Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26](=[O:29])[N:27]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]=3)[N:28]=2)=[CH:21][CH:22]=1
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)C=C(n2nc(-c3ccc(Cl)cc3)ccc2=O)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 6-(4-Chloro-phenyl)-2H-pyridazin-3-one as starting materials, the title compound were prepared as white solids.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: Cn1c(Nc2nc3ccc(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(F)cc3s1)n2C
Yield: 73.7 %

Procedure:
2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (26 mg) was prepared by following General Procedure F using 2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 357. 1H NMR (DMSO-d6, 400 MHz): δ 8.31 (m, 1H), 7.93 (d, 1H), 7.63 (d, 2H), 7.50-7.42 (m, 1H), 7.38-7.28 (m, 1H), 7.12 (t, 2H), 3.60 (s, 3H), and 2.78 (d, 3H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:23]([CH2:27]Br)[C:24]([NH2:26])=[O:25]>>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:23]([C:24]([NH2:26])=[O:25])[CH2:27]2)[CH:17]=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: NC(=O)C(Br)CBr
Reactant: CC(=O)Nc1cccc(NCCNCc2ccccc2)c1
Product: CC(=O)Nc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-[3-[[2-[(phenylmethyl)amino]ethyl]amino]phenyl]acetamide (25.6 g, 90.4 mmol) with 2,3-dibromopropanamide (41.8 g, 180.8 mmol) to obtain the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O.O>C1COCC1>[CH3:18][NH:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([CH2:9][OH:8])[CH2:12][CH2:13]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C

Procedure:
A solution of 1.52 g (40 mmol) LAH in 7 ml THF was refluxed and treated for 2.5 h with a solution of 5.15 g (20 mmol) of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester in 35 ml THF. The reaction was heated for 15 h, cooled (0° C.) and hydrolyzed with 10 ml water. The mixture was diluted with THF, dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2, dried over Na2SO4, filtered and evaporated to yield 2.89 g (100%) of trans-(4-Methylamino-cyclohexyl)-methanol, mp: 87-88° C.; MS: 143 (M).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>O1CCCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:23]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCl)Nc1ccc2[nH]ncc2c1
Yield: 32 %

Procedure:
Triethylamine (2.1 ml, 15 mmol) was added to a suspension of 5-aminoindazole (1.00 g, 7.51 mmol) in tetrahydrofuran (10 ml) at room temperature, followed by adding thereto a solution of 4-chlorobutyryl chloride (1.16 g, 8.26 mmol) in tetrahydrofuran (5 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 1 hour. Then, a 1N-aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was suspended in ethanol and stirred, followed by filtration. The solid collected by the filtration was dried under reduced pressure to obtain 4-chloro-N-(1H-indazol-5-yl)butanamide (572 mg, 32%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12](O)=[O:13].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12]([N:22]([O:23][CH3:24])[CH3:21])=[O:13]
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.082 mL, 7.81 mmol) was added to a stirred solution of 4,4,5,5,5-pentafluoropentanoic acid (1.00 g, 5.21 mmol), N,O-dimethylhydroxylamine hydrochloride (0.559 g, 5.73 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.998 g, 5.21 mmol) in dry DCM (5.35 mL) at 25° C. under N2. The reaction was stirred at 25° C. overnight. The reaction was diluted with CH2Cl2 (60 mL) and washed consecutively with 1N aq. HCl (2×), satd aq. NaHCO3, dried (Na2SO4) and concentrated in vacuo to give the desired product, as a colorless liquid. 1H NMR (500 MHz, CHCl3-d): δ 3.72 (s, 3H); 3.21 (s, 3H); 2.74 (t, J=7.8 Hz, 2H); 2.51-2.37 (m, 2H). m/z=236.2 (M+H).
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]=1)[NH2:2].[CH3:22][C:23](=O)[CH2:24][C:25](=O)[CH3:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH3:26])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:4]=2)[N:2]=1
Reactant: Cn1cnc2c(NCCc3ccccc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(NCCc3ccccc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-phenethyl-amine and 2,4-pentanedione.
Reaction SMILES: [CH3:1][Li].[CH3:3][C@:4]12[CH2:20][CH2:19][C:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C:17]=3[CH2:16][CH2:15][C:14](=[O:21])[CH:13]=4)[C@@H:8]1[CH:7]=[CH:6][C:5]2=[O:22]>C(OCC)C.O1CCCC1.N.[Cu]I.[Cu](I)I>[CH3:1][C@H:7]1[C@H:8]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:4]2([CH3:3])[C:5](=[O:22])[CH2:6]1)=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Reactant: [Li]C
Agent: I[Cu]I
Agent: [Cu]I
Agent: N
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Temperature: -20 °C

