Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>ClCCl>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:12][CH:13]=1)(=[O:41])=[O:40]
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(OS(=O)(=O)c5cccc(Cl)c5Cl)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
A solution containing cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (100 mg, 0.245 mmol), 2,3-dichlorobenzenesulfonyl chloride (180 mg, 0.735 mmol) and triethylamine (0.34 mL, 2.45 mmol) in dichloromethane (8 mL) was stirred at ambient temperature for 17 h. Additional dichloromethane was added (20 mL) and the reaction was washed with brine (10 mL), saturated aqueous NaHCO3 (10 mL), dried (NaSO4) and concentrated under reduced pressure to afford cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl 2,3-dichloro-1-benzenesulfonate as a white solid (135 mg, 90%); RP-HPLC 11.787 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z (MH+)=616.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C(O)(=O)C.[CH3:22][C:23]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:24]=1[NH2:25]>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:25][C:24]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:23]=2[CH3:22])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(C)C(c2ccccc2C=Nc2c(C)cc(C)cc2C)C(C)=C1C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (30.0 mL) were added dropwise acetic acid (1.0 mmol) and 2,4,6-trimethylaniline (10.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,4,6-trimethylphenyl)amine (3.43 g, yield 100%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:25]1[CH:24]=[N:23][C:22]([Cl:21])=[CH:27][CH:26]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccc(Cl)nc1
Temperature: 90 °C
Yield: 123.3 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.6 g, 11.5 mmol), Na2CO3 (1.83 g, 17.3 mmol) and 2-chloropyridin-5-ylboronic acid (1.81 g, 11.5 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) was added and the mixture was heated at 90° C. for 16 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (4.3 g, 70%) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1)([OH:23])=[O:22].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:21]([OH:23])=[O:22])=[CH:29][CH:28]=3)[CH:17]=1)=[CH:5]2
Reactant: O=C(O)c1ccc(N=C=S)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 4-carboxyphenyl isothiocyanate (0.183 g, 1.0 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was boiled off on the rotary evaporator (no vacuum) to give a solid. Ethyl acetate (5 mL) was added, and the mixture was allowed to stand overnight at room temperature. The insoluble material was collected by filtration and was a mixture. All material from the reaction mixture was taken up in tetrahydrofuran/ethyl acetate and more 4-carboxyphenyl isothiocyanate (0.020 g, 0.11 mmol) was added and the solvent was boiled off on the rotary evaporator. Ethyl acetate was added to the solid and the mixture allowed to stand overnight at room temperature. The insoluble material was collected by filtration (0.191 g), mp 201-203° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.ICI.[CH2:16]=[C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][CH2:18]1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]1[C:17]2([CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:19][CH2:18]2)[CH2:16]1
Reactant: C=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CCC2(CC1)CC2)OCc1ccccc1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Diethyl zinc (25 mL, 1M hexane solution) was slowly added to 100 mL of anhydrous DCM at −40° C. under nitrogen, and further slowly added TFA (2.85 g, 0.025 mol) and reacted for 0.5 h, then diiodomethane (6.67 g, 0.025 mol) was slowly added thereto. The reaction was continued for 0.5 h, then Compound 8-4 (3 g, 0.012 mol) was dissolved in 20 mL of anhydrous DCM and added dropwise to the reaction mixture under nitrogen, reacted overnight at −5° C., added saturated ammonium chloride solution to quench the reaction, followed by liquid separated, the organic phase was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 8-5 as a white solid (2.85 g, yield 86.9%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][N:15]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:6]1.[Br:25]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:25][C:11]1[S:10][C:9]([C:7]2([C:14]3[N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]4=[N:16][N:15]=3)[CH2:8][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[CH:13][CH:12]=1
Reactant: COCOC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COCOC1CC(c2ccc(Br)s2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
3-[3-(Methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (343 mg) was dissolved in acetic acid (3 ml) and then N-bromosuccinimide (193 mg) was added, followed by stirring at room temperature for 7 hours under light-shielding. The reaction solution was diluted with chloroform (40 ml) and then washed with water (10 ml), a 1M aqueous sodium hydroxide solution (10 ml), and brine (10 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 392 mg of 3-[1-(5-bromo-2-thienyl)-3-(methoxymethoxy)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (reddish purple syrup).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(F)c(F)c2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,4-difluorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a slightly yellow powder (yield 67%).
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F
Yield: 55 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg,0.199) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) gave 40 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 (m, 1H) 4.04-4.24 (m, 2H), 4.23 (s, 1H), 4.35 (m, 1H), 4.97-5.48 (m, 2H) 7.22 (m, 1H), 7.44 (m, 1H), 8.04 (m, 1H). ESI-MS 507 (M+1).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:36]1(=[O:46])[C:44]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=2[C:38](=O)[O:37]1>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[C:38]2[C:39]3[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=3[C:36](=[O:46])[O:37]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC(c1cccc(Br)c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=C1OC(=O)C2=C1CCCC2)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of EXAMPLE 285B (1.88 g, 3.4 mmol) in tetrahydrofuran (100 ml) was treated with potassium t-butoxide (1N solution in tetrahydrofuran, 3.4 ml, 3.4 mmol) at −78° C. for 1 hour, and was allowed to warm up to 0° C. over 30 minutes. A solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (0.54 g, 3.4 mmol) in tetrahydrofuran (10 ml) was then added. The reaction mixture was warmed up to room temperature, and stirred at room temperature for additional 4 hours. After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was separated by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 320 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:24])=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]12[O:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27][CH2:26]2.C=CCCC=C.C(N)C1C=CC=CC=1.ClC(OC(Cl)C)=O>CCO.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:24])=[N:21][C:22]([N:27]4[CH2:26][CH:25]5[O:32][CH:29]([CH2:30][CH2:31]5)[CH2:28]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1nc(Cl)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Agent: C=CCCC=C
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CCO
Solvent: NCc1ccccc1
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Reaction time: 18 h

