Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH:26]=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][CH:26]1[C:25]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=1[O:23][CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 93.8 %

Procedure:
A solution of 0.497 g of methyl (2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 0.012 g of pyridinum b-toluenesulphonate and 0.295 g of 2,4-dimethoxybenzaldehyde in 20 cm3 of anhydrous toluene is heated to reflux for 24 hours. The water formed during the reaction is removed by means of a Dean and Stark apparatus. After cooling to a temperature in the region of 20° C., the solution is washed with 37% (w/w) aqueous sodium hydrogen sulphite solution and then with saturated aqueous sodium bicarbonate solution. After concentration of the organic phase under reduced pressure, 0.700 g of (4S,5R)-3-t-butoxycarbonyl-2-(2,4-dimethoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine is obtained in an 80% yield in the form of a virtually equimolecular mixture of the diastereo-isomeric forms A and B, the characteristics of which are as follows:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)(C)C.C[O-].[Na+].Cl>CO>[C:6]([C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C#Cc1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of 5-(trimethylsilylethynyl)uracil (5.3 g, 24.4 mmol) in 0.2M solution of sodium methoxide in methanol (400 mL) was stirred at room temperature for 3 hours and neutralized to pH 7 with dilute hydrochloric acid. The precipitated product was filtered, washed with methanol and dried to give a first crop of the title compound. The filtrates and washings were combined, evaporated to dryness and the residue crystallised from methanol to give the second crop of product. Combination of both crops and a further recrystallisation from ethanol gave a pure product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>C(#N)C>[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC#N
Product: NCCCNc1ccc([N+](=O)[O-])cn1
Reaction time: 7.5 h

Procedure:
A solution of 2-chloro-5-nitropyridine (3.16 g, 20 mmol) in dry acetonitrile (40 ml) was added dropwise to a solution of 1,3-diaminopropane (5.0 ml) in acetonitrile (20 ml) at room temperature. After 7.5 hour, a yellow solid precipitated in the reaction mixture. The solvent was removed in vacuo and the residue was partitioned between 2.5 M aqueous sodium hydroxide and dichloromethane. The layers were separated and the aqueous portion was extracted 3× with dichloromethane. The combined organic layers were back-extracted with a saturated sodium chloride solution, then dried and concentrated in vacuo using a Buchi rotary evaporator Model R-124 to give (3-aminopropyl)(5-nitro (2-pyridyl))amine as a yellow solid (2.55 g). The amine (1.14 g, 6 mmol) was shaken with benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and diisopropylethyl amine (DIEA) (1.05 ml, 6 mmol) in acetonitrile (10 ml) at room temperature over two days. Dilution with ether gave the amino-{3-[(5-nitro (2-pyridyl))amino]propyl}carboxamidinium 4-methylbenzenesulfonate as a solid.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[O:3][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+].C(O)C>C(Cl)(Cl)Cl.[C].[Pd]>[F:48][C:2]([F:1])([F:47])[O:3][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:36][CH:35]=2)(=[O:32])=[O:33])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a mixed solution of the compound (1.3 g) obtained in Step 6, ammonium formate (1.2 g) and ethanol (13 ml) was added 10% palladium carbon (1.3 g) at 80° C. After stirring at the same temperature for 30 min, ammonium formate (1.3 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, ammonium formate (1.2 g) and 10% palladium carbon (0.65 g) were further added. After stirring at the same temperature for 1.5 hr, the reaction mixture was allowed to return to room temperature and diluted with chloroform. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (0.91 g).
Reaction SMILES: [BH4-].[Na+].[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27]C(=O)[CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3C3C=CC=CC=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:36])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH3:37][OH:38]>O1CCCC1.O>[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH:37]([OH:38])[CH2:27][CH2:28]4)[C:21]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:20][CH:19]=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:36])(=[O:7])=[O:8])([CH3:4])[CH3:5]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCC(=O)CC3)cc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3cnc(-c4ccccc4)n3C3CCC(O)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Add a solution of sodium borohydride (0.28 g) in methanol (5 mL) to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(cyclohexan-1-on-4-yl)-4(phenyl)-imidazol-5-yl)-benzimidazole (0.35 g, 0.7 mmol) in 10 mL tetrahydrofuran and 10 mL methanol. Stir the reaction mixture for 30 minutes at room temperature, dilute with water (50 mL), and extract with ethyl acetate (2×15 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure to provide 0.345 g (98%) of the title compound. MS(ES+): m/z=480.2 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]([F:18])=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO.ClCCl>[F:18][C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: CC1CCN(c2cc(Cl)c(F)cc2[N+](=O)[O-])CC1
Reactant: CN1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2[N+](=O)[O-])CC1
Yield: 93.9 %

