Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:4]=2[C:3]=1[F:24].[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C>[CH:25]1([S:28]([N:12]2[C:5]3[C:6]4[O:10][C:9]([CH3:11])=[N:8][C:7]=4[C:2]([F:1])=[C:3]([F:24])[C:4]=3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:13]2=[O:23])(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(I)cc3F)c2o1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Product: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Yield: 56.3 %

Procedure:
Intermediate I-22a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-18a: 80 mg, 0.178 mmol), cyclopropanesulfonyl chloride (37.75 mg, 0.269 mmol), TEA (54.46 mg, 0.534 mmol) and DMAP (10 mg) using procedures analogous to those described above for Intermediate I-19a to afford 55 mg of the product (56.3% yield). H1NMR (CDCl3, 300 MHz): δ 7.72-7.64 (m, 2H), 7.30-7.22 (m, 1H), 3.34-3.24 (m, 1H), 2.74 (s, 3H), 1.74-1.60 (m, 2H), 1.34-1.20 (m, 2H). LCMS: 81.9%; 549.9 (M+1).
Reaction SMILES: [CH:1]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:13][CH:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: NC1CCCCCCCCCCC1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)NC1CCCCCCCCCCC1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), cyclododecylamine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-(([2-(cyclododecylamino)-2-oxoethoxy]acetyl)amino)benzoic acid.methyl ester (yield: 92%).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16][C:15]=3[CH:23]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.B>C1COCC1>[CH:1]1([CH2:6][CH2:7][CH2:8][NH:10][C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[O:20])[O:18][C:17]([CH3:21])([CH3:22])[O:16][C:15]=3[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)c2ccc(NC(=O)CCC3CCCC3)cc2O1
Agent: B
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2ccc(NCCCC3CCCC3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide (2.57 g, 8.08 mmol) in THF (30 mL) was added a solution of borane in THF (24.3 ml, 24.3 mmol, 1M) and the resulting mixture was stirred at rt for 2 hrs. The mixture was then refluxed for 2 hrs. A solution of borane in THF (10.0 ml, 10.0 mmol, 1M) was added again and the mixture was refluxed for an additional 5 hrs. The reaction was quenched with HCl 5 N. Then the solution was made basic by the addition of an aqueous solution of NaOH (5N) and extracted with Et2O (3×). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) gave 2.1 g (86%) of the title compound as a white solid.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:7]=[N:8][C:9]([NH:12][NH2:13])=[CH:10][CH:11]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>ClCCl.CCCCCC>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][N:8]=2)[N:13]=1
Reactant: NNc1ccc(Cl)cn1
Reactant: C/C=C/C#N
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Solvent: CCCCCC
Product: CC1CC(N)=NN1c1ccc(Cl)cn1

Procedure:
A mixture of 0.20 g. of sodium metal dissolved in 50 ml. of absolute ethanol, 5.0 g. of 3-chloro-6-hydrazinopyridine and 4.8 g. of crotononitrile is heated at reflux for 18 hours. The procedure of Example 5 is followed through the evaporation of the magnesium silicate filtrate to give a yellow gum. Trituration with hexane gives a yellow solid. The solid is dissolved in dichloromethane. This solution is concentrated by heating on a steam bath while adding hexane, then is cooled in a refrigerator to separate 3.3 g. of the product of the Example as pale yellow crystals, m.p. 168°-170° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[OH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=O)=[CH:14][CH:13]=1.C(OCC)C>CCCCCC.O1CCCC1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:18])=[CH:21][CH:22]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of n-butyl lithium in hexane (1.6M, 22.87 ml) was added to a solution of diethylamine (3.74 ml) in dry tetrahydrofuran (100 ml), at ambient temperature and under an atmosphere of argon. The reaction mixture was stirred for 15 minutes. Ethyl 4-hydroxybenzoate (5 g) was then added and the reaction mixture stirred for 16 hours. Diethyl ether was added to the reaction mixture and the mixture was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel (Merck Art No. 9385) using a 1:3 (v/v) mixture of ethyl acetate/hexane as eluent to give 4-hydroxy-N,N-diethyl benzamide as a solid (1.17 g), m.p. 122.5° C.; NMR ([CD3 ]2SO): 1.1-1.15(6H,t), 3.2-3.4(4H,m), 6.75-6.85(2H,d), 7.15-7.25(2H,d), and 9.7(1H,s); m/z 194(M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 620.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]2[CH:7]=[CH:8][C:9]3[C:18]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[NH+:17][CH:16]=[C:15]1[C:10]=3[CH:11]=[CH:12][CH:13]=[CH:14]1.N>CO>[CH:1]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[C:15]([CH2:16][NH:17][C:18]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12][CH:11]=4
Reactant: c1ccc2c(c1)c[nH+]c1c3ccccc3ccc21
Agent: N
Solvent: CO
Product: c1ccc2c(c1)CNc1c-2ccc2ccccc12

