Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=[O:28].[CH3:32][N:33]([CH3:36])[CH:34]=[S:35]>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:27]([OH:28])[C:34](=[S:35])[N:33]([CH3:36])[CH3:32])[CH:29]=1
Reactant: CN(C)C=S
Reactant: COc1ccc(F)cc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)C(=S)N(C)C
Temperature: -78 °C
Yield: 28000.7 %

Procedure:
To a solution of lithium diisopropylamide, 2M in THF/n-heptane (210 mL, 583 mmol) was added THF (100 mL) and the solution cooled to −78° C. under nitrogen. This was then added dropwise over 1 h to a solution of the 5-fluoro-2-methoxybenzaldehyde (50 g, 0.32 mmol) and N,N-dimethylthioformamide (34.7 g, 389 mmol) in dry THF (200 mL). This was warmed to −5° C. and quenched with water (400 mL). The solution was filtered and washed with diethyl ether, the aqueous layer was extracted with ether (1 L). The combined organic layers were washed with water (500 mL), dried (MgSO4) and the solvent removed in vacuo to give a crystalline suspension in oil. This was triturated in ether and filtered to give a crystalline solid (21.8 g, 28%); δH (300 MHz, CDCl3) 7.16–6.81 (3H, m, ArH), 5.81–5.75 (1H, m, CHOH), 5.31–5.22 (1H, m, OH), 4.89 (3H, s, OCH3), 3.50 (3H, s, N(CH3)2) and 3.08 (3H, s, N(CH3)2).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1nc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(Cl)cc3nc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.3 %

Procedure:
To 2,6-dichloro-3-methoxyquinoxaline (4.00 g, 17.5 mmol) dissolved in dimethyl-sulfoxide (40 ml), 2,4-dimethoxybenzylamine (14.6 g, 87.3 mmol) was added at room temperature. The mixture was stirred at room temperature for 36 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (30:1) mixture and concentration gave 4.93 g of the titled compound (yield, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl.[C:36]([O:39][CH2:40]C)(=O)[CH3:37]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:24])[CH2:10][C:9]2[N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[N:7]=[C:6]([C:11]3[N:12]([CH2:40][O:39][CH2:36][CH2:37][Si:28]([CH3:34])([CH3:29])[CH3:27])[C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Under an argon atmosphere, to a solution of methyl 2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-6-carboxylate (23 g, 71 mmol) in N,N-dimethylformamide (230 ml) was added sodium hydride (6.3 g, 157 mmol) in portions of about 500 mg at an inside temperature of −10° C., and the mixture was stirred for 30 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (26 g, 157 mmol) was added dropwise over 15 min, and the mixture was further stirred for 2 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (33 g, yield 80%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]([Cl:27])([Cl:26])[CH:8]1[O:13][CH:12]([C:14]([Cl:17])([Cl:16])[Cl:15])[C:11]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:10]=2[O:9]1>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[S:22]([C:19]1[CH:20]=[CH:21][C:10]2[O:9][CH:8]([C:7]([Cl:6])([Cl:26])[Cl:27])[O:13][CH:12]([C:14]([Cl:17])([Cl:15])[Cl:16])[C:11]=2[CH:18]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: CCO
Product: CCN(CC)S(=O)(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
Diethylamine (0.8 g.) was added dropwise to a stirred suspension of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-sulphonyl chloride (4.7 g.) in absolute ethanol (20 ml.), the mixture was maintained under gentle reflux for 2 hours, and the resulting solution was allowed to cool slowly to give a crystalline product, which was recrystallised from aqueous methanol to give 6-diethylsulphamoyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 125°-126° C.
Reaction SMILES: N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=[N:30][O:31][CH2:32][CH2:33][OH:34])[CH:20]=1.O[C:36]1[CH:68]=[CH:67][C:39]([CH2:40][CH:41]2[S:45][C:44](=[O:46])[N:43]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]2=[O:66])=[CH:38][CH:37]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O1CCCC1>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=[N:30][O:31][CH2:32][CH2:33][O:34][C:36]2[CH:68]=[CH:67][C:39]([CH2:40][CH:41]3[S:45][C:44](=[O:46])[N:43]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]3=[O:66])=[CH:38][CH:37]=2)[CH:20]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1cnc2ccccc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1SC(Cc2ccc(OCCON=Cc3cnc4ccccc4c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A solution of 0.73 g of 1,1'-(azodicarbonyl)dipiperazine in 10 ml of toluene was added dropwise at room temperature to a suspension of 0.60 g of 2-(3-quinolylmethyleneaminooxy)ethanol (prepared as described in Preparation 3), 1.10 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione and 0.72 ml of tributylphosphine in 30 ml of tetrahydrofuran, and the resulting mixture was stirred for 16 hours. At the end of this time, the reaction product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.45 g of the title compound as a crystalline powder, melting at 127°-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14](N)(=O)[C:15]1C=CC=C[CH:16]=1.C(Cl)(=O)C>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:14]([CH2:15][CH3:16])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Solvent: CC(=O)Cl
Product: CCc1nc(O)c2ccc(OC)c(C)c2n1
Yield: 100 %

