Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N[C@H](CCCCNC(OC(C)(C)C)=O)C(NCC[C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=O)=O)(C)(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.[I-].[Na+]>C(#N)C>[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([CH2:27][C:21]2[CH:22]=[CH:42][C:18]([C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]4[C:27]5[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=5[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=4[CH:42]=3)=[O:16])=[CH:19][CH:20]=2)[CH2:58][CH2:57]1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)c3ccc(CN4CCN(C)CC4)cc3)cc1[C@@H](NC(C)=O)CC2
Yield: 75 %

Procedure:
A solution of N-[(5S)-3-(4-chloromethylphenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (1) (0.308 g; 0.604 mmol), 1-methylpiperazine (0.088 ml; 0.785 mmol) and sodium iodide (0.02 g; 0.121 mmol) in acetonitrile (10 ml) was stirred under argon atmosphere overnight. After evaporation to dryness, the residue was purified by flash chromatography eluting with a 5–12% gradient of methanol/dichloromethane. After evaporation of the appropriate fractions, the solid was triturated in ether/pentane to give N-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH:31]CC=C)=[CH:25][C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: C=CCNc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(OC)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cc(N)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(4-allylamino-2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.93 g) was dissolved in MeCN/water (40 mL of 84:16) under N2. Wilkinson's catalyst (79 mg) was added and the mixture was brought to boiling. After 2 h, more catalyst (170 mg) was added and the reaction continued for another 6 h. The solvent was evaporated and the residual water coevaporated with MeCN. The residue was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 2:1 to 1:2) to give N-(2,6-dichlorobenzoyl)-4-(4-amino-2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (708 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][C:5]#[C:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.Cl>>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[C@H:7]1[CH2:9][C@H:8]1[C:10]1[N:11]=[CH:12][NH:13][CH:14]=1
Reactant: CC(C)(C)CCC#C[C@@H]1C[C@H]1c1c[nH]cn1
Agent: Cl
Product: CC(C)(C)CC/C=C\[C@H]1C[C@H]1c1c[nH]cn1

Procedure:
(1R,2R)-4-(2-(5,5-Dimethyl-cis-hex-1-enyl)cyclopropyl)imidazole was prepared by the Lindlar reduction of the compound 39 when it is trityl protected. The trityl group then deprotected after the Lindlar reduction by treating it with HCl at 90° C. for 1 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:49]2[CH2:50][CH2:51][CH:46]([C:44]([C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)=[O:45])[CH2:47][CH2:48]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1 H-benzoimidazole-2-carbonyl)-piperidine hydroiodide salt to give the title compound: Rf=0.35 (silica gel, 10% methanol/ethyl acetate containing 0.1% concentrated aqueous ammonia solution).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[CH:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.3 %

Procedure:
To 5-{3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide (example 272) (0.30 g, 0.565 mmol) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.092 g, 34%). MS (ISP) 475.1 [(M+H)+]; mp 211° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15]/[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.ClCCl>[ClH:32].[C:24]1(/[C:16](=[CH:17]\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC/C(=C/c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN(CCOC/C(=C/c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (1.45 g, 3.7 mmol) was dissolved in absolute ethanol (15 ml) and 4N sodium hydroxide (1.9 ml) was added. After stirring at ambient temperature for 4 h the mixture was diluted with dichloromethane (300 ml), cooled to 0° C. and 4N hydrochloric acid (4 ml) was added. The mixture was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone, suspended in acetone (10 ml), the precipitate collected and dried in the air. This afforded 1.2 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.N1CCCCC1>CO>[CH3:17][O:16][C:11]([C:12]1[CH:14]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([NH2:10])=[CH:7][CH:6]=2)[N:1]=1)=[O:15]
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc(C=O)c(N)c1
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1ccc2ccc(N)cc2n1

