Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)(=O)[CH2:2][CH3:3].C(OCC)(=O)C>C1COCC1>[CH2:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Yield: 53.2 %

Procedure:
Following the same procedure as described in Example 47.2, N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (170 mg, 0.39 mmol) in THF (20 ml) was then treated with 1M BH3. THF (3.9 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (86 mg, 52%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14].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>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: CON(C)C(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CON(C)C(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 80 °C
Yield: 32.5 %

Procedure:
Palladium(II) acetate (0.066 g, 0.29 mmol) was added to 2,5-dichloro-4-iodopyridine (2 g, 7.30 mmol), 2-amino-N-methoxy-N-methylbenzamide (1.316 g, 7.30 mmol), cesium carbonate (4.76 g, 14.60 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.254 g, 0.44 mmol) in dioxane (100 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours and then allowed to cool to room temperature. The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxy-N-methylbenzamide (0.775 g, 33% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.18 (3H, s), 3.48 (3H, s), 6.61 (1H, d), 7.34-7.40 (1H, m), 7.45-7.47 (1H, m), 7.54-7.57 (2H, m), 8.19 (1H, s), 8.47 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=326.0 and 328.0 and 330.0.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-]>CO>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:24][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [BH4-]
Solvent: CO
Product: Clc1ccc(CN2CCC(CNCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 49 %

Procedure:
Reductive amination of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) with 2,2-diphenylacetaldehyde (0.66 equiv.) and polymer-supported borohydride in methanol at 25° C. for 16 h, followed by general workup and column chromatography (SiO2) afforded 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (70 mg, 49%): The purity was determined by RPLC (98%).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.S(=O)(=O)(O)O.O.C(=O)(O)[O-].[Na+].[CH2:25](O)[CH3:26]>C(OCC)(=O)C>[C:1]([O:13][CH2:25][CH3:26])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: CCO
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(O)c(O)c1

Procedure:
Ethyl caffeate was prepared as follows. Caffeic acid (1 g) was boiled under reflux in absolute ethanol (30 ml) in the presence of concentrated sulphuric acid (0.5 ml) for two hours. The reaction mixture was then poured into water (100 ml), and then ethyl acetate (100 ml) and 0.1M sodium bicarbonate solution (100 ml) were added. The organic phase was washed successively with 0.1M sodium bicarbonate solution (3×100 ml) and water (2×100 ml) before being dried (sodium sulphate, anhydrous), filtered and evaporated under vacuum to yield a tan coloured crystalline solid. The product was recrystallised from water giving ethyl caffeate as a tan coloured powder in 43% yield. mp 142-143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH3:20])[N:16]=[C:15]([NH2:17])[C:11]2([CH2:14][CH2:13][CH2:12]2)[S:10](=[O:19])(=[O:18])[CH2:9]1.S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@@:8]1([CH3:20])[N:16]=[C:15]([NH2:17])[C:11]2([CH2:12][CH2:13][CH2:14]2)[S:10](=[O:19])(=[O:18])[CH2:9]1
Reactant: C[C@@]1(c2ccccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
(R)-7-(2-Fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (385 mg, 1.3 mmol, Eq: 1.00) was dissolved in conc. sulfuric acid (6.37 g, 3.46 ml, 65.0 mmol, Eq: 50). At 0° C., fuming nitric acid (123 mg, 87.1 μl, 1.95 mmol, Eq: 1.5) was added dropwise. The light brown solution was stirred at 0° C. for 2 hours. The reaction mixture was poured on ice and basified with 3 N NaOH followed by extraction with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness to give the crude and pure (R)-7-(2-fluoro-5-nitro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (470 mg, 1.38 mmol, 106% yield) as a light brown foam. MS (ISP): m/z=342.1 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:32])(=O)=O.[NH2:33][C@@H:34]([CH3:44])[C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[OH:36].C(NC(C)C)(C)C.O>CN(C)C=O.C(OCC)(=O)C>[OH:36][C@H:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[C@@H:34]([NH:33][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:32])=[CH:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:13][C:14]=1[CH3:15])[CH3:44]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCOS(C)(=O)=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of benzyl 4′-(2-methanesulfonyloxyethoxy)-3′, 5′-dimethylbiphenyl-4-carboxylate (0.20 g), 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.074 g) and diisopropylamine (0.074 mL) in N,N-dimethylformamide (2 mL) was stirred at 80° C. overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=15/1-10/1) to afford benzyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}-3′,5′-dimethylbiphenyl-4-carboxylate (0.108 g).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].P(=O)(O)(O)O.Cl(O)(=O)(=O)=O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.08 h

Procedure:
The concentration of glucose isomerase produced in the culture broth was measured by the following method. 10 ml of the culture broth was centrifuged for 5 minutes at 10,000 G. The precipitated cells were charged into a test tube with an outside diameter of 15 mm containing 2.0 ml of a glucose isomerase reaction solution containing a 1/15 M phosphoric acid buffer (pH 7.0) and per liter of the phosphoric acid buffer, 400 g of glucose and 0.5 millimole of CoCl2.6H2O, and reacted at 70° C for 1 hour. Then, 2.0 ml of 5% perchloric acid was added to terminate the reaction. Fructose formed in the reaction mixture was determined by the carbazole-cysteine-sulfuric acid reaction method, and the concentration of glucose isomerase was calculated.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Nc1ccc(Sc2nc3cc(Cl)ccc3s2)cc1
Yield: 22.3 %

