of 4-ethoxycarbonyl-1-piperazinyl-thiocarbonyl chloride in 10 ml of methylene chloride at room temperature. The mixture is stirred for 1 week and the suspension filtered. The filtrate is washed with first 10% aqueous potassium carbonate, then with water, dried and evaporated to dryness to give amorphous 1-[2-(2-imidazolylmethyl)phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine, characterized by NMR.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[C:12](Cl)(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15].C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[C:12]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11])(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: NCCc1ccccc1CO
Reactant: CC(C)CC(=O)Cl
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: CC(C)CC(=O)NCCc1ccccc1CO

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and isovaleryl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-isovalerylamino-2-(2-hydroxymethylphenyl)ethane. The product was successively reacted in the same way as in steps (d), (e), (f), and (g) of Example 12 to afford 1-isobutylisoquinoline-5-acetonitrile as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH:18]=[CH:19][C:20](=[C:22]([C:37]#[N:38])[CH:23]=[CH:24][CH:25]=[C:26]3[C:31](=[O:32])[N:30]([CH3:33])[C:29](=[O:34])[N:28]([CH3:35])[C:27]3=[O:36])[CH:21]=[C:13]1[C:12]2([CH3:40])[CH3:39])(C)(C)C.[I:42][Si](C)(C)C.CO>C(#N)C>[I-:42].[C:37]([C:22](=[C:20]1[CH:19]=[CH:18][N:14]2[C:15]3[C:11]([C:12]([CH3:40])([CH3:39])[C:13]2=[CH:21]1)=[CH:10][C:9]([CH2:8][NH3+:7])=[CH:17][CH:16]=3)[CH:23]=[CH:24][CH:25]=[C:26]1[C:27](=[O:36])[N:28]([CH3:35])[C:29](=[O:34])[N:30]([CH3:33])[C:31]1=[O:32])#[N:38]
Reactant: CN1C(=O)C(=CC=CC(C#N)=C2C=CN3C(=C2)C(C)(C)c2cc(CNC(=O)OC(C)(C)C)ccc23)C(=O)N(C)C1=O
Reactant: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: CN1C(=O)C(=CC=CC(C#N)=C2C=CN3C(=C2)C(C)(C)c2cc(C[NH3+])ccc23)C(=O)N(C)C1=O
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{8-[1-Cyano-4-(1,3-dimethyl-2,4,6-trioxo-tetrahydro-pyrimidin-5-ylidene)-but-2-enylidene]-10,10-dimethyl-8,10-dihydro-pyrido[1,2-a]indol-2-ylmethyl}-carbamic acid tert-butyl ester (20 g, 0.04 mol; Sigma-Aldrich) from previous step was placed in one-necked round bottom 1 L flask equipped with magnetic stir bar and dissolved in 150 mL of acetonitrile. The flask was closed with rubber septa and flashed with dry nitrogen. 10 g of iodotrimethylsilane were added to the flask with use of syringe, and reaction mixture was stirred at room temperature for 30 min. During addition of iodotrimethylsilane the color of the flask changed from deep blue to deep orange. 25 mL of methanol were added to the reaction mixture and its color become deep blue again. The volume of reaction mixture was reduced in about half using rotary evaporator. During this operation most of the methanol was removed from the reaction mixture and the product, which is insoluble in acetonitrile, precipitates. The product was filtered, washed with acetonitrile, dried and transferred to a 500-mL conical flask equipped with magnetic stirrer. 200 mL of dichloromethane were added to the flask, and flask content was stirred with mild heating (very gentle DCM boiling) for 10 min. The mixture was filtered when still hot, the dye was washed with DCM and dried. The yield was 10 g (50% of theory based on two steps).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>C1C=CC=CC=1>[Cl:1][C:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][C:3]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)CC(C)(C)C1
Reaction time: 14 h
Yield: 36.4 %

