Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].CCN(C(C)C)C(C)C>ClCCl>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:4]
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: CCNCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)C(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Bromo-phenyl-acetyl chloride (191.0 mmol) was taken up in anhydrous dichloromethane (150 mL) and the resulting mixture was cooled to 0° C. in an ice bath. Diethylamine (14.1 g, 191 mmol) was then added drop-wise over 15 minutes, following which DIPEA (24.7 g, 191 mmol) was added over 5 minutes. The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was then washed with water, dried over MgSO4, filtered and concentrated to yield a dark brown colored oil. The oil was purified by silica gel chromatography to yield the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])=[CH:6][CH:5]=1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:14]=[C:12]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)[O:13][CH:21]=1
Reactant: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.28 g (18.5 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylamide, 2.80 g (22.2 mmol) 1,3-dichloroacetone and 30.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 20:1). All fractions containing the product were concentrated to a volume of 10 ml and the crystallized material isolated by filtration, washed with cold heptane and dried. 1.75 g (31%) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7].I[CH3:10].[H-].[Na+]>O1CCCC1>[CH3:10][O:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCC(O)CC=C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Into a round-bottom flask, was placed a solution of hepta-1,6-dien-4-ol (2.00 g, 17.8 mmol, 1.00 equiv) and iodomethane (5.00 g, 35.2 mmol, 2.00 equiv) in tetrahydrofuran (30 mL). The solution was cooled to 0° C. and sodium hydride (1.00 g, 25.0 mmol, 1.50 equiv, 60% in mineral oil) was added to the reaction in portions. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (5 mL) and diluted with of ether (30 mL). The organics was washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a colorless oil (2.00 g, 84%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>CC(N(C)C)=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:28]2[NH:18][C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.1 g, 0.3 mmol) was added to a solution of 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) in DMAC (20 ml). The mixture was stirred at room temperature for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, then dried and purified by column chromatography (silica gel-ethyl acetate/n-hexane) to afford 43 (70.0 mg, 4.0%) and 61 (1.7 g, 89.0%) as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:21])[CH:5]=[CH:4][C:3]=1[NH2:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:21])[CH:5]=[CH:4][C:3]=1[NH:22][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=1
Reactant: Cc1ccc(N)c(C)c1Oc1ncccc1-c1ccncn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)c(C)c1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolved 2,4-dimethyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (100 mg, 0.342 mmol) in dichloromethane (1.0 mL), added 3-(trifluoromethyl)benzoyl chloride (107 mg, 0.513 mmol) and triethylamine (0.12 mL). Stirred at ambient temp for 4 hours and then concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound. MS m/z=465 (M+H)+. Calc'd for C25H19F3N4O2: 464.45.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:26]([C:27]([O:29]CC3C=CC=CC=3)=[O:28])=[C:16]3[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1>C(O)C.[C].[Pd]>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:26]([C:27]([OH:29])=[O:28])=[C:16]3[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: CCOC(=O)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)OCc3ccccc3)c12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)O)c12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture comprising 14.4 g of benzyl 5-(4,6-dimethoxypyrimidin-2-yl)oxy-3-ethoxycarbonyl-2-methylbenzofuran-4-carboxylate and 4.52 g of 10% palladium carbon in 100 ml of ethanol, was subjected to hydrogenation under an ordinary pressure while stirring at room temperature. After completion of the reaction, an insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure, whereupon the precipitated crystals were washed with a solvent mixture of diethyl ether/n-hexane to obtain 10.47 g (yield: 89%) of the desired compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([S:20]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)(=[O:22])=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH:25]1[CH2:26][CH:23]([S:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:11]([CH2:10][CH:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)[C:12]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[N:13][C:14]=3[CH:19]=2)(=[O:22])=[O:21])[CH2:24]1
Reactant: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CN(C(=O)OC(C)(C)C)C4)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CNC4)ccc32)CC1
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl 3-(1-((1-acetylpiperidin-4-yl)methyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)azetidine-1-carboxylate (STEP C, 220 mg, 0.402 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. After stirring for 40 min, the mixture was concentrated. The residue was diluted with methanol (10 mL) and the solution was filtered through strong cationic exchange column (SCX). The column was washed with 1 mol/L ammonia in methanol (10 mL) to wash out the title compound (176 mg, 98%).
