Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(OCC)([O:3][CH2:4][CH3:5])[CH3:2].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>C(O)(=O)C.C(O)C>[CH2:1]([O:3][C:4](=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH3:5])[CH3:2]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC#N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(C)=C(C#N)C#N
Reaction time: 0.67 h
Yield: 91.4 %

Procedure:
Triethyl orthoacetate (97 g, 0.6 mol), malononitrile (33 g, 0.5 mol) and glacial acetic acid (1.5 g) were placed in a 1 L flask equipped with a stirrer, thermometer and a Vigreux column (20×1 in.) on top of which a distillation condenser was placed. The reaction mixture was heated and ethyl alcohol began to distill when the temperature of the reaction mixture was about 85-90° C. After about 40 min., the temperature of the reaction mixture reached 140° C. Then the reaction was concentrated in a rotary evaporator to remove the low-boiling materials and the residue was crystallized from absolute alcohol to yield the pure product (62.2 g, 91%) as a light yellow solid mp 91.6° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O-].[Na+].[Cl-]>CO.CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: C[O-]
Reactant: Oc1cccc2cnccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-hydroxyisoquinoline (10 g, 69 mmol) in MeOH (100 ml) was added a solution of sodium methoxide in methanol (30% by weight, 13.8 ml, 72.4 mmol) followed by phenyltrimethylanmmonium chloride (12.4 g, 72.4 mmol). The reaction mixture was stirred at room temperature for 2 h, after which time it was filtered and the filtrate evaporated under reduced pressure to afford an oil which was dissolved in DMF (50 ml). The reaction mixture was refluxed for 2 h after which time the reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between CH2Cl2 and 1N aqueous NaOH, the organic layer was washed twice with 1N aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc/hexane (1/1, v/v) to afford the subtitle compound as a yellow oil (6.11 g, 56%). 1H NMR (CDCl3) δ: 4.05 (3H, s), 7.00 (1H, d), 7.55 (2H, m), 8.02 (1H, d), 8.55 (1H, d), 9.22 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:27])[C:16]4([CH3:29])[CH3:28])=[CH:10][CH2:9]1)[CH3:7].[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.N1C=CN=C1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([O:27][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:16]4([CH3:29])[CH3:28])=[CH:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: 70 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
3β-Hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester (18.0 g) is suspended in 300 ml of DMF and 14.8 g of imidazol, and 13 g of tert-butyldimethylsilylchloride is added. The reaction mixture is stirred at 70° C. for 20 hours. After aqueous work-up, and crystallisation from diethyl ether/methanol, 21.0 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester is isolated. Melting point, 124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:11]C(=O)OC(C)(C)C)[CH2:6]1.[ClH:25]>>[ClH:25].[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:11])[CH2:6]1
Reactant: COc1cccc(F)c1CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Product: COc1cccc(F)c1CN1CCC[C@@H](N)C1

Procedure:
To (R)-tert-butyl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-ylcarbamate (3.52 g, 10.40 mmol) was added methanolic HCl (3 N, 50 mL) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed in vacuo to afford (R)-1-(2-fluoro-6-methoxybenzyl)-piperidin-3-amine hydrochloride. MS ESI calc'd. For C13H19FN2O [M+1]+ 239. found 239.
Reaction SMILES: C([NH:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1)C1C=CC=CC=1.Cl>C(O)C.CO.[Pd]>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1
Reactant: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 81 %

Procedure:
A solution of 750 mg (1.28 mmol) N-(6-benzylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (Example 73, step d) in 25 ml of a 5 N solution of hydrochloric acid in ethanol was evaporated to dryness and the residue was dissolved in 30 ml methanol and hydrogenated in the presence of 60 mg 10% palladium on activated charcoal (room temperature, 10 bar) for 20 h. After filtration of the catalyst and evaporation of the solvent the residue was dissolved in 30 ml ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Evaporation of the solution afforded 514 mg (81%) of the title compound as light brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13]3([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[C:4]3[C:13]4([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[N:14]4)[C:10]4([CH2:11][CH2:12]4)[CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)=[O:34])=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(N)ccc1OCC21CC1
Reactant: O=C(O)c1ccc(F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(F)cn3)ccc1OCC21CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.2 %