Procedure:
For example, 2,4-diaminobenzaldehyde 53.7 (Apin Chemicals) is reacted with one molar equivalent of methyl pyruvate 53.2 in methanol, in the presence if a base such as piperidine, to afford methyl-7-aminoquinoline-2-carboxylate 53.8. Basic hydrolysis of the product, employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 53.9. The amino-substituted carboxylic acid is then converted into the diazonium tetrafluoborate 53.10 by reaction with sodium nitrite and tetrafluoboric acid. The diazonium salt is heated in aqueous solution to afford the 7-hydroxyquinoline-2-carboxylic acid, 53.11, Z=OH. Alternatively, the diazonium tetrafluoborate is heated in aqueous organic solution with one molar equivalent of cuprous bromide and lithium bromide, to afford 7-bromoquinoline-2-carboxylic acid 53.11, X═Br. Alternatively, the diazonium tetrafluoborate 53.10 is reacted in acetonitrile solution with the sulfhydryl form of an ion exchange resin, as described in Sulfur Lett., 2000, 24, 123, to prepare 7-mercaptoquinoline-2-carboxylic acid 53.11, Z=SH.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:28]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccc(OC)cc1C=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (10 g, 65.7 mmoles) in 100 ml of sieve-dried dimethylformamide was added freshly-pulverized potassium carbonate (10 g, 72.3 mmoles) and undecyl bromide (15 ml, 67.3 mmoles). The reaction mixture was stirred at 100° C. for 1 hour, cooled to room temperature and then poured into ice-cold water/hexane. The layers were separated and the organic extract was washed with ice-cold 5% sodium hydroxide solution, water and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, treated with charcoal and concentrated in vacuo. The resulting yellow solid was recrystallized from hexane, to give 16.2 g (80%) of the product as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:25]=1[NH2:26]>>[NH2:26][C:25]1[CH:27]=[CH:28][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:30][C:24]=1[F:23]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(F)c3)c(F)cn2c1=O
Yield: 9.8 %

Procedure:
Ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (149 mg, 0.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (134 mg, 0.58 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (18 mg, 10%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([C:36]1[C:37]([N:45]2[CH2:50][CH2:49][CH:48]([N:51]3[CH2:56][CH2:55][N:54]([S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:52]3)[CH2:47][CH2:46]2)=[CH:38][C:39]([O:43][CH3:44])=[C:40]([CH:42]=1)[NH2:41])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[C:36]([CH2:34][CH3:35])[C:37]([N:45]4[CH2:46][CH2:47][CH:48]([N:51]5[CH2:52][CH2:53][N:54]([S:57]([CH3:60])(=[O:59])=[O:58])[CH2:55][CH2:56]5)[CH2:49][CH2:50]4)=[CH:38][C:39]=3[O:43][CH3:44])[N:7]=2)[CH:18]=1
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCc1cc(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 175 °C
Yield: 34.3 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (0.050 g, 0.11 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 206, Step B) (0.043 g, 0.11 mmol) and para-toluenesulfonic acid (0.049 g, 0.26 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 20 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.031 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.36 (br. s., 1H), 8.50 (s, 1H), 8.26 (d, J=5.22 Hz, 1H), 8.12 (d, J=2.11 Hz, 1H), 7.80 (dd, J=8.80, 2.02 Hz, 1H), 7.71 (d, J=9.07 Hz, 1H), 7.53 (s, 1H), 7.36-7.50 (m, 2H), 7.30 (d, J=8.80 Hz, 1H), 7.14-7.25 (m, 2H), 6.91-7.00 (m, 1H), 6.83 (s, 1H), 6.58 (d, J=5.22 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.08-3.15 (m, 4H), 3.00-3.07 (m, 2H), 2.88 (s, 3H), 2.67-2.76 (m, 2H), 2.61-2.66 (m, 4H), 2.56 (q, J=7.51 Hz, 2H), 2.38-2.46 (m, 1H), 1.80-1.91 (m, 2H), 1.50-1.68 (m, 2H), 1.11 (t, J=7.51 Hz, 3H). MS (M−H, ES−) 820.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (2.29 g) in methanol (10 mL) was added dropwise 2M trimethylsilyldiazomethane solution in hexane (11.9 mL) under ice-cooling. The reaction mixture was concentrated, and to the residue was added hexane. The precipitated crystals were collected by filtration, and the filtrate was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate=9/1 to 7/3). The product and the crystals obtained above were combined to give methyl 1-(tert-butoxycarbonylamino)-cyclopentane-carboxylate (2.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[O-2].[Mg+2].CS(C)=O.[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20]>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=[CH:21][C:19]#[N:20]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CC=Cc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
After stirring 2-bromo-6-nitrobenzaldehyde (30.4 g), magnesium oxide (75 g) and dimethyl sulfoxide (11.3 ml) sufficiently for 1 minute, diethyl (cyanomethyl)phosphonate (25.8 ml) was added thereto and the mixture was stirred for further 2 hours. After the completion of stirring, the mixture was left stand overnight. Then, ethyl acetate was added thereto, and the mixture was stirred and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate), to give 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E-isomer:Z-isomer=3:1).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:14])([CH3:13])[O:4][C:5]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:6]=12.[NH3:15]>C(O)C>[NH2:15][C@@H:7]1[C:6]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:5]=2[O:4][C:3]([CH3:14])([CH3:13])[C@H:2]1[OH:1]
Reactant: N
Reactant: Cc1ccc2c(c1)C1OC1C(C)(C)O2
Solvent: CCO
Product: Cc1ccc2c(c1)[C@@H](N)[C@H](O)C(C)(C)O2