Procedure:
The procedure of Example 4, step (b) was followed using 88 mg (0.19 mmol based on 60% purity by 1H-NMR) of 1-(5-chloro-4-fluoro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the previous step) and 105 μL (0.950 mmol) of 1-methylpiperazine at 150° C. for 16 h. Chromatography on a 10-g silica SPE column with 24% MeOH-dichloromethane afforded 60 mg (94%) of the title compound as a crystalline orange solid: Mass spectrum (ESI, m/z): Calcd. for C17H25FN4O2, 337.2 (M+H), found 337.2.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH2:10]([OH:12])[CH3:11].C(=O)C>Cl.O>[CH3:1][C:2]1([CH2:11][CH:10]=[O:12])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:3]1[OH:4]
Reactant: CCO
Reactant: Cc1c(O)cccc1O
Agent: CC=O
Agent: Cl
Solvent: O
Product: CC1(CC=O)C(O)=CC=CC1O
Reaction time: 1.5 h

Procedure:
To a solution of 621 g. of 2-methylresorcinol in 1 l. of ethanol were added 209 g. of acetaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated with stirring in an oil bath and, when the reaction mixture began to boil under reflux through exothermic reaction, heating was reduced and then heating under reflux was continued as it was for further 90 minutes. After completion of the reaction, the reaction mixture was poured into 5 l. of a cold water with stirring to give a pale brown powdery resin.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]#[N:16])=[CH:9][CH:8]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:11][CH:12]=1
Reactant: N#CC=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of 3-(4-(3-(trifluoromethyl)phenoxy)phenyl)acrylonitrile (5 g, 17.29 mmol) in Ethanol (80 mL) was added NaBH4 (4.5 g, 119 mmol). The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water (50 mL), and ethanol was removed under reduced pressure. The residue was partitioned between EA (100 mL) and water (50 mL). The organic phase was washed with saturated NaHCO3 solution (80 mL), brine (50 mL), dried over sodium sulfate, concentrated, and purified via flash chromatography to afford the title compound (4.3 g, 13.89 mmol, 80% yield) as colorless oil. LCMS: rt=1.64 min, no MS signal
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[CH2:28]([NH:31][CH3:32])[CH:29]=[CH2:30]>CN(C)C(=O)C>[CH2:28]([N:31]([CH3:32])[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1)[CH:29]=[CH2:30]
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/[C@H]1CC[C@H](CCN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(2-{4-[3-(allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 459 (MH+).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)[N:12]=[C:11]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[N:10]=1)[CH2:2]2.FC(F)(F)C(O)=O>ClCCl>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)=[O:23])=[CH:19][CH:20]=3)[N:14]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Crude tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate (approx 1.4 mmol) was taken up in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The mixture was concentrated under reduced the pressure. To the residue was added diethyl ether to give the title compound as a solid di-TFA salt, which was collected by filtration and dried under house vacuum; MS (ES+) 488.1 (M+H)+
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH2:38])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][N+:17]([O-:21])=[CH:16][C:15]=1[Cl:22])=[O:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([S:55](Cl)(=[O:57])=[O:56])[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH:38][S:55]([C:49]1[CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:47]([O:46][CH3:45])[CH:48]=1)(=[O:57])=[O:56])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:15]([Cl:22])=[CH:16][N+:17]([O-:21])=[CH:18][C:19]=1[Cl:20])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC[C@@H](N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N[C@H](CCCOC(C)=O)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.2 %

Procedure:
To a solution of 4-((S)-2-((R)-5-acetoxy-2-aminopentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (205 mg, 0.354 mmol) dissolved in DCM (2.5 mL), pyridine (58 μl, 0.710 mmol) and 3,4-dimethoxybenzene-1-sulfonyl chloride (168 mg, 0.710 mmol) were added. The mixture was stirred at RT for 48 hours. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated, to yield 284 mg of a yellow solid which was purified by preparative reverse-phase HPLC to yield 42 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH2:41][CH:40]2[NH:42][CH:37]([CH2:38][CH2:39]2)[CH2:36]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH:40]5[CH2:39][CH2:38][CH:37]4[CH2:36][N:35]([CH3:34])[CH2:41]5)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN1CC2CCC(C1)N2
Product: CN1CC2CCC(C1)N2C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl>N1C=CC=CC=1>[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: N#CC[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Yield: 79.8 %

