Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][C:7]=1[O:8][CH:9]1[CH2:12][N:11]([C:13]([CH3:33])([CH3:32])[CH2:14][CH2:15][C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH2:19])=[O:18])[CH2:10]1>ClCCl>[Cl:5][C:6]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:7]=1[O:8][CH:9]1[CH2:10][N:11]([C:13]([CH3:33])([CH3:32])[CH2:14][CH2:15][C:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH2:19])=[O:18])[CH2:12]1
Reactant: COc1ccc(Cl)c(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2cc(O)ccc2Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Boron tribromide (1M in dichloromethane, 1.42 mL, 1.42 mmol) was added to an ice-cooled solution of the product of example 117(70 mg, 0.142 mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for 1 hour. The reaction was then quenched with 0.88 ammonia (20 mL) and the solution stirred at room temperature for 18 hours. The organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mls). The combined organic solution was washed with saturated sodium hydrogen carbonate solution (10 mL) and dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate:methanol:0.88 ammonia (90/10/1), 85:15 to 50:50. The resulting gum was dissolved in methanol (5 mls) and 1N hydrochloric acid in diethyl ether (0.5 ml) added. The solution was evaporated and the solid recrystallised from ethyl acetate/methanol to give the title compound hydrochloride salt as a purple solid in 30% yield, 22 mgs.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[C:34]([O:53][CH3:54])=[C:35]([CH:50]=[CH:51][CH:52]=1)[C:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][O:26][C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:35]3[CH:50]=[CH:51][CH:52]=[C:33]([O:32][CH3:31])[C:34]=3[O:53][CH3:54])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 69.5 %

Procedure:
N4-Benzoyl-2'-O-pentylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (2.7 g, 1.1 eq) as per the procedure of Example 72 to give 3.5 g of pure product. Anal. Calcd. for C42H53N3O8. 1/2H2O: C, 69.21; H, 6.36; N, 5.76. Found: C, 69.51; H, 6.30; N, 5.71.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[CH2:11]([N:14]1[CH2:18][CH:17]([NH2:19])[CH2:16][CH:15]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=[CH2:13].C(N1CC(O)CC1C1C=CC=CC=1)C=C.C(N(CC)CC)C>O>[Cl:8][C:7]1[CH:2]=[N:3][C:4]([NH:19][CH:17]2[CH2:18][N:14]([CH2:11][CH:12]=[CH2:13])[CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: C=CCN1CC(N)CC1c1ccccc1
Agent: C=CCN1CC(O)CC1c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN1CC(Nc2ncc(Cl)c(CC)n2)CC1c1ccccc1
Temperature: 85 °C

Procedure:
1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 1.7 g (8.5 mmol) of 1-allyl-4-amino-2-phenylpyrrolidine (prepared from 1-allyl-2-phenylpyrrolidin--4-ol analogously to the route described in Example A) and 2 ml (4 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1, 8:2). This gave 0.95 g (33% of theory) of a colorless syrup (diastereomers 1:1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18]O)=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=S(Cl)[Cl:23]>>[Cl:20][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:17]([CH2:18][Cl:23])=[CH:16]2
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure C using (2-(2-chlorophenyl)-8-chloroquinolin-3-yl)methanol (0.675 g, 2.22 mmol) and SOCl2 (0.81 mL). 8-Chloro-3-(chloro-methyl)-2-(2-chlorophenyl)quinoline was obtained as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, s), 7.88 (1H, dd, J=8.2, 1.2 Hz), 7.81 (1H, dd, J=7.4, 1.2 Hz), 7.48 (1H, d, J=7.4 Hz), 7.42-7.46 (1H, m), 7.27-7.41 (3H, m), 4.63 (1H, d, J=9.8 Hz), 4.33-4.45 (1H, m) Mass Spectrum (ESI) m/e=322.0 and 324.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH3:12][C:13]1[N:14]=[C:15]([NH2:18])[O:16][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:18][C:15]2[O:16][CH:17]=[C:13]([CH3:12])[N:14]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1coc(N)n1
Product: Cc1coc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 54.1 %

Procedure:
Prepared using Method A from 10.0 g (54.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 5.39 g (55 mmol) of 4-methyl-2-amino-oxazole to give 8.3 g of title compound as a yellow solid, m.p. 207-208° C. An additional crop (4.8 g, m.p. 207-208° C.) was obtained from the mother liquor (86% combined yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To fuming nitric acid (200 ml), 1-(4-bromophenyl)-1-propanone (40 g) was added while keeping the inside temperature of the mixture at 5 to 10° C. The reaction solution was stirred at that temperature for 30 minutes and then poured into ice. The precipitate was collected by filtration, washed with distilled water, and recrystallized from methanol to obtain the title compound (18 g).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:25])([F:24])[CH2:5][N:6]=[C:7]([NH2:23])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[NH:22])[O:20][CH3:21])[N:10]=1.[CH2:26]([N:28](CC)CC)C.N#CN>CO>[C:26]([N:22]=[C:19]([O:20][CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[N:10]=[C:9]([NH:8][C:7]([NH2:23])=[N:6][CH2:5][C:4]([F:3])([F:24])[F:25])[CH:14]=[CH:13][N:12]=1)#[N:28]
Reactant: COC(=N)CCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CCN(CC)CC
Agent: Cl
Agent: N#CN
Solvent: CO
Product: COC(CCCCc1nccc(NC(N)=NCC(F)(F)F)n1)=NC#N
Reaction time: 18 h

