Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH:25](=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCC=O
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 7.01 ml, 11.0 mmol) was added to a tetrahydrofuran (50 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (3.03 g, 10.0 mmol) obtained in Example 5 and the mixture was stirred at −78° C. for 1 hour. Butanal (1.08 ml, 12.0 mmol) was added dropwise to the reaction mixture. The mixture was stirred for 15 hours while elevating its temperature to room temperature. After cooling to 0° C. and addition of a saturated aqueous ammonium chloride solution, the mixture was extracted with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The solid thus precipitated was collected by filtration and washed with hexane. The filtrate and washing with hexane were combined, followed by concentration. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane) as a high-polarity isomer to yield a colorless solid. The resulting colorless solid was recrystallized from hexane, whereby the title compound (396 mg, 11%) was obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.CCN=C=NCCCN(C)C.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>ClCCl>[O:44]=[C:39]1[CH2:40][CH2:41][C:42](=[O:43])[N:38]1[O:15][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:16]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (17d; prepared according to Example 110) (25.0 g, 72.2 mmol), EDCI (18.0 g, 93.8 mmol), and 1-hydroxypyrrolidine-2,5-dione (9.97 g, 86.6 mmol) were suspended in dichloromethane and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (500 mL) and washed with saturated NH4Cl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organics were dried over MgSO4 and concentrated under reduced pressure to afford the crude product as yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][CH:26]([SH:28])[CH3:27].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][S:28][CH:26]([CH3:27])[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CC(C)S
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CSC(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
[3-(4-Bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.87 mmol) and 2-propanethiol (0.08 g, 1.0 mmol) were combined in 1,4-dioxane (20 mL). Sodium hydride (60% in mineral oil; 0.04 g, 1.0 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was worked up to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(O)(=O)C.[CH3:18][C@:19]12[CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH2:26][C@@H:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28]4)[C@@H:23]1[CH2:22][CH2:21][C:20]2=O.C([BH3-])#N.[Na+]>CO.C1COCC1>[OH2:11].[NH2:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][C@H:20]2[CH2:21][CH2:22][C@H:23]3[C@H:24]4[C@H:34]([CH2:35][CH2:36][C@:19]23[CH3:18])[C@:32]2([CH3:33])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]4)=[CH:9][CH:8]=1)(=[O:11])=[O:12].[NH2:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][C@H:20]2[CH2:21][CH2:22][C@H:23]3[C@H:24]4[C@H:34]([CH2:35][CH2:36][C@:19]23[CH3:18])[C@:32]2([CH3:33])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]4)=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCc3ccc(S(N)(=O)=O)cc3)CC[C@@H]12
Product: O
Reaction time: 5 h

Procedure:
A solution of 3.39 g of 4-(2-aminoethyl)benzenesulfonamide in 50 ml of MeOH and 150 ml of THF was acidified with 3 ml (3.15 g) of acetic acid. Then 2.32 g of 5α-androstan-17-one was added. After a solution was obtained, 1.2 g of sodium cyanoborohydride was added. The resulting solution was stirred for 5 hours. An additional 1.2 g of sodium cyanoborohydride was added. The stirring was continued for 19 hours. The solvent was evaporated from the solution. The residue was treated with 200 ml of water, made basic with 50% NaOH solution, and extracted with CH2Cl2 (3×100 ml). The combined extracts were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 3.75 g of solid. The solid was chromatographed on a 400 g column of silica gel. The column was eluted with 10% MeOH--CH2Cl2 and 100 ml fractions were collected. The fractions were assayed by silica gel TLC (1×4") (10% MeOH--CH2Cl2). Fractions 18-30 were combined and crystallized from MeOH--H2O giving 0.76 g of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].N#N.[CH3:14][CH2:15][OH:16].[Li][CH:18](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[CH3:10][N:9]([CH3:11])[C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH2:14][C@H:15]([OH:16])[CH3:18])[CH:3]=1
Reactant: CCO
Reactant: [Li]C(C)CC
Reactant: Cc1ccc(N(C)C)cc1I
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(N(C)C)cc1C[C@@H](C)O
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
A solution of N-(3-iodo-4-methylphenyl)-N,N-dimethylamine (5.22 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.25 in EtOAc/hexane 3:7) to give (2R)-1-[5-(dimethylamino)-2-methylphenyl]propan-2-ol (0.15 g, 4%) as brown oil. 1H NMR (300 MHz, CDCl3): δ 7.03 (m, 1H), 6.58 (m, 2H), 4.02 (m, 1H), 2.90 (s, 6H), 2.65-2.78 (m, 2H), 2.23 (s, 3H), 1.62 (br, 1H), 1.29 (d, J=6.21 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6]([CH3:18])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[N+:20]([O-])([OH:22])=[O:21]>OS(O)(=O)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6]([CH3:18])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:20]([O-:22])=[O:21])=[CH:14][CH:13]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccccc2)c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Temperature: -7 °C

