Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=3)[C@@H:5]([CH3:30])[CH2:4]1)[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=3)[C@@H:5]([CH3:30])[CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of (S)-methyl 3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (80 mg, crude) in methanol (30 mL) was added sodium hydroxide (31.0 mg, 0.78 mmol) and water (1 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% NH3.H2O and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] to afford (S)-3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (40 mg, 52.0%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][O:25][CH3:26])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:27][O:28][CH3:29])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:36]>CO.[OH-].[OH-].[Pd+2]>[ClH:36].[CH3:29][O:28][CH2:27][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][O:25][CH3:26])=[N:18][C:12]=2[O:11]1
Reactant: COCC1CCCN1c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCC1CCCN1c1cnc2c(n1)O[C@@H](COC)CNC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-3-[2-(methoxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (329 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (40 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (227 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (155 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1Cl
Reactant: Sc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccccc2)cc1Cl
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.1 15 g) was added to a deoxygenated mixture of 2-chloro-4-iodoaniline (0.507 g), thiophenol (0.214 ml) and sodium methoxide (0.227 g) in ethanol (20 ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, cooled, diluted with ether (30 ml) and filtered. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-15% ethyl acetate/hexane to give the title compound (0.443 g) as a solid. M.p. 59-60° C.; NMR: 5.78 (br s, 2H), 6.8 (t, 1H), 7.04 (m, 2H), 7.15 (m, 2H), 7.2-7.35 (m, 3H); EA: C12H10ClNS requires C, 61.1; H, 4.3; N, 5.9; S, 13.6%; found: C, 60.8; H, 4.4; N, 5.7; S, 13.3%.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-:21]#[N:22].[Na+].O>CN(C=O)C>[C:9]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:3]=2[CH2:2][C:21]#[N:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: BrCc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 2′-bromomethyl-[1,1′:3′,1″]terphenyl (Tetrahedron Lett. 42; 5467-5472 (2001)) (1.65 g, 5.1 mmol) and sodium cyanide (0.27 g, 5.6 mmol) in 10 mL of DMF was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with diethyl ether and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (eluting with 0-4% ethyl acetate in hexane) to give [1,1′;3′,1″]terphenyl-2′-yl-acetonitrile as a white solid (0.78 g, 57%): MS (ESI) m/z 270.1 (M+H); HRMS calcd for C20H15N, 270.1277. Found (ESI+): 270.1274; 1H NMR (DMSO-d6): δ 3.57 (s, 2H), 7.20-7.50 (m, 13H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([O:23][CH3:24])[CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2C(C)=CC=C2C)=[N:6][C:7]=1[CH3:8].Cl.NO.C(O)C>O>[Br:1][C:2]1[C:3]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([O:23][CH3:24])[CH2:19][CH2:18]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8]
Reactant: CO[C@H]1CC[C@H](Nc2nc(-n3c(C)ccc3C)nc(C)c2Br)CC1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: CO[C@H]1CC[C@H](Nc2nc(N)nc(C)c2Br)CC1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(trans-4-methoxycyclohexyl)-6-methylpyrimidin-4-amine (1.07 g, 2.72 mmol) and hydroxylamine hydrochloride (945 mg, 13.6 mmol) in 10:1 ethanol:water (27.5 mL) was heated to reflux for 7 hours, then room temperature overnight. Another 0.5 eq of hydroxylamine hydrochloride was added and the solution was refluxed for another 4 hours, then cooled to room temperature and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0.5-3%) to afford 5-bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine (767 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].P([O-])(OCC)([S:12][CH2:13][CH3:14])=S.Cl>CCOC(C)=O>[S:12]1[CH:13]=[CH:14][N:2]=[C:1]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: CCOP([O-])(=S)SCC
Reactant: N#Cc1ccccc1O
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1ccccc1-c1nccs1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The title compound was prepared according to the method in Z. Naturforsh. 