Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[Li+].[OH-].O.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Temperature: 45 °C

Procedure:
Phenylmethyl 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 66; 381 mg, 0.82 mmol) was redissolved in tetrahydrofuran (4 ml) and LiOH (64 mg, 2.67 mmol) and water (1 ml) were added. The solution was heated at 45° C. for 90 minutes, 2M hydrochloric acid (1.33 ml, 2.66 mmol) was added and the solvent removed in vacuo. The solid was partitioned between 2M HCl (5 ml) and ethyl acetate (40 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a brown solid. 381 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)(Cl)Cl.ClCCl>[Cl:32][C:33]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:34]=1[NH:35][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[CH3:10])=[O:9]
Reactant: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Reactant: Nc1cccc(Cl)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2Cl)c(C)n1-c1ccccc1
Yield: 36 %

Procedure:
Part A: To a magnetically stirred suspension of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.4 gram, 1.85 mmol) in CHCl3 (4 ml) was added oxalyl chloride (0.34 gram, 2.685 mmol) and the resulting mixture was reacted at 58° C. for 2 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and diisopropylethylamine (0.28 gram, 2.148 mmol) was subsequently added. A solution of 2,3-dichloroaniline (0.35 gram, 2.146 mmol) in dichloromethane (5 ml) was slowly added to the resulting mixture and the resulting mixture was reacted for 2 hours at room temperature and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane) to give N-(2,3-dichlorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.24 gram, 36% yield). Melting point: 127-129° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:19].C([Li])CCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C1COCC1.CCOCC>[C:8]([C:6]1[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]([CH3:19])=[C:2]([CH:7]=1)[C:25]([OH:27])=[O:26])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C=O
Reactant: COCCOCOc1cc(C)c(Br)cc1C(C)(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-bromo-5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzene from Example ZZ (44.7 g, 135 mmol) in dry THF was cooled to -78° C. under nitrogen and treated with 1.6 M n-butyllithium (93 mL, 149 mmol). The solution was stirred at -78° C. for 45 minutes and then poured over crushed dry ice. The mixture was allowed to warm to room temperature. Et2O (100 mL) and 2N NaOH (200 mL) were added; the organic layer was separated and re-extracted with 2N NaOH. The aqueous layers were combined, acidified to pH 2 with 6N HCl, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.35 (s, 9 H), 2.57 (s, 3 H), 3.37 (s, 3 H), 3.57 (m, 2 H), 3.81 (m, 2 H), 5.35 (s, 2 H), 6.98 (s, 1 H), 8.01 (s, 1 H).
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21][CH:22]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:23][CH2:24]O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:21][CH:22]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:23][CH2:24][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2)=[O:20]
Reactant: CC(C)=CCCC(C)CCO
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 12 h
Yield: 64.4 %

