Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(CCCCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 4 h

Procedure:
4-(4-Methylphenyl)butanol (0.5 g, 3.04 mmol) is dissolved in 5 ml DMF and to it is added imidazole (310 mg, 4.56 mmol) and tert-butyldimethylsilyl chloride (685 mg, 4.56 mmol). The reaction is stirred for 4 hrs after which it is extracted in ethyl acetate and washed with water to remove all DMF. The organic layer is then dried and concentrated. The crude mixture is then purified by flash chromatography using a mixture of ethyl acetate-hexanes as the eluting medium to afford the above mentioned product.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:61])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH:45]5[CH2:49][NH:48][CH2:47][N:46]5[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[CH3:66][O:65][C:63]([N:48]1[CH2:49][CH:45]([C:42]2[NH:41][C:40]([C:37]3[CH:36]=[CH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:61])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[CH:44][N:43]=2)[N:46]([C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[CH2:47]1)=[O:64]
Reactant: COC(=O)Cl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 16.8 %

Procedure:
4-Methylmorpholine (31 μL, 0.28 mmol) was added to a suspension of {1-[2-(5-{4′-[3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-3H,1′H-[2,4]biimidazolyl-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (41.1 mg, 0.056 mmol) [prepared via reaction of 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester with HCl-solution] in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed in vacuo. The residue was taken into tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed in vacuo and the aqueous phase was decanted. The residue was dissolved in dimethylformamide (2 mL) and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA). The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (7.5 mg)
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][C@@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:36]([O:35][C:33]([NH:32][C@H:28]([CH2:27][CH2:26][NH:25][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[C:29]([OH:31])=[O:30])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (25 mg, 0.08 mmol), (R)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (crude, 0.47 mmol) and sodium methoxide (24 mg, 0.44 mmol) were suspended in 2-methoxyethanol (5 mL). The resulting mixture was heated to reflux for 2 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 20 mg. MS: (−) m/z 505.35 (M−1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28](O)=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN.F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2C=CC=CC=2N=N1>C1COCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([NH:40][CH3:44])=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 36.1 %

Procedure:
To a stirred mixture of 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (70 mg, 0.165 mmol) from Example 81 and TEA (67 mg, 0.660 mmol) in anhydrous THF (2.5 mL) at rt was added methylamine (2 M solution in THF, 413 μL, 0.825 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (109 mg, 0.248 mmol). The mixture was stirred at rt for 4.5 h. The mixture was purified by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (26 mg, 36%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.86 (d, J=1.88 Hz, 1H), 8.69 (s, 1H), 8.59 (d, J=4.52 Hz, 1H), 8.49 (d, J=1.88 Hz, 1H), 7.97 (d, J=7.54 Hz, 1H), 7.67 (d, J=1.13 Hz, 1H), 7.19-7.32 (m, 2H), 5.51 (s, 2H), 4.73 (br. s., 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.82 (d, J=4.33 Hz, 3H), 2.02 (m, 1H), 1.88 (m, 1H), 1.55-1.65 (m 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 437 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[N:19][C:18]([NH:21][NH2:22])=[N:17][C:16]=2[CH3:23])=[CH:11][CH:10]=1>CO.C(O)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[C:5]([CH3:6])=[CH:4][C:1]([CH3:2])=[N:22]3)=[N:17][C:16]=2[CH3:23])=[CH:13][CH:14]=1
Reactant: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)n(-c2nnc(-c3ccc(Cl)cc3)c(C)n2)n1
Yield: 85.1 %

Procedure:
A solution of acetylacetone (2.415 g) in methanol (10 ml) was added to a mixture of 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (4.946 g) and acetic acid (3 drops) in methanol (20 ml), and the solution was refluxed for 2 hours with stirring and allowed to stand at room temperature. The resultant crystals were collected by filtration, washed with cold methanol, and dried to give 6-(4-chlorophenyl)-3-(3,5-dimethylpyrazol-1-yl)-5-methyl-1,2,4-triazine (5.354 g), m.p. 151° to 152.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[N:22]=[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]2=[N:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1nc2ccccc2n1

Procedure:
Using general procedure 4 and purification method E (elute with isocratic 20% ethyl acetate/hexanes in this case) with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and 1,2,3-benzotriazole (0.136 g, 1.14 mmol) gives the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH2:21]C=O>C(O)C.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH:21]=[N:2][OH:3]
Reactant: NO
Reactant: COc1c(C)cc(C)c2c1C(CC=O)C1=C2CCCC1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1c(C)cc(C)c2c1C(C=NO)C1=C2CCCC1

