Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[N:15][CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.[CH:17]([Mg]Br)([CH3:19])[CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ni+2]>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[N:15][CH:14]=[CH:13][C:5]=1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7]2
Reactant: CC(C)[Mg]Br
Reactant: Clc1nc2ccnc(Cl)c2c2cnccc12
Agent: [Ni+2]
Agent: [Cl-]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2ccnc(Cl)c2c2cnccc12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,6-dichloropyrido[4,3-c]-1,6-naphthyridine (50 mg, 0.200 mmol) and 1,2-bis(diphenylphosphino)ethanenickel(II) chloride (1.056 mg, 1.999 μmol) in THF (0.4 mL). The mixture was cooled to −10° C. in a methanol-ice bath, and isopropylmagnesium bromide (220 μl 0.220 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at −10° C. for 30 min. The mixture was then allowed to warm to room temperature and then stirred for 30 min. The reaction mixture was quenched with aqueous ammonium chloride (saturated), and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford 1-chloro-6-isopropylpyrido[4,3-c]-1,6-naphthyridine as a red solid. LRMS (APCI) calc'd for (C14H13ClN3) [M+H]+, 258.1; found 258.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[Br:17]Br>CCOCC>[Br-:17].[Br-:17].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrBr
Agent: N#Cc1ccc(C=Cc2ccccc2)cc1
Solvent: CCOCC
Product: [Br-]
Reaction time: 1 h

Procedure:
4-Cyanostilbene (41 g) prepared by a known method was agitated in 300 ml of ether at room temperature, to which 33.5 g of bromine was dropwise added. After stirred for additional one hour, the reaction mixture was filtered to obtain 55.5 g of 4-cyanostilbene dibromide.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11]O)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:10][CH2:11][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: c1nc[nH]n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(CCn1cncn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution (ice bath) of 2-[N-methyl-N-(t-butoxycarbonyl)amino]ethanol (J. Med. Chem., 1999, 42(11), 2007-2020; 5 g, 28 mmol), triphenyl phosphine (9.35 g, 36 mmol) and 1,2,4-triazole (1.64 g, 24 mmol) in DCM (30 ml) was added diethylazodicarboxylate (5.64 ml, 35.7 mmol) dropwise. The ice bath was removed and the reaction mixture allowed to stir at room temperature for 1 hour. The precipitate was discarded and the filtrate was concentrated and purified by flash chromatography, eluting with a 50% EtOAc/DCM and then 100% EtOAc to give a pale yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].C1C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][CH:14]([C:15]([CH3:17])=[O:16])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1cc(OC)ccc1OC)C(C)=O

Procedure:
A mixture of 2,5-dimethoxybenzaldehyde (100 g), ethyl acetoacetate (84.5 g) and anhydrous benzene (200 ml), piperidine (6 ml) and acetic acid (12 ml) was heated at reflux for 3 hours in an apparatus fitted with a Dean-Stark trap to collect the azeotropically distilled water. The reaction mixture was cooled, benzene (300 ml) added, and the solution was washed successively with water (100 ml), cold 0.1 N hydrochloric acid (200 ml), 5% aqueous sodium bicarbonate (200 ml) and dilute acetic acid (100 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure and the residual oil distilled, b.p. 169°-170° C./0.3 mm Hg. The product, ethyl α-(2,5-dimethoxybenzylidene)acetoacetate, solidified on standing (104 g, m.p. 68°-69° C.) and was recrystallized from ethanol-pentane (m.p. 72°-73° C.). A portion (38 g) of the product was reduced catalytically in the presence of palladium on charcoal catalyst (Pd/C) in ethyl acetate (150 ml). The product, after removal of solvent, was purified by distillation under reduced pressure to give ethyl α-(2,5-dimethoxybenzyl)acetoacetate, b.p. 146°-148° C./0.3 mm Hg.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl[C:13]1[CH:21]=CC=C2[C:14]=1[C:15](=[O:23])[C:16](=O)N2.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrC(C1C=CC=CC=1)C1C=CC=CC=1>>[O:23]1[CH2:21][CH2:13][CH2:14][C@@H:15]1[CH2:16][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: BrC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using isatin to replace 4-chloroisatin, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace bromodiphenylmethane, 1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione was obtained (47%) as a thick red oil: 1H NMR (300 MHz, CDCl3) δ7.60-7.54 (m, 2H), 7.14-7.07 (m, 2H), 4.25-4.17 (m, 1H), 3.92-3.82 (m, 2H), 3.78-3.69 (m, 2H), 2.13-2.02 (m, 1H), 1.98-1.85 (m, 2H), 1.74-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ183.5, 158.8, 151.8, 138.5, 125.3, 123.8, 117.7, 111.7, 68.4, 44.7, 29.3, 25.8; MS (ES+) m/z 232.1 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)([CH3:16])([CH3:15])[CH3:14].