Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([C:32]([F:33])([F:34])[F:35])=[C:24]([F:23])[CH:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [(3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (3.5 g, 0.010 mol) in MeOH (60 ml) was added 3-fluoro-4-trifluoromethyl-benzaldehyde (2.10 g, 0.0109 mol). Then a solution of NaBH3CN (0.79 g, 0.012 mol) in MeOH (15 ml) and AcOH (0.1 ml) were added. The reaction mixture was stirred overnight at RT, concentrated under vacuo, diluted with EtOAc, washed with H2O. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 3.31 g (6 2%) of the title compound as a colorless oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Br:16][C:17]1([C:20]([OH:22])=O)[CH2:19][CH2:18]1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=O.NC(CC)CO>C(Cl)Cl>[Br:16][C:17]1([C:20]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:22])[CH2:19][CH2:18]1
Reactant: O=C(O)C1(Br)CC1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCC(N)CO
Solvent: ClCCl
Product: O=C(NCCCCO)C1(Br)CC1
Yield: 76 %

Procedure:
7.45 g of N,N′-dicyclohexylcarbodiimide is added at 0° C. under nitrogen to a solution of 5.0 g of 1-bromocyclopropanecarboxylic acid 4 and 4.18 g of N-hydroxysuccinimide in 87 ml of methylene chloride, and it is stirred for 1.5 more hours. Then, 7.46 ml of 2-amino-1-butanol is added, and it is stirred for 2 hours at room temperature. After dilution with methylene chloride, it is filtered, concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane. 5.44 g of 1-bromo-N-[(1-hydroxymethyl)propyl]-cyclopropane-1-carboxamide 78 is obtained as a yellowish oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].O=[C:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([OH:22])=[O:21].C([BH3-])#N.[Na+]>>[C:20]([CH:19]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])([OH:22])=[O:21]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCC(=O)O)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
As described in Example 5, treat 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and 2-oxoglutaric acid with sodium cyanoborohydride to isolate the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[P:37]([O-:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40].CN1[CH2:51][CH2:50][O:49]CC1>CC#N.[NH4+].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([P:37]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:44])=[C:8]([P:37]([O:49][CH2:50][CH3:51])([O:38][CH2:39][CH3:40])=[O:41])[CH:7]=1
Reactant: COC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c1)NC(=O)OC(C)(C)C
Reactant: CN1CCOCC1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1P(=O)(OCC)OCC
Temperature: 95 °C
Reaction time: 48 h
Yield: 10.5 %

Procedure:
To 3-(3,4-bis-trifluoromethanesulfonyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (2 g, 3.47 mmol), diethyl phosphite (1 mL, 7.65 mmol) and 4-methyl morpholine (0.93 mL, 8.3 mmol) in MeCN (10 ml) was added Pd(PPh3)4 (167 mg, 0.15 mmol). The mixture was allowed to stirred for two days at 95° C. then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over magnesium sulfate, concentrated, and chomatographed over silica gel (5% MeOH/EtOAc) to an oil (0.2 g, 37% yield). MS [M+H]+ 552 & [M+Na] 574.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]([CH2:33][CH:34]([CH3:37])[CH2:35]Cl)[CH3:32])=[CH:27][CH:26]=1>CCCCCC.O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]([CH3:32])[CH2:33][CH:34]([CH3:37])[CH2:35][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:9][CH2:10][CH2:11][CH2:12][S:13]2)=[CH:38][CH:39]=1
Reactant: Clc1ccc(C2SCCCS2)cc1
Reactant: CC(CCl)CN(C)CCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(CN(C)CCc1ccc(Cl)cc1)CC1(c2ccc(Cl)cc2)SCCCS1
Reaction time: 2 h