Procedure:
5.2 ml of a 5% solution of methyllithium in diethyl ether are mixed with 570 mg of copper(I) iodide by portions at -5° C. Stirring is performed at a temperature between -5° and 0° C. until the copper iodide is fully dissolved. Then it is cooled to -20° C. and a solution of 1.1 g of 4,9,15-estratriene-3,17-dione in 15 ml of absolute tetrahydrofuran is slowly added drop by drop. It is stirred for 20 minutes at -20° C., then poured in concentrated aqueous ammonia solution and extracted with ethyl acetate. After chromatography with silica gel with hexane/ethyl acetate and crystallization of the main fraction from ethyl acetate/diisopropyl ether, 720 mg of 15β-methyl-4,9-estradiene-3,17-dione with a melting point of 125° to 126° C. are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: CC(CO)(CO)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a suspension of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (10.06 g, 75 mmol) in MeOH was dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether and stirred at room temperature overnight. After solvent was concentrated under reduced pressure, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate as an oil (3.79 g, 34%). 1H NMR (300 MHz, CDCl3) δ 3.81 (d, 2H), 3.67 (s, 3H), 3.60 (d, 2H), 2.89 (br, 2H), 0.96 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.CN(C)CCN(C)C.C([Li])CCC.C(N(CC)[C:24](=[O:39])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])C>C1COCC1>[N:27]1[C:26]2[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][C:24](=[O:39])[C:25]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CCN(CC)C(=O)c1cccnc1Nc1ccccc1C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2Nc2ncccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (7.61 mL, 53.89 mmol) and tetramethylethylenediamine (8.13 mL, 53.89 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 34.2 mL, 54.77 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min., then 0° C. for 10 min. This solution was transferred into a solution of N,N-diethyl-2-(o-tolylamino)nicotinamide in THF (100 mL) at 0° C. The resulting solution was stirred overnight and quenched by adding saturated ammonium chloride solution (20 mL). The solvent was then removed under reduced pressure and the residue dissolved in dichloromethane (100 mL), washed with water (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% hexane in ethyl acetate) to afford the pure desired product, 6,11-dihydro-5H-benzo[f]pyrido[2,3-b]azepin-5-one (2.2 g) as a yellow solid. 400 MHz 1H NMR (DMSO-d6) δ: 10.20 (s, 1H), 8.47-8.53 (m, 1H), 8.16-8.13 (m, 1H), 7.41-7.39 (m, 1H), 7.32-7.25 (m, 2H), 7.19-7.15 (m, 1H), 6.98-6.95 (m, 1H), 3.72 (s, 2H); LCMS (M+H)=211.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([OH:10])=[O:9].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C(O)(=O)C>[Cl:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:13](=[O:14])[CH2:12][Cl:11])[C:3]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nn1ccc(Cl)c1C(=O)O
Solvent: CC(=O)O
Product: O=C(CCl)Nn1ccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of 1-amino-3-chloro-1H-pyrrole-2-carboxylic acid (12.51 g, 55% purity, 0.04 mol) in 500 mL of glacial acetic acid were added under argon 17 mL of chloroacetyl chloride (0.21 mol) and the mixture was stirred at room temperature during 1.5 hours. Afterwards, the reaction mixture was poured into ice-water and extracted with ethyl acetate (2×400 mL). The organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuum giving a dark oil that was crystallized from a 1/1 diethyl ether/petroleum ether mixture. Filtration of the solid obtained afforded 7.28 g of a white solid corresponding to the title compound (61% yield, 85% purity). This solid was used in the next step without further purifications.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:41])[CH2:16][C@@H:17]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:20]=2[N:19]2[C:37]([CH3:40])=[N:38][N:39]=[C:18]12)C(=O)[O-])(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:41])[CH2:16][C@@H:17]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:20]=2[N:19]2[C:37]([CH3:40])=[N:38][N:39]=[C:18]12
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN(C(=O)[O-])C(C)(C)C)c1nnc(C)n1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN)c1nnc(C)n1-2
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl[5-({[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetyl}amino)pentyl]carbamate (for a preparation see Reference compound H) (0.2 g, 0.34 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.053 ml, 0.68 mmol) dropwise at 0° C. The reaction mixture was stirred for 3 h from 0° C. to room temperature. The reaction mixture was concentrated to dryness to afford the title compound as a hygroscopic yellow oil (200 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][C@@H:30]([N:33]=[N+]=[N-])[C@H:29]([OH:36])[CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][C@@H:30]([NH2:33])[C@H:29]([OH:36])[CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: [N-]=[N+]=N[C@@H]1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C[C@H]1O
Temperature: 70 °C
Yield: 113.9 %

Procedure:
19A (78.0 mg, 0.15 mmol) was dissolved in a mixture of THF/H2O (1.2 ml/0.2 ml) and PPh3 (60.0 mg, 0.23 mmol) was added. The mixture was heated at 70° C. for 2 h. After cooled to rt, the reaction mixture was concentrated in vacuo and purified by prep HPLC to give 19B (85.0 mg, 93%) as a TFA salt. It has an analytical HPLC retention time=1.84 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=498+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:9]([O:11]C)=[O:10])=[CH:6][NH:7][CH:8]=1.I[CH2:14][CH3:15].[OH-].[Na+]>C(O)C.CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:4]([CH3:3])[C:5]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH3:15]
Reactant: CCI
Reactant: COC(=O)c1c[nH]cc1C
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCn1cc(C)c(C(=O)O)c1
Yield: 73.1 %