Procedure:
2,5-Dichlorobenzothiazole (0.049 moles, 10.0 g), 4-aminothiophenol (0.049 moles, 6.1 g) and DMAP (0.049 moles, 6.0 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 25% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-5-chlorobenzothiazole 3.2 g, 22%. Mass spec (FD) 292. Calculated for C13H9ClN2S2 : C, 53.33; H, 3.10; N, 9.57. Found: C, 53.03; H, 3.30; N, 9.70.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:14][CH:13]1[C:30]([OH:32])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]([C:41]1([NH2:47])[CH2:43][CH:42]1[CH2:44][C:45]#[N:46])=[O:40]>>[CH3:37][O:38][C:39]([C:41]1([NH:47][C:30]([CH:13]2[CH2:14][CH:15]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:16][N:12]2[C:10](=[O:11])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:32])[CH2:43][CH:42]1[CH2:44][C:45]#[N:46])=[O:40]
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C3)nccc2c1
Reactant: COC(=O)C1(N)CC1CC#N
Product: COC(=O)C1(NC(=O)C2CC(Oc3nccc4cc(OC)ccc34)CN2C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)CC1CC#N

Procedure:
1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-cyanomethyl-cyclopropanecarboxylic acid methyl ester was prepared according to the method presented in the synthesis of compound 31. Treatment of 1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carboxylic acid (387 mg, 0.69 mmol) and 1-amino-2-cyanomethyl-cyclopropanecarboxylic acid methyl ester occurred under the same conditions, adjusted for scale, to afford the desired methyl ester (349 mg, 74%). LCMS found 638.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]1.[H-].[Na+].[CH:19]1([N:22]2[C:26](S(C)(=O)=O)=[N:25][N:24]=[C:23]2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:21][CH2:20]1>>[CH:19]1([N:22]2[C:26]([O:16][CH:14]([C:11]3[N:12]=[N:13][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])[N:10]=3)[CH3:15])=[N:25][N:24]=[C:23]2[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Reactant: Cc1ccc(F)c(-n2nnc(C(C)O)n2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from 1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].C1C2[C:38](=CC=CC=2)[CH:37]=[C:36](N)N=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[N:17]=[CH:18][C:19]3[C:23]([CH:24]=1)=[CH:38][CH:37]=[CH:36][CH:20]=3)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: Nc1cc2ccccc2cn1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1cc2ccccc2cn1

Procedure:
The product from Example 11, Part D (200 mg, 0.6 mmol) and isoquinolin-3-amine (131 mg, 0.91 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (95 mg, 35%). 1HNMR (300 MHz, CDCl3) δ 8.28 (d, J=9 Hz, 1H), 8.15 (d, J=9 Hz, 1H), 7.91 (s, 1H), 7.75 (m, 2H), 7.70 (d, J=8 Hz, 1H), 7.64 (m, 1H), 7.45 (m, 2H), 7.32 (m, 2H), 7.20 (t, J=9 Hz, 1H), 7.02 (m, 2H), 5.29 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.26 (d, J=15 Hz, 1H), 2.55 (m, 2H), 2.00 (m, 2H). MS: m/z (MH+) 458.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:14]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl.C(Cl)(Cl)Cl.O>[C:2]1([NH:1][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:37][CH:36]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a mixture of 7.02 g of aniline and 4.48 g of pyridine in 200 ml of methylene chloride is added 20 g of product from Example 3. The reaction is stirred at room temperature for 2 hours; diluted with chloroform and water and heated to dissolve the solids. The layers are separated and the organic layer is washed with hot dilute hydrochloric acid. The organic layer is dried, concentrated in vacuo and the residue is recrystallized from chloroform/hexane to give 23.1 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:24])([F:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH2:18][C:17]([F:24])([F:23])[F:16])(=[O:21])=[O:20])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC(F)(F)F)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 2,2,2-trifluoro-ethanesulfonyl chloride (55 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2,2,2-trifluoroethanesulfonamide (0.014 g).
Reaction SMILES: [NH2:1][C@@:2]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:7][O:6][C@@H:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[CH2:4][C@H:3]1[CH2:13][OH:14].FC1C=C(F)C=CC=1[C@@]1(N[C:44]([NH:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[S:45])[C@H](CO)C[C@H]([C@@H]2C[C@H]2C)OC1>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C@@:2]1([NH:1][C:44]([NH:46][C:47](=[O:54])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[S:45])[C@H:3]([CH2:13][OH:14])[CH2:4][C@H:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[O:6][CH2:7]1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H]([C@@H]2CCCO2)C[C@H]1CO
Reactant: C[C@@H]1C[C@H]1[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2ccc(F)cc2F)CO1
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H]([C@@H]2CCCO2)C[C@H]1CO)c1ccccc1