Procedure:
To a solution of 1 mmol 1-(1-benzyl-piperidin-4-yl)-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine dissolved in EtOH (10 mL) was added 1 mmol 8-oxa-3-aza-bicyclo[3.2.1]octane, (Newth, F. H. and Wiggins, L. F. Journal of the Chemical Society. 1948, pages 155-158) prepared from 1,5-hexadiene by the four-step process of RuCl3-catalyzed NaIO4 oxidation, conversion to the bis tosylate, cyclization with benzyl amine, and deprotection with 1-chloroethyl chloroformate followed by methanol (Scheme 46). The reaction was stirred for 18 h. The solvents were evaporated and the reminder was triturated with diethyl ether/hexane. The solid was filtered off and washed with hexane. Drying on the fritted funnel provided a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([N:15]4[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][CH:17]=[N:16]4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1>>[CH:20]([C:19]1[N:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)[N:16]=[CH:17][N:18]=1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)c1ncnn1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)c1ncnn1-c1nc2c(s1)CCOc1ccc(-c3cn[nH]c3)cc1-2

Procedure:
Following the procedure for 484, Step 4, 9-bromo-2-(5-isopropyl-[1,2,4]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to afford 489 as a white solid. LCMS (Method C): RT=10.17 min, [M+H]+=379. 1H NMR (DMSO-d6): 12.95 (1H, bs), 8.42 (1H, d, J=2.3 Hz), 8.18 (1H, s), 8.07 (1H, bs), 7.81 (1H, bs), 7.51 (1H, dd, J=8.3, 2.3 Hz), 7.06 (1H, d, J=8.3 Hz), 4.36 (2H, t, J=5.0 Hz), 4.12-4.04 (1H, m), 3.38 (2H, t, J=5.0 Hz), 1.47 (3H, s), 1.46 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4](O)[CH:3]=1.P(Cl)(Cl)([Cl:12])=O>CN(C=O)C>[Cl:12][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(N)cc(O)n1
Solvent: CN(C)C=O
Product: Cc1nc(N)cc(Cl)n1
Temperature: 80 °C

Procedure:
6-Amino-2-methylpyrimidin-4-ol (5 g) was suspended in phosphorous oxychloride (50 ml) and heated at 80° C. for 1 hour. A few drops of DMF was added and the reaction heated to 105° C. for 3 hours to give an orange solution. The reaction was cooled, concentrated in vacuo and azeotroped with toluene. The residue was cautiously partitioned between ethyl acetate and ice-cold saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried and concentrated in vacuo to afford 6-chloro-2-methylpyrimidin-4-amine as a yellow solid which was used without further purification (3 g, 68%); NMR Spectrum (300 MHz, CDCl3) 2.50 (s, 3H), 5.00 (br s, 2H), 6.30 (s, 1H); Mass Spectrum MH++CH3CN 185. 6-Chloro-2-methylpyrimidin-4-amine (2.45 g) was suspended in 1-methylpiperazine (24 ml) and the reaction heated at 140° C. for 20 minutes in a microwave reactor. The reaction was cooled and concentrated in vacuo. The residue was dissolved in methanol and neutralised with polymer-bound carbonate resin for 1 hour, then filtered and concentrated to give an orange solid that was triturated with ethyl acetate to give 2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine as a cream solid (2.64 g, 81%); NMR Spectrum (300 MHz, CDCl3) 2.20 (s, 3H), 2.30 (s, 3H), 2.40 (m, 4H), 3.50 (m, 4H), 4.40 (br s, 2H), 5.40 (s, 1H); Mass Spectrum MH+ 208.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][C:51]1[S:52][C:53]([CH2:56][NH2:57])=[CH:54][N:55]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:53]4[S:52][C:51]([CH3:50])=[N:55][CH:54]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1ncc(CN)s1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1ncc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)s1
Yield: 45 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (2-methylthiazol-5-yl)methanamine, the title compound was obtained as a colorless solid in 45% yield: mp 213-215° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.07-7.01 (m, 3H), 6.29 (br s, 1H), 4.62 (d, J=5.3 Hz, 2H), 4.46 (s, 2H), 4.10-4.05 (m, 2H), 3.48-3.43 (m, 2H), 2.71 (s, 3H), 2.61 (s, 3H); MS (ES+) m/z 446.1 (M+1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16][C:13]2=[N:14][CH:15]=1>>[CH2:1]([N:16]1[C:13]2=[N:14][CH:15]=[C:10]([F:9])[CH:11]=[C:12]2[CH:18]=[C:17]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccccc1

