Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[F:42])[CH:37]=[O:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[C:36]([CH:37]=[O:38])[CH:39]=[CH:40][C:41]=4[F:42])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)ccc4F)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol), and K2CO3 (360 mg, 2.60 mmol) in microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: [F:1]C1C=CC(CC(=O)C)=CC=1.FC1C=CC(CC(=O)C)=CC=1S(Cl)(=O)=O.CO[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:39][C:38]([NH:40][C:41](=[O:43])[CH3:42])=[N:37][C:36]=2[CH3:44])=[CH:31][C:30]=1[S:45](=[O:48])(=[O:47])[NH2:46].COC1C=CC(CC(=O)C)=CC=1>>[F:1][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:39][C:38]([NH:40][C:41](=[O:43])[CH3:42])=[N:37][C:36]=2[CH3:44])=[CH:31][C:30]=1[S:45](=[O:48])(=[O:47])[NH2:46]
Reactant: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1S(N)(=O)=O
Reactant: CC(=O)Cc1ccc(F)cc1
Agent: CC(=O)Cc1ccc(F)c(S(=O)(=O)Cl)c1
Agent: COc1ccc(CC(C)=O)cc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(F)c(S(N)(=O)=O)c2)s1

Procedure:
The title compound is prepared from 4-fluorophenyl acetone via 2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Example 47a) following an identical sequence of reactions used for the synthesis of N-[5-(4-methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 30) from 4-methoxyphenyl acetone.
Reaction SMILES: ClCCC[N:5]1[C:10](=O)[C:9]2[C:12](F)=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7](C)(C)[CH2:6]1.C(N(CC)CC)C.C1(N2CCNCC2)C=CC=CC=1.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.CC(C)=O.C([O-])(=O)C([O-])=O>[SiH2:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][NH:5][CH2:6]1
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2c(F)cccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: c1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)CNC[SiH2]2

Procedure:
The procedure is carried out as in Example 11, using 1.15 g of 3-(3-chloropropyl)-1,1-dimethyl-5-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, 1.1 cm3 of triethylamine and 1.3 g of 1-phenylpiperazine in 23 cm3 of toluene (23 cc). After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (98.5-1.5 by volume) as eluent, 0.3 g of 1,1-dimethyl-5-(4-phenyl-1-piperazinyl)-3- [3-(4-phenyl-1-piperazinyl)-propyl]-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline; melting point =166° C., and 0.3 g of an oil are obtained, which oil, when dissolved in 3 cm3 of acetone and treated with 0.24 g of oxalic acid, yield 1,1-dimethyl-5-fluoro-4-oxo-3-3-(4-phenyl-1-piperazinyl) 3-propyl]-1,2,3,4,-tetrahydro-3,1-benzazasiline in the oxalate form; melting point =99° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:28][CH2:27]3)=[C:22]([C:23]#[N:24])[CH:25]=2)=[O:15])[C:10]([CH3:16])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)cc1C(=O)O
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1nn(Cc2ccccc2)cc1C(=O)Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C#N)c1
Yield: 46.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-benzyl-3-methylpyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.8 g), the title compound (0.63 g) was obtained, melting point: 193° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:38][CH2:37][CH2:36][CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)=[N:31]1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Reactant: Nc1ccn(CCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 65 mg, 0.20 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (74 mg, 83%) as a colorless gum: [α]32589=−23.3° (c=0.15, methanol); ES-HRMS m/e calcd for C22H29N3O5S (M+H)+ 448.1901, observed 448.1901; 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 1H, CH), 1.76-2.29 (m, 10H, 5×CH2), 2.62 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.33 (m, 2H, OCH2), 3.90 (m, 1H, ArCHCO), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.56 (t, J=5.1 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.45 (brs, 1H, Ar), 7.46 (brd, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[C:21]([O:24][CH3:25])[CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c2c1
Yield: 64.7 %

Procedure:
1.00 g (4.59 mmol) of 4-chlorobenzenesulfonylisocyanate and 698 mg (4.18 mmol) of 2-amino-5-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 992 mg of the above-identified compound (yield 64.8%). Properties: colorless crystal, Melting point: 192°-194° C., PMR (δppm, DMSO-d6): 3.79 (3H,s), 7.08 (1H,d), 7.30 (2H,m), 7.75 (2H,d), 8.16 (2H,d), 11.48 (1H,br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30]C(=O)C)[CH:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:30])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C)nn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)nn1
Temperature: 85 °C
Yield: 44 %

Procedure:
To a solution of the compound of Example 17 (300 mg, 0.675 mmol) in ethanol (10 ml) was added aqueous solution of NaOH (338 mg, 8.44 mmol, 12.5 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 44% yield (0.12 g). LC-MS (ESI): Calculated mass: 402.4; Observed mass: 403.4 [M+H]+ (rt: 1.03 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([NH:19][CH2:20][C:21]#[CH:22])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:12]([O:11][C:9]([NH:19][CH2:20][C:21]#[C:22][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][CH2:20][NH:19][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: O=C(NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)nc1)OCc1ccccc1
Temperature: 65 °C
Yield: 86.4 %

