Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:37].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[O:37])[C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
4-[4-(2-Methyl-benzoylamino)-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester (1.12 g, 2.24 mmol) was dissolved in acetone (25 mL) and a 15% aqueous solution of magnesium sulfate (2.5 mL). The solution was cooled in an ice bath and potassium permanganate (1.9 g, 12.3 mmol) was added and the solution was stirred for 15 min at which time the solution was allowed to warm to room temperature and stirred for 3 hr. The solution was concentrated and diluted with 150 mL water. The product was exhaustively extracted from the aqueous layer with methylene chloride. The organic was then washed with brine, dried over anhydrous magnesium sulfate, concentrated and purified on silica (Isco flash column, 0 to 40% ethyl acetate in hexane). The title compound was isolated in 17% yield (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][C:24]([NH:27][S:28]([C:31]1[S:35][C:34](Cl)=[N:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25]>>[OH:22][CH2:23][C:24]([NH:27][S:28]([C:31]1[S:35][C:34]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[N:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (example B.14) according to general procedure II. Obtained as a yellow solid (60 mg, 45%). MS (ISP) 528.0 [(M+H)+]; mp 204-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[NH2:1]
Reactant: COc1ccc(N)cc1OC
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1OC
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
Following the procedure reported in JACS 1996, 118, 1028-1030, 4-aminoveratrole (3.06 g, 20.0 mmol) was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml) at room temperature. Tetrabutylammonium tribromide (1.15 eq, 11.09 g) was added and the mixture was allowed to stir for 20 minutes. The mixture was extracted with saturated aqueous sodium sulfite solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 10:1 to 7:3 Hexanes/Ethyl Acetate) to give 2-bromo-4,5-dimethoxy-aniline 1.403 g (30%) of a yellow oil.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([CH:33]=O)[CH2:29][CH2:28]1)#[N:26]>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([C:25]#[N:26])[CH2:28][CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 103 %

Procedure:
A solution of 24.0 g of tetrabromomethane in 100 ml of methylene chloride was placed at -15° C. in a sulphonation flask under argon gasification and treated within 10 minutes with a solution of 38.0 of triphenylphosphine in 50 ml of methylene chloride. The clear orange solution was stirred at -10° C. for a further 10 minutes and subsequently a solution of 5.0 g of trans-4-cyanocyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise thereto at -5° C. within 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes, then poured into 1 l of 10% ethyl acetate/petroleum ether and freed from precipitated triphenylphosphine oxide by filtration. The concentrated filtrate was again digested with 500 ml of 10% ethyl acetate/petroleum ether, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (14 g) on silica gel with 10% ethyl acetate/petroleum ether gave 11.0 g of trans-4-(2,2-dibromovinyl)cyclohexanecarbonitrile which was still contaminated with triphenylphosphine. A second low-pressure chromatography of this material on silica gel with 3% ethyl acetate/petroleum ether gave 9.04 g (85%) of pure trans-4-(2,2-dibromovinyl)cyclohexanecarbonitrile, m.p. 77.5°-78.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([O:41][C:42]([F:45])([F:44])[F:43])[CH:35]=2)O1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:59].Cl>>[ClH:1].[ClH:59].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([O:41][C:42]([F:43])([F:45])[F:44])[CH:35]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC1(C)OB(c2ccc(O)c(OC(F)(F)F)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3ccc(O)c(OC(F)(F)F)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (55 mg, 0.15 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenol (68 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (71 mg, 79%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.04-7.97 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 5.70-5.60 (m, 1H), 3.07 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.50-2.40 (m, 2H), 2.08-1.97 (m, 3H), 1.74-1.62 (m, 2H), 1.39-1.27 (m, 2H). ESI MS m/z 503 [M+H]+; HPLC>99% (AUC), tR=9.80 min.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:27][CH2:26][CH2:25][N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[C:3]3=[N:10][CH:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (400 mg, 1.44 mmol) in iPrOH (20 mL) was added 2-morpholino-ethanamine (244 mg, 1.88 mmol) followed by diisopropylethylamine (242 mg, 1.88 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (150 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 410 g, 76.8%). LC-MS: [M+H]+ 372.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:5][CH:1]1[CH2:4][CH2:3][CH:1]([O:5][C:6](=[O:20])[NH:7][CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=3)[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Reactant: O=Cc1ccccc1
Product: N#Cc1ccc2c(c1)CC(NC(=O)OC1CCC(O)CC1)CN2Cc1ccccc1