[C:28]1(=[O:33])[CH2:32][CH2:31][CH:30]=[CH:29]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C.C1CCCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:27])[CH:19]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:30]1[CH2:31][CH2:32][C:28](=[O:33])[CH2:29]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1C=CCC1
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C2CCC(=O)C2)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Under argon, 4.4 ml (31.5 mmol) of diisopropylamine were initially charged in 50 ml of THF, the mixture was cooled to −30° C. and 13.7 ml (31.5 mmol) of a 2.3 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to −20° C., 5 g (24.3 mmol) of tert-butyl(4-methylphenyl)acetate, dissolved in 30 ml of THF, were added slowly, and the mixture was stirred at this temperature for 2 hours. The reaction solution was then cooled to −78° C., and 2.2 ml (25.7 mmol) of 2-cyclopenten-1-one, dissolved in 20 ml of THF, were added slowly. After the addition had ended, the solution was stirred at this temperature for another hour. After TLC check (mobile phase cyclohexane/ethyl acetate 9:1), saturated ammonium chloride solution was added and the mixture was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave 3020 mg (10.47 mmol, 43% of theory) of the title compound as a colorless oil.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[C:53]([OH:61])[C:54]([NH2:60])=[CH:55][CH:56]=4)[O:51][C:50]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:60][C:54]1[C:53]([OH:61])=[C:52]2[C:57]([C:58](=[O:59])[C:49]([C:46]3[CH:47]=[CH:48][C:43]([C:39]4([NH2:38])[CH2:40][CH2:41][CH2:42]4)=[CH:44][CH:45]=3)=[C:50]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[O:51]2)=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(O)c(N)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: Nc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1O
Yield: 45 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(7-amino-8-hydroxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a yellow solid (9 mg, 45%). 1H NMR (400 MHz, DMSO-d6): δ 7.48 (m, 2H), 7.39 (d, J=8.6 Hz, 1H), 7.37-7.27 (m, 5H), 7.09-7.05 (m, 2H), 6.78 (d, J=8.6 Hz, 1H), 5.76-5.69 (br s, 2H), 2.39-2.32 (m, 2H), 2.10-2.02 (m, 2H), 2.02-1.93 (m, 1H), 1.68-1.60 (m, 1H). LCMS (Method E): RT=2.81 min, [M+H]+=399.
Reaction SMILES: Cl.[NH2:2][C@@:3]([C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[F:16])([CH:6]([F:8])[F:7])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](Cl)=[O:26]>O>[F:7][CH:6]([F:8])[C@:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[NH:2][C:25](=[O:26])[CH2:24][O:5][CH2:4]1
Reactant: O=C(Cl)CCl
Reactant: N[C@@](CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1COC[C@](c2ccccc2F)(C(F)F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol HCl salt (0.5 g, 1.56 mmol) in IPAc (5 ml) was added under argon a solution of K2CO3 (0.862 g, 6.24 mmol) in 5 ml water below 25° C. After stirring for 30 min at 25° C. to provide a diphase clear solution, cooled down to −5° C., a solution of 2-chloroacetyl chloride (0.41 g, 3.59 mmol) in IPAc (2 mL) was added slowly with the temperature below 10° C. After stirring for 30 min at 20° C., the organic phase was collected and used for next step directly. THF (3 ml) was added to the above solution, the mixture was cooled to 0° C. The solution was added under argon KOtBu (0.35 g, 3.12 mmol) below 10° C. After stirring at 20° C. for 3 h, water was added to quench the reaction. The organic phase was washed by 1N HCl water solution (5 ml). The organic phase was collected and used for next step directly. The above solution was added water (5 ml) and Pd/C (10%, 50 mg), the mixture was stirred under H2 (1.5 bar) at 25° C. for 3 h. The catalyst was filtered out. The filtration was washed by 15% NaCl water solution. The solvent was removed under vacuum to provide the title compound as yellowish solid. ESIMS: 246 [(M+H)+]. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.30 (m, 1H), 7.81 (m, 1H), 7.30 (m, 2H), 6.55 (t, 1H), 4.1 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
