Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([C:9]#[C:10]C(O)C)(C)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O1CCOC[CH2:17]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:9]#[CH:10])[CH:5]=[C:4]([CH3:17])[N:3]=1
Reactant: C1COCCO1
Reactant: CC(O)C#CC1(C)C=CN=C(N)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cc(C)nc(N)n1

Procedure:
A mixture of 4.44 g of 4-(2-amino-4-methylpyrimidin-4-yl)-3-butyne-2-ol, 1 g of sodium hydroxide, 5 ml of dioxan and 50 ml of toluene was refluxed for two hours. The toluene layer was decanted from the residue, concentrated under reduced pressure and chromatographed on a silica gel dry column. The product band eluted with (2:3:0.5) ethyl acetate/dichloromethane/THF. Extraction with THF and concentration of the solvent gave 0.75 g of the title compound as a solid, 129°-130° dec.; IR(nujol) 2119 (w, C≡C) cm-1 ; PMR(60 MHz, CDCl3) δ2, 3(s, CH3, 3H), 3.1(s, C≡CH, 1H), 5.3-5.6(bs, NH2, 2H), 6.6(s, Het-H, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (95 mg, 0.37 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (56.8 mg, 0.368 mmol) and 1,1′-dimethyltriethylamine (128 μL, 0.74 mmol) in n-butanol (2 mL) was stirred at 120° C. for 5 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.40 (m, 1H), 8.05 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.62 (d, J=4 Hz, 1H), 7.31 (br, 2H), 7.24 (d, J=8 Hz, 1H), 7.19 (dd, J=8, 8 Hz, 1H), 5.89-5.81 (m, 1H), 2.83 (d, J=4 Hz, 3H), 1.62 (d, J=8 Hz, 3H), 1.12-1.04 (m, 2H), 0.95-0.79 (m, 2H); LC-MS (ESI) m/z 377.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[Cl:16][CH2:17][CH:18](OS(C)(=O)=O)[CH3:19].O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH:18]([N:11]([C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:19]
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Reactant: CC(CCl)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1N(C(C)CCl)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
5.2 g of a 80% mineral oil dispersion of sodium hydride are added in small portions, at room temperature, to a suspension of 31.5 g (0.158 moles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 400 ml of dry toluene. The resulting mixture is heated slowly, within about one hour, to 100° C., and then 27.3 g (0.158 moles) of 1-chloro-2-methanesulfonyloxy-propane are added dropwise to the mixture at the same temperature within 0.5 hours. The reaction mixture is stirred at 100°-110° C. for 12 hours, thereafter it is cooled, placed into an ice bath, and 100 ml of water are introduced dropwise. The aqueous phase is separated, the toluene phase is washed with 100 ml of water, twice with 100 ml of 1 n aqueous sodium hydroxide and finally with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The thick, yellow, oily residue, weighing 33.9 g, is distilled under reduced pressure. 26.15 g of 1-chloro-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained as a slightly opalescent oil; b.p.: 150°-154° C./26.6 Pa.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:14])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([NH:39][CH:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:8])=[C:4]([F:14])[CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 87.3 %

Procedure:
4-amino-5-ethoxy-2-fluorobenzoic acid (Intermediate 171; 190 mg, 0.95 mmol), HATU (545 mg, 1.43 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 164 mg, 1.43 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (0.58 ml, 2.86 mmol) added. The mixture was stirred over night and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (3% ammonia in methanol/DCM) to yield the title compound as a white crystalline solid (245 mg, 86%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][O:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(O)C>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([O-:14])(=[O:11])=[O:13])=[CH:20][CH:19]=1.[C:1]([C:4]1[CH:9]=[CH:8][N+:7]([CH3:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccncc1
Solvent: CCO
Product: CC(=O)c1cc[n+](C)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
4-Acetylpyridine (30.0 g, 0.25 mol) and p-toluene sulfonic acid methyl ester (55.8 g, 0.30 mol) in 500 ml ethanol were heated under reflux for 5 hours. The solvent was removed under vacuum in a rotary evaporator and the residue was taken up in ether. After separating off the ether phase, the product slowly crystallized out. The product was dried under vacuum. Yield: 59.9 g (82.5%);
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CC)Oc1cccc(C=O)c1
