Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[C:17]1([C:23]2([CH2:26][NH2:27])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CCC>O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:27][CH2:26][C:23]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[NH:11]
Reactant: NCC1(c2ccccc2)CC1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: N=C(NCC1(c2ccccc2)CC1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide and 4.37 of 1-phenylcyclopropanemethylamine in 100 ml. of n-butanol and 25 ml. of water is heated at reflux for 24 hours. The solution is cooled, diluted with water to a final volume of 2 liters and is allowed to stand. Filtration gives a tan solid which is dissolved in ethyl acetate and purified by silica gel column chromatography. Crystallization of the product from diethyl ether gives the desired final product as colorless crystals, m.p. 136.5°-138.5° C.
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]4[C@@H:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][N:18]([C@H:27]([CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)[C:28]([O:30]CC5C=CC(OC)=CC=5)=[O:29])[CH2:17]4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[F:1][C:2]1[CH:47]=[CH:46][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]4[C@@H:20]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:19][N:18]([C@H:27]([CH:40]5[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]5)[C:28]([OH:30])=[O:29])[CH2:17]4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5cc(F)ccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3cnc4cc(F)ccc43)CC2)[C@@H](c2ccccc2)C1
Yield: 90.1 %

Procedure:
The title compound was prepared from 41 mg of α-(R)-(3-(S)-((4-(5-fluoro-benzoimidazol-1-yl)-piperidin-1-ylmethyl))-4-(S)-phenyl-pyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (from Step D) and 4 mL of TFA, 0.3 mL of anisole, using a procedure analogous to that described in Example 95, Step E to provide 30 mg of the title compound as a solid. ESI-MS 519 (M+H); TPLC A: 1.65 min.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:27])([F:26])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:8].CO>C(Cl)Cl>[F:27][C:6]([F:5])([F:26])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1cccs1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCc2cc(O)ccc2C1c1cccs1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.66 ml, 0.66 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-(6-methoxy-1-thiophen-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (0.150 g, 0.439 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The resulting red solution was stirred at 0° C. for 30 min, then warmed to rt and stirred at rt for 20 hr. MeOH (5 ml) was slowly added to the reaction mixture with stirring and the resulting solution was concentrated in vacuo to give 0.138 g of a black residue. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.006 g (4% yield) of white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:27][CH2:26][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
2,6-Dichloropurine (20.00 g, 106 mmol) is dissolved in THF (250 ml) under an atmosphere of argon. Diisopropylamine (16.38 g, 127 mmol) is added followed by 2,2-diphenylethylamine (25.00 g, 127 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 6 hours. 50% of the solvent is removed in vacuo and replaced with MeOH. The resulting precipitate is filtered off and dried to give the title compound. 1H nmr (d6-DMSO, 400 MHz); 8.05(br s, 1H), 7.35-7.10(m, 10H), 4.55(m, 1H), 4.10(rri, 2H), MS (ES+) m/e 350 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:31]=[C:32]([S:38](Cl)(=[O:40])=[O:39])[C:33]([F:37])=[CH:34][C:35]=1[F:36]>O1CCCC1>[Cl:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([S:38]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][N:12]=2)(=[O:40])=[O:39])[CH:31]=1
Reactant: COc1ccc(CNc2ncccn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
A solution of (2,4-dimethoxybenzyl)-pyrimidin-2-yl-amine (Preparation 12, 736 mg, 3 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C. before the addition of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.30 mL, 3.30 mmol). The reaction was allowed to warm to 0° C. for 30 minutes before cooling again to −78° C. The resulting solution was added to a solution of 3-chloro-4,6-difluorobenzenesulfonyl chloride (890 mg, 3.6 mmol) in tetrahydrofuran (10 mL) at −78° C. After 30 minutes at this temperature the reaction was warmed to room temperature and stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (50-100% dichloromethane in heptane gradient elution) to afford the title compound as a white solid (260 mg, 19%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH:24]#[C:25][CH3:26]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24]#[C:25][CH3:26])=[CH:14][N:13]=2)[CH2:8]1
Reactant: C#CC
Reactant: Clc1ccc(CNC2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Reaction time: 8 h