Procedure:
The benzo[c]phenanthridine methosulfate (I, R5 is methyl, X is methosulfate) is also the intermediate from which 5,6-dihydrobenzo[c]phenanthridine (II) is obtained by reaction with aqueous ammonia. When the reaction between a benzo[c]phenanthridinium methosulfate and aqueous ammonia is followed by a reaction with methanol or any other alcohol, 5,6-dihydro-6-alkoxybenzo[c]phenanthridines are obtained (II, R5 is methyl, R6 is alkoxy).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.COCCN(S(F)(F)[F:28])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:28][C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1C1(O)CCC=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC=CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a solution of (Z)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-4-enol (1.35 g, 5.70 mmol) in dry DCM (60 mL) was added dropwise a solution of deoxo-Fluor® (50% in THF, 6.2 mL, 17.1 mmol) and the reaction mixture was stirred at room temperature for 90 min. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution (70 mL) was added, dropwise initially, and extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (15-20% EtOAc/hexane) gave (Z)-5-(1-fluorocyclohept-4-enyl)-1-methyl-4-nitro-1H-pyrazole as an off-white solid (615 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=CC=1[F:62])#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:62])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Reactant: C#Cc1ccccc1F
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2-fluorobenzene.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.Cl.[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:50]=2)=[CH:42][C:41]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:39]>Cl.CN(C)C=O>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:50]=2)[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[CH:42][C:41]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:39]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(CNCc2ccc(C(=O)OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(Cc2ccc(C(=O)OC)c(OCc3ccccc3)c2)C(=O)CCCCCNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Dissolved N-Cbz-6-aminohexanoic acid (784 mg, 2.96 mmole) into 10 mL of N,N-dimethylformamide and cooled to 0° C. Added triethylamine (1.65 mL, 11.8 mmole), stirred for 10 minutes, then added isobutylchloroformate (385 uL, 2.68 mmole). Stirred for 45 minutes and then added the crude methyl 4-[({[4-(methoxycarbonyl)-3-(phenylmethoxy)phenyl]methyl}-amino)-methyl]-2-(phenylmethoxy)benzoate hydrochloride from the step above (830 mg, 1.48 mmole). Let warm to room temperature and stirred for 3 hours. Diluted the reaction mixture with 1 N HCl and extracted with ethyl acetate. Dried the ethyl acetate layers with brine and anhydrous magnesium sulfate. Filtered, removed solvents in vacuo, and chromatographed on silica gel. Collected 870 mg (76% yield) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.[C:41](Cl)(=[O:51])[O:42][C@@H:43]1[CH:48]2[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]2)[CH2:44]1>CC#N>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:41]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:51])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(CNc3ccccc3Cl)c2)cc1OC
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CC#N
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3Cl)c2)cc1OC
Temperature: 80 °C
Yield: 52.4 %