376, 877-880 (1982) or Helv. Chim. Acta 36, 886-890 (1953). o-Cyanophenol (55 mmol, 6.55 g) in EtOAc (160 mL) was treated with diethyl dithiophosphate (9.15 mL, 55 mmol) and HCl(g) was bubbled into the stirred solution at a moderate rate for about 45 min. without external cooling. After stirring at about 20° C. under N2 (g) for about 16 h., excess HCl was removed by N2 (g) sparge and saturated aqueous Na2CO3 (100 mL) was added carefully with stirring. The organic phase was separated and washed (3×) with saturated Na2CO3 until no further orange color resulted in the aqueous phases. The organic phase was dried over Na2SO4 (s) and concentrated in vacuo. An orange crystalline impurity (~3.0 g; m.p. 215° C., El-MS m/z 255) precipitated upon addition of ether and was removed by filtration. The filtrate was concentrated in vacuo and recrystallized from Et2O/hexanes to afford 2.9 g (m.p. 117° C.; GC-MS m/z 153) of the desired thioamide. This material (2.0 g, 13 mmol) was dissolved in EtOH (5 mL) and α-bromoacetaldehyde dimethyl acetal (1.55 mL, 13 mmol) was added. The mixture was refluxed under N2 (g) atmosphere for 3.5 h. and Et2O (15 mL) was added to complete the precipitation of the 2-(thiazol-2-yl)phenol as its hydrobromide salt which was recrystallized from MeOH/CHCl3 /Et2O to produce 1.55 g of pure HBr salt (LSIMS m/z 178 (MH+)). This material could be alkylated directly if an extra equivalent of base was included to neutralize the HBr, or it could be free-based by extraction from saturated aqueous NaHCO3 with Et2O followed by drying over Na2SO4 (s) and concentration of etheral phases in vacuo.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:16]=C4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:64](=[O:69])([O:67][CH3:68])[O:65][CH3:66]>>[CH3:46][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:16][C@H:66]4[O:65][C:64]([O:67][CH3:68])=[O:69])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COC(=O)OC
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(=O)Nc3ccccc3)C[C@H](OC(=O)N(C)C)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of 50 mg of pyridinium p-toluenesulfonate. The mixture was stirred in an atmosphere of argon gas at room temperature for 10 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 150 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.CC1(C)[O:25][C:24](=O)[C:21]2([CH2:23][CH2:22]2)[C:20](=[O:27])[O:19]1.C(OCC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:23][CH2:22][CH:21]([C:20]([OH:27])=[O:19])[C:24]2=[O:25])=[CH:9][CH:8]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Yield: 56.6 %

Procedure:
A solution of 561 mg (2.6 mmol) 4-(3-fluoro-benzyloxy)-phenylamine and 448 mg (2.6 mmol) 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione in 2 ml dichloromethane is refluxed for 16 hours. 5 ml of diethylether is added and the precipitate filtered off to yield 485 mg (57%) of a colorless solid. MS: m/e=330.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[N:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.26 mmol) in pyridine (1 mL) was treated with 1-pyrrolidinecarbonyl chloride (0.29 mmol). The reaction stirred for 18 h at room temperature and was then concentrated. Purification of the residue by Gilson reverse phase HPLC provided the title product as a white powder (52%). ESMS [M+H]+: 401.2
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[C:21]1([NH2:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OCC)(=O)C>[C:21]1([NH:27][C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid (5.29 g, 40.7 mmol, 1.0 eq.) in anhydrous THF (50 mL) under nitrogen was added dropwise triethylamine (4.12 g, 40.7 mmol, 1.0 eq.) with stirring for 30 minutes at 0° C., followed by the addition of thionyl chloride (4.84 g, 40.7 mmol, 1.0 eq.) with stirring for another 30 minutes at 0° C. To the resulting mixture under nitrogen was added dropwise a solution of phenylamine 9 (4.17 g, 44.8 mmol, 1.1 eq.) in anhydrous THF (25 mL) with stirring for 1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetate and extracted with 2N NaOH (to pH>10). The aqueous phase was titrated with 2N HCl to pH 1-2 and then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated in vacuo to give 1-phenylcarbamoyl-cyclopropanecarboxylic acid as a white solid (5.08 g, 60.8%). 1H NMR (400 MHz, CDCl3): 10.50 (br s, 1H), 7.56-7.54 (m, 2H), 7.35-7.31 (m, 2H), 7.15-7.10 (m, 1H), 1.94-1.91 (m, 2H), 1.82-1.79 (m, 2H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1
Reactant: COc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1
Yield: 80 %

Procedure:
The bromination of anisole with one equivalent of bromine is chloroform, at room temperature, is reported to give an 80% yield of monobromoanisole. Grignard, Bellet and Courtot, Ann. Chim. 4, 28 (1915). The preparation of dibromoanisole from anisole, and of tribromoanisole from dibromoanisole, in carbon tetrachloride, is also reported. Kohn and Sussman, Monatsh. Chem. 46, 575 (1925). "Several days" reaction time is reported for the preparation of several tribromophenyl alkyl ethers. Yields are not reported. Baiford and Birosel, J. Am. Chem. Soc., 51, 1776 (1929). The bromination of anisole with three equivalents of bromine yields 1.5% tribromoanisole. Similarly, the bromination of monobromoanisole with two equivalents of bromine in chloroform is reported to give only small quantities of tribromoanisole, and tribromoanisole is reported not to brominate further. D. M. Birosel, Univ. Phillipines Natural Applied Sci. Bull. 1, 145 (1931).
