Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][CH3:23].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:21]([NH:24][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]2)=[O:20])[CH2:22][CH3:23]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Reactant: CCCN
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Yield: 63.6 %

Procedure:
2-(tert-butoxycarbonylamino)-5-carboxyindan (30 mg, 0.11 mmol) synthesized in Reference Production Example 4, n-propylamine (20 μl, 0.24 mmol), triethylamine (0.20 ml, 1.4 mmol), propanephosphonic acid anhydride (0.3 ml) (see Japanese Unexamined Patent Publication (Kokai) No. 55-100346), and dimethylaminopyridine (acatalytic amount) in methylene chloride (0.25 ml) were stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and then washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 3:7) to obtain N-propyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (22 mg, 0.070 mmol) having the following physical properties:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.I[CH2:31][CH3:32].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH3:32])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (400 mg, 0.96 mmol), iodoethane (92.5 μL, 1.2 mmol) and triethylamine (201.5 μL, 1.4 mmol) in 4 mL of DMF was heated at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH/DCM: 1/9) to afford 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 1HNMR (DMSO-d6) δ 8.01 (s, 1H), 7.35 (m, 1H), 7.02 (d, 1H), 6.22 (s, 1H), 2.97 (d, 2H), 2.62 (m, 1H), 2.34 (q, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (t, 2H), 1.64 (m, 4H), 1.01 (t, 3H); ESMS m/z 444.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][NH:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:9]
Reactant: COc1ccc(C=O)cc1Br
Reactant: C[C@@H](N)c1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN[C@H](C)c2cccc(F)c2)cc1Br
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
(R)-1-(3-Fluorophenyl)ethanamine 115 (1.24 g, 8.92 mmol) and 3-bromo-4-methoxybenzaldehyde 114 (1.92 g, 8.92 mmol) were mixed in 100 mL anhydrous methanol in a round bottom flask. After the mixture was stirred at 20° C. for 10 min, the flask was cooled in an ice-water bath. To this flask was added sodium cyanoborohydride (0.56 g, 8.92 mmol) followed by acetic acid (0.54 g, 8.92 mmol). The resulting mixture was stirred for 12 h and allowed to warm to 20° C. After removing most of the methanol, the remaining residue was dissolved in 200 mL ethyl ether and washed with saturated sodium bicarbonate, 3 times. The organic phase was dried over sodium sulfate. After removing the solvent under reduced pressure, the remaining residue was subjected to a silica gel column using 50% ethylacetate in hexane as the eluant to yield a colorless oil as the pure product (R)—N-(3-bromo-4-methoxybenzyl)-1-(3-fluorophenyl)ethanamine 116 (2.3 g, yield=93%). LCMS (M+1) 338, calc. for C16H17BrFNO 338; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.26 Hz, 3H) 3.46-3.60 (m, 2H) 3.78 (q, J=6.39 Hz, 1H) 6.84 (d, J=8.22 Hz, 1H) 6.90-6.98 (m, 1H) 7.09 (t, J=9.00 Hz, 2H) 7.16 (dd, J=8.41, 2.15 Hz, 1H) 7.27-7.34 (m, 1H) 7.48 (d, J=1.96 Hz, 1H).