Procedure:
A mixture of 2,5-dibromopyridine (3.00 g), N-Cbz-propargylamine (5.99 g), PdCl2(PPh3)2 (89.8 mg), and CuI (6.0 mg) in diisopropylamine (51 ml) was heated at 65° C. for 7 hours under nitrogen atmosphere. The mixture was cooled to room temperature, and the precipitates were filtered, washed with water, and dried under reduced pressure to give 8-1 (4.96 g) as a crystalline compound; m.p. 156-158° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7]2)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16].O>C1COCC1>[CH3:14][N:15]([CH3:16])[C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2
Reactant: CNC
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1=Cc2cc([N+](=O)[O-])ccc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
To a solution of 5-nitro-2-indanone (885 mg, 5 mmol) in THF (15 mL) was added dimethylamine (2N in THF, 5 mL, 10 mmol) dropwise. The reaction mixture was stirred at r.t. for 5 h. Water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. The concentrated crude product was filtered through a short pad of silica gel (EtOAc:hexane=1:1) and the filtrate was concentrated to give dimethyl-(5-nitro-1H-inden-2-yl)-amine as a dark red solid (1.0 g, 98%). Dimethyl-(5-nitro-1H-inden-2-yl)-amine (1.0 g, 4.9 mmol) was hydrogenated using Pd/C (10% dry, ca. 300 mg) and H2 in MeOH:THF (1:1, 30 mL) at 1 atm at r.t. for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The concentrated filtrate was further purified via short silica gel column chromatography (EtOAc: MeOH=6:4) to give the title compound as a yellow solid (830 mg, 82%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:22]2.CC(C)(C)C(Cl)=O.C[N+]1(C)[C@H]2CC3C=CC(O)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1>C1COCC1>[CH3:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH2:28][CH2:29][C:30]([N:8]1[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]1=[O:12])=[O:31])=[CH:22]2
Reactant: Cc1ccc2[nH]c(CCC(=O)O)cc2c1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@@H]1C5
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c(CCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To the suspension of (4S)-4-phenyl-1,3-oxazolidin-2-one (6.85 g, 42 mmol) in anhydrous THF (130 mL) was added BuLi (26.3 mL, 42 mmol) at −78° C. and the mixture was stirred under argon (0.5 h). To the above suspension was added a solution of active ester prepared by reacting 3-(5-methylindolyl)propanoic acid 7 (10.23 g, 50.39 mmol) in anhydrous THF (130 mL) and trimethylacetyl chloride (5.10 g, 50.39 mmol) in the presence of N-methyl morphine (6.06 g, 50.39 mmol) at 0° C. under argon, followed by stirring at −78° C. (1 h). The combined reaction mixture was stirred at −78° C. for an additional 2 h, then the solution was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice-cold saturated NH4Cl solution (120 mL), extracted with EtOAc, washed with brine and dried (Na2SO4). Evaporation provided a residue, which was purified by silica gel flash chromatography to provide 8 as colorless oil. (12.7 g, 87% yield). 1H NMR (d6-DMSO) δ 7.36-7.23 (m, 8H), 6.94 (dd, 1H, J=1.5 Hz & 8.5 Hz), 6.28 (dd, 1H, J=0.8 Hz & 3.1 Hz), 5.43: (dd, 1H, J=3.5 Hz & 8.6 Hz), 4.70 (t, 1H, J=8.8), 4.40 (s, 1H), 4.40-4.37 (m, 2H), 4.15 (dd, 1H, J=3.5 Hz & 8.8 Hz), 3.41-3.30 (m, 2H), 2.36 (s, 3H). FABMS (+Ve) m/z 348 [M+], 349 [MH+]. Anal. Calcd for C21H20N2O3 C, 72.40; H, 5.79; N, 8.04. Found C, 72.33; H, 5.77; N, 8.15.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[CH:23]=[N:24][C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)=[CH:20][CH:21]=3)=[N:26][NH:27]2)=[CH:32][CH:31]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccc(Br)cc65)ccc34)cn2)CC1
Yield: 88.2 %