Reaction SMILES: [CH:1]([NH:4][CH:5]=[NH:6])([CH3:3])[CH3:2].Br[C:8](=[CH:12]OC)[C:9](=[O:11])[CH3:10].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[N:6][CH:12]=1)(=[O:11])[CH3:10]
Reactant: CC(C)NC=N
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cncn1C(C)C
Temperature: 8 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 13.9 g (0.162 mol) of N-isopropylformamidine (which was prepared in Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 8° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 3.28 g (yield: 20%) of 5-acetyl-1-isopropylimidazole as pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[CH2:12][OH:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: CCOc1cc(CO)c(Br)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1cc(C=O)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-bromo-5-ethoxy-4-methylphenyl)methanol (2.30 g, 9.38 mmol) in DCM (40 mL) was added Dess-Martin periodinane (5.97 g, 14.08 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ether and was then concentrated. The residue was taken up in ether and was washed with of a mixture of 10% aqueous Na2S2O3 and saturated aqueous NaHCO3 (1/1), water and brine. The aqueous washings were back-extracted with ether and the organic layer was washed with water and brine. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to afford the title intermediate as a white solid
Reaction SMILES: Cl.C(OC([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([NH2:27])[CH:20]=2)[C:14](=[O:28])[CH2:13]1)=O)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[NH2:27][C:21]1[CH:20]=[C:19]([CH2:18][N:15]2[CH2:16][CH2:17][NH:12][CH2:13][C:14]2=[O:28])[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1N
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(CN2CCNCC2=O)cc1N
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 4-(3-Amino-4-cyano-benzyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester hydrochloride (4.0 g, 10.0 mmol) in CH3OH (45 ml) and CH2Cl2 (10 ml) is added 10% Pd on carbon (0.6 g). The mixture is stirred under an atmosphere of H2 for 2 hours then is filtered through a pad of celite. The filtrate is concentrated and the residue purified by column chromatography eluting with 10% 7M NH3 in CH3OH/CH2Cl2 to yield the title compound (1.62 g, 7.0 mmol). 1H NMR (DMSO, 300 MHz) δ7.34 (d, 1H), 6.64 (s, 1H), 6.46 (d, 1H), 6.04 (bs, 2H), 4.40 (s, 2H), 3.28 (s, 2H), 3.14 (m, 2H), 2.87 (m, 2H), 2.77 (bs, 1H). MS (ion spray): m/z 231 (M+H)+.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8][C:7]1=[S:20])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:20][C:7]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:16])[F:17])[NH:11][C:10]=2[C:9](=[O:19])[N:8]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(SC)nc(=O)c2[nH]c(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To the solution of 3-pentyl-2-thioxo-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one (600 mg, 2 mmol) in a 2 M solution of sodium hydroxide in water (12.0 mL) was added dimethyl sulfate (0.30 mL, 3.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched with acetic acid. The resulting solution was extracted with methylene chloride three times. The combined organic layer was dried, filtered and concentrated to give the desired product (0.60 g, 95.6%). LCMS calculated for C12H16F3N4OS: (M+H) 321.1. found 321.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.030 g, 0.050 mmol) in dichloromethane (2 mL) was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-10% methanol in dichloromethane) to give the title compound as a white solid (0.023 g, 0.047 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1 H), 7.56 (dd, J=4.0, 8.4 Hz, 1 H), 7.38 (d, J=2.4 Hz, 1 H), 7.17-7.10 (m, 2H), 6.84-6.81 (m, 1 H), 6.61 (d, J=9.6 Hz, 1 H), 6.08 (q, J=7.2 Hz, 1 H), 4.87-4.68 (m, 2 H), 4.52-4.14 (m, 1 H), 3.67-3.53 (m, 3 H), 3.50-3.21 (m, 3 H), 3.04-2.91 (m, 1 H), 2.82-2.76 (m, 1 H), 2.62-2.55 (m, 1 H), 2.28-2.20 (m, 1 H), 2.13-2.02 (m, 1 H), 1.99 (d, J=6.8 Hz, 3 H), 1.53 and 1.40 (d, J=6.4 and 6.8 Hz, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2, found 486.4.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].NN>>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: NN
Product: Nc1ccc([N+](=O)[O-])cc1S

Procedure:
Commercially available 6-nitrobenzothiazole can be treated with hydrazine to obtain the 2-amino-5-nitro-benzenethiol, which can subsequently be reacted with chloroacetoacetate to give the (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester. Reduction of the nitro group to the amino group can be accomplished by reaction with tin(II) chloride. Subsequent reaction with methansulfonyl chloride can be used to obtain the corresponding sulfonamide. Protection of both nitrogens with a suitable protecting group such as a Boc group can be achieved by using standard methods for protecting amino groups. The sulfide can be oxidized using a suitable oxidizing reagent (e.g., MCPBA) to give the sulfone. Finally, deprotection of the amino groups using trifluoroacetic acid can be used to afford the desired (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester intermediate.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=1)[NH2:12])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:12])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(N)c1