Procedure:
The following two procedures were adapted from Organic Preparations and Procedures Int., 29 (4), 471-498. A 500-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehyde (38 g, 240 mmol) in benzene (240 mL). See FIG. 3. To the solution was added ethoxycarbonylmethylene triphenylphosphorane (84 g, 240 mmol). The mixture was stirred for 14 h. After that time, the solvent was evaporated and the residue was triturated with hexanes (2 L) to extract the product away from the PPh3 by-products. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using a 100% hexane-1:1 hexane/ethyl acetate gradient to afford a 37% yield (20 g) of 103a.
Reaction SMILES: [OH2:1].[OH:2][CH2:3][CH:4]([O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)[CH2:5][OH:6].[C:20]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)(N1C=CN=C1)=[O:21]>CN(C)C=O>[N:9]1([C:8]([O:2][CH2:3][CH:4]([O:7][CH2:8][N:9]2[CH:17]=[N:16][C:15]3[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]2=3)[CH2:5][O:6][C:20]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[O:21])=[O:1])[CH:10]=[CH:15][N:16]=[CH:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2COC(COC(=O)n2ccnc2)COC(=O)n2ccnc2)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
A mixture of 55 mg (0.2 mmole) of 9-(1,3-dihydroxy-2-propoxymethyl)guanine monohydrate, 130 mg (0.8 mmole) of 1,1'-carbonyldiimidazole, and 2 ml of dry dimethylformamide was stirred under nitrogen at 95°-100° for 1.5 hours, during which time a clear solution was obtained followed by precipitation of product. After cooling, the precipitate was collected on a filter and washed with some dimethylformamide and then with acetone to give 37 mg of white crystals, m.p. 252°-253° dec. The NMR spectrum was in accord with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:26][OH:27]>>[CH3:26][O:27][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19]
Reactant: CO
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Product: COC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 63 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazole-1-ylcarbonyl)-1,3-dihydro-indol-2-one (5.3 mg, 0.016 mmol) in 1.0 mL of methanol was stirred at room temperature for 64 h and filtered. The red solid was washed with methanol and dried in a vacuum oven overnight to afford 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid methyl ester (3.0 mg, 63%) as a red solid. 1H NMR (400 MHz, DMSO-d6) d 12.63 (s, 1H, NH-1′), 7.84–7.86 (m, 1H), 7.69 (s, 1H, H-vinyl), 7.56–7.68 (m, 1H), 7.19–7.22 (m, 2H), 6.06 (d, J=2.34 Hz, 1H, H-4′), 4.08 (s, 3H, OCH3), 2.40 (s, 3H, CH3), and 2.36 (s, 3H, CH3). MS m/z (relative intensity, %) 297 (100, [M+1]+.)
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)(C)(C)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:21].[N:31]1([CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]4[CH:28]=[CH:29][CH:30]=[C:24]4[CH:23]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Reactant: C1COCCN1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCN3CCOCC3)cc12

Procedure:
6-(3-morpholin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 29% overall yield using the method described in example 87, starting from 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 101A) and morpholine.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH:15][CH3:16]>CCO>[CH3:14][N:15]([CH3:16])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (1 g; 5.4 mmol) in EtOH (5 mL) was added dimethylamine (730 mg; 16.2 mmol). The resulting mixture was stirred at RT for 18 h and 4 h at 70° C. The reaction mixture was then partitioned between water (10 mL) and Et2O (15 mL), washed with Et2O (10 mL). The aqueous phase was acidified to pH ˜5 with AcOH and washed with Et2O (2×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give the title compound as a yellow powder (1.02 g, 90%). 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (bs, 1H), 8.24 (d, J=2 Hz, 1H), 7.92 (dd, J=8.9, 2 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 2.92 (s, 6H). HPLC (Method A) Rt 2.44 min (purity: 97.2%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:24][CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[CH2:22][CH2:23][CH2:24][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1)=[O:18])[CH3:21]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CCOC(=O)C1CCCNC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(c2ccc(C#N)c3ccccc23)C1
Temperature: 115 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
1-Cyano-4-fluoronaphthalene(1.0 g, 5.84 mmol) and ethyl nipecotate (3.63 mL, 23.4 mmol) were dissolved in pyridine (5 mL) and stirred at 115° C. for 20 hours. After cooling to rt ethyl acetate (50 mL) was added and the solution washed with HCl (0.4 M, 2×30 mL). The combined aqueous layers were extracted with ethyl acetate (30 mL). The combined organic layers were washed with sat. sodium hydrogen carbonate (30 mL), brine (30 mL), dried and evaporated. The crude product was purified by silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane to give the title compound (1.23 g, 68%) as a yellowish oil