Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[SH:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC1C=CC(S(O[CH2:30][C:31]([F:34])([F:33])[F:32])(=O)=O)=CC=1>O>[F:32][C:31]([F:34])([F:33])[CH2:30][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
1.7 g of sodium hydride was added to 30 ml of dry dimethylformamide, and then 7.5 g of tert-butyl 2-mercaptoethylaminoformate. Upon the end of the addition, the mixture was stirred for 1 h, and then slowly added with 2,2,2-trifluoroethyl (4-methylphenyl)sulfonate. Upon the end of the addition, the mixture was warmed to room temperature, and stirred overnight. The mixture was poured to water, extracted with diethyl ether, washed with 0.5M sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, distilled to remove the solvent, and subjected to a column chromatography to obtain 5.4 g of light yellow oily liquid, yield 53.8%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[N:21][C:22]#[N:23])SC)=[CH:13][CH:12]=1)#[N:10]>O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:22]([N:21]=[C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])#[N:23]
Reactant: NCCC(=O)O
Reactant: CSC(=NC#N)Nc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CN=C(NCCC(=O)O)Nc1ccc(C#N)cc1
Yield: 63.4 %

Procedure:
A mixture of 12.3 g (0.138 mol) of β-alanine and of 5.52 g (0.138 mol) of sodium hydroxide in 100 cm3 of water is added to a solution of 20 g (0.092 mol) of N-(4-cyanophenyl)-N'-cyano-S-methylisothiourea in 300 cm3 of 95% ethanol. The mixture is heated to reflux for 4 hours. After cooling, the solution is filtered then concentrated to dryness in vacuo. The residue obtained is dissolved in 200 cm3 of a 2% sodium carbonate solution. The resulting solution is washed by dichloromethane (3×50 cm3) then acidified by a 3N HCl solution until a pH close to 2 is obtained. The white solid formed is filtered, then washed with water (2×10 cm3) and dried in vacuo. After recrystallization in water, 15 g (yield 63%) of N-[cyanoimino(4-cyanophenylamino)methyl]-3-aminopropanoic acid, which is a solid having a melting point of 158°-162° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[C:40]1(=[O:56])[N:44]([CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)[C:43](=[O:51])[C:42]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]12.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:47]4[CH2:48][CH2:49][CH2:50][C@@H:45]([N:44]5[C:43](=[O:51])[C:42]6=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]6[C:40]5=[O:56])[CH2:46]4)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Reactant: O=C1c2ccccc2C(=O)N1C1CCCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
10.00 kg (22.06 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 12.59 kg (33.09 mol) of 3-(phthalimido)piperidine D-tartrate and 17.5 litres of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 140° C. After the temperature has been attained, 11.41 kg (88.24 mol) of diisopropylethylamine are metered in within 20 minutes. The feed vessel is flushed with 2.5 litres of N-methyl-2-pyrrolidone and the reaction mixture is subsequently stirred at 140° C. for 2 hours. After the reaction has ended, the reaction mixture is cooled to 60° C. and diluted with 80 litres of methanol. The resulting suspension is stirred at 50° C. for 30 minutes, then cooled to 23° C. and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed 3 times with 20 litres each time of methanol. Drying is effected at 45° C. in a drying cabinet under inertization.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH3:41])[C:32]2[NH:37]C(=O)[O:35][C:34](=O)[C:33]=2[CH:40]=1.N1C=CC=CC=1>ClCCl.C(N(CC)C=O)C.C(#N)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH3:41])[C:32]2[N:37]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=3)[O:15][C:34](=[O:35])[C:33]=2[CH:40]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Reactant: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Agent: CCN(C=O)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylic acid (i.e. product of Step C) (7.9 g, 24 mmol) stirred in dichloromethane (100 mL) was added N,N-diethylformamide (4 drops). Oxalyl chloride (4.45 g, 35 mmol) was added dropwise over a period of 45 minutes. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The isolated acid chloride was dissolved in dry acetonitrile (10 mL) and added to a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (i.e. product of Step D) (4.9 g, 23 mmol) stirred in dry acetonitrile (14 mL). Pyridine (10 mL) was added, and the solution heated at reflux 6 hours. After cooling using an ice bath, a precipitate of white solid (9.15 g) was collected. The 1H NMR spectrum of the collected precipitate showed peaks consistent with the title compound and residual 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione starting material. A small portion of the collected precipitate was recrystallized from acetonitrile to yield the pure title product melting at 178–180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][S:20][C:21](=[N:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])SC.C(N(CC)CC)C>C(#N)C>[CH3:19][S:20][C:21]([N:10]1[CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)=[N:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)SC
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Yield: 79.7 %