Procedure:
2.77 g (0.012 mol) of 2-(4-chlorophenyl)-m-dithiane and 10 ml of abs. tetrahydrofuran were cooled to -70° in a sulphonation flask while gassing with argon and treated with 7.50 ml (0.012 mol) of butyllithium in hexane. Thereupon, the mixture was stirred at -20° for 2 hours. A solution of 2.50 g (0.0096 mol) of rac-4-chloro-N-(3-chloro-2-methylpropyl)-N-methylphenethylamine in abs. tetrahydrofuran was added dropwise thereto at -70° within 15 minutes, whereupon the mixture was left to stand at -20° for 18 hours and at room temperature for 3 hours. The reaction solution was then poured into water and extracted three times with ether. The ethereal extracts were dried over magnesium sulphate and evaporated. The residual oil was chromatographed on silica gel with toluene-hexane (1:1). After evaporating the solvent and warming the residue at 50° for 18 hours under reduced pressure there was obtained rac-N-(4-chlorophenethyl)-2-(4-chlorophenyl)-β,N-dimethyl-m-dithiane-2-propanamine as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:29]C1C=CC=C(C(OO)=O)C=1.S(=O)(O)[O-].[Na+].[CH2:45]([NH2:49])[CH:46]([CH3:48])[CH3:47]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10]([NH:49][CH2:45][CH:46]([CH3:48])[CH3:47])[N:9]=2)[CH:5]=[C:6]([Cl:29])[CH:7]=1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)CN
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(NCC(C)C)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
83.8 mg (0.203 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 70.2 mg (0.407 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of toluene and excessive amounts of 74.2 mg (1.02 mmol) of isobutylamine was added at room temperature and stirred at 80° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])OC(C)(C)C)=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:7]=1)[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]=C=O)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:41][C:24]([NH:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:16][CH:17]=2)=[O:30])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(-c2cccc(C)n2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Product: CCc1nc(-c2cccc(C)n2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 26 from tert-butyl 2-{4-[2-ethyl-4-(6-methylpyridin-2-yl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonyl isocyanate. MS (ESI) m/z 524 [M+H]+, 522 [M−H]−, 1H-NMR (DMSO d-6)δ1.20 (3H, t, J=7.3 Hz), 2.49 (3H, s), 2.67 (2H, q, J=7.5 Hz), 2.78 (2H, t, J=7.1 Hz), 3.25-3.32 (2H, m), 6.66 (1H, t, J=5.5 Hz), 7.10 (2H, 1, J=6.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz), 7.7-7.76 (4H, m), 7.93 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:6]([CH2:20][OH:21])=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:6]([CH2:20][O:21][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2]
Reactant: C1=COCCC1
Reactant: CCc1nc(CC)c(C(=O)OC)c(-c2ccc(F)cc2)c1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1nc(CC)c(C(=O)OC)c(-c2ccc(F)cc2)c1COC1CCCCO1
Yield: 87.8 %

Procedure:
A solution of 2,6-diethyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyridinecarboxylic acid, methyl ester (10.0 g, 0.0315 mol), dihydropyran (4.3 ml, 0.0473 mol) and 6.17 g of p-toluene sulfonic acid was stirred (25° C.) for 24 hours, taken up in dichloromethane (400 ml), washed with saturated NaHCO3 (1×170 ml), washed with brine (1×170 ml), dried (MgSO4), and chromatographed on silica (85:15 hexane:ethyl acetate) to yield 11.1 g of the title compound.
Reaction SMILES: COC1C=CC(CC2C=CC=C(OC)C=2)=C(C=1)OC1C=CC(O)=CC=1.Cl.ClCCN1CCCCC1.C[O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([O:67]C)[CH:62]=2)=[C:42]([CH:59]=1)[O:43][C:44]1[CH:58]=[CH:57][C:47]([O:48][CH2:49][CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:46][CH:45]=1>>[OH:67][C:63]1[CH:62]=[C:61]([CH:66]=[CH:65][CH:64]=1)[CH2:60][C:41]1[CH:40]=[CH:39][C:38]([OH:37])=[CH:59][C:42]=1[O:43][C:44]1[CH:45]=[CH:46][C:47]([O:48][CH2:49][CH2:50][N:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)=[CH:57][CH:58]=1
Reactant: COc1cccc(Cc2ccc(OC)cc2Oc2ccc(OCCN3CCCCC3)cc2)c1
Agent: COc1cccc(Cc2ccc(OC)cc2Oc2ccc(O)cc2)c1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1cccc(Cc2ccc(O)cc2Oc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 49.1 %