To the product from Example 184 (1.0 mg, 0.00165 mole) in H2O (15 mL) and CH3CN (10 mL) was added LiOH (210 mg, 0.005 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (460 mg after lyophilization) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[S:5][CH:6]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:6]1[S:5][C:4]([NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(NC(=O)C2CC2)n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NC(=O)C2CC2)sc1Br
Reaction time: 0.5 h

Procedure:
To N-(4-methylthiazol-2-yl)cyclopropanecarboxamide (10.05 g) in acetic acid (100 ml) under an ice-water bath was added bromine (3.2 ml). After 30 min, water (100 ml) was added. Filtration, washing with water (3×) and drying under vacuum afforded N-(5-bromo-4-methylthiazol-2-yl)cyclopropanecarboxamide as a white solid (12.47 g). H NMR (500 MHz, CDCl3) 2.39 (s, 3 H), 1.64-1.60 (m, 1 H), 1.27-1.24 (m, 2 H), 1.00-0.96 (m, 2 H) ppm; LC/MS: 261 (M+1)/2.91 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[CH3:19][O:18][C:17]1[C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=2)=[CH:3][C:4]([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(Cn2nnc3ccccc32)cc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc3ccccc32)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A suspension of 1-(3-Bromo-4-methoxy-benzyl)-1H-benzotriazole (I-106) (477 mg, 1.50 mmol), 3-nitrophenylboronic acid (250 mg, 1.50 mmol), palladium(0) bis(dibenzylideneacetone) (43 mg, 0.075 mmol), and triphenyl phosphine (39 mg, 0.15 mmol) in dimethylformamide (10 mL) and 1 M aqueous sodium carbonate (4.5 mL, 4.5 mmol) was heated to 85° C. with stirring overnight. The solvent was removed under vacuum and the residue suspended in ethyl acetate (20 mL). The organic suspension was washed with water (3×20 mL) and brine, dried over sodium sulfate, decolorized over activated carbon, and the solvent removed under vacuum to give crude material. The residue was purified dissolving in ethyl acetate (5 mL) and adding hexanes (25 mL) until a solid formed. This was repeated 3 times to give P-482 (210 mg, 39% yield). 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3): 3.82 (s, 3H), 5.86 (s, 2H), 6.98 (d, J=8.2 Hz, 1H), 7.30-7.37 (m, 2H), 7.37-7.52 (m, 3H), 7.52-7.59 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.18 (dd, J=8.2, 1.2 Hz, 1H), 8.35 (d, J=1.6 Hz, 1H) ppm. LCMS=93.9% purity.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].[CH:12](=[O:15])[CH2:13][CH3:14].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([CH3:14])[CH:12]=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C=O)=Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 124 g (1 mole) of 4-fluorobenzaldehyde and 8 g (0.143 mole) of potassium hydroxide in 500 ml ethanol at room temperature was added dropwise a solution of 52.2 g (0.9 mole) of propionaldehyde in 100 ml ethanol. After stirring for 0.5 hour, the mixture was acidified with acetic acid and concentrated by rotary evaporation. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted three times with additional methylene chloride. The combined organic layers were dried and concentrated. Distillation through a 12-inch vacuum jacketed column gave 113.5 g (77%) of pale yellow low-melting crystalline product, b.p. 70°-72° C. (0.4-0.7 mm).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6]2.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>>[Si:21]([O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Product: COC(=O)C1Cc2cc(O[Si](C)(C)C(C)(C)C)ccc2CN1
Yield: 83 %

Procedure:
Prepared as in Example 12-1c from methyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (Example 13-3c) and tert-butylchlorodimethylsilane. Yield 83%, yellowish. MS 322 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([OH:16])([CH3:17])[CH3:14])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromopyridine in diethyl ether (5 ml/mmol) was cooled to −78° C., and n-butyllithium 2.5M in hexanes (1.05 eq) was added slowly. After 2 h in the cold, acetone (1.3 eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product from the organic phase was triturated with 1:1 ether-hexane and filtered to afford the 2-Bromo-5-(1-hydroxy-1-methylethyl)pyridine compound as a solid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCc1ccco1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccco2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, furfurylamine and DIEA to give 2-[(furan-2-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one LC-MS m/e 336 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Li+].O1CCCC1>CO>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Temperature: 50 °C