Procedure:
Part A: A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (CAS: 13068-12-7) (9.20 gram, 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) was heated at reflux temperature for 20 hours. An additional portion of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol) was added and the resulting mixture was heated at reflux temperature for another 16 hours. After concentration in vacuo, dichloromethane was added and the resulting solution was washed twice with water and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo the residue was further purified by flash chromatography (diethyl ether/petroleum ether=1/1 (v/v)) to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (12.5 gram, 80% yield based on [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester) as an amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN1CCCC1=O.C(N(CC)CC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:20](=[O:21])[CH2:19][N:18]([CH3:23])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-nitrophenyl)piperazine and N,N-dimethylglycine hydrochloride were allowed to undergo the reaction using WSC hydrochloride and HOBt in 1-methyl-2-pyrrolidone in the presence of triethylamine. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-[4-(4-aminophenyl)piperazin-1-yl]-2-dimethylaminoethanone. NMR2: 2.30 (6 H, s), 3.74-3.76 (4 H, m), 6.64-6.68 (2 H, m).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[NH2:13][C:14]1[CH:24]=[C:23]2[C:17]([C:18]([Cl:29])=[C:19]([O:25][CH2:26][CH2:27][Br:28])[O:20][C:21]2=[O:22])=[CH:16][CH:15]=1.NC(N)=S>>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:24]=[C:23]3[C:17]([C:18]([Cl:29])=[C:19]([O:25][CH2:26][CH2:27][Br:28])[O:20][C:21]3=[O:22])=[CH:16][CH:15]=2)=[S:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: Nc1ccc2c(Cl)c(OCCBr)oc(=O)c2c1
Reactant: O=C(O)c1cccc(N=C=S)c1
Agent: NC(N)=S
Product: O=C(O)c1cccc(NC(=S)Nc2ccc3c(Cl)c(OCCBr)oc(=O)c3c2)c1
Yield: 64 %

Procedure:
7-(m-Carboxyphenylthiocarbamoylamino)-4-chloro-3-(2-bromoethoxy)isocoumarin was prepared from the reaction of m-carboxyphenyl isothiocyanate with 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarin, yield 64%, m.p. 157°-158° C.; mass spectrum m/e 361 (M+ -(COOH)PhNH+1). Anal. Calc.: C, 45.85; H, 2.84. Found: C, 45.73; H, 2.86. The bromoethoxy compound was then reacted with thiourea to give the product, yield 21%; mass spectrum (FAB+) m/e 493 (M+ -Br).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.Cl.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20]Cl)[CH3:17].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl.CCOCC>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([CH2:17][CH2:16][N:18]([CH2:22][CH3:23])[CH2:19][CH3:20])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CCN1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (100 mg, 0.48 mmol), 2-diethylaminoethyl chloride hydrochloride (91 mg, 0.53 mmol), K2CO3 (0.08 mL, 1.44 mmol), and NaI (0.02 mL, 0.53 mmol) were suspended in DMF (2 mL), and stirred overnight at room temperature. The reaction solution was diluted with H2O, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was converted into the HCl salt by dissolving in MeOH and adding 2M HCl in ether (2 equiv.) dropwise. The resulting precipitate was filtered to provide 65 (54 mg, 37% yield) as a white solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(c1ccc2[nH]ccc2c1)N1CCCC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and pyrrolidine (0.210 g, 70%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: ClCCN1CCCC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1(c2ccc(OCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (389 mg, 1.65 mmol), 1-(2-chloro-ethyl)-pyrrolidine (210 mg, 1.57 mmol), DMF (4.5 ml) and K2CO3 (885 g, 6.40 mmol) was heated to 130° C. for 30 minutes. The mixture was cooled to ambient temperature; water (9 ml) was added and the mixture was extracted with EtOAc (3×4.5 ml). The organic phase was washed with brine (10 ml), NaOH solution (2M, 10 ml) and water (10 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo at 35° C. and the residue subjected to chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (150 mg, 27%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.89 (d, 2H), 4.10 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.89 (t, 2H), 2.67-2.58 (m, 4H), 2.40 (s, 2H), 2.13-2.05 (m, 2H), 1.97 (s, 6H), 1.88 (ddd, 2H), 1.84-1.77 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:21])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Temperature: 35 °C

Procedure:
To a solution of methyl 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-2-naphthalenecarboxylate (Compound E5, 430.0 mg, 1.44 mmol) in 3.0 mL of EtOH and 3.0 mL THF was added NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). The resulting solution was warmed to 35° C. for 6 h, cooled to room temperature and quenched with 1M HCl. The mixture was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH2:14]([O:16][C:17]1[CH:25]=[C:24]([NH2:26])[C:23]([Cl:27])=[CH:22][C:18]=1[C:19]([OH:21])=O)[CH3:15].[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>O1CCCC1.C(O)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][N:34]1[CH2:35][CH2:36][CH:37]([NH:40][C:19](=[O:21])[C:18]2[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:17]=2[O:16][CH2:14][CH3:15])[CH2:38][CH2:39]1
Reactant: NC1CCN(CC2CCCO2)CC1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCO2)CC1
Reaction time: 0.5 h