Procedure:
A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (7 g, see J. Med. Chem. 26, 1582, 1983) in concentrated ammonia solution (90 ml) and ethanol (160 ml) was stirred at room temperature for 5 days. Evaporation of solvent gave the title compound (7 g) as a crude solid which was used directly, without purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([N:15]1[CH2:21][CH:20]2[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)=[O:14].O.NN>CCO>[NH2:3][CH2:12][C:13]([N:15]1[CH2:16][CH:17]2[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH2:19][CH2:18]2)[CH2:21]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)CN1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)CN)C2
Yield: 42.5 %

Procedure:
To a stirred solution of tert-Butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.187 mmol) in EtOH (1.9 mL) was added hydrazine monohydrate (19.0 mg, 0.375 mmol) at room temperature and the mixture was refluxed for 1 h. After cooling, the precipitates formed were filtered off. The filtrate was evaporated in vacuo and the residue was purified by preparative TLC (SiO2, 20×20 cm, 1 mm, CH2Cl2/MeOH/aqueous NH3=92/6/2) to afford a product (21.4 mg, 42%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>N1C=CC=CC=1>[C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)(=[O:35])[CH2:37][OH:38]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(trifluoromethyl)benzamide (200 mg, 0.450 mmol) produced in Example C8(iv) in pyridine (5 mL) was added acetoxyacetyl chloride (121 μL, 1.12 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and a mixture of the obtained residue, methanol (3 mL), pyridine (2 mL) and 0.5N aqueous sodium hydroxide solution (3 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was precipitated with ethyl acetate and hexane to give the title compound (92 mg, 41%) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:18]/[C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 34 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). Pyrrole-2-carboxaldehyde (16 mg, 0.18 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (10 ml) and the precipitated solid was collected by filtration and washed with water to give 15 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:12]([Br:13])=[C:11]([NH:14][C:15]([C@@H:17]2[CH2:19][C@H:18]2[CH3:20])=[O:16])[S:10][N:9]=1.[CH3:21][N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28]2)=[N:23]1>COCCOC>[Br:13][C:12]1[C:8]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][N:22]([CH3:21])[N:23]=3)[CH:28]=2)=[N:9][S:10][C:11]=1[NH:14][C:15]([C@@H:17]1[CH2:19][C@H:18]1[CH3:20])=[O:16]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Reactant: Cn1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Temperature: 83 °C
Yield: 51 %

Procedure:
Add a 2; M aqueous solution of sodium carbonate (606.3; mL, 1.21; mol) to a stirring mixture of (1R,2R)-2-methyl-cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (148.1; g, 0.404; mol) and 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (123.40; g, 0.444; mol) in HPLC grade 1,2-dimethoxyethane (1.21; L) and degas using vacuum and nitrogen. Add bis(triphenylphosphine) palladium(II) dichloride (56.77; g, 80.84; mmol) in one portion, heat at 83° C. for 10; h, cool to room temperature and filter through a pad of Celite® using ethyl acetate to give a biphasic solution. Separate the layers and extract the aqueous layer three times with dichloromethane (200; mL). Combine all the organic layers, wash with brine (200; mL) and concentrate to approximately a volume of 400; mL. Separate into two portions and purify each by silica gel chromatography by gradient 50:50; to 10:90; eluting with n-hexane:ethyl acetate to give the title compound as a light brown solid (107.32; g, 51%). MS (m/z): 391,393; (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]([CH3:22])[CH2:14][C:15]3([CH3:21])[CH3:20])=O)[C:4]([CH3:23])=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](=[S:25])[NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]([CH3:22])[CH2:14][C:15]3([CH3:21])[CH3:20])[C:4]([CH3:23])=[N:3]1
Reactant: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1C(C)CC2(C)C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nn(C)c(C)c1C(=S)Nc1cccc2c1C(C)CC2(C)C
Temperature: 0 °C
Yield: 128.9 %

Procedure:
1.1 g of 1,3,5-trimethyl-N-(1,1,3-trimethyl-4-indanyl)pyrazole-4-carboxamide, 0.79 g of phosphorus pentasulfide and 15 ml of hexamethylphosphoramide (HMPA) were stirred at 100° C. for 8 hours. After cooling, the reaction mixture was poured into ice water and extracted with ether. The extracts ether layer were dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residue was chromatographed on silica gel to obtain 0.75 g of 1,3,5-trimethyl-N-(1,1,3-trimethylindane-4-yl)pyrazole-4-carbothioamide (yield 65%).