Reactant: NCCCOc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C(CC)Oc1cccc(CNCCCOc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(3-formylphenoxy)butyrate (5.0 g, 21.2 mmol) was dissolved in 1,2-dichloroethane (20 mL). Subsequently, 3-(4-fluorophenoxy)propylamine (4.65 g, 27.5 mmol) was added thereto, and the resultant mixture was stirred for 20 minutes. Subsequently, sodium triacetoxyborohydride (95%, 7.1 g, 31.8 mmol) and small amount of acetic acid were added thereto, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The reaction mixture was extracted with chloroform, and the organic layer was washed with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (6.7 g, 81%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[O:27]([CH2:34]C(Cl)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:38]([NH2:41])[CH:39]=[CH2:40]>>[CH2:38]([NH:41][C:24]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:12][N:8]1[C:6](=[O:7])[CH2:34][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:26])[CH:39]=[CH2:40]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: C=CCN
Product: C=CCNC(=O)[C@@H]1CC(=NOCc2ccc(OC)cc2)CN1C(=O)COc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and allylamine the title compound was obtained in 72% purity by LC/MS.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:39]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:29][CH:30]=3)[S:7][C:6]=2[CH:39]=1
Reactant: COC(=O)CCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cc2c(-c3ccc(OCCCC(=O)O)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
6-Hydroxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-2-[4-[4-methoxy-4-oxobutoxy]phenyl]benzo[b]thiophene (147 mg) was dissolved in THF:MeOH:H2O (3:1:1, 3.0 mL), treated with lithium hydroxide monhydrate (12 mg) in one portion, and allowed to stir at ambient temperature for 4 days. The reaction mixture was neutralized with dilute HCl and concentrated in vacuo. The residue was dissolved in methanol. The solution was transfered to a clean vial and solvent was removed with a stream of nitrogen to give the product as an off-white solid. (100 mg).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]1([C@H:28](O)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:1][C@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:29]
Reactant: BrBr
Reactant: C[C@@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@H](Br)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Bromine (3.2 g, 20.0 mmol) was added to a suspension of triphenylphosphine (5.2 g, 19.8 mmol) stirring in ACN at −15° C. The reaction was warmed to room temperature and stirred for 50 minutes then cooled to −35° C. and (R)-(+)-1-phenylethanol (1.6 g, 13.1 mmol) was added. The reaction was allowed to warm to −10° C. over 70 minutes and was then quenched with H2O and submitted to standard aqueous workup to afford the title compound which was used without further purification.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=O)[NH:2]1.O=P(Cl)(Cl)Cl.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH3:23]>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:23])[C:3]1=[N:2][CH2:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4]1
Reactant: CNCCOC
Reactant: O=C1NCc2ccccc2CN1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCN(C)C1=NCc2ccccc2CN1
Temperature: 106 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of 4,5-dihydro-1H-benzo[e][1,3]diazepin-3(2H)-one (Boyer, J. H. et al., J. Chem. Soc., Perkin Trans. I, 2137-2140 (1988)) (70 mg, 0.43 mmol) and POCl3 (805 μL, 8.63 mmol) was heated at 106° C. for 2 h. The reaction mixture was then concentrated in vacuo, dissolved in CHCl3 and azeotroped with PhMe. The residue was dissolved in THF (1.0 mL) and treated with 2-methoxy-N-methylethanamine (70 μl, 0.65 mmol). The resulting reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (29 mg, 28%). 1H NMR (CDCl3) δ 7.38-7.31 (m, 2H), 7.31-7.21 (m, 2H), 5.95 (br s, 1H), 4.61 (d, J=4.6 Hz, 2H), 4.39 (d, J=4.6 Hz, 2H), 3.56-3.51 (m, 2H), 3.42 (s, 3H), 3.40-3.36 (m, 2H), 3.10 (s, 3H); MS(ESI+) m/z 234.1 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[N:22]=[C:21]([CH2:23][NH:24][C:25](=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:26]([CH2:34][CH:35]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]=[N:19]1)=O)C1C=CC=CC=1.[H][H]>CCO.CO.[Pd]>[NH2:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[N:22]=[C:21]([CH2:23][NH:24][C:25](=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:26]([CH2:34][CH:35]2[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:38]2)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]=[N:19]1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2N)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of tert-butyl 3-((3-((2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)-1,2-bis(tert-butoxycarbonyl)guanidino)methyl)azetidine-1-carboxylate (390 mg, 0.526 mmol) in EtOH (10 mL) and MeOH (10.00 mL) was added Pd/C (5%, 112 mg, 53 μmol) and hydrogen baloon after evacuation and backfilled with H2. After 1 h, the reaction mixture was filtered over celite pad, and the filtrate was concentrated in vacuo to afford title compound (302 mg, 95%). The crude residue was used as such in the following step. LCMS: Rt=0.74 min, m/z=608.4 (M+1) Method 2m_acidic.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].N12CCCN=C1CC[CH2:17][CH2:16][CH2:15]2.IC(C)C>CN(C)C=O.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH:16]([CH3:17])[CH3:15])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Solvent: O