Procedure:
The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and acetic acid chloride as acid chloride [B], which gave the title compound (2.2 g, 100%). 1H-NMR DMSO-D6 δ 1.2 (m, 3H), 2.38 (s, 3H), 2.6 (m, 2H), 3.90 (s, 3H), 7.18 (d, 2H), 7.96 (d, 2H), 11.88 (s, 1H).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:30][CH:29]=1
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Reactant: Sc1ccc(Br)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(CSc2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
Methanesulfonyl chloride (0.28 mL, 3.6 mmol) was added dropwise to a solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 600 mg, 3 mmol), triethylamine (0.627 mL, 4.5 mmol), and CH2—Cl2 (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, then at ambient temperature for 2 h. The mixture was washed with water, and the organics were concentrated. The resulting crude material was mixed with 4-bromobenzenethiol (567 mg, 3 mmol) and K2CO3 (829 mg, 6 mmol) in DMF (10 mL), and the mixture was stirred at ambient temperature overnight. The mixture was charged with water, and extracted with EtOAc. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% EtOAc/hexanes to give 292 mg (26%) of 1-methylethyl 4-{[(4-bromophenyl)thio]methyl}-1-piperidinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.37 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz), 4.95-4.82 (m, 1H), 4.15-4.09 (m, 2H), 2.80 (d, 2H, J=6.9 Hz), 2.72-2.60 (m, 2H), 1.85-1.77 (m, 2H), 1.70-1.60 (m, 1H), 1.24-1.08 (m, 8H); LRMS (ESI), m/z 372/374 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:26]([C:23]1[CH:24]=[CH:25][C:19]2[CH:18]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[S:21][C:20]=2[CH:22]=1)=[O:27]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)N(C)C)cc2s1
Yield: 75.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid (175 mg, 0.387 mmol), DMAP (142 mg, 1.16 mmol), EDC (111 mg, 0.580 mmol), and dimethylamine hydrochloride (47 mg, 0.580 mmol) are reacted analogous to Example 3 to afford the title compound (140 mg, 76%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([Sn](Cl)(Cl)CCCC)[CH2:28]CC.C(=O)C.C1([SiH3])C=CC=CC=1>C1COCC1>[CH2:27]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)=[O:16])[CH3:28]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: CC=O
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CCN(c1ccccc1)c1ccccc1NC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h
Yield: 530 %

