Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 43 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(4-(trifluoromethyl)benzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 4-(trifluoromethyl)phenylboronic acid (0.033 g; 0.173 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.0082 mmol), sodium carbonate (0.037 g; 0.346 mmol), sodium iodide (0.052 g; 0.346 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.034 g (42%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].O>CN1C(=O)CCC1>[C:21]([NH:25][C:6]1[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc(Cl)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carboxamide (10.0 g), DIPEA (11 mL) in NMP (30 mL) were stirred at 25° C. tert-Butylamine (6.6 mL) was charged to the mixture, and the mixture was stirred at 25° C. for 16 h. Water (100 mL) was added to the mixture at 25° C. The mixture was stirred for 1 h. The suspension was filtered, washed with water (50 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 24 h to give 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide as a white solid (8.7 g, 84%). 1H NMR (DMSO-d6) δ 9.41 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 1.42 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[C:24]([O:26][CH2:27][CH2:28][N:29]5[C:37](=[O:38])[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:30]5=[O:39])[CH:23]=[CH:22][N:21]4[C:40]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>CO.C(Cl)Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[C:24]([O:26][CH2:27][CH2:28][N:29]5[C:37](=[O:38])[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:30]5=[O:39])[CH:23]=[CH:22][N:21]4[C:40]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(OCCN5C(=O)c6ccccc6C5=O)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3nc4nc(OCCN5C(=O)c6ccccc6C5=O)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
[1-(4-{7-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl}-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (530 mg) was dissolved in methanol/DCM (1.3 mL/2.1 mL), treated with HCl in dioxane (4.08 mL of a 4M solution) and the mixture stirred overnight at rt. The reaction mixture was poured onto ice, made alkaline with 2N aqueous sodium hydroxide and extracted with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give the crude title product as a yellow oil. Purification was achieved by trituration at 0° C. with diisopropyl ether. The resulting precipitate was filtered and dried to give the title compound as a solid (390 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.5 %

Procedure:
To a suspension of 2,6-dichloronicotinic acid (1.92 g), N,O-dimethylhydroxylamine hydrochloride (1.46 g) and triethylamine (2.1 mL) in N,N-dimethylformamide (30 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g), and then the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium hydrogen carbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (1.61 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][C@@H:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[C:13]4[CH:26]=[CH:27][CH:28]=[CH:29][C:12]=4[C:11]=3[N:10]=2)=[CH:4][C:3]=1[CH2:30][CH2:31][OH:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([O:32][CH2:31][CH2:30][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][C@@H:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[C:13]4[CH:26]=[CH:27][CH:28]=[CH:29][C:12]=4[C:11]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[F:1])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)ccc1F
Product: CS(=O)(=O)OCCc1cc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)ccc1F

Procedure:
This was synthesized by using (R)-2-(2-fluoro-5-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol and methanesulfonyl chloride as described in general procedure 6 to afford the desired product. M.p.=99-100° C. 1H NMR 400 MHz (DMSO-d6) δ 9.58 (s, 1 H), 8.32-8.28 (m, 2 H), 7.82-7.81 (m, 1 H), 7.72-7.68 (m, 1 H), 7.51-7.42 (m, 2 H), 7.26-7.11 (m, 3 H), 7.04-7.01 (m, 2 H), 6.77 (t, 1 H), 4.64 (t, J=6.8 Hz, 1 H), 4.44-4.40 (m, 2H), 3.19-2.94 (m, 7H). LCMS m/e 508 (M+H)=508.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH:18]([CH3:20])[CH3:19])[C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH:18]([CH3:20])[CH3:19])[C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][N:8]([CH2:9][CH:10]([O:11][CH3:12])[O:13][CH3:14])[S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1cc(Br)cc(OC(C)C)c1C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CN(Cc1cc(Br)cc(OC(C)C)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
To a mixture of N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-2,2-dimethoxyethanamine (108c, 3.5 g, 10 mmol) and Na2CO3 (1.6 g, 15 mmol) in THF (40 mL) and H2O (20 mL) was added TsCl (2.0 g, 11 mmol). The reaction mixture was stirred at room temperature for 5 hours, then extracted with EtOAc (4×40 mL). The combined organic layers were washed with H2O (2×30 mL) and brine (2×100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to give N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (108d, 4.7 g, 93%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][N:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)cnc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
