Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH3:14][C:15]1[C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:18]([CH3:32])[O:17][N:16]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:32])=[CH:27][CH:26]=1)(=[O:29])=[O:30]
Reactant: CC(C)CNc1c(F)cccc1F
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2c(F)cccc2F)cc1
Reaction time: 16 h

Procedure:
To a solution of (2,6-difluorophenyl)(2-methylpropyl)amine (80 mg, 0.432 mmol) in pyridine (1 mL) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (156 mg, 0.518 mmol) and the reaction stood at room temperature, in air, for 16 hours. The solvent was removed in vacuo and the crude then passed through a sulfonic acid (SCX) SPE (solid phase extraction) cartridge eluting with methanol followed by 2M ammonia/methanol solution. The product-containing fractions were concentrated in vacuo and the crude then passed through an aminopropyl (NH2) SPE cartridge eluting with methanol followed by 2M ammonia/methanol solution. The appropriate fractions were combined and concentrated in vacuo, then further purified by MDAP (Method F) to give the required product, 0.6 mg. LCMS (M+18) 468, RT 1.28 mins.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])(O)=[O:18].[Na+].C(Cl)(Cl)=O.[NH2:26][C:27]1[CH:44]=[CH:43][C:30]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]3[NH:38][C:39](=[O:42])[N:40]([CH3:41])[C:33]=23)=[CH:29][C:28]=1[F:45]>C(Cl)Cl.C1(C)C=CC=CC=1.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:17]([NH:26][C:27]2[CH:44]=[CH:43][C:30]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]4[NH:38][C:39](=[O:42])[N:40]([CH3:41])[C:33]=34)=[CH:29][C:28]=2[F:45])=[O:18])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: Cn1c(=O)[nH]c2nccc(Oc3ccc(N)c(F)c3)c21
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)c3)c21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Tert-butyl-1-phenyl-1H-pyrazol-5-amine (550 mg, 1.8 mmol) was dissolved in CH2Cl2 (25 mL) and an equal volume of saturated NaHCO3 (aq) was added. The biphasic mixture was stirred and cooled to 0° C. with an ice/water bath. After 10 minutes, 2 equiv. of a 1.9 M solution of phosgene in toluene were added. The mixture was vigorously stirred for 10 minutes, the organic layer was isolated, washed with H2O, dried (MgSO4) and concentrated to about 5 mL. This solution was added to a solution of the 7-(4-amino-3-fluorophenoxy)-1-N-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (8a) (200 mg, 1.4 mmol) in THF. The solution was stirred for 15 hours at room temperature, the solvents were evaporated and the solid residue was washed with Et2O and CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)#[N:2].[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:2]1[NH:14][N:15]=[N:16][C:1]=1[CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCSc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCc2nn[nH]n2)cc1
Yield: 15.7 %

Procedure:
A mixture of 4-cyanomethylsulfanylbenzoic acid (27.2 g, 0.14 mol), sodium azide (11.8 g, 0.18 mol) and ammonium chloride (9.7 g, 0.18 mol) in DMF (1000 mL) was refluxed overnight under N2. The mixture was concentrated in vacuo. The residue was suspended in cold water and extracted with diethyl ether. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. Water was added and the precipitate was filtered off. The aqueous layer was concentrated in vacuo, water was added and the precipitate filtered off. The combined impure products were purified by column chromatography using DCM:MeOH=9:1 as eluent, affording the title compound (5.2 g, 16%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[CH3:14][Mg]Cl.C1COCC1.C[O-].[Na+].[BH4-].[Na+].[BH4-]>CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[CH:8]([NH2:9])[CH3:14]
Reactant: Cn1ccc2nc(C#N)c(Br)cc21
Reactant: C[Mg]Cl
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1Br
Temperature: 7.5 °C
Reaction time: 2 h