Procedure:
To a stirring solution of compound 112 (1.00 g, 2.89 mmol) in THF was added dibutyltin dichloride (0.175 g, 0.577 mmol) and acetaldehyde (1.182 g, 26.8 mmol) and the reaction mixture was stirred 15 minutes. Phenylsilane (0.375 g, 3.46 mmol) was added and the reaction mixture was stirred at room temperature 60 h then solvent evaporated. The resulting crude product was purified by Isco (80 g column, 10%-50%) to afford title compound 113 (1.145 g, 100%) as a yellowish oil. LRMS (ESI): (calc) 374.16. (found) 375.4 (MH)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19]([N:54]1[CH2:55][CH2:56][N:51]([CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:52][CH2:53]1)=[O:21])([CH3:11])([CH3:12])[CH3:13]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
DIPEA (22.14 g, 171.3 mmol) was added to a stirred solution of tert-butoxycarbonylamino-acetic acid (10 g, 57.1 mmol) in DMF (40 mL). HOBT (9.25 g, 68.5 mmol) and EDCI.HCl (12.61 g, 68.5 mmol) were then added at room temperature. After 2 minutes N-benzylpiperazine (12.1 g, 68.5 mmol) was added, and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 13.4 g (70.5% yield) of [2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester as white powder. 1H NMR (CDCl3): δ 7.3 (m, 5H), 5.5 (bs, 1H), 4.0 (d, 2H), 3.7-3.6 (t, 2H), 2.5 (s, 2H), 3.4 (t, 2H), 2.4 (s, 4H), 1.3 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
To a suspended solution of methyl 5-benzyloxy-2-hydroxybenzoate (3.91 g) and cesium carbonate (6.41 g) in acetone (100 ml) was added methyl iodide (1.41 ml), and the mixture was stirred at 50° C. for 6 hr. The reaction mixture was concentrated, dissolved again in ethyl acetate and washed with saturated brine. The organic layer was dried (over MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage cartridge 40+M, ethyl acetate:n-hexane=15:85→1:4) to give methyl 5-benzyloxy-2-methoxybenzoate (3.72 g, 90%) as colorless crystals.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Br:18])[CH:11]=1)[C:6]([CH3:9])([OH:8])[CH3:7])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.C1N=CN([C:52](N2C=NC=C2)=[O:53])C=1>[NH4+].[Cl-].C1COCC1.O>[Br:18][C:12]1[CH:11]=[C:10]([C@@H:5]2[C:6]([CH3:9])([CH3:7])[O:8][C:52](=[O:53])[NH:1][CH2:4]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc([C@@H](CN=[N+]=[N-])C(C)(C)O)cc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H]2CNC(=O)OC2(C)C)cc1Br
Temperature: 60 °C
Yield: 79.6 %

Procedure:
To a 25 mL round bottom flask containing (S)-4-azido-3-(3-bromo-4-methoxyphenyl)-2-methylbutan-2-ol (38 mg, 0.12 mmol) were added PPh3 (48 mg, 0.18 mmol), THF (2 mL) and water (0.2 mL). The resulting reaction mixture was heated to reflux for 2 hrs. Volatiles were removed under vacuum. To the residue was added 2 mL THF, DIEA (0.063 mL, 0.36 mmol) and CDI (39 mg, 0.24 mmol). The resulting reaction mixture was heated at 60° C. for 3 hrs. It was then diluted with 10 mL saturated NH4Cl and extracted with 15 mL EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on a Combiflash prepacked silica gel column which was eluted with EtOAc to give 30 mg of the desired product (intermediate N). 1H NMR (500 MHz, CDCl3): δ 7.41 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 3.90 (s, 3H), 3.65 (t, J=11.4 Hz, 1H), 3.46 (br, 1H), 3.0 (br, 1H), 1.34 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6](Cl)(=[O:8])=[O:7])=[N:2]1.O1CCCC1.S(Cl)(Cl)(=O)=O.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:8])=[O:7])=[N:2]1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: O=S(=O)(Oc1ccccc1)c1nc[nH]n1
Reaction time: 16 h