Procedure:
To a solution of methyl 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valerimidate dihydrochloride (0.5 g.) in MeOH (10 ml.) was added triethylamine (0.125 g.) and cyanamide (0.08 g.) and the mixture was stirred for 18 hours at 20°. Volatile material was evaporated in vacuo and the residue was triturated with a mixture of ether and EtOH to give crude methyl N-cyano-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valerimidate as a white solid which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.[Si:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1)(=[O:31])[CH3:30].[Si:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: OCCCc1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)n1cc(CCCO)c2ccccc21

Procedure:
A solution of the indole 29 (29 g, 86 mmol), CH2Cl2 (450 mL), 1,8-diazobicyclo[5.4.0]undec-7-ene (38 mL, 0.26 mol), 4-dimethylaminopyridine (1.0 g, 8.5 mmol), and acetic anhydride (32 mL, 0.34 mol) was stirred for 1 week at ambient temperature. The reaction mixture was concentrated and then diluted with ether. The ether was then washed with H2O, 5% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 5% ethyl acetate/hexanes) gave the acylated product 30 (27 g) as a yellow oil. TLC Rf=0.56 (20% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1c(F)cccc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1F

Procedure:
(RS)-(2,6-Difluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-phenyl)-2-methoxy-acetamide. Off-white solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[Cl:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH:29][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NCCOc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOc1ccc(Oc2cccc(Cl)n2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
At room temperature, 1.1 g of triethylamine and then 1.0 g of cyclopropanecarboxylic acid chloride are dripped into 2.6 g of 2-[4-(6-chloropyridin-2-yloxy)-phenoxy]-ethylamine in 50 cm3 of dichloromethane. The reaction is slightly exothermic. The mixture is stirred at room temperature for 14 hours.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][NH:8][CH3:9].[CH2:10]([O:12][C:13]([C:15]1[C:16]([S:27][CH2:28][CH3:29])=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20](F)[CH:19]=2)=[O:14])[CH3:11].CCCCCC>CCO>[CH2:10]([O:12][C:13]([C:15]1[C:16]([S:27][CH2:28][CH3:29])=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20]([N:8]([CH3:9])[CH3:7])[CH:19]=2)=[O:14])[CH3:11]
Reactant: CNC
Reactant: CCOC(=O)c1c(SCC)nc2cc(F)ccc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c(SCC)nc2cc(N(C)C)ccc2c1C
Temperature: 90 °C
Yield: 38 %

Procedure:
2.8 g (20.5 mmol) K2CO3 and a 40% aq. dimethylamine solution (20.5 ml) were added to a solution of 2.0 g (6.8 mmol) 2-ethylsulfanyl-7-fluoro-4-methyl-quinoline-3-carboxylic acid ethyl ester in EtOH (20 ml) and the mixture was heated for 16 h at 90° C. in a closed vessel. Then the reaction solution was concentrated to small volume under vacuum and the residue was taken up with water. It was then extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 25:1) of the residue yielded 810 mg (2.55 mmol, 38%) 7-dimethylamino-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: C([Li])CCC.C(=O)=O.CC(C)=O.[C:13](#[N:15])[CH3:14].[CH2:16]1[N:27]2[C:28]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]=[N:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:17]1>O1CCCC1>[CH2:16]1[N:27]2[C:28]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([CH2:14][C:13]#[N:15])[NH:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:17]1
Reactant: CC#N
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#CCC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 2 h
Yield: 78.7 %

Procedure:
n-Butyllithium (10 ml of a 2.5M solution) and tetrahydrofuran (THF, 10 ml) were placed in a 250 ml 3-neck flask under nitrogen and chilled to -60° C. (dry ice/acetone). Acetonitrile (1 g) in tetrahydrofuran (10 ml) was added in one portion. A precipitate formed in a short time. Thirty minutes thereafter, a solution of 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (4.5 g) in tetrahydrofuran (20 ml) was added. The cold bath was then removed and the reaction mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (350 ml) and poured into saturated ammonium chloride solution (500 ml). The organic phase was separated and washed with brine (50%, 500 ml). The insolubles were collected by filtration. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to a solid. The solids were combined and purified by flash chromatography (silica, 80 g, eluted with dichloromethane) to afford 4.2 g of product. Recrystallization from a large volume of ethanol/isopropanol gave 2.48 g of crystalline product, m.p. 218°-220° C.
Reaction SMILES: CC[O-].[Na+].[SH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([CH3:14])[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[N:7]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].O>C(O)C>[NH2:13][C:12]1[C:11]2[C:6](=[N:7][C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:9][C:10]=2[CH3:14])[S:5][C:26]=1[C:27]([NH2:29])=[O:28]
Reactant: COc1ccc(-c2cc(C)c(C#N)c(S)n2)cc1OC
Reactant: NC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C)c3c(N)c(C(N)=O)sc3n2)cc1OC
Yield: 94.3 %