Procedure:
To a solution of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (0.10 g, 0.36 mmol), 4-(dimethylamino)pyridine (DMAP; 44 mg, 0.36 mmol), and 3,7-dimethyl-oct-6-en-1-ol (61 mg, 0.39 mmol) in methylene chloride (20 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI; 75 mg, 0.39 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to give 798 (97 mg, 65%) as a solid: 1H NMR (CDCl3) 0.91 (3H, d, J=6.9 Hz), 1.34-1.37 (2H, m), 1.56-1.60 (9H, m), 1.67-1.69 (8H, m), 1.81 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.35 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05 (1H, s), 4.11 (2H, t, J=6.9 Hz), 4.21 (1H, s), 5.09 (1H, t, J=6.9 Hz); LC-MS (ESI) m/z calcd for C25H42N2O3 [M+H]+ 419.32. found [M+H]+ 419.22; mp 49 C. Anal. Calcd for C25H42N2O3: C, 71.73; H, 10.11; N, 6.69. Found: C, 70.27; H, 9.83; N, 6.39.
Reaction SMILES: C(C[O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)#N.[H-].[Na+].IC.[Li+].CC([N-][CH:26]([CH3:28])[CH3:27])C.[CH3:29][N:30](C)C=O>O1CCCC1>[C:29]([C:26]([CH3:27])([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)[CH3:28])#[N:30]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)c1ccc(OCC#N)cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(OC(C)(C)C#N)cc1OC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
Methyl 4-(cyanomethoxy)-2-methoxy-benzoate (960 mg, 4.34 mmol) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (4 mL). Sodium hydride (521 mg, 13.0 mmol) was added and the reaction mixture was allowed to stir for 5 min. Iodomethane (1.35 mL, 21.7 mmol) was added and the reaction mixture was allowed to stir for 10 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate was dried over sodium sulfate, filtered and evaporated to dryness. The crude material was then dissolved in tetrahydrofuran (10 mL) and was cooled to −78° C. under an atmosphere of argon. LDA (2.2 mL of 2.0 M, 4.4 mmol) was added and the reaction mixture was stirred at −78° C. for 45 minutes. Iodomethane (1.35 mL, 21.7 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was evaporated to dryness, and then partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed two times with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to give methyl 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate (31%). ESI-MS m/z calc 249.1, found 250.3 (M+1)+. Retention time: 1.59 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[ClH:17].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:21]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cccc3Cl)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.18 g, 0.85 mmol), 2-chloro-6-fluoro-benzoyl chloride (0.318 g, 1.65 mmol), and 1,4-dioxane (10 mL). Stir and heat the mixture at reflux. After 2 hr., cool the reaction mixture to ambient temperature and concentrate. Load the mixture onto an SCX column (10 g), wash with methanol, and elute with 2M ammonia/methanol. Concentrate the eluent to obtain the free base of the title compound (0.30 g, 94%) as an oil. Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.045 g, 0.85 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 376.1237; Calc. m/z 376.1228; m.p. 155° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10](=[CH:11][O:12]C)[CH2:9][CH2:8][N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]([CH:11]=[O:12])[CH2:9][CH2:8][N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6]1)=[O:4]
Reactant: COC=C1CCN(Cc2ccccc2)CC1(Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of the compound of Example 200, Step B (3.02 g, 8.26 mmol) in THF (40 mL) and 10% aqueous HCl solution (40 mL) was allowed to stir at room temperature for 14 h. The solution was adjusted to pH 9 with 5N NaOH and extracted twice with CH2Cl2. The combined organic layers were washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 3-5% EtOAc/CH2Cl2 as the eluant afforded the compound of Example 200, Step C as a mixture of isomers (1.89 g): +APcl MS (M+1)+ 352; 1H NMR (400 MHz, CDCl3) δ: 9.82 and 9.81 (s, 1H), 7.02-7.45 (arom, series of m, 10 H), 3.64 and 3.60 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.ClCCl.[Os](=O)(=O)(=O)=O>[O:23]=[C:2]([CH3:1])[CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C=C(C)CC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1(CC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(2-methylallyl)piperidine-1,4-dicarboxylate (2.2 g, 7.4 mmol) in dioxane/water (60 mL, 1/1) under nitrogen was added osmium tetroxide (0.038 g, 0.15 mmol) and sodium periodate (2.88 g, 13.5 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was then diluted with dichloromethane (50 mL), and washed with 20% Na2S2O3 (20 mL). The organic layers were combined and washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrates were concentrated and the residue was purified by column chromatography eluting with 0-60% ethyl acetate/hexane to afford 1-tert-butyl 4-methyl 4-(2-oxopropyl)piperidine-1,4-dicarboxylate. LC-MS (IE, m/z): 322.26 (M+23)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:14].[OH-]>>[NH2:14][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2ccncc2)ccn1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cc(-c2ccncc2)ccn1

Procedure:
The title compound was prepared by heating 2-chloro-[4,4′]bipyridinyl and NH4OH (30% in H2O) in a bomb at 210° C. for 48 hours: MS (m/z): Calcd. C10H9N3 (M+): 171, found (M+H)+: 172.1
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=2)[CH2:3][CH2:2]1.C1(NC2SC(C(Cl)=O)=C(C)N=2)CC1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:34][CH:35]([C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)[C:36]#[N:37]>C(N(CC)CC)C>[C:36]([CH:35]([NH:34][C:11]([C:7]1[S:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[CH3:10])=[O:13])[C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)#[N:37]
Reactant: Cc1nc(NC2CC2)sc1C(=O)O
Reactant: N#CC(N)c1ccco1
Agent: Cc1nc(NC2CC2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1ccco1
Yield: 38.9 %