Yield: 89.8 %

Procedure:
Methyl 7-chloro-2oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (351 mg, 1.55 mmol), 1 M aqueous lithium hydroxide (0.774 mL, 1.55 mmol) and tetrahydrofuran (5 mL) were combined and heated to 50° C. for 2 hours. To the reaction was added 1 M aqueous lithium hydroxide (0.774 mL, 1.55 mmol) and methanol (10 mL) and the reaction was heated to reflux for 6 hours and then allowed to cool to ambient temperature overnight. The reaction solution was concentrated in vacuo to remove the tetrahydrofuran and methanol. The residual aqueous layer was extracted with ethyl acetate (2 mL). To the aqueous layer was added water (2 mL) ethyl acetate (2 mL) and 3 M aqueous hydrochloric acid. A precipitate formed. The mixture was filtered and the solids were washed with water and ethyl acetate. The solids were dried under a stream of nitrogen to give the title compound (296 mg, 90%). 1H NMR (400 MHz, DMSO-d) 5 ppm 11.54 (s, 1H) 11.12 (s, 1H) 7.54 (d, J=1.37 Hz, 1H) 7.38 (d, J=1.37 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)[CH:3]=1.[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[F:32])[CH3:19].CS(Cl)(=O)=O>N1C=CC=CC=1.CCOC(C)=O>[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([S:28](=[O:29])(=[O:30])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)=[CH:24][C:23]=1[F:32])[CH3:19]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Reactant: Nc1ccc(Cl)cc1-n1nnc2ncccc21
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine (153.5 mg, 0.626 mmol) in pyridine (2 mL) was added 4-chlorosulfonyl-2-fluoro-benzoic acid ethyl ester (200 mg, 0.752 mmol) followed by methanesulfonyl chloride (32 μL, 0.47 mmol) at 0° C. under a nitrogen atmosphere. The resultant reaction mixture was allowed to warm to room temperature and stirred for overnight. The following day, reaction mixture was diluted with EtOAc (25 mL), washed with 2N HCl (2×15 mL), dried (Na2SO4) and evaporated. The resulting bis-sulfonamides crude mixture was treated with 1N TBAF (in THF, 2 mL) at room temperature for 1 hour. The reaction mixture was then diluted with EtOAc (25 mL), washed with 2 N HCl (2×15 mL), water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated. The resulting crude product was purified by SiO2 chromatography using 50→100% EtOAc in hexanes solvent system to obtain 4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-2-fluoro-benzoic acid ethyl ester. Step 2: The title compound was prepared via conversion from its ethyl ester according to general procedure Y: MS (ES) M+Na expected 484.0, found 484.0.
Reaction SMILES: S(Cl)(Cl)=O.CO.[N:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([OH:15])=[O:14].[C:16](=O)([O-])O.[Na+]>O>[N:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(O)c1cnccn1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cnccn1
Temperature: 61 °C
Yield: 74.6 %

Procedure:
106.6 g of thionyl chloride was added dropwise over 1 hour at 4° to 6° C. to 1200 ml of methanol under argon. 100.1 g of pyrazinecarboxylic acid was added at 9° C. and the mixture was heated for 2 hours at 61° C., with the acid passing completely into solution. After cooling to room temperature, a solution of 145 g of sodium hydrogen carbonate in 1.4 l of water was added slowly. The methanol was distilled off on a rotary evaporator at 50 to 120 mbar and a bath temperature of 45° C., and the residue was extracted three times with dichloromethane (400 ml, 100 ml, 100 ml). Concentration of the organic phase provided 83.15 g of crude product, which was recrystallized from ca. 250 g of diisopropyl ether. The yield of the title compound was 70.6 g, plus 10.28 g from the mother liquor (total: 72.5 percent). Other data concerning the title compound was:
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:38]=CC(N)=C[CH:33]=1>>[Cl:31][C:32]1[CH:38]=[CH:9][C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:11][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-chloroaniline instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 369 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (1H, br. s.) 10.12 (1H, s) 9.99 (1H, s) 8.04 (1H, d, J=5.47 Hz) 7.91 (1H, d, J=0.10 Hz) 7.71 (2H, d, J=8.93 Hz) 7.52 (1H, d, J=5.37 Hz) 7.37-7.43 (2H, m) 7.33 (1H, dd, J=3.25, 2.61 Hz) 6.85 (1H, d, J=5.42 Hz) 6.46 (1H, dd, J=3.49, 1.88 Hz)