Reaction SMILES: [ClH:1].NC(=O)[C@@H](N[C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.Cl.[NH2:35][C@@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([O:39][CH3:40])=[O:38]>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:35][C@@H:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:37]([O:39][CH3:40])=[O:38])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 43 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (S)-methyl 2-amino-2-phenylacetate hydrochloride (Aldrich, 30 mg, 0.10 mmol) in a manner similar to that which is described in Step C of Example 1 to give (S)-methyl 2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate, hydrochloride salt (21 mg, 43% yield). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.04 (d, 1H, J=7.0 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.75-7.88 (m, 3H), 7.42 (m, 7H), 6.72 (d, 1H, J=7.0 Hz), 6.12 (s, 1H), 5.45 (d, 1H, J=7.0 Hz), 3.63 (s, 3H), 3.43-3.38 (m, 2H); MS(ESI+) m/z 453.26 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: CCNCC
Product: CCN(CC)Cc1cc(-c2ccc(C)cc2)nn(CC(C)C)c1=O
Yield: 95 %

Procedure:
Following the procedure of Example 9 (4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a pale yellow oil (yield: 95.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])(=[O:28])[CH3:27]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (10 g., 81.88 mmol) was dissolved in 150 ml dichloromethane under argon. Triethylamine (17.12 ml, 0.123 mol) and dimethylaminopyridine (5 mg.) were added, and the resulting stirred solution was treated with acetic anhydride (8.5 ml, 90 mmol). After stirring for fifteen hours, the reaction mixture was transferred to a separatory funnel using an additional 50 ml dichloromethane. The organic layer was washed with water (2×100 ml) and concentrated to give a light brown oil weighing 14.85 g. Plug filtration through silica gel using dichloromethane furnished 13.3 g (quant.) of a light orange oil which was shown by NMR and IR to be pure enough for use in subsequent reactions (see Tables 3 and 7). ##STR33##
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])C.[C:12]1([CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(#N)C>C(Cl)Cl>[C:12]1([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[O:25])=[CH:27][CH:28]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1csc(N)n1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Nc1nc(C(=O)O)cs1)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 70 %

Procedure:
2-Amino-4-thiazolecarboxylic acid ethyl ester (6.85 g, 39.8 mmol) was allowed to react with 4-phenylmethoxybenzoyl chloride (10.72 g, 43.8 mmol) according to the procedure in Example 1. The reaction was completed in 18 hours. After workup and flash chromatography on silica gel eluting with 1-7% acetonitrile in methylene chloride, the ethyl ester of 2-[[4-phenylmethoxybenzoyl]amino]-4-thiazolecarboxylic acid was obtained (70% yield) and was hydrolyzed to the corresponding acid with 1.0N NaOH as described in Example 1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH:9]1[C:18]([O:20]CC)=[O:19])(=[O:7])=[O:6].[OH-].[Na+].Cl>O1CCOCC1.CCO>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][CH:9]1[C:18]([OH:20])=[O:19])(=[O:7])=[O:6]
Reactant: CCOC(=O)C1CN(S(C)(=O)=O)CCN1S(=O)(=O)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(S(=O)(=O)CCCCl)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A mixture of ethyl (2RS)-1-(3-chloropropylsulfonyl)-4-methanesulfonylpiperazine-2-carboxylate (203 mg) and 1N aqueous sodium hydroxide (0.9 ml) in dioxane (2 ml) and EtOH (1 ml) was stirred for 2 hours at ambient temperature. The mixture was acidified with 1N HCl (0.9 ml) and concentrated in vacuo. The resulting crystals were collected with H2O, and washed with H2O and Et2O to give 165 mg of (2RS)-1-(3-chloropropylsulfonyl)-4-methanesulfonylpiperazine-2-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])O[C:7]2=[O:17])[CH2:3][CH2:2]1.C([C:20](CC)(C([O-])=O)[C:21]([O-])=[O:22])C.N12CCCN=C1CCCCC2.[NH2:40][CH2:41][C:42]([OH:44])=[O:43].[OH-].[Na+]>O.O1CCOCC1>[CH:1]1([CH2:4][CH2:5][N:6]2[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:9]([OH:16])=[C:20]([C:21]([NH:40][CH2:41][C:42]([OH:44])=[O:43])=[O:22])[C:7]2=[O:17])[CH2:2][CH2:3]1
Reactant: NCC(=O)O