Procedure:
1.4g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.6g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.2g of amino-furan-2-yl-acetonitrile hydrochloride and 3.2ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.83g (Yield 35%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:16])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(Cl)c(I)c1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: O=C(Nc1ccc(Cl)c(I)c1)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(4-chloro-3-iodo-phenyl)-nicotinamide was prepared from 4-chloro-3-iodo aniline (perpared as described in WO03/062241) and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after suspension in small volume of CH2Cl2 and filtration. HRMS m/z calcd for C12H7N2OCl2I [M+H]+: 392.9053. Found: 392.9054.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A mixture of 2-chloro-6-methyl-nicotinic acid (2 g, 12 mmol), N,O-dimethylhydroxylamine hydrochloride (1.14 g, 12 mmol), EDCI (2.68 g, 14 mmol), HOBt (81 mg, 16 mmol) and DIPEA (1 mL) in DCM (100 mL) was stirred at RT overnight. The reaction mixture was then partitioned between water and DCM, the organic layer separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, gradient from 0 to 25% in 25 minutes) to afford 2.4 g of 2-chloro-N-methoxy-6,N-dimethyl-nicotinamide as a white solid.
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.CCOCC>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1ccccc1Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccccc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flash and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the cooler is discharged 5.75 ml. of acetonitrile in 10 ml. of ether are added. The reaction is cooled in a dry ice-acetone bath and 13.3 g. of 2-chlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtrate through magnesol. The filtrate is evaporated with the addition of hexanes giving β-amino-2-chlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[C:11]([OH:13])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:11]([C:10]1[S:9][N:8]=[N:7][C:6]=1[CH3:5])(=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nnsc1C(=O)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: Cc1nnsc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To 2.0 g (15 mmol) of thionyl chloride was added 0.50 g (3.5 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid. After heating the mixture with stirring for 2 hours, the thionyl chloride was distilled off under reduced pressure, and the residue was added to a solution of 1.8 g (15 mmol) of aluminum chloride in 20 ml benzene and made to react with heating for 3 hours. After the reaction was completed, the reaction mixture was poured into ice water, the objective product was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium chloride and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 4:1 mixture of n-hexane and ethyl acetate. Thus, 0.69 g of the objective compound was obtained.
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1O.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:12]([O:1][CH:12]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Br:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: [OH-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1ccc(C(OC(c2ccccc2)c2ccc(Cl)cc2Br)c2ccccc2)c(Br)c1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
In a 500 ml three neck round bottom flask equipped with a magnetic stirrer, thermometer, condenser, addition funnel and nitrogen inlet, is placed 30 ml of dimethylsulfoxide. Potassium hydroxide (20 g, 0.36 mol.) is added to this followed by the dropwise addition of 2-bromo-4-chlorophenol (50 g, 0.24 mol) in 25 ml of dimethylsulfoxide. This solution is stirred for half an hour, then benzylbromide (41 g, 0.24 mol) is added dropwise, and the reaction stirred for another 3 hours. The reaction is then poured into 150 ml of ice water and extracted with 100 ml of toluene. The toluene phase is washed with 50 ml of 1N sodium hydroxide followed by 75 ml of water, dried with magnesium sulfate and evaporated under reduced pressure to yield 65 g of 2-bromo-4-chlorophenyl benzylether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])=[CH:31][C:27]=1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[CH3:23][CH:20]1[CH2:19][CH2:18][N:17]([C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:28](=[O:29])[C:27]3[CH:31]=[C:32]([CH2:35][NH:36][C:37]([C:39]([CH3:40])([CH3:42])[CH3:41])=[O:38])[CH:33]=[CH:34][C:26]=3[Cl:25])=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: CC1CCN(c2ccc(N)cc2C(=O)Nc2ccc(Br)cc2)CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC1CCN(c2ccc(NC(=O)c3cc(CNC(=O)C(C)(C)C)ccc3Cl)cc2C(=O)Nc2ccc(Br)cc2)CC1

Procedure:
Prepared analogously to Example 4c from N-(4-bromophenyl)-2-(4-methyl-piperidin-1-yl)-5-amino-benzoic acid amide and 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid with to TBTU and TEA in THF. Purification via chromatography (silica gel, eluent PE:EtOAc 6:4)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ncc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1N
Yield: 17.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxypyridin-3-amine (80 mg, 0.14 mmol) was hydrolyzed with lithium hydroxide (12 mg, 0.28 mmol) in THF/methanol/water (2/2/1 mL) to yield 10 mg (17.1% yield) after purification by preparative TLC(Silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.37 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.717-7.712 (d, 1H), 7.61 (s, 1H), 7.36-7.29 (m, 2H), 7.10-6.98 (m, 3H), 5.41 (s, 2H), 4.00 (s, 3H). MS: m/z=415.2 (M+1), HPLC: 88.73% in method B.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[C:34]([NH2:35])=[C:33]([NH2:36])[C:31](=[O:32])[NH:30][C:28]1=[S:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:35][C:34]1[N:27]([CH2:26][C:25]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:24]=2)[C:28](=[S:29])[NH:30][C:31](=[O:32])[C:33]=1[NH:36][C:10](=[O:11])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)(OCc1ccccc1)C(=O)Cl
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(N)c(NC(=O)C(C)(C)OCc3ccccc3)c(=O)[nH]c2=S)cc1OCc1ccccc1
Yield: 75.3 %

Procedure:
A solution of 2-benzyloxy-2-methyl-propionyl chloride (30.70 g, 144 mmole) in THF (100 ml) was added at 0-5° C. over 15 minutes to a stirred suspension of 1-(3-benzyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil (40.58 g, 100 mmole) and triethylamine (31.4 ml, 225 mmole) in THF (400 ml). After 1 hour the solid was filtered off and the solution evaporated to dryness in vacuo. The residue was suspended in a mixture of diethyl ether (400 ml), water (100 ml) and saturated sodium bicarbonate solution (60 ml). After crystallization for 60 hours the solid was collected and washed with ether and water to give 6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-5-(2-benzyloxy-2-methyl-propionylamino)-2-thiouracil (42.23 g, 75.3%). Crystallization from ethyl acetate gave mp 123-125/184-187° C.