Procedure:
Synthesized from 4-[5-methoxy-2-(3-methoxybenzyl)phenoxy]phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[5-methoxy-2-(3-methoxybenzyl)phenoxy]phenoxy}ethyl}piperidine (228 mg) was used according to an analogous synthetic method to Example 364 to provide the title compound (105 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A round-bottomed flask was charged with 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenol (233) (0.300 g, 0.842 mmol), Cs2CO3 (0.824 g, 2.53 mmol), DMF (4 mL), and ethyl 4-bromobutanoate (0.602 mL, 4.21 mmol) under N2. The reaction mixture was refluxed for 15 h and cooled at room temperature. Reaction mixture was partitioned between water and EtOAC (1:1, 100 mL) and the layers were separated. The aqueous phase was further extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (1×25 mL), dried (Na2SO4), and then concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to give 0.356 g (90%) of the title compound (288) as a colorless oil. LCMS (ESI) m/z 493.27 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]2C[CH2:13][N:12]([CH2:15]C)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[Cl:19].CN(C)CCCN>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:15])[CH3:13])=[O:7])=[CH:4][C:3]=1[Cl:19]
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Agent: CN(C)CCCN
Product: CN(C)CCCNC(=O)c1ccc(N)c(Cl)c1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 3-Dimethylamino-1-propylamine (Aldrich; 1.685 g, 16.5 mmol), as a tan coloured solid (3.25 g, 85%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[CH3:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:32])[CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>CCO>[CH3:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:32])[CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH3:11])[CH2:30][CH2:31]3)=[CH:18][C:16]=2[N:17]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: Cc1ccccc1OCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCOc4ccccc4C)CC3)ccc2s1

Procedure:
To a solution of 2-bromo-1-(2-methylphenoxy)ethane (1.09 g, 5.09 mmol, crude) in EtOH (15 mL) was added (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (1.5 mL, 8.6 mmol). The solution was stirred at reflux for 14 hours. Upon cooling, the solution was concentrated to an oil and then purified on an Isco™ (100% EtOAc hold 2 min, 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to afford (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]piperazinyl }propan-2-ol.
Reaction SMILES: CN1C2C=C3C(=O)COC3=CC=2CC1=O.[C:16]1([N:22]2[C:30]3[CH:29]=[C:28]4[C:31](=[O:34])[CH2:32][O:33][C:27]4=[CH:26][C:25]=3[CH2:24][C:23]2=[O:35])C=CC=C[CH:17]=1.C(N1C2C=C3C(=O)COC3=CC=2CC1=O)CC.C(N1C2C=C3C(=O)COC3=CC=2CC1=O)(C)C>>[CH2:16]([N:22]1[C:30]2[CH:29]=[C:28]3[C:31](=[O:34])[CH2:32][O:33][C:27]3=[CH:26][C:25]=2[CH2:24][C:23]1=[O:35])[CH3:17]
Reactant: O=C1COc2cc3c(cc21)N(c1ccccc1)C(=O)C3
Agent: CC(C)N1C(=O)Cc2cc3c(cc21)C(=O)CO3
Agent: CCCN1C(=O)Cc2cc3c(cc21)C(=O)CO3
Agent: CN1C(=O)Cc2cc3c(cc21)C(=O)CO3
Product: CCN1C(=O)Cc2cc3c(cc21)C(=O)CO3