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: O=c1oc(=O)n(CCC2CC2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)c1c(O)c2cccnc2n(CCC2CC2)c1=O
Temperature: 150 °C
Yield: 2.4 %

Procedure:
A mixture of 1-(2-cyclopropylethyl)-2H-pyrido[2,3-d][1,3]oxazine-2,4 (1H)-dione (Prepared according to PCT Int. Appl. (2003), WO 2003059356 A2)(0.232 g, 1.00 mmol) and diethylmalonate (0.152 mL, 1.00 mmol) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.00 mmol). 1,4-dioxane (1.0 mL) was added and the solution was heated to 150° C. for 20 min. in a Biotage Initiator microwave synthesizer (http://www.biotage.com). Following cooling, glycine (0.113 g, 1.50 mmol) was added and the solution was heated to 200° C. for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous sodium hydroxide (2.0 mL), diluted with water and extracted with diethyl ether. The aqueous layer was then acidified with 6M aqueous hydrochloric acid and extracted twice with ethyl acetate. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The mixture was purified via preparative HPLC(YMC 75×30 mm column, 0.1% TFA in water and 0.1% TFA in acetonitrile) to afford the title compound as a white solid (0.008 g; 2.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1H), 10.5 (t, J=5.6 Hz, 1H), 8.83 (dd, J=4.5, 1.8 Hz, 1H), 8.46 (dd, J=8.0, 1.9 Hz, 1H), 7.43 (dd, J=8.0, 4.7 Hz, 1H), 4.41-4.60 (m, 2H), 4.13 (d, J=5.6 Hz, 2H), 1.55 (q, J=7.3 Hz, 2H), 0.67-0.82 (m, 1H), 0.32-0.41 (m, 2H), −0.09-0.04 (m, 2H). MS(ES+) m/e 332 [M+H]+.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.O[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[CH:40][CH:41]=[N:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:66]>C1COCC1>[ClH:66].[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:37]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:38]=3[N:39]=[CH:40][CH:41]=[N:42]4)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: Oc1cccc2nccnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)c2nccnc2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
TMAD (0.55 g, 3.20 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 5-hydroxyquinoxaline*(0.45 g, 3.08 mmol) and PPh3 (0.85 g, 3.24 mmol) in THF (20 mL). The reaction was stirred at room temperature for 1.5 h and at 65° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica using toluene/EtOAc (1:1) as eluent. The resulting solid was crystallized twice from diethyl ether/petroleum ether to remove PPh3O. The recrystallized material (0.50 g) was dissolved in MeOH (15 mL) and 1 M HCl (3.5 mL) was added. The resulting mixture was stirred at room temperature for 4 h (only 10% N-Boc-deprotection had occurred according to HPLC/MS). The mixture was concentrated and the residue was treated with CH2Cl2/TFA/H2O (50:45:5; 20 mL) for 1 h. After concentration in vacuo, the residue was dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was lyophilized to give a yellow oil that was dissolved in 1 M HCl. The solution was concentrated and MeOH and diethyl ether was added. The precipitate formed was collected and dried in vacuum to give 0.32 g (76%) of the title product. Pos-EI-MS shows M+ and 8 ions supporting the stated structure. HRMS m/z calcd for C18H20N6O2(M)+352.1648, found 352.1662.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])([O-])=O.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd].O>[NH2:1][C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1N)C(F)(F)F
Yield: 96 %

Procedure:
A suspension of N-[2-nitro-4-(phenylsulphonyl)phenyl]2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (J. Med. Chem., 1996, 39, 4592) (0.293 g) in methanol (5 ml) was added to a stirred suspension of 10% palladium on carbon (0.03 g) in methanol (2 ml) under an atmosphere of argon. A solution of ammonium formate (0.176 g) in water (2 ml) was added and the mixture was heated under reflux for 2 hours then cooled. Ethyl acetate (20 ml) was added and the mixture was filtered through diatomaceous earth. The filter was washed with ethyl acetate (2×10 ml) and the filtrates were combined, washed with water and brine then dried. Volatile material was removed by evaporation to give the title compound (0.261 g) as a solid. NMR: 1.55 (s, 3H), 5.3 (s, 2H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.4 (m, 2H), 7.5-7.7 (m, 3H), 7.85 (d, 2H), 9.6 (s, 1H); MS (ESP−): 387.