Procedure:
To a flask was added 10 g of thoroughly dried 1,2,4-triazole-3-sulfonyl chloride and 150 ml of tetrahydrofuran. The resulting mixture was stirred under nitrogen until most of the sulfonyl chloride dissolved. Phenol, 6.2 g, was then added at room temperature followed by the slow addition of 9 ml of triethyl amine. A precipitate became apparent and the resulting mixture was stirred for an additional 16 hours. The tetrahydrofuran was evaporated from the mixture and the residue washed with 200 ml of water followed by extraction with 200 ml of ethyl acetate. The ethyl acetate solution was dried using sodium sulfate, filtered and concentrated to yield 10.77 g of the desired intermediate as a white solid.
Reaction SMILES: C(C1C=C[S:6]C=1)(=O)C.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.[CH2:19]([CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:6][C:28]2[CH2:27][CH:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30][C:29]=2[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: CC(=O)c1ccsc1
Reactant: N#CCC(=O)c1ccsc1
Agent: [S]
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccsc1)CCC(Cc1ccccc1)C2
Yield: 65 %

Procedure:
The procedure of Example 1 was followed except that 3-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophen-3-carbonyl)acetonitrile (Steps A and B). 4-Benzyl-cyclohexanone (Rosowsky et al., (1999) J. Med. Chem. 42: 1007-1017), 2-(thiophen-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 65%; IR (KBr) cm−1: 3401, 2920, 1560, 1547, 1419, 1260, 700; 1H NMR (CDCl3):δ0.79 (m, 1H), 1.29 (m, 2H), 1.49 (m, 1H), 2.17 (m, 3H), 2.66 (m, 2H), 7.02 (bs, 2H), 7.28 (m, 8H); mp: 57-58° C. (petroleum ether).
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH3:20]O>>[N:14]1([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:20])[CH:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CO
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: C1CCNCC1
Product: COC(=O)Cc1ccc(N2CCCCC2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of methyl (4-bromomethyl-phenyl)acetate (6.00 g, 24.7 mmol) in methanol (60 ml) was added piperidine (6.30 g, 74.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours. The solvent was then evaporated under reduced pressure. The residue was poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo to afford methyl (4-piperidin-1-yl-methyl-phenyl)acetate as a pale red oil (5.98 g, 24.2 mmol, 98%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5]([CH3:8])([OH:7])[CH3:6].[C:11](=O)([O:19]C1C=CC=CN=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C1COCC1>[C:11](=[O:19])([O:7][C:5]([CH3:8])([CH3:6])[C:4]([F:10])([F:9])[F:3])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(O)C(F)(F)F
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of NaH (1.03 g, 25.8 mmol) in THF (70 mL) was added 1,1,1-trifluoro-2-methylpropan-2-ol (3 g, 23.42 mmol). The reaction was stirred at 0° C. for 20 min. A solution of dipyridin-2-yl carbonate (5.06 g, 23.42 mmol) in THF (30 mL) was then added to the mixture. The resulting solution was stirred at room temperature for overnight. Filtered the resulting solid byproducts and washed with EtOAc (2×20 mL). The combined organic layers was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting white pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (1.24 g, 21%) was directly used as a reagent.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.CCOC(C)=O.[NH4+].[Cl-]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 27.5 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([OH:55])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48].Br[CH2:69][CH2:70][F:71]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([O:55][CH2:69][CH2:70][F:71])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: FCCBr
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and 1-bromo-2-fluoro ethane, and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.07, 1.14, 2.36, 2.65, 3.60, 3.72, 3.79, 3.82, 4.27, 4.42, 4254, 4.62, 5.09, 5.95, 6.98, 7.11, 7.25, 7.38; IR (diffuse reflectance) 2350 (w), 2337 (w), 2058 (w), 1952 (w), 1940 (w), 1710 (s), 1569, 1552, 1483 (s), 1459, 1419 (s), 1397, 1353, 1287, 1228, cm−1 HRMS (FAB) calcd for C29H34ClFN4O4+H 557.2330, found 557.2338.