Procedure:
Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml; 0.04 moles) were added successively to a stirred suspension of 2-ethoxy-4-amino5-chlorobenzoic acid (8.6 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature between -5° and -10° C. After stirring at this temperature for 0.5 hours, a solution of 1-(2-tetrahydrofurylmethyl)-4-aminopiperidine (8.0 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5° to -10° C. for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give an oil which was treated with the stoichiometric amount of fumaric acid in boiling absolute ethanol. N-[1-(2-Tetrahydrofurylmethyl)-piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide hydrogen fumarate (10.6 g) was thus obtained, m.p. 199°-201° C. (d).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: CSc1ccc(CCl)cc1
Product: CCOP(=O)(Cc1ccc(SC)cc1)OCC

Procedure:
4-Methylmercaptobenzyl chloride (160 g, 0.94 mol) was added dropwise, under nitrogen, with stirring to 183 g (1.1 mole) of triethylphosphite which was heated at reflux. When the addition of the 4-methylmercaptobenzyl chloride was completed, the mixture was refluxed for additional 4 hours. The product was distilled under vacuo to yield 229 g (89%) of water clear, viscous liquid bp 142°-145° C. (0.025 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:24]C.B(Br)(Br)Br.Cl.[OH-].[Na+]>ClCCl.O>[NH2:21][CH2:20][C:19]([C:10]1[NH:11][C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:24])[CH:4]=2)[N:9]=1)([CH3:23])[CH3:22]
Reactant: COc1cc(-c2nc(C(C)(C)CN)[nH]c2-c2ccncc2)ccc1Cl
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 5 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A solution of Example 2 (356 mg, 1 mmol) in dichloromethane (20 ml) cooled to 5° C. was treated with boron tribromide (1M in dichloromethane, 5 ml) followed by additional dichloromethane (10 ml). The solution was stirred at 5° C. for 2 hours then at room temperature for a further 2 hours. 2M hydrochloric acid (1 ml) and water (5 ml) were then added and the reaction heated to 50° C. for 15 min. After cooling the mixture was neutralised with 15% sodium hydroxide solution and the resultant precipitate collected by filtration to afford the title compound as a yellow solid (206 mg, 60%); MS(ES+) m/e 343/345 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:16]1[C:15]([C:14]([F:13])([F:25])[F:24])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[N:17]1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (1.81 g), 3,5-bis(trifluoromethyl)-1H-pyrazole (2.0 g) and potassium carbonate (1.63 g) were stirred in DMF (20 ml) at 60° C. for 1 hour. After finishing the reaction, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride (100 ml) and dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-3,5-bis-(trifluoromethyl)-1H-pyrazole (3.3 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[C:25]([Br:26])=[CH:24][N:23]=[C:22]3[NH:27][CH:28]=[C:29]([NH:30][C:31](=[O:40])[C:32]4[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=4)[C:21]=23)[CH2:15]1.CCN(C(C)C)C(C)C.C(OC)(OC)OC.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[Br:26][C:25]1[C:20]([N:16]2[CH2:17][CH2:18][CH2:19][C@@H:14]([NH:13][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:15]2)=[C:21]2[C:29]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=3)=[CH:28][NH:27][C:22]2=[N:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
2-(tert-Butyldimethylsilyloxy)acetaldehyde (0.037 mL, 0.19 mmol) was added to a mixture of (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (70 mg, 0.13 mmol, Example 62), DIEA (0.068 mL, 0.39 mmol), and trimethyl orthoformate (280 mg, 2.6 mmol) in MeOH (3 mL), and the reaction was stirred at room temperature for 18 hours. NaBH4 (9.8 mg, 0.26 mmol) was then added, and the reaction was stirred for 1 hour. The mixture was poured into a saturated solution of NaHCO3, and extracted with CH2Cl2. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by column chromatography on silica gel eluting with 2% MeOH:CH2Cl2 to provide (R)-N-(5-bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (32 mg, 39% yield).
Reaction SMILES: [C:1]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[N:16]=2)[NH:11][C:10]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[C:1]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[N:16]=2)[N:11]([C:20]([NH2:21])=[O:26])[C:10]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2ccccc2)c2nc(Cl)ccc21
Reaction time: 20 h

Procedure:
The title compound was prepared from 3-benzoyl-5-chloro-4-azaoxindole (Example 32) according to the procedure of Example 25, using 3-benzoyl-5-chloro-4-azaoxindole (2.73 g, 10.0 mmol), N-chlorosulfonyl isocyanate (1.3 mL, 15 mmol) and acetonitrile (80 mL). The reaction time was 20 hours. The crude N-chlorosulfonyl carboxamide was hydrolyzed by stirring in DMSO (15 mL) for 20 hours. The crude product was recrystallized from acetic acid and washed with methanol. Yield: 0.36 g (11%).