Procedure:
In the same manner as in Reference Example 37 and using 60% sodium hydride (340 mg, 8.62 mmol), N,N-dimethylformamide (25 mL), methyl 4-methyl-1H-pyrrole-3-carboxylate (1.00 g, 7.19 mmol), iodoethane (860 μL, 10.8 mmol), ethanol (6 mL) and 8N aqueous sodium hydroxide solution (1.8 mL) as starting materials, the title compound (805 mg, 73%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])[CH3:2].Cl.C(O[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=N)C.C(N(CC)CC)C>O>[CH2:1]([O:3][C:4]([C@@H:5]1[C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[O:7][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:18]1)=[O:19])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(S(C)(=O)=O)cc1

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) is reacted at about 0° C. in a reaction vessel with benzenecarboximidic acid ethyl ester hydrochloride (Compound IV hydrochloride salt wherein R2 is phenyl and R4 is ethyl) (about 7.1 g, 0.03828 moles) in 1,2-dichloromethane (about 650 mL) containing triethylamine (3.9 g, 0.03828 moles). Thereafter, water is added (about 500 mL). Next, the organic layer is separated and washed with dilute hydrochloric acid (about 1 N) and dilute sodium bicarbonate (about 1N). The washed organic layer is dried over anhydrous sodium sulfate. The dried organic layer is heated to evaporate the 1,2-dichloromethane to yield (4S-trans)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolecarboxylic acid ethyl ester (Compound IIIk).
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.Cl.O1CCOC[CH2:17]1>CO>[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:17])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: O=C(O)C12CC3CC(C1)C(O)C(C3)C2
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(O)C(C3)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To a stirred solution of 4-hydroxyadamantane-1-carboxylic acid (4.47 g, 22.8 mmol) in MeOH (75 mL) was added 4 M HCl in dioxane (25 mL, 100 mmol). The mixture was stirred at rt for 2 d and concentrated. The residue was purified by chromatography on a 40-g silica cartridge eluted with a 0-80% EtOAc in hexanes gradient to afford methyl 4-hydroxyadamantane-1-carboxylate (4.04 g, 84%) as a clear, colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A mixture of 4-bromo-6-fluoro-1H-indole (D16), (200 mg, 0.935 mmol), 4-benzyloxyphenylboronic acid (426 mg, 1.87 mmol), copper (II) acetate (332 mg, 1.87 mmol) and triethylamine (0.26 mL, 188 mg, 1.87 mmol) in dichloromethane (5 mL) was stirred in air at room temperature for 16 hours. The mixture was filtered through celite, concentrated and purified by chromatography on silica gel (elution with 0-20% ethyl acetate in hexanes) to give the title compound as a pink solid (D19), (205 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:5]3=[N:6][CH:7]=2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 64.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.364 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65) (115 mg, 0.364 mmol) using sodium carbonate (115 mg, 1.093 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.0182 mmol) in DME/water (15/2 ml). This afforded 147 mg (64.1% yield) after purification by column (Silica gel 60/120) using 25% ethyl acetate in chloroform as eluent. MS: m/z=630.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)=[CH:2]1.[C:14]([CH2:16]C(O)=O)#[N:15].C([O-])(=O)C.[NH4+].N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)/[CH:9]=[CH:16]/[C:14]#[N:15])=[CH:2]1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: N#C/C=C/c1cccc(-c2ccsc2)c1
Yield: 35.6 %

Procedure:
1.0 g of 3-(3-thienyl)benzaldehyde, 0.5 g of cyanoacetic acid, 15 mg of ammonium acetate and 1 ml of s pyridine were dissolved in 1.5 ml of xylene, and the mixture was refluxed for 5.5 hours. The solvent was evaporated, and the residue was dissolved in a mixture of ethyl ether and water, then the resulting solution was acidified with diluted hydrochloric acid. The organic layer separated was worked up in a customary manner, and the product purified by medium-pressure liquid chromatography [silica gel column, hexane/ethyl acetate=7/1→5/1] to give 0.4 g of (E)-3-(3-thienyl)cinnamonitrile as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([NH2:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([NH:25][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2ccc(Cl)nc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 80 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitrobenzene-1-sulfonyl chloride (800 mg, 3.65 mmol), 2-chloro-quinolin-8-ylamine (Intermediate 26), pyridine (0.67 ml, 0.8 mmol) and DMAP (cat.) in DCM (30 ml) gave the title compound (800 mg, 80%) after purification by column chromatography with DCM as the eluent.