Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[C@@:32]([OH:36])([C:34]#[CH:35])[CH3:33]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:35]#[C:34][C@@:32]([C:27]4[N:26]=[CH:31][CH:30]=[CH:29][N:28]=4)([OH:36])[CH3:33])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#C[C@](C)(O)c1ncccn1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(I)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[C@](O)(C#Cc1ccc2c(C(=O)N3CCOCC3)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Reaction time: 18 h

Procedure:
To solution of 4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine (60 mg, 0.13 mmol) in triethylamine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (15.4 mg, 0.01 mmol), copper(I) iodide (2.5 mg, 0.01 mmol) and (2S)-2-(pyrimidin-2-yl)but-3-yn-2-ol (30 mg, 0.20 mmol). After 18 hr at RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished the title compound as an off-white solid: 1H NMR (500 MHz, DMSO-d6) delta 1.79-2.05 (3H, m), 3.59-3.68 (2H, m), 3.71-3.79 (4H, m), 3.89-4.01 (2H, m), 6.17-6.37 (1H, m), 6.98-7.10 (1H, m), 7.12-7.27 (2H, m), 7.32-7.42 (1H, m), 7.47-7.58 (1H, m), 7.92-8.05 (1H, m), 8.26-8.39 (1H, m), 8.80-9.04 (3H, m); LC-MS: m/z=+471.05 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[Cl:16][C:12]1[CH:11]=[C:10]([N:7]2[CH:8]=[N:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ncn(-c2cccc(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
14.8 g (62.3 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester was taken up in 70 mL THF and treated with 40 mL 4M aqueous NaOH solution at RT for 12 h. The reaction mixture was diluted with water, THF was removed by distillation, ice water was added and the mixture was acidified with 4 M aqueous HCl solution. The precipitated was filtered off, washed with water and triturated with diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Fc1ccc(CS)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(F)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 78% yield following oxidation. 1HNMR (CDC13) δ 4.60 (2H, s), 6.65 (1H, d, JH,H=11.83), 7.20-7.65 (8H aromatic+1H ethylenic).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[C:25]([Br:33])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[C:25]([Br:33])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: Nc1cc(Br)cc2cccnc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(Br)cc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a stirred solution of 80 mg (0.279 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 8-amino-6-bromoquinoline (93 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature or one day. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 3:1) to yield the title compound (110 mg, 85.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H). (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H). (3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+MeOH—H2O).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([F:18])([F:30])[F:31])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCC(O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was added by little and little under ice-cooling a solution of optically active 1,1,1-trifluoro-2-decanol (0.96 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand overnight at room temperature in order to effect a reaction before the mixture obtained was poured in ice-water. Extraction was effected with methylene chloride and the extracted phase was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water in due order before it was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crude product which was purified by toluene/silica from ethanol to obtain the titled compound (1.84 g).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=12.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:2]2[CH:3]=[C:4]3[C:5]([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)=[N:1]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1

Procedure:
1,1-Dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (1.80 g, 7.58 mmol), 4-cyanophenyl boronic acid (2.23 g, 15.16 mmol; commercially available from e.g. Aldrich), copper(II) acetate (4.15 g, 22.76 mmol), pyridine (1.21 ml, 15.16 mmol) and powdered 4 Å molecular sieves (5.33 g) were stirred in dichloromethane (80 ml) at room temperature in air for 40 hours. The mixture was filtered through a pad of Kieselguhr and the filtrate evaporated. The residue was dissolved in ethyl acetate and the solution washed with 5% sodium bicarbonate solution (×3), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography eluting with 10-40% ethyl acetate in n-pentane to give the title compound (D10). MS (ES+) m/e 339 [M+H]+
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (167 mg, 0.51 mmol) and 4-bromo-benzenesulfonamide (121 mg, 0.51 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 57%). MS (ISP) 483.4 [(M+H)+]; mp 259-261° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][NH:37]2)=[O:33])=[CH:4][N:3]=1.[C:42](O)(=[O:44])[CH3:43]>>[C:42]([N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]1[CH2:35][NH:34][C:32]([C:5]1[C:6]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1)=[O:33])(=[O:44])[CH3:43]
Reactant: CC(=O)O
Reactant: COc1cc(-c2csc3c(C(=O)NCC4CCCCN4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(C(=O)NCC4CCCCN4C(C)=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
4-Amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-(piperidin-2-ylmethyl)thieno[3,2-c]pyridine-7-carboxamide (0.090 g, 0.16 mmol) and acetic acid (0.012 g, 0.17 mmol) were treated according to General Procedure D to provide the title compound. LCMS Conditions a: 3.11 minute, 611.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:30]([C:26]2[N:27]=[CH:28][O:29][C:25]=2[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:31])[CH:13]=[N:12]1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(CCCCC(C)=O)c2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:3][C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)=[CH:3]\[CH2:4][OH:5]
Reactant: CCOC(=O)C=C(C)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(/C=C/c1ccc(C(F)(F)F)cc1)=C\CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
After a solution in which 150 mg (0.53 mmol) of ethyl (4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate ((2E)/(2Z)=5/1) as described in Reference example 8 were dissolved in 2 ml of toluene was stirred at 0° C., 0.7 ml (1.06 mmol) of a 1.SM diisobutyl aluminum hydride-toluene solution were added to the solution. After 20 minutes, ice-water was added to the reaction mixture and the mixture was stirred for 10 minutes. The insolubles were removed by filtration using Celite and the filtrate was extracted with ethyl acetate and dried, followed by evaporation of the solvent to obtain an oil. The oil was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of 30 to 40% ethyl acetate-hexane to obtain 90 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH:42]([NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:50][CH:42]([C:43]5[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=5)[CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:51])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 4 supra) (686 mg, 2.5 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude [4-(3-{2-[2-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester. (Yield 140 mg, 32.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:29][CH3:30])=[C:5]([O:27][CH3:28])[C:6]2[N:12](C(OCC(Cl)(Cl)Cl)=O)[C@@H:11](O)[C@@H:10]3[CH2:22][CH2:23][CH2:24][N:9]3[C:8](=[O:25])[C:7]=2[CH:26]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:29][CH3:30])=[C:5]([O:27][CH3:28])[C:6]2[N:12]=[CH:11][CH:10]3[CH2:22][CH2:23][CH2:24][N:9]3[C:8](=[O:25])[C:7]=2[CH:26]=1
Reactant: COc1cc2c(c(OC)c1OC)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OC)N=CC1CCCN1C2=O
Reaction time: 0.67 h
Yield: 95.2 %