Procedure:
Under cooling, (1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (intermediate 1.1.1, 3.10 g, 12.0 mmol) was dissolved in conc. H2SO4 (7 mL). The mixture was cooled to −7° C. and HNO3 (65%, 0.77 mL) was added dropwise under stirring, keeping the temperature below 0° C. The reaction mixture was allowed to come to room temperature and stirred for 20 min at room temperature. The reaction mixture was poured into ice water, extracted with dichloromethane and the organic layer was concentrated under reduced pressure. The resulting product is a mixture of regioisomers, with the 4-nitro isomer as the main product.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[C:11](I)[CH:10]=[CH:9][N:8]=1.[B:14](OCCCC)([O:20]CCCC)[O:15]CCCC.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:12]=[C:11]([B:14]([OH:20])[OH:15])[CH:10]=[CH:9][N:8]=1
Reactant: Fc1cc(I)ccn1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: OB(O)c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol) in dry diethyl ether (20 mL) at −78° C. was added a solution of 2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and the reaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate (2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture was allowed to warm to room temperature over 2 hours. Water (5 mL) was added followed by 2N aqueous sodium hydroxide solution (10 mL) to dissolve the solids. The organic phase was separated. The aqueous phase was acidified to pH3 using 6N hydrochloric acid and the resulting white solid was collected by filtration and dried under vacuum to give the title compound, 0.74 g (78%). 1H NMR (DMSO-d6) δ 8.65 (br s, 2H), 8.21 (d, 1H), 7.59 (t, 1H), 7.37 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=O)[CH:4]=[N:3]1.[NH2:16][O:17][CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)C>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH:14]=[N:16][O:17][CH2:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc(C=O)c1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CON)cc1
Solvent: CCO
Product: Cn1ncc(C=NOCc2ccc(C(=O)OC(C)(C)C)cc2)c1Oc1ccccc1
Yield: 80.1 %

Procedure:
1.0 Gram (0.0049 mole) of 1-methyl-5-phenoxypyrazole-4-carbaldehyde and 1.1 g (0.0049 mole) of tert-butyl 4-aminooxymethylbenzoate were added to 20 ml of ethanol, and the resulting mixture was heated under reflux to carry out reaction. After completion of the reaction, ethanol was removed by evaporation, after which water was added to the residue and extraction was carried out with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.6 g of the desired compound.
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[O:16]1[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=[CH:12]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: CCOC(=O)C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cnco1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Toluenesulfonylmethyl isocyanide (TosMIc) (12.31 g, 1 wt, 1 eq) is dissolved in DCM (61.6 ml, 5 vols) at 0° C. under N2. In a separate vessel, ethyl glyoxalate (50 wt % solution in toluene, 20.6 g, 20.0 ml, 1.67 wt) is diluted with DCM (61.6 ml, 5 vols) under N2 and DBU (12.48 g, 12.35 ml, 1.3 eq, 1.01 wt) is added resulting in a purple solution. The second solution is added to the TosMIc solution over 1 hr, maintaining temperature at 0° C., then checked by HPLC for completion after a further 20 mins. The reaction is quenched by slow addition of 2M HCl (10 vols, 123 ml) and the DCM layer separated. The aqueous layer is re-extracted with DCM (5 vols, 61.6 ml), and the combined organics dried over Na2SO4, then evaporated on Buchi, 25° C., 100 mbar to remove DCM and toluene. Distilled at 12 mbar, jacket temperature 105° C., vapour temperature 60-80° C. to afford ethyl oxazole-5-carboxylate as a colourless oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([O:14][C:15]2([O:21][CH:22]3[CH2:27]CCCC3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:13]CCCC1.[CH:28]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O(CCO)C1C=CC=CC=1.COC1(OC)CCCCC1>>[O:7]([CH2:27][CH2:22][O:21][C:15]1([O:14][CH2:8][CH2:13][O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCCCC1
Reactant: O=C1CCCCC1
Reactant: C1CCC(OC2(OC3CCCCC3)CCCCC2)CC1
Agent: COC1(OC)CCCCC1
Solvent: OCCOc1ccccc1
Product: c1ccc(OCCOC2(OCCOc3ccccc3)CCCCC2)cc1
Yield: 29 %

Procedure:
Non-simple 1,1-dialkoxycyclohexanes are very difficult to make by reacting cyclohexanone with alcohols having long straight chains, branched chains, or aromatic groups. For example, 1,1-di(cyclohexyloxy)cyclohexane was made with a yield of 29% by reacting cyclohexanol with cyclohexanone, as described in U.S. Pat. No. 3,072,727. Non-simple 1,1-dialkoxycyclohexanes are typically made by transketalization, namely, by mixing and heating such alcohols with an already formed simple 1,1-dialkyoxycyclohexane, namely, with methoxy, ethoxy, or isopropoxy groups. For example, 2-phenoxyethanol can be mixed with 1,1-dimethoxycyclohexane to form 1,1-di(2-phenoxyethoxy)cyclohexane. This reaction is described in U.S. Pat. No. 6,165,676 and U.S. Pat. No. 6,391,512.
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12](#[N:14])[CH3:13].C([O:17][C:18](=O)[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C>O1CCCC1>[CH2:21]([O:20][CH2:19][C:18](=[O:17])[CH2:13][C:12]#[N:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(=O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 151.1 %

