Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]Br.[CH2:33]([O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>O>[CH2:33]([O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[CH:48][C:49]([O:52][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:50][CH:51]=2)=[N:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: FC(F)(COCCOCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCOCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 2-(2-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)ethoxy)ethyl bromide (7.7 g of 90% purity by gas chromatography 11.8 mmol) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 11.0 mmol). The resulting product was isolated by addition of water (50 mL) to the reaction mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by distillation using a Kugelrohr apparatus (b.p. 185°-210° C. at 0.01 torr; yield 5.6 g).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[N:14]2)=[CH:9][CH:8]=1.[C:22]1(C)C=CC=C[CH:23]=1>>[CH2:22]([O:20][C:19]([C:16]1[CH:15]=[N:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=2)[C:17]=1[CH3:18])=[O:21])[CH3:23]
Reactant: COc1ccc(-n2ncc(C(=O)O)c2C)cc1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1C
Temperature: 80 °C

Procedure:
Thionyl chloride (3.84 g) was added to a solution of 1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (5.0 g) described in Reference Example 5 in toluene (20 ml) at room temperature, stirred at 80° C. for an hour and the solvent and an excess amount of thionyl chloride were evaporated. Pyridine (10 ml) and ethanol (20 ml) were added to the resulting residue and stirred at 40° C. for 0.5 hour. After completion of the reaction, the solvent was evaporated and ethyl acetate and 1N aqueous solution of sodium hydroxide were added. The mixture was extracted with ethyl acetate three times and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.2 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH2:36])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1(C=CC(=O)C=CC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:18]1([NH:17][C:15]([C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([NH:36][C:34]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=5)=[O:35])[N:3]=[C:4]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1ccccn1
Reactant: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)CNc1nc(NC(=O)c2ccccn2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 140 °C
Yield: 29.6 %

Procedure:
To a solution of 100 mg (0.23 mmol) 4-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide in 2 mL toluene were added 88 mg (0.7 mmol) pyridine-2-carboxamide, 76 mg (0.23 mmol) caesium carbonate, 8.4 mg (0.01 mmol) 1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) and 10.8 mg (0.02 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and the mixture was heated at 140° C. for 2 h in a microwave tube. The mixture was filtered and purified by HPLC to yield 32 mg (28%) of the title compound. UPLC-MS: RT=1.32 min; m/z (ES+) 470.5 [MH+]; required MW=469.5. 1H-NMR (300 MHz, d6-DMSO): δ=9.88 (1H, s), 8.76 (1H, s), 8.73 (1H, d), 8.56 (1H, d), 8.13-8.04 (2H, m), 7.99 (2H, d), 7.88 (1H, t), 7.76 (1H, s), 7.72 (1H, d), 7.69 (1H, m), 3.31 (2H, t), 2.87 (1H, m), 2.06 (1H, m), 0.92 (2H, d), 0.69 (2H, m), 0.55 (2H, m) ppm.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:17]([OH:19])=[O:18].[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:27]=12)=O>C(Cl)Cl>[C:42]([O:41][C:39]([N:32]1[C:28]2=[N:29][CH:30]=[CH:31][C:26]([CH2:24][NH:15][C@H:16]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[C:27]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (2R,3S)-2-amino-3-methylpentanoic acid (43.1 mg, 0.329 mmol), and DCM (2 mL). The mixture was stirred at room temperature for 30 min, after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C21H29N3O6, 420; found, 420.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]#[N:9]
Reactant: NC(=O)c1sc2ccccc2c1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1sc2ccccc2c1Cl
Temperature: 25 °C

Procedure:
A stirred mixture of 0.2 mole of 3-chlorobenzo-[b]thiophene-2-carboxamide in 150 ml. of phosphorus oxychloride was refluxed for three hours. The reaction mixture was then cooled to room temperature and poured onto 1 kg of ice to give a solid product which was collected by filtration. Recrystallization from 1-chlorobutane gave 3-chlorobenzo[b]thiophene-2-carbonitrile, m.p. 124°-125° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[C:27]1([S:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(S(=O)(=O)c3ccccc3)c3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1cn(CC2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
A stirred solution of 4-[3-(phenylsulfonyl)-1H-indol-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.10 mmol) in dioxane is treated with 4N HCl in dioxane (4.5 mL, 18 mmol), stirred for 5 h at ambient temperature and concentrated in vacuo. Crystallization of the resultant solid residue from ethanol:ether affords the title compound as a white solid, 351 mg (82% yield), mp>250° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
In this example, a mixture containing 5.93 g of N-bromosuccinimide, 5.0 g of methyl phenylacetate; and a catalytic amount (about 0.1 g) of benzoyl peroxide in 50 ml of carbon tetrachloride was warmed to reflux and then refluxed for about 12 hours. The mixture was then cooled to about 0° C. and filtered. The filtrate was concentrated by evaporation under vacuum affording 7.1 g of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:39]3[CH2:40][CH2:41][CH:36]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:37][CH2:38]3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C1CCN(C2CCNCC2)C1
Product: CC1(C)c2cc(N3CCC(N4CCCC4)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 4-pyrrolidin-1-yl-piperidine.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O>C(O)(=O)C.C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[C:31]([CH3:32])=[CH:30][CH:26]=[C:27]5[CH3:29])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CCC(C)=O
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Temperature: 25 °C