Temperature: 80 °C
Yield: 151.1 %

Procedure:
A solution of 5-(tert-butyl-dimethyl-silanyloxy)-2-nitro-aniline (1.9 g, 7.08 mmol) in methanol (40 ml) is introduced in a hydrogenation vessel with 10% palladium on carbon catalyst (0.226 g). The reaction mixture is heated at 80° C. for 3 hours under an hydrogen atmosphere (P=1 bar). The reaction mixture is then filtered on Celite® and concentrated under reduced pressure. The residue is dissolved in 10 ml of ethyl acetate and filtered through a silica gel plug (40 ml) that is washed with 600 ml of ethyl acetate. The organic filtrates are concentrated under vacuum to yield 2.55 g of 4-(tert-butyl-dimethyl-silanyloxy)-ortho-phenylenediamine used without further purification in the following step. Analytical LC/MS (method B): retention time=3.12 min., m/z=239.15 (positive ion mode).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N[C:11]1C=CC(Cl)=NC=1>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:11])=[CH:7][N:6]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COc1ccc(N)cn1
Product: CNc1ccc(OC)nc1

Procedure:
The reaction procedure of Reference Example 24 was repeated except that 5-amino-2-methoxypyridine was used in lieu of 5-amino-2-chloropyridine to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:13][C:14]([O:16]C)=[O:15])[C:3]=12>Cl.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])[C:3]=12
Reactant: COC(=O)COc1nsc2nc(C)cc(C)c12
Agent: Cl
Solvent: O
Product: Cc1cc(C)c2c(OCC(=O)O)nsc2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
Ester 25 (150 mg, 0.59 mmol) was suspended in conc. HCl (3 mL) and heated with stirring at 100° C. for 5 h until hydrolysis completed. The mixture was cooled to room temperature, diluted with water (350 mL), and the precipitate was collected to give the title compound (138 mg, 98% yield). C10H10N2O3S; white solid; mp 270° C. (decomposed); IR vmax (neat) 3423, 2928, 1716, 1591, 1504, 1440, 1392, 1363, 1308, 1204, 1125, 1038, 985, 862 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.20 (1H, s), 5.03 (2H, s), 2.66 (3H, s), 2.58 (3H, s); 13C NMR (100 MHz, DMSO-d6) δ 171.0, 169.0, 160.9, 160.6, 145.3, 121.7, 115.1, 64.4, 24.1, 14.4; ESI-HRMS (negative mode) calcd for C10H6N2O3S: 237.0334. found: m/z 237.0332 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[O:11][C:10](=[O:23])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:30].[Na+]>CN(C=O)C.O.Cl>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([O:8][CH2:9][C:10]([OH:23])=[O:30])[C@H:12]([OH:11])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [OH-]
Reactant: O=C1COC(c2ccccc2)(c2ccccc2)[C@@H](C(=O)OCc2ccccc2)O1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)OCc1ccccc1

Procedure:
14 g (36 mmol) of benzyl (S)-5,5-diphenyl-2-oxo-1,4-dioxane-6-carboxylate were dissolved in 50 ml of DMF and, with ice-cooling, 43 ml of 1 N NaOH solution were added. After ten minutes, the mixture was diluted with 300 ml of water and neutralized with 43 ml of 1 N hydrochloric acid and the aqueous phase was extracted with ether. The ether phase was dried, the solvent was distilled off and the residue (8.8 g, 21 mmol of an oil) was directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:12])=[CH:5]2.[H-].[Na+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:36][C:35]1[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=1)[C:6]([C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:12])=[CH:5]2
Reactant: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the title compound of Example 3 Step D (39.0 mg, 0.10 mmol) in DMF (1.0 mL) was added NaH (4.3 mg, 60% suspension in mineral oil, 0.11 mmol). After 10 min, a solution of 4-trifluoromethylbenzyl bromide (26.0 mg, 0.11 mmol) in DMF (0.5 mL) was added, and the reaction mixture was stirred for 18 h, whereupon it was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc, and the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10%, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=4.65 min, m/z 542.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 2H), 7.71 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.33-7.23 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 5.88 (ABq, J=16.5 Hz, Δν=86 Hz, 2H), 3.91 (s, 3H), 3.69 (dddd, J=9.0, 9.0, 5.5, 5.5 Hz, 1H), 3.10 (dd, J=13.5, 9.0 Hz, 1H), 2.85 (dd, J=13.5, 5.5 Hz, 1H), 1.79-1.74 (m, 2H), 1.58-1.53 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[ClH:1].[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]3=[O:26])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C1CCCC(=O)N1CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCC(=O)N1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine, hydrochloride (10g) is converted to its free base and mixed with 11.0g of N-(4-bromobutyl)glutarimide and 18g of sodium carbonate in 200 ml of toluene. The mixture is refluxed for 5 hours, cooled to 25° C, and 50 ml of water is added. After stirring for 15 minutes, the layers are separated and the organic layer is filtered through fritted glass and extracted with 10% hydrochloric acid. The acid layer is made alkaline (pH 10) with sodium hydroxide producing an insoluble gum that crystallizes on standing. The supernatant is decanted and the residue is recrystallized by dissolving in methanol and slowly diluting with an equal volume of water. An oil is produced that crystallizes on standing.