Procedure:
A mixture of tert-butyl (6′-aminodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (115 mg, 0.333 mmol), 5-fluoropyridine-2-carboxylic acid (62.3 mg, 0.433 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (83.0 mg, 0.433 mmol), 1-hydroxybenzotriazole (58.5 mg, 0.433 mmol), N,N-diisopropylethylamine (0.074 mL, 0.433 mmol) and CH2Cl2 (1.2 mL) was stirred for 2.5 days at ambient temperature. The reaction mixture was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 10 to 90%) to afford tert-butyl (6′-{[(5-fluoropyridin-2-yl)carbonyl]amino}dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (136 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[NH:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:32]=[N:31]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Product: O=C(Nc1nc2ccc(-c3cn[nH]c3)cn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 112 but starting from N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (Boron-Mol, 85 mg, 0.36 mmol, 1.2 mol eq.) as a white solid (6.2 mg, 7%). HPLC, Rt: 2.26 min (purity: 99%). LC/MS M+(ESI): 305.2.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([O-])=[O:24])=[N:21][CH:22]=1)=O)(C)(C)C.[Li+].CCN(C(C)C)C(C)C>>[CH:1]1([NH:7][C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][NH2:15])=[CH:22][N:21]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])nc1
Reactant: NC1CCCCC1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccc(C(=O)NC2CCCCC2)nc1
Yield: 22 %

Procedure:
Use the General Procedure 6-2, using cyclohexylamine (1 mL), lithium 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (1 g, 3.96 mmol) and DIEA (5 mL) as cosolvent, to give the title compound as a white solid (200 mg, 22%). MS (ES+) m/z: 234 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:31](=[O:32])[N:6]2[CH:7]([C:15]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:8]([CH:11]=[C:12]([Br:14])[Br:13])=[CH:9][S:10][C@H:5]12)=[O:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(OCC)(=O)C>[CH:1]([NH:3][CH:4]1[C:31](=[O:32])[N:6]2[C:7]([C:15]([O:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])=[C:8]([CH:11]=[C:12]([Br:13])[Br:14])[CH2:9][S:10](=[O:41])[C@H:5]12)=[O:2]
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Br)Br)=CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Br)Br)CS(=O)[C@H]12
Yield: 44 %

Procedure:
To a solution of benzhydryl 7-formamido-3-(2,2-dibromovinyl)-2-cephem-4-carboxylate (4.2 g) in ethyl acetate (42 ml) was added a solution of m-chloroperbenzoic acid (1.72 g) in ethyl acetate at -20° to -10° C. and the resultant mixture was stirred at -10° C. for 45 minutes. The precipitates were collected by filtration to give benzhydryl 7-formamido-3-(2,2-dibromovinyl)-3-cephem-4-carboxylate-1-oxide (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:16][CH2:17][OH:18].[I-].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][OH:18])[CH3:14]
Reactant: OCCBr
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCO)cc1OC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
2-(3,4-Dimethoxyphenyl)-N-methylethylamine (2.77 ml, 0.015 mol) and 2-bromoethanol (1.13 ml, 0.015 mol) were dissolved in N,N-dimethylformamide (10 ml). To the resulting solution, potassium iodide (2.45 g, 0.015 mol) was added, followed by stirring at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and, thereafter the solvent was evaporated under vacuum; after adding a saturated aqueous solution of sodium bicarbonate, three extractions were conducted with ethyl acetate. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The residue was purified by being subjected to column chromatography on silica gel using a 9:1 solvent system of chloroform and methanol as an eluent and the fractions containing the end product were collected and the solvent was evaporated under vacuum, followed by drying to yield the end compound 2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethanol (1.35 g) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]3[NH:19][C:18]4=[CH:20][S:21][CH:22]=[C:17]4[N:16]=3)[CH:8]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]3[NH:16][C:17]4=[CH:22][S:21][CH:20]=[C:18]4[N:19]=3)=[O:31])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1nc(CSc2nc3cscc3[nH]2)cc(N2CCOCC2)n1
Product: O=S(Cc1cc(N2CCOCC2)ncn1)c1nc2cscc2[nH]1

Procedure:
180 mg of 2-(6-morpholino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole were oxidized with m-chloroperbenzoic acid in analogy to Example 1g. 140 mg of 2-(6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole were obtained (melting point 107° C. [decomposition]).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:17]([CH:14]1[CH2:16][CH2:15]1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccc(Br)cc2CN1C1CC1