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)sc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of 6-nitro-2-benzothiazolinone (5.0 g, 25.5 mmol) in anhydrous N,N-dimethylformamide (51 mL) under N2 is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.96 mL, 33.1 mmol) dropwise. Following a slight exotherm, the reaction mixture is heated up to 50° C. and treated with 2-iodopropane (12.7 mL, 127 mmol). The resulting mixture is quickly heated up to 75° C., stirred at this temperature for 40 mins, cooled to ambient temperature and diluted with ice (100 mL) and water (100 mL). The precipitate is isolated by filtration and recrystallized from ethyl acetate/hexanes to give the title compound, mp 138-142° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)(=[O:39])=[O:38])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc2ccccc2c1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 2-naphthalenesulfonyl chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].C(N(CC)[P:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])C.N1C=NN=N1.ClC1C=C(C=CC=1)C(OO)=[O:48]>C1COCC1.ClCCl>[C:32]([O:31][P:25]([O:1][CH2:2][C:3]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4])([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:48])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(CO)(NC(=O)OCc1ccccc1)c1ccccc1
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCC(C)(NC(=O)OCc1ccccc1)c1ccccc1)OC(C)(C)C
Temperature: -45 °C
Yield: 76.8 %

Procedure:
The product of Example 442A (2.7 mmol), di-tert-butyl diethylphosphoramidite (0.80 mL, 2.7 mmol), and 1-H-tetrazole (0.50 g, 6.8 mmol) in THF (25 mL) were reacted at room temperature for 12 hours. Subsequently the reaction was diluted with dichloromethane (25 mL) and cooled to −45° C. and followed by treatment with meta-chloroperoxybenzoic acid (0.66 g, 3.0 mmol) for 0.5 hours. The reaction was extracted with ethyl acetate (70 mL) and the organic extracts washed with 10% sodium carbonate (2×) and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-25%) to give the title compound as a colorless oil (0.99 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[NH2:21][C:22]1[N:27]=[C:26]([OH:28])[CH:25]=[C:24]([NH2:29])[N:23]=1>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25]2[C:26]([OH:28])=[N:27][C:22]([NH2:21])=[N:23][C:24]=2[NH:29][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: Nc1cc(O)nc(N)n1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2nc(N)nc(O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
500 mg (1.85 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are mixed with 349 mg (2.77 mmol) of 2,6-diaminopyrimidin-4-ol, dissolved in 10 ml of isopropanol, and heated under reflux under argon for 2 days. The mixture is filtered and the remaining solid is washed with isopropanol. 660 mg (94% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH3:16])[CH:12]=[C:11]([CH3:17])[CH:10]=2.[Si:18]([CH3:22])([CH3:21])(Cl)[Cl:19].[Li]>CCCCCC.CCOCC.C1COCC1>[Cl:19][Si:18]([CH:8]1[C:9]2[C:14](=[C:13]([CH3:16])[CH:12]=[C:11]([CH3:17])[CH:10]=2)[CH:15]=[C:7]1[CH3:6])([CH3:22])[CH3:21]
Reactant: CC1=Cc2c(C)cc(C)cc2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=Cc2c(C)cc(C)cc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 2.5 M n-BuLi solution in hexane (9.6 mL) was added dropwise at 0° C. under nitrogen to a solution of 3.6 g of 2,4,6-trimethylindene in 35 mL of Et2O. During the addition a white-off suspension was formed. After 10 min the mixture was allowed to warm up to r.t. and stirred for 30 min, with final formation of a white suspension. Then a solution of Me2SiCl2 (4 mL) in 35 mL of THF was cooled to 0° C. and slowly added to the lithium salt suspension, also cooled to 0° C. After 30 min the yellow reaction mixture was allowed to warm up to r.t. and stirred for 24 h. Then the solvents were removed in vacuo and the light orange oil with a powder was characterized by 1H-NMR spectroscopy. The product was used as such in the next step without further purification.