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 79) (100 mg) and acetonyl acetone(0.04 mL)and acetic acid (20 drops) were dissolved in benzene (10 mL) and refluxed with Dean-Stark apparatus for 2 hours. After cooling to room temperature, the solution was then diluted with 10 mL of aqueous saturated NaHCO3 and extracted with 2×10 mL of of EtOAc. The combined organic extracts were then dried (MgSO4) and concentrated under reduced pressure. The residue was purified with preparatory thin-layer chromatography (SiO2, 5% MeOH in CH2Cl2) to yield 17 mg of the title compound. Mass spectrum (ESI) 408.1 (M+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[S:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[S:41][C:40]4[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=4[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cc2ccccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cc3ccccc3s2)CC1
Yield: 49.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.54 g) as starting compound, potassium carbonate (0.8 g) and 6-bromo-1-(2-benzo[b]thienyl)-1-hexanone (0.45 g) were reacted and treated in the same manner as in Example 172 to give 0.38 g of 4-amino-5-chloro-N-((1-(6-(2-benzo[b]thienyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[O:28][CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Reactant: Brc1ccco1
Product: Cc1c2n(c3c(-c4ccco4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (21 mg, 37%), MS (ISP) m/z=285.5 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromofurane (44.1 mg, 0.3 mmol).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:14][N:15](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:6]=3[C:5]=2[N:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1
Reactant: CCOC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CCc1cnc(SC)nc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1n[nH]c2c1CCc1cnc(SC)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Ethyl 8-(methylsulfanyl)-1-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.0 g, 1.99 mmol) in DCM (20 ml) was treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred at r.t. for 1 hour and the solvent removed in vacuo. The residue was triturated with diethyl ether filtered and dried to provide the title compound 500 mg (96%). LC/MS (254 nm) HPLC method 2 Rt 3.62 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:35]([CH:32]4[CH2:34][CH2:33]4)(=[O:37])=[O:36])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCN(S(=O)(=O)C3CC3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added cyclopropanesulfonyl chloride (1.1 equiv., 31 μl) and the reaction mixture was allowed to warm up to room temperature overnight. DCM/brine extraction and purification on silica gave 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (101 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:22]#[N:23])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(C#N)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-cyanophenylboronic acid (126 mg, 0.86 mmol) the subtitle compound was obtained (65 mg, 31%). 1H NMR (DMSO) δ 8.75(d, 1H), 8.57(dd, 1H), 8.35(t, 1H), 8.29(d, 1H), 8.21(dt, 1H), 8.00(d, 1H), 7.97(dt, 1H), 7.93(d, 1H), 7.80(t, 1H), 7.74(d, 1H), 4.17(s, 3H).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[OH-].[Na+].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11](=O)[O:10][C:8]2=[O:9]>C(Cl)Cl>[CH2:2]([N:4]1[C:8](=[O:9])[C:7]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:10])[CH3:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCn1c(=O)[nH]c2ccccc2c1=O
Reaction time: 4 h
Yield: 27.4 %

Procedure:
To a mixture of 12.23 g of ethylamine hydrochloride , 35 ml 4M sodium hydroxide and 175 ml methylene chloride was added 16,3 g isatoic anhydride. This mixture was stirred for 4 hours and the aqueous phase was made basic with 4 M sodium hydroxide. The organic phase was evaporated in vacuo. The residue was dissolved in 300 ml of tetrahydrofuran (THF) and 75 ml phosgene solution (20% in toluene) was added. The resulting mixture was stirred at 80° C. for two hours. The precipitate was filtered off and the mother liquor was evaporated leaving 5.2 g of the title compound. M.p. 189.8°-189.9° C.
Reaction SMILES: [S:1]([Cl:4])([Cl:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[S:1]([Cl:4])([Cl:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([Cl:3])=[O:27])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 154.9 %