Procedure:
To a first vessel charged with toluene (5.1 L) was added 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (300 g, 1.27 mol) under nitrogen. The solution was cooled to 5-10° C. A 3M solution of CH3MgCl in THF (637 mL, 1.91 mol) was added slowly over a 35 minute period while maintaining the temperature of the reaction mixture below 30° C. The reaction mixture was stirred for 2 hours at 15-20° C. To a second vessel charged with methanol at 0-5° C. was added sodium methylate (24.4 mL) under nitrogen. Sodium borohydride (72.2 g, 1.91 mol) was added to the methanol solution portion-wise over a 20 minute period at 0-5° C. The borohydride solution was stirred for 1 hour. The contents of the first vessel were then transferred into the second vessel slowly over a 2 hour period while maintaining the temperature of the reaction mixture in the second vessel below 30° C. Following the transfer of the Grignard solution, the first vessel was rinsed with toluene (0.60 L) which was added to the second vessel. The first vessel was next charged with methanol (0.60 L) over a 10 minute period at a temperature less than 30° C. The methanol solution was subsequently transferred to the second vessel, and the reaction mixture was stirred at 0-5° C. for an additional 2 hours. The reaction mixture was then transferred into a third vessel charged with a 2M HCl solution (2.40 L) at 5-15° C. over a period of 1.25 hours. Following the transfer, the second vessel was rinsed with toluene (0.60 L), which was added to the third vessel, and the reaction mixture was stirred for 16 hours. The mixture was warmed to 40-45° C. and 2M NaOH (1.0 L) was added slowly over a 20 minute period until the pH of the aqueous phase was 8.5. The reaction mixture was stirred for an additional 40 minutes, and the pH of the aqueous phase was confirmed to be 8.5. The organic and aqueous phases were separated. The aqueous phase was extracted with toluene (2×3.0 L). The organic layers were combined and screened to remove particulates. The filtrate was concentrated under vacuum at 50° C. until distillation ceased. Isopropanol (3.0 L) was added, and the reaction mixture concentrated under vacuum at 50° C. Additional isopropanol (300 mL) was added to give the title compound as a solution in IPA (230.7 g by gravimetric assay).
Reaction SMILES: C[Al](C)C.[C:5]([C:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])#[N:6].[CH3:20][CH:21]([CH3:44])[CH:22]([NH:27][C:28]([C:30]1[S:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=2)=[CH:33][N:34]=1)=[O:29])[C:23]([O:25][CH3:26])=[O:24].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(Cl)Cl.O>[C:5]([C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:41][C:38]2[CH:39]=[CH:40][C:35]([C:32]3[S:31][C:30]([C:28]([NH:27][CH:22]([CH:21]([CH3:44])[CH3:20])[C:23]([O:25][CH3:26])=[O:24])=[O:29])=[N:34][CH:33]=3)=[CH:36][CH:37]=2)=[O:16])=[CH:18][CH:19]=1)([CH3:8])[CH3:9])#[N:6]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: COC(=O)c1ccc(C(C)(C)C#N)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc2)s1)C(C)C
Temperature: 80 °C

Procedure:
Trimethyl aluminium (0.36 ml, 2M solution in toluene) was added to a solution of methyl 4-(2-cyanopropan-2-yl)benzoate (Intermediate 5, 100 mg) and methyl 2-(5-(4-aminophenyl) thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 150 mg) in toluene (12 ml). The reaction mixture was heated to 80° C. for 4 hours in a sealed tube. Reaction mass was cooled to RT, water was added and neutralized with saturated aqueous solution of ammonium chloride. Methylene chloride was added to it. Organic and aqueous layers were separated. Organic layer was washed successively with 1N HCl, saturated NaHCO3 and brine solution. It was then dried over sodium sulfate and concentrated to obtain dark brown residue which was purified by silica gel column chromatography in EtOAc-Petroleum ether to obtain pale brown solid. The solid was crystallized in CHCl3-petroleum ether to obtain title compound as off white solid. Yield: 75 mg (33%); 1HNMR (DMSO-d6, 300 MHz): δ 10.49 (s, 1H), 8.75 (d, 1H), 8.41 (s, 1H), 8.04 (d, 2H), 7.93 (d, 2H), 7.81 (d, 2H), 7.71 (d, 2H), 4.33 (m, 1H), 3.68 (s, 3H), 2.27 (m, 1H), 1.74 (s, 6H), 0.95 (m, 6H); MS (ES+) m/z 505.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:26]=1)[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:36][C:37]([S:44][S:45][CH3:46])([CH3:43])[CH2:38][CH2:39][C:40](O)=[O:41].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:13]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:40](=[O:41])[CH2:39][CH2:38][C:37]([CH3:43])([S:44][S:45][CH3:46])[CH3:36])[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH:26]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CSSC(C)(C)CCC(=O)O
Reactant: COCCOCCOCCNc1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COCCOCCOCCN(C(=O)CCC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.8 %