Procedure:
500 Milligrams of hydroxylamine hydrochloride was added to an ethanol-chloroform (5:1) solution containing 910 mg of 5,7-dimethyl-8-methoxy-9-formylmethyl-1,2,3,4-tetrahydro-9H-fluorene in 18 ml of ethanol-chloroform and the mixture was refluxed with heating for 2 hours. The reaction mixture was diluted with chloroform and then washed with saturated aqueous sodium chloride solution and subsequently the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 670 mg of 5,7-dimethyl-8-methoxy-9-hydroxyiminomethyl-1,2,3,4-tetrahydro-9H-fluorene
Reaction SMILES: [Si:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C.[Cu]I>[C:15]([O:14][C:13](=[O:19])[N:12]([CH3:20])[CH2:11][C:10]1[CH:9]=[CH:8][CH:23]=[C:22]([C:6]#[C:5][Si:1]([CH3:4])([CH3:3])[CH3:2])[CH:21]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
TMS-Acetylene (2.2 mL, 15.0 mmol) was added dropwise to commercially available tert-butyl 3-bromobenzyl(methyl)carbamate (3.0 g, 10 mmol), CuI (100 mg, 0.5 mmol) and palladium dichlorobistriphenylphosphine (210 mg, 0.3 mmol) in triethylamine (30 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 70° C. for 12 hrs before cooling to room temperature and evaporating in vacuo. The residue was triturated with diethyl ether (30 mL), filtered and the filtrate evaporated in vacuo and purified by column chromatography (5% ethyl acetate in hexane) to yield A314.1 (3.2 g, 100%) as a brown oil. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.34 min, M+Na+=340.34
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:19])=[O:12])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c2cc[nH]c12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c2[nH]ccc12