Reaction SMILES: [OH:1][C@@H:2]([CH3:35])[CH2:3][O:4][NH:5][C:6]([C:8]1[C:9]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:10]2[CH:16]=[N:15][N:14](CC3C=CC(OC)=CC=3)[C:11]2=[N:12][CH:13]=1)=[O:7]>C(O)(C(F)(F)F)=O>[OH:1][C@@H:2]([CH3:35])[CH2:3][O:4][NH:5][C:6]([C:8]1[C:9]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:10]2[CH:16]=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)NOC[C@H](C)O)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)CONC(=O)c1cnc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ((S)-2-hydroxypropoxy)-amide (500 mg, 0.85 mmol) was dissolved in TFA (5 mL) and the resulting mixture heated at 65° C. for 3 hours before being concentrated in vacuo. The resultant residue was dissolved in dichloromethane (10 mL) and methanol (2 mL) then stirred vigorously with aqueous saturated sodium bicarbonate solution (20 mL) for 2 hours. The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic fractions filtered through a hydrophobic frit then concentrated in vacuo. The resultant residue was purified by reverse-phase HPLC (gradient 10-95% methanol/water+0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm) to yield the title compound as a white solid (106 mg, 27%). LCMS (Method A): RT=7.19 min, [M+H]+=472. 1H NMR (DMSO-d6, 400 MHz) 13.51 (1H, s), 10.37 (1H, s), 8.45 (1H, s), 7.80 (1H, dd, J=9.68, 1.89 Hz), 7.63-7.60 (1H, m), 7.25 (1H, t, J=8.42 Hz), 6.74 (1H, s), 3.88-3.81 (1H, m), 3.73-3.69 (2H, m), 1.05 (3H, d, J=6.34 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C1COCC1>[NH2:6][C:5]1[C:4]([F:9])=[C:3]([C:2]([Cl:1])=[CH:8][CH:7]=1)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
A flame dried flask equipped with a stir bar and rubber septum was charged with 4-chloro-2-fluoroaniline (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to −78° C., and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at −78° C. for 20 minutes, and then a THF solution (25 mL) of 1,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to −78° C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at −78° C. for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at −78° C. for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.37-7.48 (m, 5H), 7.07 (dd, 1H, J=8, 2), 6.87 (t, 1H, J=8), 5.61 (br s, 2H), 5.40 (s, 2H).
Reaction SMILES: C[Mg]Br.CCO[CH2:7][CH3:8].[N:9]1[C:16]([Cl:17])=[N:15]C(Cl)=[N:12][C:10]=1[Cl:11]>ClCCl.O>[Cl:11][C:10]1[N:9]=[C:16]([Cl:17])[N:15]=[C:7]([CH3:8])[N:12]=1
Reactant: CCOCC
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
A solution of methylmagnesium bromide in ether (3M, 30 ml, 90 mmole) was added dropwise to a stirred solution of cyanuric chloride (3.91 g, 21.20 mmole) in anhydrous dichloromethane at −10° C. After the addition was complete, the reaction mixture was stirred at −5° C. for 4 h, after which time water was added dropwise at a rate such that the temperature of the reaction stayed below 10° C. After warming to room temperature, the reaction mixture was diluted with additional water and methylene chloride and passed through a pad of cilite. The organic layer was dried and evaporated to give 2,4-dichloro-6-methyl-1,3,5-triazine of 4 as yellow solids (3.02 g, 87%). 1H NMR (CDCl3) δ 2.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][N:9]([CH3:21])[C:8]=12.Br[C:23]1[C:24]([O:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[N:25][CH:26]=[C:27]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[O:34][C:24]1[C:23]([C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:21])[CH:10]=2)=[CH:28][C:27]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=1
Reactant: COc1nccc2c(B3OC(C)(C)C(C)(C)O3)cn(C)c12
Reactant: CS(=O)(=O)Cc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1nccc2c(-c3cc(CS(C)(=O)=O)cnc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
The product from Example 59A (0.061 g, 0.212 mmol), the product from Example 60E (0.08 g, 0.212 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.8 mg, 6.35 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (6.2 mg, 0.021 mmol) and potassium phosphate (0.157 g, 0.74 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (2 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred at 60° C. for 2 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated to afford the title compound (0.1 g, 100%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (93.6 mg, 74%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12>>[CH3:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:22]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[CH2:25][N:19]3[CH:18]=[CH:17][CH:16]=[C:20]3[CH2:21]2)=[O:12])=[CH:9][CH:8]=1
Reactant: CCCCCOc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: CCCCCOc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
As described for Example 343 4-(n-pentyloxy)benzoyl chloride is reacted with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine to the desired product as a solid: mass spectrum(CI), 375(MH+).