Procedure:
2.1 g (31.4 mmol) sodium ethylate are dissolved in 40 ml absolute ethanol. 3.0 g (10.5 mmol) 2-mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridine-3-carbonitrile and 1.2 g (12.6 mmol) 2-chloroacetamide are added and refluxed for 1 h. Following cooling, 10 ml water are added and the precipitate is sucked off, suck dried and dried in vacuo at 50° C. 3.4 g (94%) 3-amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]-pyridine-2-carboxamide is obtained.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:18]([C:31](OCC)=[O:32])=[CH:17]2.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH:12][C:31]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)=[O:32])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 0 °C

Procedure:
23.8 ml (47.57 mmol) of a 2M solution of trimethylaluminum in toluene are added to a solution, stirred at 20° C. under an argon atmosphere, of 4.48 g (34.89 mmol) of 6-chloro-3-aminopyridine in 317 ml of toluene. The solution is then brought to 120° C. and 10 g (31.71 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate are added in several steps (WO 2006/024776). The reaction mixture is refluxed for 4 hours and is then cooled to 0° C. 15 ml of water are added to the reaction medium, which is then extracted with twice 200 ml of ethyl acetate. The organic phases are combined and washed twice with 50 ml of water and once with 50 ml of a saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is triturated in 100 ml of ethyl ether, the product is filtered, and 10 g of expected product are recovered in the form of a powder.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:27]2[CH:30]=[CH:31][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(OCc3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 12.0 g of 4-benzyloxybenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 165°-166° C). 1H NMR (CDCl3) δ 2.91 (dd, 2 H), 3.56 (dd, 2 H), 5.09 (s, 2 H), 5.65 (dd, 1 H), 6.98-7.04 (m, 2 H), 7.30-7.44 (m, 7 H).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:31]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(c4ccccc4)c4ccc(Cl)cc4)[C@@]3(C)CC[C@@H]12
Yield: 80 %

Procedure:
The title compound was prepared in a yield of 80% in a similar manner to that described in Example 2 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and α-(4-chlorophenyl)benzylamine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Product: CCc1c(OCc2cccc(Sc3cc(C#N)ccn3)c2)ccc(C(C)=O)c1O
Yield: 80 %

Procedure:
Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.35 g, 5.56 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (1.00 g, 5.56 mmol) affords the title compound (1.80 g, 80%). MS (APCI-neg) m/z (rel intensity): 403 (M−H, 100%).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([O:27][CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>B(F)(F)F.CCOCC.C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([C:24]1[CH:25]=[CH:26][C:21]([O:27][CH3:28])=[CH:22][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OC)cc1

Procedure:
A solution of 290 mg. (1 mmol.) of N-t-butyoxycarbonyl-2-acetoxyglycine n-butyl ester, 0.5 ml. of anisole and 3 drops of boron trifluoride etherate in 5 ml. of methylene chloride was stirred at 25° for 4 hours. The solvent was removed and the residue was chromatographed on silica gel and eluted with 1:1 chloroform-hexane to give the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24]OS(C)(=O)=O)[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24][N:1]=[N+:2]=[N-:3])[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Temperature: 90 °C
Yield: 45 %

Procedure:
Sodium azide (1.10 g, 16.90 mmol) was added to the mixture of methanesulfonic acid 1-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-ylmethyl ester and methanesulfonic acid 3-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-3H-[1,2,3]triazol-5-ylmethyl ester, obtained in Example 9, in DMF (10 mL) and heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The solution was washed with water (100 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Removal of volatiles and purification of the residual material by silica gel column chromatography (eluent, 1:9–3:7 ethyl acetate/hexane) yielded compounds 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-4-ylmethyl azide (13A) (800 mg, 45%) followed by 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-5-ylmethyl azide (13B) (850 mg, 50%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:10]=1[CH3:11].O>CO>[CH3:11][C:10]1[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[N:6][C:5]=1[O:2][CH3:1]
Reactant: C[O-]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nnc(-c2ccccc2)cc1C
Yield: 89.9 %

Procedure:
Sodium methoxide (243 g) is cautiously added to a solution of 3-chloro-4-methyl-6-phenylpyridazine (307 g, 1.5 mol) in 3.4 L of methanol. The mixture is heated to refluxing temperature for approximately eight hours under an atmosphere of nitrogen and then poured into water (4.5 L). The resulting precipitate is collected, washed with water, and dried to give 270 g (90%) of product with a melting point of 62°-64° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4].[I-:42].[Na+].CCCCCC>CC(C)=O>[I:42][CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CI

Procedure:
A solution of 2-bromo-N,N-dioleylacetamide (0.81 g; 1.27 mmol) and sodium iodide (0.76 g; 5.08 mmol) in acetone is refluxed overnight. Hexane (10 ml) is added and the precipitate is filtered off to give, after evaporating the filtrate under reduced pressure, 2-iodo-N,N-dioleylacetamide (0.87 g; 100%) in the form of a yellowish liquid.