To a solution of 1J (120 mg, 0.36 mmol) in CH3CN (4 mL) at RT was added DIPEA (94 μL, 0.54 mmol), followed by benzenesulfonyl chloride (51 μL, 0.4 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (100 mg, 71%). LC/MS (method A): retention time=3.96 min, (M+H)+=470. 1H NMR (CD3SOCD3, 400 MHz): δ8.60 (d, J=2.3 Hz, 1H), 8.35 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.94 (dd, J1=7.1 Hz, J2=1.5 Hz, 2H), 7.70 (dd, J1=8.5 Hz, J2=1.3 Hz, 2H), 7.66-7.69 (m, 1H), 7.61-7.64 (m, 2H), 7.54 (t, J =7.5 Hz, 2H), 7.34-7.46 (m, 1H), 7.25 -7.34 (m, 5H), 5.16 (dd, J1=47.0 Hz, J2=15.2 Hz, 2H), 4.44-4.50 (m, 1H), 3.20 (dd, J1=15.9 Hz, J2=6.0 Hz), 3.06-3.13 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH:40]=O)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1.C([O-])=O.[Na+].C([BH3-])#N.[Na+]>CO>[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH2:40][NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]4[N:5]([CH2:4][C:3]5[C:2]([F:1])=[CH:28][C:27]([F:29])=[CH:26][C:25]=5[F:30])[N:6]=[C:7]5[C:12]=4[CH:11]=[CH:10][CH:9]=[C:8]5[C:21]([F:22])([F:23])[F:24])[CH:15]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: Nc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Agent: O=C[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(NCc3ccc4[nH]ccc4c3)c2)c(F)c1
Yield: 23.5 %

Procedure:
A solution of ({3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}amine (0.1 g, 0.24 mmol), indole 5-carboxaldehyde (0.035 g, 0.24 mmol), sodium formate (0.189 g, 3 mmol) and sodium cyanoborohydride (0.188 g, 3 mmol) in methanol (3 mL) was heated at 60° C. overnight. The reaction mixture was cooled, and concentrated in vacuo. The residue was partitioned with ethyl acetate and ammonium hydroxide. The organic phase was concentrated in vacuo to afford crude product, which was purified by flash chromatography (silic gel 60, methylene chloride) to afford the title compound (0.031 g, 24%).
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.C[O:20][C:21](=[O:36])[CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([SH:34])=[CH:26][C:25]=1[CH3:35]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:30]([C:28]1[C:27]([S:34][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:26][C:25]([CH3:35])=[C:24]([CH:29]=1)[O:23][CH2:22][C:21]([OH:36])=[O:20])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)COc1cc(C(C)(C)C)c(S)cc1C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCC(=O)O)cc2C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
1.86 g (7.9 mmol, 2 equivalents) tosyl bromide and 1.05 mL (7.9 mmol) NEt3 were combined in 200 mL CCl4 and the mixture chilled in an ice bath under nitrogen. To this mixture was added a solution of 1.06 g (3.95 mmol) of (5-tert-butyl-4-mercapto-2-methyl-phenoxy)acetic acid methyl ester (prepared in Example MMMM) in 125 mL of CCl4 over 3 hours, and the reaction was allowed to come to ambient temperature overnight. The mixture was then diluted with CH2Cl2, washed with aqueous ammonium chloride and aqueous sodium chloride, and dried (Na2SO4). Concentration gave a residue which was chromatographed on silica gel eluting with 3:1 hexanes:EtOAc to yield the title compound. 1H NMR (CDCl3) δ 1.25 (s, 9 H), 2.14 (s, 3 H), 2.43 (s, 3 H), 3.82 (s, 3 H), 4.68 (s, 2 H), 6.75 (s, 1 H), 7.14 (s, 1 H), 7.25 (d, 2 H), 7.50 (d, 2 H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1.[CH2:18](Cl)Cl.C=O.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: Cc1nc2c(N3CCNCC3)ncc(Br)n2n1
Reactant: ClCCl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(N3CCN(C)CC3)ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2-methyl-8-(piperazin-1-yl)-[1,2,4]-triazolo[1,5-a]pyrazine (0.5 g, 1.7 mmol), CH2Cl2 (20 mL), MeOH (10 mL), 40% aqueous formaldehyde (2 mL) and NaBH3(CN) (0.5 g, 8.0 mmol). The resulting solution was stirred at room temperature for 0.5 h. Work-up: the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2, to afford 0.4 g (76%) of the product as a yellow solid. MS m/z: 311 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[P:8]([O-:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[F:16][C:17]([F:34])([F:33])[C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([OH:28])[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=1>C(Cl)(Cl)(Cl)Cl>[CH2:10]([O:9][P:8]([O:12][CH2:13][CH3:14])([O:28][C:22]1[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=[C:18]([C:17]([F:33])([F:16])[F:34])[C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:15])[CH3:11]
Reactant: CCOP([O-])OCC
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)Oc1cc(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Triethylamine (25.2 ml, 0.18 mol) was added dropwise to a cooled (0° C.) solution of diethyl phosphite (23.2 ml, 0.18 mol) and product of Example 4 (50.0 g, 0.17 mol) in carbon tetrachloride (100 ml). The reaction mixture, which had developed a heavy flocculent precipitate, was stirred at 0° C. for 30 minutes before being warmed to room temperature for an additional 24 hours. The reaction mixture was washed consecutively with 1N aq hydrochloric acid (1×250 ml), 0.5N aqueous sodium hydroxide (4×100 ml) and water (1×250 ml) before being dried (MgSO4), filtered and evaporated (aspirator) to a yellow oil (61.53 g). Kugelrohr distillation (120° C. at 25 Pa) afforded the product as a very pale yellow oil (59.03 g). Yield-82%, nD25 1.4197.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][C:10]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 32.3 %