Procedure:
The ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to a method similar to that described in Example 4.1, from benzyl alcohol and the ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate prepared in the preceding step.
Reaction SMILES: O=[C:2]1[CH:11]([C:12]([O:14]C)=O)[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:20][C:18]1[N:19]=[C:12]([OH:14])[C:11]2[CH2:10][CH2:9][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[C:2]=2[N:17]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2

Procedure:
A solution of Example 1B (4.5 g, 21.4 mmol), guanidine hydrochloride (6.13 g, 64.2 mmol), and K2CO3 (9.46 g, 68.5 mmol) in DMF (30 mL) was heated at 105-110° C. for 3 hours. The mixture was then filtered through a layer of diatomaceous earth, and the filter pad was washed with a small amount of DMF. Approximately two volumes of water were then added, and the pH of the resulting mixture was adjusted to pH 6-7 with HOAc. The precipitate was collected, washed with H2O, and dried under vacuum to provide the title product. 1H NMR (300 MHz, DMSO-d6) δ 10.50-10.61 (m, 1 H), 5.98-6.08 (m, 2 H), 2.20 (t, 2 H), 1.95-2.04 (m, 2 H), 1.68-1.76 (m, 2 H), 1.61-1.68 (m, 2 H), 1.48-1.58 (m, 4 H), 1.34-1.45 (m, 2 H). MS (DCI+) m/z 220 (M+H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([Cl:20])=[O:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Temperature: 50 °C

Procedure:
Trans-4-(trans-4-ethylcyclohexyl)cyclohexanecarboxylic acid (2.4 g, 0.01 mol) and thionyl chloride (10 ml) were introduced into a flask and warmed to 50° C. to obtain a uniform reaction liquid in 3 hours, followed by distilling off excess thionyl chloride under reduced pressure to obtain as a remaining oily substance, trans-4-(trans-4-ethylcyclohexyl)cyclohexanecarboxylic acid chloride. This acid chloride was added to a solution obtained by dissolving 2,4-difluorophenol (1.3 g, 0.01 mol) in pyridine (10 ml), followed by adding dry toluene (100 ml), sufficiently shaking the mixture, allowing it to stand over night, pouring the reaction liquid into water, washing with 6N hydrochloric acid, then with 2N NaOH aqueous solution, washing with water till the aqueous layer became neutral, drying the toluene layer with anhydrous sodium sulfate, drying, distilling off toluene under reduced pressure and recrystallizing the remaining oily substance from ethanol to obtain the objective trans-4-(trans-4-ethylcyclohexyl)cyclohexanecarboxylic acid-2,4-difluorophenyl ester. Yield 2.1 g (60%). It had a C-N point (phase transition point) of 76.3°-76.7° C. and a N-I point of 151.7° C. C, N and I are defined as in Table 1.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].Br[C:18]1C=CC(Br)=C[CH:19]=1.[CH2:25](C(CCCC)CBr)[CH2:26]CC>>[CH3:1][CH:2]([CH:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH:6]([CH:7]([CH2:25][CH3:26])[CH3:8])[CH2:9][CH3:10])[CH2:18][CH3:19]
Reactant: CCCCC(CBr)CCCC
Reactant: Brc1ccc(Br)cc1
Reactant: CCC(CC)CCC(CC)c1ccccc1
Product: CCC(C)C(CC)CCC(c1ccccc1)C(C)CC

Procedure:
1,4-Di-2-butylhexylbenzene (20b) was synthesized according to the same procedure as 20a with 1,4-dibromobenzene (24 g, 0.102 mol) and 2-butylhexylbromide (54.1 g, 0.245 mol). (18.3 g, 50%) 1H NMR (CDCl3): δ 0.84-0.92 (12H, m), 1.23-1.34 (24H, m), 1.54-1.65 (2H, m), 2.49 (4H, d), 7.03 (4H, S). MS (EI): calcd, 358.6. found M+, 358.2.