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (Ark Pharm, Cat. No. AK-26333) (0.5 g, 0.002 mol), cyclopropylamine (0.17 mL, 0.0024 mol) and potassium carbonate (0.45 g, 0.0032 mol) in ethanol (5 mL) was stirred at 40° C. for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was directly used in nest step reaction without further purification. LCMS (M+H)+=252.0/254.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1>[Pd].CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Into the reaction flask was added tert-butyl [3-({5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)phenyl]carbamate (1.0 g, 2.4 mmol), 50 mL of methanol, and 10% palladium on carbon (0.10 g, 0.097 mmol). The reaction mixture was hydrogenated at 25 psi for 3 h. The mixture was filtered and concentrated to give the desired product (0.9 g, 89%). LCMS for C24H33NaN3O4 (M+Na)+: m/z=450.2
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[NH2+]1CCCCC1.O>C1(C)C=CC=CC=1>[C:19]([O:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:25][CH:24]=2)=[CH:15][CH:14]=1)=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of 3.41 g (10 mmole) tert-butyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate and 1.29 g (11 mmole) 2,4-thiazolidinedione in toluene containing a catalytic amount of piperidinium acetate was refluxed in a Dean-Stark water trap for 3 hours. The reaction was followed by TLC and more 2,4-thiazolidinedione was added during the reaction time. The solution was cooled to room temperature filtered and the precipitate was refluxed in methanol. Another filtration gave 3.2 g (yield 72.6%) 5-(4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione as a light yellow, solid substance.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][C:35]=1[CH3:40].NN>CO.C1COCC1>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[CH3:40])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (196 mg, 0.34 mmol) in MeOH/THF (2 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified on silica (50% MeOH in CHCl3 (0.5% NH4OH) to give a free base of the title compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (107 mg, 51%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.96 (s, 1H), 7.90 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 4.66 (m, 1H), 3.91 (s, 3H), 3.33-3.14 (m, 4H), and 2.10 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]=[C:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])[CH3:2]>C1COCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(C=C(C)C)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(C)cc(CC(C)C)n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 98.3 %

Procedure:
To a solution of 4-methyl-6-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (175 mg, 0.80 mmol) in THF (5 mL) and ethanol (5 mL), Pd/C (50 mg, 10% Pd) is added. The mixture is stirred at 50° C. for 15 h under 1 bar of H2. The catalyst is filtered off over celite and the solvent of the filtrate is evaporated to give 6-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (174 mg) as a colourless oil; LC-MS: tR=0.84 min, [M+1]+=222.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]O)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1>[C:25]([CH2:16][CH:15]1[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:10][CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:27]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CC#N)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (2.0 g) in THF (40 mL) were added triethylamine (2.22 mL) and methanesulfonyl chloride (0.82 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue (1.6 g) in DMF (9.0 ml) was added sodium cyanide (345 mg), and the mixture was stirred at 80° C. for 2 days. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (331 mg).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Br[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu](I)I>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Brc1nc2ccccc2s1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 28 mg (0.24 mmol) of L-Proline in N,N-dimethylformamide (3 mL) at ambient temperature was added 51 mg (0.24 mmol) of 2-bromobenzothiazole, 100 mg (0.72 mmol) of potassium carbonate, and 6 mg (0.03 mmol) of copper iodide. The reaction mixture was stirred at 100° C. overnight. It was then filtered and purified by reverse-phase HPLC (TMC Pro-Pac C18; 0-60% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 35 mg 60% of the title compound as a light brown solid. 1H NMR (DMSO-d6): δ 7.78 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 4.48 (d, J=7.3 Hz, 1H), 3.52-3.61 (m, 2H), 2.37 (m, 1H), 2.01-2.11 (m, 3H). LC/MS 249.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)=[O:30].OO>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][S:25](=[O:30])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCCSC2)C(=O)Nc2cnccn2)cc1Cl
Reactant: O=CO
Agent: OO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCS(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A slurry of 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-thiopyran-3(R)-yl)-propionamide (prepared as in Example 18, 10.0 mg, 0.0227 mmol) in formic acid (68.5 μL, 1.816 mmol) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (7.7 μL, 0.068). The resulting solution was stirred at 0° C. for 10 min. The reaction was quenched by the addition of a 10% aqueous sodium sulfite solution (1 mL) and then extracted with ethyl acetate (2×5 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 93/7 chloroform/methanol) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(1-oxo-hexahydro-1λ4-thiopyran-3(R)-yl)-N-pyrazin-2-yl-propionamide (10.0 mg, 96.5%) as a beige gum: EI-HRMS m/e calcd for C19H22ClN3O4S2 (M+Na)+ 478.0632. found 478.0632.