Procedure:
Using pyrrolidin-2-one (119 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (664 mg) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 1, the title compound (206 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=O.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]1[O:47][NH2:48]>C(Cl)Cl.O>[CH3:1][C:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[C:3]([NH:48][O:47][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][O:41]1)=[O:5]
Reactant: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoic acid (286 mg, 0.887 mmol) in methylene chloride (8.87 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.2 mmol), 1-hydroxy benzotriazole monohydrate (240 mg, 1.6 mmol), triethyl amine (220 uL, 1.6 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (150 mg, 1.3 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated in vacuo to afford 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 302.9 mg. LCMS: (M−1) 420.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@@H:14]1[CH2:18][C@@H:17]([C:19](=[O:35])[NH:20][C@:21]3([C:26](=[O:34])[NH:27][S:28]([CH:31]4[CH2:33][CH2:32]4)(=[O:30])=[O:29])[CH2:23][C@H:22]3[CH2:24][CH3:25])[N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])[CH2:6]2.[ClH:43].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:43].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@@H:14]1[CH2:18][C@@H:17]([C:19](=[O:35])[NH:20][C@:21]3([C:26](=[O:34])[NH:27][S:28]([CH:31]4[CH2:32][CH2:33]4)(=[O:30])=[O:29])[CH2:23][C@H:22]3[CH2:24][CH3:25])[NH:16][CH2:15]1)=[O:12])[CH2:6]2
Reactant: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3R,5S)-1-(tert-butoxycarbonyl)-5-((1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate (1.35 g, 2.16 mmol) in DCM (5 mL) was added 4 N HCl in dioxane (4.32 ml, 17.3 mmol). The reaction mixture was stirred at rt for 2 hours. The solvent was removed and the residue was suspended in ethyl ether (30 mL) and stirred for 30 min. The solid was collected by filtration to give (3R,5S)-5-((1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate dihydrochloride (1.10 g, 91%) as white solid. LCMS (APCI+): 525.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CN1CCCC1=O.C(OCC)(=O)C.P([O-])([O-])([O-])=O>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: Cc1cc2ccsc2c(Cl)n1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(C)cc3ccsc23)c(OC)c1
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-5-methyl-thieno[2,3-c]-pyridine (100 mg, 0.544 mmol) and 2,4-dimethoxybenzylamine (0.245 mL, 1.63 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was heated to 180° C. in an oil bath for 19 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and aqueous phosphate buffer (1.0 M, pH 7, 20 mL). The separated organics were sequentially washed with water (10 mL), aqueous phosphate buffer (1.0 M, pH 7, 10 mL), water (10 mL), and brine (10 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (5-25% ethyl acetate/hexanes, linear gradient) to give N-(2,4-dimethoxybenzyl)-5-methylthieno[2,3-c]pyridin-7-amine. MS ESI calc'd. for C17H19N2O2S [M+H]+ 315. found 315.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[CH2:5]([N:12]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:13]([N:12]([CH2:20][CH2:21][CH2:22][C:23]([NH2:24])=[O:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCCCN(Cc1ccccc1)Cc1ccccc1
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Hydrogen peroxide (30% w/v; 5.6 ml), tetra-n-butylammonium hydrogensulphate (1.70 g) and 5N aqueous sodium hydroxide (4 ml) were added to a stirred solution of 4-(N,N-dibenzylamino)butyronitrile (2.64 g) in dichloromethane (10 ml) with water cooling. The mixture was stirred vigorously at room temperature for 17 hours and dichloromethane (100 ml) was added. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (10 ml), dried (Na2SO4) and concentrated in vacuo to give a viscous oil (4.12 g). The product was chromatographed on silica with eluant 20% ethyl acetate/toluene→ethyl acetate and recrystallised from cyclohexane to give the title compound (1.86 g, 66%), m.p. 76°-77° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:14]1([NH2:21])[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1>CN(C)C=O>[CH3:12][CH:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH:17]3[CH2:18][CH2:19][CH:14]([NH2:21])[CH2:15][CH2:16]3)[C:3]=2[CH:10]=1)[CH3:13]
Reactant: NC1CCC(N)CC1
Reactant: CC(C)c1cc2c(Cl)ncnc2s1
Solvent: CN(C)C=O
Product: CC(C)c1cc2c(NC3CCC(N)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100-mL round-bottom flask was added a solution of commercially available 4-chloro-6-(propan-2-yl)thieno[2,3-d]pyrimidine (3 g, 14.10 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), TEA (4.3 g, 42.49 mmol, 3.01 equiv), and cyclohexane-1,4-diamine (9.6 g, 84.07 mmol, 5.96 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.5 g (85%) of 1-N-[6-(propan-2-yl)thieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine as a yellow oil.