Procedure:
The title compound was prepared from (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester, prepared as described in Example 1C, and benzaldehyde by procedures analogous to those described in Example 3A and 31.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([Cl:44])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([N:26]([CH:36]5[CH2:38][CH2:37]5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[C:23]5=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1.[C:45](Cl)(=[O:47])[CH3:46].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:45]([N:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([Cl:44])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([N:26]([CH:36]5[CH2:37][CH2:38]5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[C:23]5=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1)(=[O:47])[CH3:46]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CNC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(C)=O)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-((3-(4-(azetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (100 mg, 0.164 mmol) in DCM (1.0 mL) was added TEA (0.069 mL, 0.492 mmol) followed by acetyl chloride (0.014 mL, 0.197 mmol) in a drop wise manner. The reaction mixture was allowed to warm to room temperature and stirred for overnight. The reaction mixture was diluted with dichloromethane (50 mL) and poured into a separating funnel containing saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was precipitated from DCM/Hexane (Dissolved in minimum amount of DCM, precipitated by adding Hexane), filtered and dried to get the 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (110 mg) as a off white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22][C:23]1[O:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH2:28]O)[N:27]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH3:22][C:23]1[O:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:27]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1nc(CO)c(C(F)(F)F)o1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c(C(F)(F)F)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.281 g, 1.0 mmol) and (2-methyl-5-(trifluoromethyl)oxazol-4-yl)methanol (0.18 g, 1.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added tributylphosphine (0.30 g, 1.5 mmol) at 0° C., followed by additional of N,N,N′,N′-tetramethylazodicarboxamide (0.26 g, 1.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and stirred at ambient temperature for 16 h. The reaction mixture was quenched with aqueous ammonium chloride (25%, 50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 1′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.30 g, 68%) as a colorless solid: mp 136-137° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 7.32 (ddd, J=7.7, 1.2, 1.2 Hz, 1H), 7.19 (dd, J=7.6, 1.0 Hz, 1H), 7.07-7.03 (m, 2H), 6.70 (s, 1H), 6.29 (s, 1H), 5.93 (dd, J=5.0, 0.7 Hz, 2H), 4.98 (q, J=16.4 Hz, 2H), 4.75 (dd, J=20.8, 9.4 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.5, 163.6, 155.1, 148.2, 141.9, 141.5, 137.6 (d, 3JCF=2.1 Hz), 133.5 (q, 2JCF=42.7 Hz), 131.6, 128.7, 123.5, 123.0, 119.8, 119.2 (q, 1JCF=266.9 Hz), 109.0, 103.0, 101.3, 93.1, 79.3, 57.2, 34.9, 13.4; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[N:27]([CH3:38])[C:28]2[C:33]([C:34]=1O)=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=2)=[O:25].C(OCC)(=O)C>CCCCCC>[CH3:22][O:23][C:24]([C:26]1[N:27]([CH3:38])[C:28]2[C:33]([C:34]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=1)=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=2)=[O:25]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1C
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c2cc(OC)ccc2n1C
Yield: 15 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylic acid methyl ester (40 mg, 0.17 mmol) as the source alcohol. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 13 mg (15%) of the titled compound. ESI-MS m/z 509 (MH+), 507 (M−H−).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=1[CH3:11])=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>CN(C)C=O>[CH3:11][C:10]1[NH:9][C:8](=[O:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=1[C:3]1[N:18]=[C:15]([CH3:16])[S:17][CH:2]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Reactant: CC(N)=S
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(C#N)c(=O)[nH]c2C)cs1
Reaction time: 5 h
Yield: 38.2 %

Procedure:
C-1. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile--A mixture containing 25.4 g of 5-(bromoacetyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 7.5 g of thioacetamide and 100 ml of dimethylformamide was heated with stirring on a steam bath for 5 hours and then concentrated on a rotary evaporator. To the residual material was added 100 ml of water and 10 ml of concentrated aqueous ammonium hydroxide. The resulting mixture was filtered and the filtrate reacidified by adding acetic acid. The solid that separated was collected, washed with water and dried, and then recrystallized from dimethylformamide to produce 8.8 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile, m.p. 305°-307° C. with decomposition.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH2:5][CH:4]([NH2:9])[CH2:3]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1>C(O)(C)C.C(#N)C>[Cl:10][C:11]1[N:16]=[C:15]([NH:8][CH:6]2[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([NH2:9])[CH2:5]2)[C:14]([F:18])=[CH:13][N:12]=1
Reactant: CC1CC(N)CC(N)C1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CC(C)O
Product: CC1CC(N)CC(Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylcyclohexane-1,3-diamine, 76a, (2.2 g, 17.2 mmol) in isopropyl alcohol (40 ml) and acetonitrile (40 ml) was added 2,4-dichloro-5-fluoropyrimidine (1.4 g, 8.6 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified on silica gel eluted with 1-20% methanol/dichloromethane, to give 0.6 g of racemic N1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine: 1H NMR (300 MHz, MeOD) δ 7.85 (d, J=3.5 Hz, 1H), 4.07 (ddd, J=11.9, 7.9, 4.1 Hz, 1H), 3.54 (qd, J=11.3, 4.2 Hz, 1H), 2.82 (tt, J=11.4, 3.7 Hz, 1H), 2.16 (dd, J=15.0, 13.0 Hz, 1H), 1.89 (t, J=13.4 Hz, 2H), 1.50 (dd, J=76.0, 21.9 Hz, 2H), 1.10 (dt, J=17.9, 9.0 Hz, 1H), 0.99 (dd, J=8.5, 5.0 Hz, 3H), 0.81 (ddd, J=23.8, 12.0, 8.2 Hz, 1H); LCMS RT=1.24 (M+1) 259.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:14]#[N:15].[Na+]>CS(C)=O.O>[C:10]([C:4]1[CH:5]=[C:6]([CH2:8][C:14]#[N:15])[CH:7]=[C:2]([Br:1])[C:3]=1[OH:13])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(CCl)cc(Br)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cc(CC#N)cc(Br)c1O
Reaction time: 15 h
Yield: 58 %