Procedure:
{(2R,4R,5S)-5-Amino-5-(2,4-difluorophenyl)-2-[(2S)-tetrahydrofuran-2-yl]tetrahydro-2H-pyran-4-yl}methanol (C101) was converted to the product using the method described for the synthesis of N-({(3S,4R,6R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-6-[(1R,2R)-2-methylcyclopropyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C90) in Example 20. Yield: 1.3 g, 2.7 mmol, 70% over 2 steps from (C100). LCMS m/z 477.2 [M+H+].
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:29])[N:17]([CH3:28])[C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[N:15]=1)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:28][N:17]([C@H:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[C:16]([C:14]1[N:15]=[C:11]([CH2:10][CH2:9][CH2:8][NH:7][CH3:6])[S:12][CH:13]=1)=[O:29]
Reactant: CN(CCCc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCCc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of methyl-{3-[4-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-carbamoyl)-thiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (0.133 g, 0.3 mmol) was added a solution of 1M HCl in dioxane (0.65 mL) at RT. After stirring overnight at RT, the solvent was evaporated under reduce pressure. The resulting solid was triturated with diethylether, and filtered to give 2-(3-methylamino-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide hydrochloride salt (0.097 g, 94%). 1H-NMR (400 MHz, CDCl3): δ=9.82-9.58 (br, 2H), 7.79 (s, 1H (conformers)), 7.12-7.03 (m, 4H), 5.43-5.54 (m, 1H (conformers)), 3.45-3.22 (m, 2H), 3.21-3.02 (m, 2H), 2.98-2.64 (m, 5H), 2.61-2.24 (m, 5H), 2.22-1.66 (m, 4H). MS: m/z=330 (M+1). MS: m/z=344 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]2[N:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=[C:21]2[CH:20]1[CH2:32]OS(C)(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]2[N:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=[C:21]2[CH:20]1[CH2:32][N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1Cn1cnnc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
To a solution of 47 mg (0.683 mmol) of [1,2,4]triazole in 1.0 mL of DMF was added 189 mg (1.365 mmol) of potassium carbonate. The mixture was heated at 50° C. for 15 min. To this was added 182 mg (0.455 mmol) of 7-N-(tert-butoxycarbonyl)-8-(methanesulfonyloxymethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine. The mixture was stirred at 50° C. for 14 h. DMF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with three portions of ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated to give 107 mg of an orange oil. The mixture was eluted on a preparative TLC plate (silica gel, 50% ethyl acetate/hexane). The plate was scraped and the product eluted from the silica gel with 80:15:1 chloroform/methanol/ammonium hydroxide to give the title compound.
Reaction SMILES: [H-].[Na+].I.[N:4]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][CH2:8][C:7]=2[S:6][C:5]=1[NH2:18].Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>O1CCCC1>[N:4]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][CH2:8][C:7]=2[S:6][C:5]=1[NH:18][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2c(s1)CCCc1ccccc1-2
Agent: Cl
Agent: I
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(s1)CCCc1ccccc1-2)c1ccncc1
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
Added sodium hydride (17 mg; 0.7 mmol) to a stirred suspension of 5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-ylamine hydroiodide 17 (80 mg; 0.23 mmol) in dry tetrahydrofuran under nitrogen at room temperature. After 15 minutes, isonicotinoyl chloride hydrochloride (62 mg; 0.35 mmol) was added and the mixture allowed to stir for 1 hr. at room temperature and then concentrated in vacuo. The residue was triturated with water the solid material was filtered off. Purification using reverse phase HPLC (eluent: acetonitrile/water/0.1% trifluoroacetic acid) provided 20 mg of N-(5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-isonicotinamide 18 as the trifluoroacetate salt. EI-HRMS m/e calcd for C18H15N3OS (M+) 321.0936, found 321.0935.
Reaction SMILES: Br.C(O[C:7]([NH:9][NH:10][CH:11]1[CH2:21][CH2:20][C:14]2([NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)=O)(C)(C)C.[Br:22][CH:23](C=O)[CH:24]=O.[OH-].[Na+]>O.CC(O)=O>[Br:22][C:23]1[CH:7]=[N:9][N:10]([CH:11]2[CH2:12][CH2:13][C:14]3([NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)[CH2:20][CH2:21]2)[CH:24]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)NNC1CCC2(CCC(=O)N2)CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC2(CCC(n3cc(Br)cn3)CC2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrobromic acid (1.04 mL of a 48 wt % solution in water; 9.18 mmol; 2.0 eq.) was added to a solution of N′-(2-Oxo-1-aza-spiro[4.5]dec-8-yl)-hydrazinecarboxylic acid tert-butyl ester (1.30 g; 4.59 mmol; 1.0 eq.) and 2-Bromo-malonaldehyde (865 mg; 5.51 mmol; 1.2 eq.) in AcOH (13 mL). The reaction mixture was stirred at RT for 2 hour. It was then basified to pH 5 by addition of a 5N NaOH solution and extracted with DCM (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as the pure cis-isomer (1.0 g, 94%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH3:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH3:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccccc1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.