Reaction SMILES: [I-].CO[C:4]1[C:20]2[C:8](=[CH:9][C:10]3[N:11](C(=O)C)[C:12]4[C:17]([C:18]=3[NH+:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:7]=[CH:6][CH:5]=1.[C:24]([O-:27])([O-])=O.[Na+].[Na+].[CH2:30](O)C>>[CH3:24][O:27][C:16]1[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=1)=[N:11][C:10]1[C:18]=2[N:19]([CH3:30])[C:20]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[CH:9]=1
Reactant: COc1cccc2cc3c([nH+]c12)c1ccccc1n3C(C)=O
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: [I-]
Agent: [Na+]
Product: COc1cccc2nc3cc4ccccc4n(C)c-3c12

Procedure:
A solution of 4-methoxy-10-acetylquindolinium iodide obtained in Example 37 dissolved in approximately 50 mL of ethanol-free chloroform was adsorbed onto anhydrous Na2CO3 (1 g/100 mg iodide salt) and applied to a column filled with basic alumina. The mixture was eluted with CHCl3 until the UV active impurities eluted. Elution with CHCl3 -MeOH (97:3) provided the title compound as a purple solid; 1H NMR (CDCl3) δ 8.74 (s, 1H), 8.22 (d, J=8.4, 1H), 7.85 (d, J=8.4, 1H), 7.73 (d, J=8.4, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.18 (d, J=7.6, 1H), 7.08 (m, 1H), 5.07 (s, 3H), 4.12 (s, 3H); 13C NMR (CDCl3) δ 159.8, 150.5 (2 carbons), 144.1, 141.5, 131.2, 127.2, 126.3, 124.4, 124.1, 122.2, 119.5, 117.6, 114.1, 109.4, 56.5, 45.3; MS (LSIMS, m/z) 263 (MH+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C@H:12]2[C@@H:18]([CH2:19][NH:20][S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22])[O:17][CH2:16][CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].[Cl-].[NH4+]>CO>[Cl:4][C:5]1[CH:6]=[C:7]([C@H:12]2[C@@H:18]([CH2:19][NH:20][S:21]([CH2:24][CH2:25][O:2][CH3:1])(=[O:23])=[O:22])[O:17][CH2:16][CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C=CS(=O)(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COCCS(=O)(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 28% solution (5 ml) of sodium methoxide in methanol was added dropwise to a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-{[(ethenylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (235 mg) in methanol (1 mL), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (215 mg).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH3:29][N:30]1[CH:34]=[C:33]([C:35](=[O:38])[CH2:36][CH3:37])[CH:32]=[C:31]1[CH:39]=O>>[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:2]1[C:39]([C:31]2[N:30]([CH3:29])[CH:34]=[C:33]([C:35](=[O:38])[CH2:36][CH3:37])[CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: O=Cc1ccnc2ccc(F)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: CCC(=O)c1cc(C=O)n(C)c1
Product: CCC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(F)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-fluoroquinoline-4-carbaldehyde, followed by 1-methyl-4-propionyl-1H-pyrrole-2-carbaldehyde. 517 (M+H).