Procedure:
A solution of 1-(3-Bromo-5-chloromethyl-2-hydroxy-phenyl)-ethanone 212 (7.6 mmol) in 6 mL DMSO is added dropwise to a suspension of 8.2 mmol of NaCN in 4 mL DMSO. The mixture is stirred for 12-18 h and diluted with 80 mL water to yield a solid. The solid is isolated and recrystallized from ethanol to yield (3-acetyl-5-bromo-4-hydroxy-phenyl)-acetonitrile 213 in a 58% yield.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:22][CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: CC(C)N1CCC(CC2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(CC2CCN(c3ccc(C(=O)OC(C)(C)C)nc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
1-(1-Methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) (0.25 g), 1,1-dimethylethyl 5-bromo-2-pyridinecarboxylate (may be prepared as described in Description 12) (0.29 g), BINAP (0.06 g) and Cs2CO3 (1.82 g) were added to toluene (50 ml) under argon and the reaction mixture degassed by sequential freezing in dry ice followed by warming to room temp under vacuum (3×). After stirring for 5 min Pd(OAc)2 (0.05 g) was added, degassed again, and the reaction mixture heated at 100° C. for 24 h. The reaction mixture was filtered and evaporated, after which chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E4) as a yellow solid (0.25 g). MS electrospray (+ion) 424 (MNa+)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13]2)=[CH:8][CH:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]2[CH3:22])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1c[nH]c2cc(C3OCCO3)ccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C3OCCO3)ccc2c1=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Compound 8 was dissolved in anhydrous DMF (Aldrich) in a 500 mL 1-neck round bottom flask. Anhydrous potassium carbonate (EM Science) was added and the mixture was stirred for 15 min. After addition of iodomethane (Aldrich), the mixture was stirred at room temperature overnight, after which it was concentrated and partitioned between CH2Cl2 and aq. sodium thiosulfate. The CH2Cl2 layer was rinsed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to 19.30 g crude 9 (brownish solid). 1H NMR spectrum was satisfactory; however, TLC (MeOH:DCM 1:9) shows small amounts of lower polarity impurities and some high polarity impurities (possibly largely inorganic). Attempts to purify via re-precipitation from THF/water or CH2Cl2/hexane were unsatisfactory. Chromatography on a silica gel plug (gradient 1-2-4-6-10% methanol in CH2Cl2) provided purified product (17.93 g, 95% yield).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH3:16][CH:17]1[O:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:23][CH:21]1[O:22][CH:17]([CH3:16])[CH2:18][N:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:20]1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Reactant: CC1CNCC(C)O1
Product: CC1CN(c2nnc(N)nc2-c2ccc(F)cc2)CC(C)O1
Yield: 19.4 %

Procedure:
6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (110 mg, 20%) was prepared from 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.50 g, 1.87 mmol) and 2,6-dimethylmorpholine (1.06 g, 9.36 mmol) according to the general procedure of Example 2.
Reaction SMILES: Cl[Si:2]([CH3:17])([CH3:16])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:5]=[C:4]1[CH3:15].CCN(CC)CC.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCCCCC>[CH:25]1([NH:31][Si:2]([CH3:17])([CH3:16])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[CH:5]=[C:4]2[CH3:15])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: NC1CCCCC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) silane (5.67 g, 0.0216 moles) was stirred in hexane (50 mL) as NEt3 (2.18 g, 0.0216 moles) and cyclohexylamine (2.13 g, 0.0216 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (6.62 g, 94.3 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.I[C:15]1[N:16]=[C:17]([CH3:25])[N:18]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:15]2[N:16]=[C:17]([CH3:25])[N:18]([CH2:20][C:21]([F:23])([F:24])[F:22])[CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(I)cn1CC(F)(F)F
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC(F)(F)F

Procedure:
The title compound, MS: m/e=300.0 (M+H+), was prepared in accordance with the general method of example A, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 4-iodo-2-methyl-1-(2,2,2-trifluoro-ethyl)-1H-imidazole.