Procedure:
10% Cd/Pb couple (1.25 g, 10 mmol Cd) was added to a rapidly stirring solution of the Troc-carbamate, 119 (1.00 g, 2.1 mmol) in a mixture of THF (13 mL) and 1N NH4OAc (B mL). Upon addition, the reaction mixture went cloudy. After 40 minutes, TLC showed the reaction to be complete and the reaction mixture was diluted with EtOAc (200 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Evaporation of the solvent yielded the product as a yellow glass (0.581 g, 2.0 mmol). 1H NMR (270 MHz, CDCl3) δ 7.73 (d, 1H, J=4.57 Hz), 7.08 (s, 1H), 4.0-3.4 (m, 12H), 2.4-1.8 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of Example 1.4 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.26 g, 1 mmol) and 4-methoxy-benzoyl chloride (2 mmol) to give the title compound: Rf =0.44 (silica gel, 6% methanol in dichloromethane).
Reaction SMILES: CO[N:3]([CH3:21])[C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])=O.[CH3:22]NC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:22][N:3]([CH2:4][CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])[CH3:21]
Reactant: CNC
Reactant: CON(C)C(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1CC1Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (0.029 g, 0.13 mmol), dimethylamine (0.7 ml, 1.4 mmol, 2M/THF), and methyl alcohol (5 ml) was treated with sodium triacetoxyborohydride (0.28 g, 1.13 mmol) and stirred at ambient temperature for 1 h. The solution was concentrated in vacuo and the residue applied directly to a silica gel column and eluted with chloroform, methyl alcohol, triethylamine 95:5:0.1 to afford 5-(2-Dimethylaminomethyl-cyclopropylmethyl)-1H-indol-3-carbonitrile (23 mg, 69%) as a light salmon colored solid. 1H-NMR (400 MHz, CDCl3) 8.88 (1H, br s), 7.66 (2H, dd, J=19.4, 2.3 Hz), 7.33 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4, 1.5 Hz), 2.72 (2H, m), 2.25 (6H, s), 2.24 (2H, m), 0.88 (2H, m), 0.53 (1H, m), 0.45 (1H, m).
Reaction SMILES: [CH3:1][Sn:2]([CH3:11])([CH3:10])[C:3]1[S:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1.[I-].[Na+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1)=[O:17]>>[N:18]1([C:16](=[O:17])[CH2:15][O:9][CH2:8][C:6]2[S:7][C:3]([Sn:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=2)[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1
Reactant: O=C(CCl)N1CCSCC1
Reactant: C[Sn](C)(C)c1ccc(CO)s1
Agent: [I-]
Agent: [Na+]
Product: C[Sn](C)(C)c1ccc(COCC(=O)N2CCSCC2)s1

Procedure:
The 1-thiomorpholin-4-yl-2-(5-trimethylstannanyl-thiophen-2-ylmethoxy)-ethanone employed is prepared analogously to example (3a) (stage b)) starting from (5-trimethylstannanyl-thiophen-2-yl)-methanol (7.66 g; 27.67 mmol; described, in example (3a), stage a)), sodium iodide (4.07 g; 27.34 mmol) and 2-chloro-1-thiomorpholiri-4-yl-ethanone (5.92 g; 32.94 mmol)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[O:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[O:28][C:29]([CH2:32][N:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)o1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)o3)c(=O)[nH]2)o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.29 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone in pyridine (15 ml) was heated under reflux for about 20 hr. The pyridine was evaporated at reduced pressure. The last traces of pyridine were removed by azeotroping with water and water removed by azeotroping with n-propanol. The oily residue was chromatographed on a silica gel column eluting with methanol in ethyl acetate (10% v/v). Evaporation of the eluant yielded 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone as an oil which was converted to its trihydrochloride using an excess of ethanolic HCl. The salt was recrystallised from isopropanol yielding a white solid (0.72 g) m.p. 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Yield: 68.9 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.44 g, 1.06 mmol) was reacted with NBS (0.19 g, 1.06 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.36 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][N:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-fluorobenzyl bromide (30.4 g, 114 mmol, 1 eq), 1-methylsulfonylpiperazine (20.0 g, 114 mmol, 1 eq) and K2CO3 (31.6 g, 228 mmol, 2 eq) in acetonitrile (500 mL) was stirred at 40° C. for 18 h. The reaction mixture was allowed to cool to room temperature, the mixture was filtered through Celite, and washed with EtOAc. The filtrate was concentrated in vacuo to yield 1-(4-Bromo-2-fluoro-benzyl)-4-methanesulfonyl-piperazine (Intermediate 5).