Procedure:
In a stream of argon, 156.2 ml (0.248 mole) of a solution of 1.6 moles of n-butyllithiumhexane was added to 150 ml of anhydrous tetrahydrofuran. The mixture was cooled to -78° C., and a solution of 15.8 ml (0.293 mole) of acetonitrile in 50 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 1 hour. A solution of 55.2 g (0.248 mole) of ethylbenzyloxyacetate in 100 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 15 minutes and at room temperature for 50 minutes. The mixture was then poured into 200 ml of ice water. The aqueous layer was washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 70.9 g of crude 4-benzyloxy-3-ketobutanenitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].[C:33](OC(=O)C)(=[O:35])[CH3:34].O>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28])(=[O:35])[CH3:34]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(CNc2cc(Nc3ccc(N4CCOCC4)cc3)ncc2CC(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
22 mg of 4-[(3-aminobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide (the compound of Example 103) was dissolved in 0.5 mL of pyridine, to which 5.4 mg of acetic anhydride was added, and stirred at room temperature for 4 hours. To the reaction mixture, water was added, stirred, and the solvent was evaporated. The residue was purified by silica gel thin layer chromatography (chloroform: methanol=10:1) to obtain 2.6 mg (11%) of 4-{[3-(acetylamino)benzyl]amino}-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide (Example 104-1) as a white solid. Furthermore, 11.6 mg (44%) of 4-{[3-(acetylamino)benzyl]amino}-6-[acetyl(4-morpholinophenyl)amino]pyridine-3-carboxyamide (Example 104-2) was obtained as a yellowish brown oil.
Reaction SMILES: [CH3:1]I.[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Br:20])[N:7]=[C:6]([C:21](=[S:23])[NH2:22])[C:5]=1[S:24]([CH3:26])=[O:25]>>[CH3:1][S:23][C:21]([C:6]1[C:5]([S:24]([CH3:26])=[O:25])=[C:4]([NH2:3])[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[Br:20])[N:7]=1)=[NH:22]
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Reactant: CI
Product: CSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c(N)c1S(C)=O

Procedure:
In a manner similar to that described in EXAMPLE 2, methyl iodide was reacted with 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide (Compound 6, prepared as described in applicants' concurrently filed, copending application referenced in EXAMPLE 2 above) to give 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid methyl ester having a melting point of 203.5° C. This compound is referred to hereinafter as Compound 4.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].Cl.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1.CCOCC>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:25]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1cnccc1C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cnccc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 0.26 g (0.59 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-3-o-tolyl-isonicotinamide in 5 ml tetrahydrofuran 3.6 ml of a 1M solution of BH3 in tetrahydrofuran was added and the reaction mixture stirred for 16 h at 60°. After addition of 5 ml 3M HCl in ether the reaction mixture was stirred for 3 h at 60° C. The solution was cooled to room temperature and 10 ml 3N sodium hydroxide solution and 10 ml ethyl acetate were added. Stirring was continued for ½ h, the phases separated and the aqueous phase extracted twice with 15 ml ethyl acatate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.13 g (51%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.CSC(=N)N[N+]([O-])=O.S1C=CC(CSC[CH2:27][NH:28][C:29]([NH:31][N+:32]([O-:34])=[O:33])=N)=N1.CNC(=N[N+]([O-])=O)SC>>[S:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH3:27])=[N:31][N+:32]([O-:34])=[O:33])=[N:7]1
Reactant: NCCSCc1ccsn1
Reactant: N=C(NCCSCc1ccsn1)N[N+](=O)[O-]
Agent: CNC(=N[N+](=O)[O-])SC
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-nitroguanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:27][S:28]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:9])=[CH:6][N:5]=[C:4]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2sccc2C)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccsc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(3-methyl-thiophen-2-yl)-methanone (Example 197) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C16H22N5O3S2 [(M+H)+] 396.1159, observed 396.1162.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:7]1)C.[BH4-].[Li+].O>C1COCC1>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7]1)=[O:13]
Reactant: CCOC(=O)CC1CCCN(C(=O)c2cc3ccccc3[nH]2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc2ccccc2[nH]1)N1CCCC(CCO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
To a solution of 500 mg of indole-2-carboxylic acid and 530 mg of ethyl piperidin-3-yl acetate in 8 mL of DMF were added 610 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 430 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 2 hours. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 519 mg of ethyl[1-(1H-indol-2-ylcarbonyl)piperidin-3-yl]acetate. To a solution of 392 mg of the resulting ethyl[1-(1H-indol-2-ylcarbonyl)piperidin-3-yl]acetate in 7 mL of THF was added 30 mg of lithium borohydride, followed by stirring at room temperature for 1 day. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [hexane:ethyl acetate=1:0-2:1], and then crystallized from diisopropyl ether to obtain 92 mg of 2-[1-(1H-indol-2-ylcarbonyl)piperidin-3-yl]ethanol as a white solid.