Procedure:
Dissolve (2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (130 mg, 0.27 mmol) in dichloromethane (10 mL) and triethylamine (10 mL). Add trans-dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.014 mmol) and copper(I) iodide (3 mg, 0.016 mmol). Bubble propyne into the mixture for 1 min. Stir the mixture overnight, filter it through a pad of Celite®, concentrate and chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound as a residue. Dissolve the residue in methanol, add 1 N HCl in methanol (1 mL). Concentrate and dry in vacuum oven at 60° C. to give the title compound as its hydrochloride salt as a light yellow solid (95 mg, 89%). δ 1H NMR (400 MHz, MeOH-d4) δ 8.03 (d, 1H, J=1.6 Hz), 7.84 (d, 1H, J=8.8 Hz), 7.69-7.68 (m, 2H), 7.49 (dd, 1H, J=8.0, 2.2 Hz), 6.95 (d, 1H, J=9.6 Hz), 4.53-4.45 (m, 2H), 4.28-4.23 (m, 1H), 4.10-4.06 (m, 1H), 3.90-3.83 (m, 2H), 3.72-3.66 (m, 1H), 2.73-2.65 (m, 1H), 2.50-2.41 (m, 1H), 2.03 (s, 3H), MS (ES): m/z=360 [M+H].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(Cl)ccc1C#N
Temperature: 90 °C

Procedure:
To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90° C. over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([O:17][CH3:18])[C:11]([N:13](OC)[CH3:14])=[O:12].[Cl:26][C:27]1[S:37][C:30]2[NH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:29]=2[CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CN([CH:51]=[O:52])C>C(OCC)(=O)C>[CH2:19]([CH:9]([NH:8][C:34]([C:32]1[NH:31][C:30]2[S:37][C:27]([Cl:26])=[CH:28][C:29]=2[CH:33]=1)=[O:35])[CH:10]([O:17][CH3:18])[C:11](=[O:12])[NH:13][CH2:14][O:52][CH3:51])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Reactant: COC(C(=O)N(C)OC)C(N)Cc1ccccc1
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCNC(=O)C(OC)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)sc2[nH]1
Reaction time: 0.08 h

Procedure:
Triethylamine was added dropwise to a solution of 3-amino-2,N-dimethoxy-N-methyl-4-phenyl-butyramide (PCT International Application Publication No. WO 96/39385) (1.65 g, 5.71 mmol) in DMF (15 mL) and cooled in an ice bath. A solution of 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (U.S. Pat. No. 6,399,601) (1.1 g, 5.71 mmol) in 15 mL of DMF was added dropwise followed by the addition of HOBT (1.16 g, 11.4 mmol) neat. The reaction mixture was stirred for 5 min and N-ethyliminomethylene-N,N′-dimethyl-propane-1,3-diamine (1.10 g, 5.71 mmol) was added neat. The resulting mixture was stirred at room temperature for 18 hrs. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated ammonium chloride, water, and brine. The ethyl acetate was dried and evaporated in vacuo to yield 2.54 g of crude product. Chromatography over silica gel, eluting with ethyl acetate/hexanes (1:2), afforded 1.43 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[F:22][C:2]1([F:1])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC(F)(F)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cc3n(c2c1)CC(F)(F)CNC3=O
Temperature: 60 °C
Yield: 83.3 %

Procedure:
Ethyl 4,4-difluoro-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (470 mg, 1.5 mmol) is suspended in ethanol (17 mL) and 1M NaOH solution (4.8 mL, 4.8 mmol) is added. The reaction mixture is heated at 60° C. for 1 h 50 min. Acetic acid (15 mL) and water (100 mL) are added and the resulting white solid is filtered and rinsed with water to afford the title compound (350 mg, 82%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[C:24]1[S:28][C:27]([CH3:29])=[N:26][CH:25]=1>CCCCCCC.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[S:28][C:27]([CH3:29])=[N:26][CH:25]=3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1-c1cnc(C)s1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnc(C)s1
Yield: 69.5 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (130 mg, 0.59 mmol) and 3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamine (131 mg, 0.59 mmol) using in analogous manner the procedure described in example 206c). Column chroma-tography (20 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound as an off-white solid (165 mg, 69%). MS ISP (m/e): 403.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.90 (s, 1H), 7.82 (s, 1H), 7.45 (d, 1H), 7.29 (m, 5H), 7.14 (s, 1H), 6.98 (dd, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.87 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H). Mp 138-141° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([C:21]3([OH:32])[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:44].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:33]1[N:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][N:34]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([C:21]3([O:32][CH3:44])[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]3)=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CCC(O)(c2ncc(-c3cc(C)cc(N(C(=O)OC(C)(C)C)c4nccc(C(F)(F)F)n4)c3)s2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(OC)(c2ncc(-c3cc(C)cc(N(C(=O)OC(C)(C)C)c4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 0 °C