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (43.1 g, 426 mmol), pyridine (240 ml) and tosyl chloride (119.5 g) were mixed at 0° C. for 4 hours. The mixture was poured in ice-cooled 1N hydrochloric acid and stirred, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off with an evaporator. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain (3S)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (87.0 g, 340 mmol). Yield, 80 %.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[H-].[Na+].CN(C)C=O>O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1C
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C
Temperature: 180 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (7.95 g), 2-chloropyridine (5 ml), sodium hydride (0.60%, oil, 2.32 g) and N,N-dimethylformamide (150 ml) was stirred overnight at 180° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (8.31 g, yield 73%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 79-80° C.
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:9](OCC)=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2].CO>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:6]1[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][CH:7]=1
Reactant: CCOC(=O)c1cnc(C(C)C)s1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1ncc(CO)s1
Yield: 25 %

Procedure:
Using the procedure of Example 5B, but replacing ethyl 2-isopropyl-4-thiazolecarboxylate with ethyl 2-isopropylthiazole-5-carboxylate provided, after silica gel chromatography using 3% methanol in chloroform, the desired compound, Rf 0.3, (5% methanol in chloroform) in 25% yield. 1H NMR (d6 -DMSO) δ1.30 (d, J=7 Hz, 6H), 3.22 (heptet, J=7 Hz, 1H), 4.61 (dd, J=6, 1 Hz, 2H), 5.45 (t, J=6 Hz, 1H), 7.48 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4].[ClH:29].[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[ClH:1].[ClH:29].[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C@H:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:32]2[CH2:31][CH:30]3[O:37][CH:34]([CH2:35][CH2:36]3)[CH2:33]2)=[CH:15][C:16]=1[F:21]
Reactant: C1CC2CNCC1O2
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)CCl)C1
Agent: Cl
Product: O=C(CN1CC2CCC(C1)O2)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-{[(chloroacetyl)amino]methyl}-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 8-oxa-3-azabicyclo[3.2.1]octane monohydrochloride, and in the same manner as in Example 336, steps B and C, the title compound was obtained.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[CH:17][CH:16]=[C:15]([C:19]([C@@H:21]3[N:26]4[CH2:27][C@H:28]([CH:29]=[CH2:30])[C@@H:23]([CH2:24][CH2:25]4)[CH2:22]3)=[O:20])[C:13]=2[CH:14]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[CH:17][CH:16]=[C:15]([C@H:19]([OH:20])[C@@H:21]3[N:26]4[CH2:27][C@H:28]([CH:29]=[CH2:30])[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:13]=2[CH:14]=1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(=O)c1ccnc2ccc(OC)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12

Procedure:
600 ml. anhydrous pyridine, 100 g. crystallized quinidinone, and 300 ml. 25% solution of diisobutylaluminum hydride (DIBAH) in toluene were in a reaction vessel and the reaction was allowed to proceed until the reduction was completed as indicated by thin layer chromatography. The mixture was then heated under vacuum (25 mm Hg) to remove the pyridine. The reaction mixture was then treated with 750 ml. of a 50/50 mixture of water and ethanol, and after refluxing for 2 hours and cooling, 92.7 g. of quinidine base were obtained, exhibiting a melting point of 174.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(F)cc1F
Yield: 56 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4-difluorobenzenesulfonyl chloride (11.7 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 56% yield (9.5 mg). MS (ESI+) calcd mass for C13H9F2N5O2S 337.044502, found 337.044202.
Reaction SMILES: Cl[C:2]1[C:6]([S:7][CH2:8][CH2:9][CH3:10])=[N:5][S:4][N:3]=1.[OH-:11].[Na+]>CS(C)=O>[CH2:8]([S:7][C:6]1[C:2]([OH:11])=[N:3][S:4][N:5]=1)[CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CCCSc1nsnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCSc1nsnc1O

Procedure:
A mixture of 3-chloro-4-propylthio-1,2,5-thiadiazole (10 g), 2 N NaOH (100 mL), and DMSO (10 mL) was heated to reflux for 24 h. The solution was cooled and extracted with ether. The aqueous fraction was acidified with conc. HCl and cooled in ice-water for 3 h. The resulting solid was collected, washed with a small amount of cold water to give a white solid (8.15 g). Recrystallization from heptane gave white crystals, m.p. 84-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3=[N:18][S:19](=[O:23])(=[O:22])[CH2:20][CH2:21][N:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:17]3=[N:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21][N:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1C
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Platinum(IV) oxide (25 mg) was added to a solution of 9-[4-(3,4-dimethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (93.8 mg) in THF (dry) (10 mL) and MeOH (10 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (71.8 mg) as colorless crystals.