Procedure:
To a mixture of 3,5-bis((tert-butyldimethylsilyloxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (267a) (525 mg, 0.995 mmol) and 4-methyl-4-(methyldisulfanyl)pentanoic acid (232 mg, 1.193 mmol) in anhydrous dichloromethane (9.0 mL) was added EDC (229 mg, 1.193 mmol) and DMAP (12.15 mg, 0.099 mmol). The reaction was stirred at room temperature for five hours. The mixture was diluted with dichloromethane and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30% Ethyl acetate/Hexanes) gave N-(3,5-bis((tert-butyldimethylsilyloxy) methyl)phenyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-methyl-4-(methyldisulfanyl)pentanamide (267b) (335 mg, 48%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[C:26]3[CH:32]=[CH:31][NH:30][C:27]3=[N:28][CH:29]=2)[CH:19]=1.[OH-].[K+].O.[CH3:36]O>>[F:1][C:2]1[C:7]([CH:8]([O:9][CH3:36])[C:32]2[C:26]3[C:27](=[N:28][CH:29]=[C:24]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[CH:25]=3)[NH:30][CH:31]=2)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13]
Reactant: CO
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(c1c(F)ccc(NS(=O)(=O)C(C)C)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (60, 220.0 mg, 0.83 mmol) in methanol (15 mL) was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 150.0 mg, 0.77 mmol, prepared as described in Example 17) and potassium hydroxide (537.0 mg, 9.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in dichloromethane to give the compound (61, 160 mg, 45.3%). In this step, minor compound Propane-2-sulfonic acid {2,4-difluoro-3-[methoxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide was also formed and isolated. MS(ESI) [M+H+]+=460.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=O)=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:6]([CH:12]=[N:11][CH:10]=2)[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23])=[O:24]
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(SC)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(SC)cc1F
Temperature: 95 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a suspension of 2-(2-fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (309 mg, 0.89 mmol) in toluene (15.6 mL) was added phosphorous oxychloride (91 μl, 0.98 mmol) and the reaction mixture heated to 95° C. and stirred for 1 hour. The cooled reaction mixture was quenched by the addition of water (ca. 2 mL) then concentrated in vacuo. The resultant residue was taken up in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and brine. The organic phase was isolated, dried (Na2SO4), filtered, concentrated in vacuo, and the residue subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl acetate in hexane) to afford the title compound as a yellow solid (150 mg, 51%). LCMS (method B): RT=3.44 min, [M+H]+=332.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:25])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:25])[N:7]([CH2:17][CH:18]2[CH2:19][CH2:20]2)/[C:8](=[N:10]/[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C(F)(F)F)n(CC2CC2)n1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CC1
Yield: 54.4 %