Reaction SMILES: OO.[CH2:3]([SH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:12][C:13]([NH2:15])=[S:14].[ClH:16]>C(O)C.C(OCC)C.O>[ClH:16].[CH2:3]([S:11][S:14][C:13](=[NH:12])[NH2:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NC(N)=S
Reactant: CCCCCCCCS
Agent: Cl
Agent: OO
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCSSC(=N)N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen peroxide (30% aqueous, 28.0 g) was added dropwise over 45 minutes to a stirred mixture of n-octanethiol (32.27 g, 0.221 mole), thiourea (20.1 g, 0.264 mole), concentrated hydrochloric acid (35 ml), water (35 ml) and ethanol (500 ml) maintained at 0°-10° C. After the addition was complete the reaction mixture was stirred at room temperature for 2 hours during which time a thick white precipitate formed. The mixture was filtered and the filtrate evaporated giving a solid residue. This was dissolved in ethanol (150 ml), diluted with diethyl ether (800 ml) and allowed to stand overnight at 0° C. Filtration gave white crystals of the product (46.3 g; 82%), melting point=77°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]Cl)([CH3:16])[CH3:15]>>[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[NH2:9])([CH3:16])[CH3:15]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Product: COc1ccc(N)cc1OCCN(C(C)C)C(C)C

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 2-diisopropylaminoethyl chloride hydrochloride, following a procedure similar to that described in Descriptions 1 and 2 (81%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][C@H:21]1[C:26](=[O:30])[NH:27][CH2:28][CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:22][C@H:21]1[C:26](=[O:30])[NH:27][CH2:28][CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
13.81 ml of triethylamine and subsequently 7.65 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 23.20 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and then the mixture was stirred at 0° to 5° C. for 30 minutes. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 26.54 g of the title compound as colorless crystals, melting at 138°-140° C.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11](F)[N:10]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:10]=1
Reactant: Cc1c(F)c(N)nc(F)c1F
Reactant: COc1ccc(CN)cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(N)c(F)c(C)c2F)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To 3 ml of N-methylpyrrolidone were added 1.35 g of 2-amino-3,5,6-trifluoro-4-methylpyridine together with 3.0 g of p-methoxybenzylamine, and the mixture was stirred under nitrogen atmosphere at 140° C. for 18 hours and allowed to cool. After adding 30 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 20 g; eluent: chloroform:n-hexane, 1:1, and then, chloroform) to obtain 0.90 g of the title compound as a pale yellow crude oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1COS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C@H:2]1[CH2:3][O:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1O[C@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (777 mg, 3.0 mmol), 2-methoxyphenol (372.5 mg, 3.0 mmol) and Cs2CO3 (1.3 g, 4.0 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum spirit 40-60) to give subtitled compound (425 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[CH:11]=1.CI.[Mg].[C:15](=[O:17])=[O:16]>CCOCC>[CH3:10][C:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:15]([OH:17])=[O:16])=[CH:11][C:6]=2[S:7][CH:8]=1
Reactant: O=C=O
Reactant: Cc1csc2cc(Br)ccc12
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: Cc1csc2cc(C(=O)O)ccc12
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-3-methylbenzo[b]thiophene (16.8 g) and methyl iodide (23.8 g) was added dropwise to a stirred mixture of dry ether (150 ml) and magnesium (11.06 g) at such a rate that gentle reflux was maintained. When the addition was complete, the mixture was heated under reflux with stirring for 30 minutes, then cooled and poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated, 2N hydrochloric acid (100 ml) was added and the mixture was shaken. The ether layer was separated and the aqueous layer was extracted with ether. The ether solutions were combined, dried (Na2SO4) and evaporated to give a solid which was crystallized from ethyl acetate to give 3-methylbenzo[b]thiophene-6-carboxylic acid (7.71 g), m.p. 230°-232° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCCCCC.CCOC(C)=O>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
Combine tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (4.720 kg, 20.6 mol) with DCM (40 L) and TEA (3020 mL, 21.63 mol) in a 50 L reactor under a nitrogen atmosphere. Cool the solution to about 0° C. and slowly add methane sulfonyl chloride (2.478 kg, 21.63 mol) in DCM (5 L) while keeping the reaction temperature below 10° C. After the addition is complete stir the mixture for 18 h at 15° C. at which time TLC (1:1, hexane:EtOAc) shows no starting material remaining Wash the mixture with water (30 L) and allow the phases to separate. Concentrate the organic phase to a solid. Slurry the solid in MTBE (6 L), collect by filtration, and dry in a vacuum oven at 50° C. to provide the title compound as a white solid (5.67 kg, 91%).