Procedure:
Thionyl chloride (140 g, 1.18 mol) was added to 4'-benzyloxybiphenyl-4-carboxylic acid (300 g, 0.98 mol), followed by refluxing the mixture for about 2 hours, thereafter removing excess thionyl chloride under reduced pressure to obtain 4'-benzyloxybiphenyl-4-carboxylic chloride (295 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22].[CH2:23](NC1C=CC=CC=1C)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]1=[O:22]
Reactant: C=CCNc1ccccc1C
Reactant: N[C@H]1CC=CCN(c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N1CC=CC[C@H](N)C1=O

Procedure:
(S,Z)-3-Amino-1-o-tolyl-3,4-dihydro-1H-azepin-2(7H)-one trifluoroacetate (17 mg, 0.051 mmol) was synthesized as described for the preparation of Intermediate 52 using N-allyl-2-methylaniline in step A. Anal. Calcd. for C13H16N2O m/z 216.2. found: 217.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>CCCCCCC>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Solvent: CCCCCCC
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
In 1 gal pressure reactor, a mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (120 g) prepared in accordance with Step C, above, and ammonium hydroxide (28-30%, 2.4 L, 20 vol) was heated in the sealed pressure reactor to 98-103° C. and stirred at this temperature for 2 hours. The reaction was cooled slowly to room temperature (20° C.) and stirred overnight. The solids were filtered and washed with minimum amount of the mother liquor and dried under vacuum. The solids were added to a mixture of EtOAc (15 vol)/water (2 vol) and heated to complete dissolution at 60-70° C. and the aqueous layer was removed and discarded. The EtOAC layer was charged with water (1 vol) and neutralized with aq. HCl to ˜pH 5.4-5.5. and added water (1 vol). The aqueous layer was removed and discarded at 60-70° C. The organic layer was washed with water (1 vol) at 60-70° C. and the aqueous layer was removed and discarded. The organic layer was filtered at 60° C. and concentrated to 3 volumes. EtOAc (6 vol) was charged into the mixture and heated and stirred at 72° C. for 10 min, then cooled to 20° C. and stirred overnight. EtOAc was removed via vacuum distillation to concentrate the reaction mixture to ˜3 volumes. The reaction mixture was maintained at ˜65-70° C. for ˜30 mins. Product crystals having the same crystal form as those prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptanes slurry were charged. Heptane (9 vol) was slowly added at 65-70° C. The slurry was stirred at 65-70° C. for 2-3 hours and then cooled slowly to 0-5° C. The product was filtered, washed with EtOAc/heptane (3/1 v/v, 4 vol) and dried at 45° C. under vacuum to obtain N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (102.3 g, 88%).
Reaction SMILES: C[O:2][C:3](=[O:12])[CH:4]=[CH:5][C:6]1[N:7]=[C:8]([Br:11])[S:9][CH:10]=1.[OH-].[Li+]>O1CCCC1.O>[Br:11][C:8]1[S:9][CH:10]=[C:6]([CH:5]=[CH:4][C:3]([OH:12])=[O:2])[N:7]=1
Reactant: COC(=O)C=Cc1csc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1csc(Br)n1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Dissolve 3-(2-bromo-thiazol-4-yl)-acrylic acid methyl ester (5.9 g, 23.78 mmol) in tetrahydrofuran (48 mL) and add a solution of lithium hydroxide (636 mg, 26.16 mmol) in water (10 mL). Stir the mixture overnight. Extract the mixture with ethyl acetate and wash twice with water. Acidify the aqueous layer with 1N HCl in water until the mixture is at pH 3-4. Filter the resulting white solid, then wash the solid with ethyl acetate, followed by diethyl ether and then water. Dry the white solid to give 5.05 g (91%) of the desired material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]([CH3:23])([CH3:22])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:12]=1[C:20]#[N:21])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]([CH3:23])([CH3:22])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:12]=1[C:20]#[N:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OC(C)(C)C
Yield: 100.2 %

Procedure:
To a solution of tert-butyl(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)carbamate (45 g, 134 mmol) in ethyl acetate (200 mL) and ethanol (100 mL) was added 10% palladium on carbon (4.5 g). The reaction was stirred under H2 at 40 psi, and upon completion, the mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to provide tert-butyl(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)carbamate as a white solid (41 g, 100%). 1H NMR (DMSO-d6), 400 MHz: δ 1.26 (s, 6H), 1.34 (s, 9H), 4.00 (s, 2H), 5.96 (br s, 2H), 6.15 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.0 Hz, 1H), 6.63 (br s, 1H), 7.14 (t, J=8.0 Hz, 1H). MS 206 (MH+).