Procedure:
A suspension of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2-chloroanilino)methyl]benzoate (72 mg, 0.123 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (138 mg, 0.612 mmol) in anhydrous CH3CN (1 mL) was heated at 80° C. for 3 minutes under microwave irradiation. After cooling to room temperature, the solvent was removed in vacuo. Purification of the crude material by preparative HPLC afforded the title compound as a yellow solid (47.8 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34].[CH3:36][O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:42]3[CH:41]=[CH:40][CH:39]=[C:38]([O:37][CH3:36])[CH:43]=3)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(Br)cc2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3cccc(OC)c3)cc2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 1.00 g (1.81 mmol) of the bromide from Example 11A, reaction by general method [D] with 0.33 g (2.18 mmol) of 3-methoxyphenylboronic acid, 0.06 g (0.09 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.23 g (2.18 mmol) of sodium carbonate in 20 ml of 1,2-dimethoxyethane and 1 ml of water results in 466 mg (44% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C.C(OCC)(=O)C>[CH:18]([N:10]1[C:11]2[C:7](=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[CH:9]1)([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: COc1ccc([N+](=O)[O-])c2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c2ccn(C(C)C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxy-4-nitro-1H-indole (S) (1 eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. 2-Iodopropane (1.1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water and ethyl acetate were added. The ethyl acetate layer was separated and washed repeatedly (3×) with water. The ethyl acetate layer was concentrated then evaporated to dryness. Further purification by column chromatography produced the pure desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]([O:14]CC)=O)[O:9][N:8]=1.O/[N:18]=[C:19](\[NH2:27])/[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[H-].[Na+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]2[O:14][N:27]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:18]=2)[O:9][N:8]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)no1
Reactant: Cc1ccc(/C(N)=N/O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(-c3cc(-c4ccccn4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of ethyl 3-(pyridin-2-yl)isoxazole-5-carboxylate (13.6 g, 62.5 mmol) and (Z)—N′-hydroxy-4-methylbenzimidamide (9.68 g, 62.5 mmol) in N,N-dimethylformamide (210 mL) cooled in an ice-bath was added 60% sodium hydride (6.25 g, 156 mmol) portion-wise. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated, water (500 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solid was collected vacuum filtration, triturated with methanol, and re-collected to give 5-(3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (17.8 g, 93% yield) as a solid. The compound had an HPLC retention time=3.86 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=305+. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3H), 7.35 (d, J=8.28 Hz, 2H), 7.41-7.47 (m, 1H), 7.83-7.91 (m, 2H), 8.09 (d, J=8.28 Hz, 2H), 8.20 (d, J=8.03 Hz, 1H), and 8.76 (d, J=5.02 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[C:20]([I:24])[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc3[nH]c(=O)ccc3c2O1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1Cc2cc(I)c3[nH]c(=O)ccc3c2O1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
2-(t-Butoxycarbonyl)aminomethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (882 mg) and N-iodosuccinimide (756 mg) were dissolved in a solvent mixture (44 ml) of chloroform-methanol (5:1). After refluxing for 2.5 hours with heat, N-iodosuccinimide (756 mg) was added to the mixture, followed by further 2 hour refluxing with heat. Further, N-iodosuccinimide (400 mg) was added to the mixture, which was then refluxed for 1.5 hours with heat. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent=chloroform:methanol=200:1) to obtain 903 mg of 2-(t-butoxycarbonyl)aminomethyl-5-iodo -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (73.2%). This compound was recrystallized from a solvent mixture of chloroform-n-hexane to obtain pale yellow powdery crystals (mp.: 173°-174° C.).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1)[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH2:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[CH3:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 62 %

Procedure:
(±)-2-[2-(2-Ethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in example 1c using 0.40 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.25 g of 2-ethylindoline [which can be prepared according to patent WO2009065920] and 0.39 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 250 ml of pyridine and 6.5 ml of N,N-dimethylformamide. After purification by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out successively with 99/1 then 98/2 and 97/3 v/v dichloromethane/methanol mixtures, at a flow rate of 30 ml/min, 0.35 g of (±)-2-[2-(2-ethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is obtained in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)[C:13]([N:15]([CH2:26][C:27](O)=[O:28])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:56][C:57]([CH3:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:58][NH2:59].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:13](=[O:14])[N:15]([CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:26][C:27](=[O:28])[NH:59][CH2:58][C:57]([CH3:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:56])[CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The compound from Step 3 (1.3 g, 1.8 mmol) was dissolved in methylene chloride (10 mL). β,β-dimethylphenethylamine hydrochloride (Example 1, Step 6) (0.370 g, 2 mmol) was added followed by diisopropylethylamine (1 mL, 5.7 mmol) and PyBOP (1.04 g, 2 mmol) dissolved in methylene chloride (10 mL). The reaction was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to give a white solid; 1.09 g (70% yield). MS-APCI: M+1=863.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]O)[CH:13]=2)=[C:8]([CH3:20])[CH:7]=1>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Cl:3])[CH:13]=2)=[C:8]([CH3:20])[CH:7]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc(CO)c1
Reactant: O=S(Cl)Cl
Product: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride was added to (4′-chloro-2′-methylbiphenyl-3-yl)methanol under cooing with ice-methanol, followed by stirring at room temperature for 1 hour to obtain 4-chloro-3′-(chloromethyl)-2-methylbiphenyl.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36]CCCN)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].[CH2:41]([NH:45]C(=O)OC(C)(C)C)[CH2:42]C=C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:42][CH2:41][NH2:45])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: C=CCCNC(=O)OC(C)(C)C
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The same procedure was employed as used for the synthesis of (2S,3S,4R,5S,6R)-2-(3-(4-(5-aminopentyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (16), using tert-butyl but-3-en-1-ylcarbamate as the reagent for the Heck reaction.