Procedure:
The title compound (E/Z=3:4, 65 mg, 88%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 3 h) using 5-bromoindolin-2-one (32 mg, 0.15 mmol) and 3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-6-carbaldehyde (46 mg, 0.143 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.41 (s, 1H), 10.80 (s, 1H), 8.76 (s, 1H), 8.20-8.03 (m, 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.67 (d, 1H), 7.48-7.40 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); Z isomer: δ 13.48 (s, 1H), 10.84 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.20-8.03 (m, 5H), 7.38 (d, J=8.0 Hz, 1H), 6.98 (d, J=9.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); MS ESI 515.4 [M+H]+, calcd for [C26H23BrN6O+H]+ 515.1.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O>[CH2:26]([O:25][C:23]([CH2:22][O:21][N:20]=[C:14]([C:12]1[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=1)[C:15]([OH:17])=[O:16])=[O:24])[CH3:27]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: CCOC(=O)CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
Sodium bicarbonate (0.84 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (2 g.) in water (120 ml.) to prepare a solution. Ethyl 2-aminooxyacetate hydrochloride (4.56 g.) was added to the solution and stirred at ambient temperature for 3 hours while adjusting a pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.44 g.), mp. 112° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH2:26][S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:26][S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)C1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
A solution of 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester (3.1 g, 5.7 mmol) in ethyl acetate was treated sequentially with ethanol and tin (II) chloride dihydrate (20.2 g, 89.5 mmol), stirred at 75° C., under nitrogen, for 2 hours, 20 minutes, poured into excess water and extracted with ethyl acetate. The combined extracts were washed sequentially with 2.5 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo for 20 minutes at 80° C. to yield 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester as a yellow solid, 2.37 g (82% yield), mp 162-4° C.; Mass spectrum (+EI, [M+H]+) m/z 517. 1HNMR (500 MHz, DMSO-d6): δ8.60-8.63 (m, 1H), 8.26 (dd, 1H, J=12.81 Hz and 8.23 Hz), 8.03-8.08 (m, 2H), 7.58-7.72 (m, 3H), 7.27-7.40 (m, 5H), 6.56-6.61 (m, 2H), 6.06 (s, 1H), 5.03-5.09 (m, 2H), 4.72 (s, 2H), 4.67 (s, 2H), 4.30 (s, 1H), 3.32-3.42 (m, 2H), 3.15-3.21 (m, 2H), 1.74-1.81 (m, 1H), 1.66-1.63 ppm (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:6]([O:8]C)=O.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:6]([C:5]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:8])[CH2:6][C:5]2[CH:10]=[CH:11][C:12]([CH3:13])=[CH:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Product: COc1cc(C(O)(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc(OC)c1C(C)C
Yield: 20 %

Procedure:
This material was prepared as a 20% yield from methyl 3,5-dimethoxy-4-i-propylbenzoate and 4-methylbenzyl bromide using the same method as described in example 1 (b). 1HNMR (CDCl3, ppm): δ 1.30 (d, J=7.1 Hz, 6H), 2.31 (s, 6H), 3.02 (d, J=13.5 Hz, 2H), 3.25 (d, J=13.5 Hz, 2H), 3.52 (m, 1H), 3.71 (s, 611), 6.45 (s, 2H), 6.8-7.2 (m, 8H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1cccc(F)c1
Product: N#Cc1cc(-c2cccc(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (76 mg, 95%), MS (ISP) m/z=320.5 [(M+H)+], mp 210.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:16].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1cccc(Br)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C(N)=O)c1cccc(Br)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (Example 367, Step 1) (200 mg, 0.89 mmol) in dimethylsulfoxide (4 mL) was added hydrogen peroxide (0.42 mL, 4.8 mmol) and potassium carbonate (1.23 g, 8.89 mmol). The reaction was then stirred overnight at 70° C. The resulting slurry was cooled to ambient temperature, filtered and directly purified by reverse phase HPLC (10-100% acteonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)N.[CH3:9][O:10][CH2:11][C:12](=O)[CH3:13]>C(O)C>[CH3:9][O:10][C:11]1[C:8]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[NH:1][C:12]=1[CH3:13]
Reactant: NNc1ccccn1
Reactant: COCC(C)=O
Solvent: CCO
Product: COc1c(C)[nH]c2ncccc12
Yield: 40.8 %

Procedure:
A solution of 7,4 g (68 mmol) 2-hydrazinopyridine and 6,0 g (68 mmol) methoxyaceton in 50 ml of ethanol was refluxed for 1 h. The solvent was removed under reduced pressure. The resulting oil was dissolved in diethylene glycol and refluxed for 1,5 h. The mixture was allowed to cool and was poured into ice-water. Extraction with methylene chloride gave an black oily residue which was treated with boiling petroleumether (60-80). After decanting the solvent was allowed to cool and the precipitated product filtered of affording 4,5 g (41%) pure title compound as a yellow solid.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH:7]([CH3:10])[CH2:8][OH:9]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH:7]([CH3:10])[CH2:8][O:9][P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(Br)CO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)COP(=O)(Cl)Cl
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 42 g of phosphorous oxychloride in 110 ml of carbon tetrachloride was added dropwise with stirring a solution of 25 g of 2-bromo-1-propanol in 25 ml of carbon tetrachloride. This mixture was stirred overnight, then taken to dryness, evaporated twice from toluene and dried. The residue was distilled on a Kugelrohr 75° C., 0.05 mm, giving 26.1 g of the desired compound as a colorless oil.