Procedure:
A mixture of Example 27D (11.6 g, 40 mmol) and dimethyl sulfate (20.2 g, 160 mmol) in toluene (10 mL) was heated in a microwave at 150° C. for 30 min. The mixture was concentrated and purified by flash chromatography (silica gel, MeOH/Et3N (10:1)/EtOAc in 10-60% gradient) to yield 6.6 g (54.4%) of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 0.41-0.53 (m, 4H), 1.15-1.27 (m, 1H), 1.38 (s, 9H), 3.98 (s, 3H), 4.20 (d, J=7.12 Hz, 2H), 6.70 (s, 1H); MS (ESI) m/z 304 [M+H]+, 302 [M−H].
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH2:11][N:10]([S:12]([C:15]2[N:16]=[N:17][NH:18][CH:19]=2)(=[O:14])=[O:13])[CH2:9]1)=[O:5].[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:20][CH:21]2[CH2:22][CH2:23]2)[CH2:9][N:10]([S:12]([C:15]2[N:16]=[N:17][N:18]([CH3:29])[CH:19]=2)(=[O:13])=[O:14])[CH2:11]1)=[O:5]
Reactant: O=C(NCC1(CC2CC2)CN(S(=O)(=O)c2c[nH]nn2)C1)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)N2CC(CNC(=O)c3ccc(Cl)cc3Cl)(CC3CC3)C2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,4-dichloro-N-{[3-(cyclopropylmethyl)-1-(1H-1,2,3-triazol-4-ylsulfonyl)azetidin-3-yl]methyl}benzamide (0.1 g; 0.23 mmol) in DMF (5 ml) at 0° C. was added potassium carbonate (0.062 g; 0.45 mmol) followed by methyl iodide (0.048 g; 0.021 ml; 0.34 mmol) and the solution stirred for 18 hours at ambient temperature. LC/MS shows three new products of identical mass ion m/e=458:460 (3:2). Water (1 ml) was added, the solvent stripped at reduced pressure, and the residue azeotroped twice with toluene. The crude product was purified by preparative TLC on silica gel eluted with 4% Methanol DCM to give the title compound as the most polar isomer (24 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([Na])=[N:2]1.Br[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[C:17]1(C)[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.FC1C=CC(C#N)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(C)C=O>[CH:11]1[C:12]([C:13]#[N:14])=[CH:15][CH:16]=[C:9]([CH:8]([N:2]2[N:1]=[CH:5][N:4]=[CH:3]2)[C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: [Na]c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A glass reactor was charged with 24.3 grams of 1,2,4-triazolylsodium and 500 grams of dimethylformamide. At a temperature between −10° C. and 0° C., 50 grams of 4-(bromomethyl)benzonitrile (53.2 grams with a purity of about 94 percent by weight, containing about 6 percent by weight of 4-tolunitrile) were added in portions. After stirring at 0° C. for 1 hour, 30.9 grams of 4-fluorobenzonitrile were added, and, while maintaining a temperature of −5° C. to −10° C., 245 grams of a 40 percent solution of sodium bis(trimethylsilyl)amide in THF were added dropwise. After the addition was completed, the reaction was quenched by the addition of 200 grams of 50 percent acetic acid, followed by precipitation of the product by the addition of 1500 grams of water. The resulting suspension was stirred and cooled to about 15° C., and the precipitate was collected and rinsed with water. The wet precipitate was dissolved in 350 grams of dichloromethane, and the solution washed with 250 grams of water. The organic phase was separated, concentrated to a volume of about 200 ml, diluted with 250 grams of toluene, and concentrated to a volume of about 300 ml. The resulting suspension was stirred at ambient temperature for 1 hour, and the precipitate was collected, rinsed with toluene, and dried, yielding 52 grams of crude letrozole product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:10]=1)=[O:4].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=S)=[CH:24][CH:23]=1.CI>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=4)=[N:20][C:14]=3[CH:13]=2)[CH:10]=1)=[O:4]
Reactant: CNc1ccc(Oc2cncc(C(=O)OC)c2)cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CO
Solvent: CI
Product: COC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) in methanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C.–65° C. for 2 hours. The reaction mixture was cooled down to room temperature and methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, taken up in ethyl acetate and washed with water and brine, dried, evaporated under reduced pressure. Column chromatography yielded methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate. MS: MH+=452
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14]([OH:16])=[O:15]>>[CH3:23][O:22][C:18]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Reactant: OB(O)c1ccccc1
Product: COc1cc(C(=O)O)cc(-c2ccccc2)c1OC
Yield: 88 %

Procedure:
5,6-Dimethoxybiphenyl-3-carboxylic acid was prepared by coupling phenylboronic acid with 3-iodo-4,5-dimethoxybenzoic acid according to Method P. The crude product was purified via flash column chromatography on silica gel (5% MeOH in CH2Cl2 as an eluent) to give the desired acid in 88% yield. ESMS: m/z 257.3 [M−H].
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCCC(O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.84 (br.s., 1H), 4.74 (t, J=6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 1.85-1.72 (m, 1H), 1.72-1.58 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1) 294.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:34][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([CH3:29])[CH:31]=1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: Cc1cccc(CN)c1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Product: COc1ccc2c(c1)CCN(CC(=O)NCc1cccc(C)c1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 3-methylbenzylamine