Procedure:
Starting with the requisite 1-substituted-5-hydroxyoxindole and following the procedures of Preparation B, 5-methyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole, 5-phenyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole, 5-n-propyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and 5-i-propyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole are prepared.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[C:14]([O:23][C:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[NH:26][N:25]=2)=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:26]1[C:27]([C:29]([F:32])([F:31])[F:30])=[CH:28][C:24]([O:23][C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)=[N:25]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: FC(F)(F)c1cnc(Oc2cc(C(F)(F)F)[nH]n2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
Potassium carbonate (0.69 g, 5.0 mmol) and ethyl isocyanate (0.28 g, 5.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole (1.66 g, 5.0 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5→1/1), to give a white solid of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole-1-carboxamide (0.83 g, yield: 51.6%). mp: 52-54° C./1H-NMR (CDCl3, TMS, ppm): δ 1.34 (t, J=7.1 Hz, 3H), 3.75-4.30 (m, 2H), 5.66 (s, 1H), 7.98 (d, J=1.5 Hz, 1H), 8.64 (m, 1H), 10.20-10.40 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1[nH]cnc1CNCCN
Reactant: CN=C=O
Product: CNC(=O)NCCNCc1nc[nH]c1C

Procedure:
By the procedure of Example 24, N-(5-methyl-4-imidazolylmethyl)ethylenediamine is reacted with methyl isocyanate to give, after concentrating and separating the residue by column chromatography, the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:42][CH2:41][C:32]2([O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[CH2:31][CH2:30]1.C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([C:6]1[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]([CH:29]2[CH2:42][CH2:41][C:32]3([O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]3)[CH2:31][CH2:30]2)[C:2](=[O:1])[C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:55][N:54]=[N:53][N:22]=2)=[CH:13][CH:14]=1)[CH2:24][CH3:25]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.026 g), azidotrimethylsilane (1.2 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.06 g, 28%).
Reaction SMILES: [CH3:1][NH:2][S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4].Cl[C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH2:29]([O:28][C:26]([N:2]([CH3:1])[S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4])=[O:27])[CH2:30][CH3:31]
Reactant: CCCOC(=O)Cl
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)NC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCOC(=O)N(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N(CCC)CCC)c([N+](=O)[O-])c1
Yield: 80.6 %

Procedure:
A mixture of 4.5 g (0.0125 mol) N1 -methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide, 3.06 g (0.025 mol) n-propyl chloroformate, 3.5 g (0.025 mol) potassium carbonate, and 75 ml dimethoxyethane was heated at reflux for 2 hours. The reaction mixture was filtered and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 4.5 g of the product, m.p. 110°-113°C, as an orange solid.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][S:20][CH3:21])=[C:14]([NH:23][CH3:24])[CH:13]=1.[OH2:25]>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][S:20][CH3:21])=[C:14]([CH:13]=1)[N:23]([CH3:1])[CH:24]=[O:25]
Reactant: O
Reactant: CNc1cc(F)ccc1C(=O)CSC
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CSCC(=O)c1ccc(F)cc1N(C)C=O
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (16.5 ml) and formic acid (11.2 ml) was stirred and heated at 50°-60° under nitrogen for 2 hours. The mixture was cooled to ambient temperature and 1-(4-fluoro-2-methylaminophenyl)-2-(methylthio)ethanone (4.0 g), prepared in a similar manner to that described in Example 4, added over a period of 5 minutes. The mixture was stirred at ambient temperature for 2.75 hours and then cooled in an ice/salt bath to maintain the temperature below 30° whilst, water (50 ml) was added over a period of 30 minutes. The mixture was extracted with dichloromethane (2×25 ml), the organic phases combined, washed with water (2×20 ml) and then evaporated in vacuo to give an oily product. Purification of the oily product by high performance liquid chromatography carried out using a Gilson system fitted with a 2" Dynamax silica column and eluting with dichloromethane/methanol (99:1) at 16 ml/min gave 5'-fluoro-N-methyl-2'-(methylthio)acetylformanilide in the form of a pale yellow oil.