Procedure:
Under N2 atmosphere, 7-methyl-1H-indole-4-carboxylic acid (1 g, 5.71 mmol), sulfuric acid (300 μL, 5.63 mmol) and methanol (50 mL) were heated at reflux for 10 h. The MeOH was removed in vacuo and the residue dissolved in 30 mL DCM. The solution was washed with water and saturated NaHCO3, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% EtOAc:Hex; 25 g-HP-silica gel column) to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3H), 4.00 (s, 3H), 7.08 (d, J=7.58 Hz, 1H), 7.20-7.26 (m, 1H), 7.38 (t, J=2.78 Hz, 1H), 7.88 (d, J=7.58 Hz, 1H), 8.32 (br. s., 1H).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:49]1[N:54]=[CH:53][CH:52]=[CH:51][N:50]=1.[H-].[Na+].CN(C)C=O>O>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:49]5[N:54]=[CH:53][CH:52]=[CH:51][N:50]=5)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4nn(-c5ncccn5)nc34)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of Intermediate D (500 mg, 0.82 mmol), 2-chloropyrimidine (343 mg, 3.0 mmol), 60% NaH (60 mg, 1.5 mmol), and dimethlyformamide (10 mL) was stirred under argon and heated at 120° C. for 20 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (4×100 mL). The extract was dried over anhydrous sodium sulfate, the volatiles were removed under reduced pressure, and the residue was chromatographed using silica gel and dichloromethane/ethyl acetate (95:5) as an eluent. The obtained product was recrystallized from ethanol to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(pyrimidin-2-yl)-2H-benzo[d][1,2,3]triazole (Example 12), orange crystals, 340 mg (61%). 1H NMR (400 MHz, CDCl3): δ 8.99 (d, J=5.1 Hz, 2H, pyrimidine), 8.02 (d, J=8.8 Hz, 4H, p-phenylene), 7.66 (s, 2H, benzotriazole), 7.47 (t, J=4.8 Hz, 1H, pyrimidine), 7.28 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.18 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph). UV-vis spectrum (dichloromethane): λmax=451 nm. Fluorimetry (dichloromethane): λmax=600 nm.
Reaction SMILES: F[C:2]12[O:14][CH2:13][CH2:12][O:11][CH:3]1[CH:4]=[C:5]([CH:9]=[CH:10]2)[CH2:6][CH2:7][NH2:8].Cl[C:16]1[C:17]2[C:30]([CH3:31])=[CH:29][S:28][C:18]=2[N:19]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[N:21]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]2[N:21]=[C:16]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:2]4[O:14][CH2:13][CH2:12][O:11][C:3]=4[CH:4]=3)[C:17]3[C:30]([CH3:31])=[CH:29][S:28][C:18]=3[N:19]=2)[CH:23]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCCC1=CC2OCCOC2(F)C=C1
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (250 mg, 1.04 mol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (235 mg, 1.144 mol). PTSA (357 mg, 2.08 mol) was added, the reaction mixture stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 and was purified through flash chromatography by using 100-200 mesh silica gel. The resulting compound (E)-5-bromo-6-methoxy-2-(4-((trifluoromethyl) thio)benzylidene)-2,3-dihydro-1H-inden-1-one 104 was eluted at 10% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:5]([Cl:13])=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O.O>CCOCC>[Cl:13][C:5]1[C:4]([Cl:3])=[CH:12][C:8]([C:9](=[O:11])[CH3:1])=[CH:7][N:6]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
62 ml of a 1.6 M solution (100 mmol) of methyllithium in ether are added to a solution of 9.6 g (50 mmol) of 5,6-dichloronicotinic acid in 250 ml of absolute ether at 0° C. When the addition has ended, the mixture is subsequently stirred at 0° C. for a further 30 minutes and 200 ml of water are then added, while cooling with ice. The phases are separated and the aqueous phase is extracted once more with 50 ml of ether. The combined organic phases are dried over sodium sulphate and evaporated. 9 g (95% of theory) of 2,3-dichloro-5-acetylpyridine, melting point 80° C., are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 52.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-4-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (52 mg, 53% over 2 steps) as a red solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.37 (s, 1H), 8.21 (m, 3H), 8.02 (d, J=8.8 Hz, 1H), 7.72 (dd, J=9.3, 2.9 Hz, 1H), 7.36 (s, 2H), 7.18 (d, J=9.2 Hz, 1H), 4.52 (d, J=13.2 Hz, 2H), 3.44 (m, 1H), 3.14 (t, J=11.8 Hz, 2H), 2.83 (m, 1H), 2.15 (d, J=11.5 Hz, 2H), 1.69 (dd, J=24.5, 7.9 Hz, 2H), 1.21 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 99.0% (AUC), tR=10.73 min.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.CO.C[O-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>O>[CH2:18]([O:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: OCc1ncccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCOc1cccnc1CO
Temperature: 22 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Hydroxy-2-(hydroxymethyl)pyridine hydrochloride (50 g, 339.6 mmol) and methanol (250 mL) are combined under nitrogen and cooled to 22° C. To the vigorously stirred mixture is added 4.5 M sodium methoxide in MeOH (170.8 mL, 747.2 mmol). The mixture is stirred at room temperature for 2 h and then the solvent is evaporated. The resulting material is dissolved in DMSO (250 mL), allyl bromide (41 g, 339.6 mmoles) is added, and the mixture stirred for 18 h at room temperature. The reaction mixture is added to water (800 mL) and extracted with methylene chloride (3×80 mL). The organic portions are combined and dried over sodium sulfate, filtered, and the solvent evaporated to afford the title compound (34.4 g, 62%). LC-ES/MS m/z 166.1 [M+H]+.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:43])([F:42])[CH2:25][O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52]>>[Cl:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[CH2:45][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][CH2:25][C:24]([F:42])([F:23])[F:43])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]3)[C:30]2=[N:35]1
Reactant: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3[nH]nnc23)C1
Reactant: Clc1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3nn(Cc4ccccc4Cl)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)-1-[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 429.4 (MH+).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:22]2[N:21]=[C:20]([N:6]3[C:14]4[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH:25]=[CH:24][N:23]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(C#N)ccc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-n3ccc4cc(C#N)ccc43)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-1H-indole-5-carbonitrile (prepared by TBDMS protection of 1H-indole-5-carbonitrile using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 441 mg (26%)
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:12])([CH:10]=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:19].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[CH:1]([CH:4]1[CH2:5][CH2:6][C:7]([CH3:12])([C:10]([OH:19])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)C1CCC(C)(C=O)CC1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)C1CCC(C)(C(=O)O)CC1
Yield: 100.4 %

Procedure:
A flask was charged with 10 g of 4-isopropyl-1-methyl cyclohexane carbaldehyde, 200 mL of tert-butanol and 100 mL of 2-methyl-2-butene. While stirring the contents of the flask, a solution prepared by dissolving 13 g of sodium chlorite and 11 g of sodium dihydrogenphosphate in 80 mL of water was added to the flask at 0° C. After stirring the contents of the flask at room temperature for 40 min, a part of tert-butanol in the flask was distilled off, and then a small amount of sulfuric acid was added to the flask. The resulting reaction mixture was extracted with an ether, and the thus obtained extract solution was concentrated and then purified by a silica gel column, thereby obtaining 11 g of 4-isopropyl-1-methyl cyclohexanecarboxylic acid.