Procedure:
To a solution of ethyl 4-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate (0.148 g, 0.24 mmol) and DMF (1.2 mL) was added iodomethane (0.042 g, 0.29 mmol). The solution was cooled to 0° C. and then 60% sodium hydride in mineral oil (0.011 g, 0.27 mmol) was added and the reaction was allowed to warm up overnight. The next morning, iodomethane (1.14 g, 8.03 mmol) was added and the mixture was cooled to 0° C. Sodium hydride in mineral oil (60%, 0.011 g, 0.27 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was complete after warming. The solution was cooled to 0° C. and carefully quenched with methanol and then water. The mixture was extracted with dichloromethane. The organic layer was washed three times with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography was used to yield ethyl 4-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-4-methoxycyclohexanecarboxylate. MS ESI: [M+H]+ m/z 621.2.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([F:24])([CH2:9][CH2:10][C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:4]([O:6]CC)=[O:5].[OH-].[Na+:28].O.CO>C(OCC)(=O)C>[F:1][C:2]([F:25])([F:26])[C:3]([F:24])([CH2:9][CH2:10][C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[C:4]([O-:6])=[O:5].[Na+:28]
Reactant: CCOC(=O)C(F)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C([O-])C(F)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-trifluoromethyl-2,5,5,6,6,7,7,8,8,8-decafluoro-octanoate (14.8 g, 0.035 mol), sodium hydroxide (1.64 g, 0.041 mol), water (25 mL) and methanol (25 mL) was stirred at ambient temperature for 2 hr and at 60° C. for 2 hr. After cooling, ethyl acetate was added to extract the product. The organic layer was separated, washed with brine, and dried over magnesium sulfate, and then the solvent was removed in vacuo. After drying overnight under high vacuum, the sodium 2-trifluoromethyl-2,5,5,6,6,7,7,8,8,8-decafluorooctanoate salt product, formula above, was obtained as a white to light brown low melting point solid in almost quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]([CH:15]=C)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]([CH:15]=[O:30])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2F)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.40 g) in a mixed solvent of acetone (5.00 mL)-acetonitrile (5.00 mL)-water (5.00 mL) were added osmium oxide (fixed catalyst I) (0.14 g) and sodium periodate (1.17 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.40 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[C:11]([N+:20]([O-])=O)[C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:23])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.CN(C=O)C.[Pd]>[CH:1]1([N:6]2[C:15]3[C:10](=[C:11]([NH2:20])[C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:23])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)c(N)c2c1=O
Yield: 91 %

Procedure:
A solution of 16 (6.0 g, 15 mmol) in EtOH-DMF (4:1, v/v, 250 mL) was hydrogenated under atmospheric pressure over 10% Pd/C (600 mg) at room temperature overnight. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo to dryness to yield 17 (5.0 g, 90%) which was used crude in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nccc(-c3c[nH]nc3-c3ccc(F)cc3)n2)cc1
Yield: 80 %

Procedure:
This compound was synthesized by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine, was obtained as a off-white solid in 80% yield, mp: 183-185° C.; Anal. Calc'd for C21H18FN5O: C, 67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=1)(=[O:5])=[O:4].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[CH3:1][NH:2][S:3]([C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]3[CH:16]=[CH:15][C:14]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:13][C:12]=3[C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: CNS(=O)(=O)c1ccc2sc3ccccc3c2c1
Product: CNS(=O)(=O)c1ccc2sc3ccc(S(=O)(=O)Cl)cc3c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
N-Methyldibenzo[b,d]thiophene-2-sulfonamide (1.56 g) was added to chlorosulfonic acid (3.27 g) and the mixture was stirred at RT for 5 h. The mixture was then treated with ice cold water, the precipitate was filtered off, washed with cold water and dried to give the title compound (1.6 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH3:13]>C1C=CC=CC=1>[NH2:13][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: N
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: c1ccccc1
Product: CSc1nc(N)c(C=O)c(Cl)n1
Yield: 80 %

Procedure:
To the solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2 g, 7.36 mmol) in benzene (20 mL) was introduced NH3 gas for 30 minutes (hereinafter “min”). The formed solid was then filtered and recrystallized from EtOAc (15 mL) to give 1.18 g (80%) of pure 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.50 (s, 3H), 7.28 (t, 3H, J=45 Hz, D2O exchangeable), 8.65 (d, 3H, J=41 Hz, D2O exchangeable), 10.11 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:1]([C:5]1[C:14]([O:15][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3C(C)(C)C)c2cc1OC
Temperature: 140 °C
Reaction time: 5.5 h
Yield: 9.1 %

Procedure:
2-Tert-butyl-[1,8]naphthyridin-3-ol (40 mg), 4-chloro-6,7-dimethoxyquinoline (132 mg), and 4-dimethylaminopyridine (72 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 5.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (7 mg, yield 9%).