Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[H-].[Na+].CS(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:37]([O:1][CH2:2][CH:3]1[CH2:4][O:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][CH2:8]1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: OCC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOCC1COC(c2ccccc2)OC1
Temperature: 50 °C
Yield: 96.8 %

Procedure:
A suspension of 7.769 g (40 mM) of 5-hydroxymethyl-2-phenyl-1,3-dioxane n1 and 2.08 g (52 mM) of 60% sodium hydride in oil in 150 ml of anhydrous benzene is heated at 50° C. for 1 hour then a solution of 17.28 g (54 mM) of n-hexadecyl methanesulfonate in 50 ml of anhydrous benzene is added. The reaction mixture is heated under refluxing for 7 hours. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Crystallization of the residue from n-pentane-methanol affords 16.203 g (97% yield) of the titled compound n2.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH3:19]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
Heat 5 kg of 2-carboxyindole suspended in ethanol in the presence of sulfuric acid to boiling for 8 hours. Evaporate off the ethanol, then take up with 40 liters of ethyl acetate and wash the organic solution with an aqueous sodium hydroxide solution and dry.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Mg]Br)C=C.[CH2:19]1[CH2:23][O:22][CH2:21]C1>>[O:22]1[CH2:21][CH:23]1[CH2:19][C:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: C1CCOC1
Agent: C=CC[Mg]Br
Product: OC1(CC2CO2)CCCCCCCCCCC1
Temperature: 0 °C

Procedure:
An oven-dried 500-mL three-neck round-bottom flask was charged with cyclododecanone (6.00 g, 32.9 mmol) and 50 mL dry THF. A 100-mL addition funnel with allyl magnesium bromide (1.0 M solution in THF, 36.2 mL, 36.2 mmol) was attached and the flask was cooled in an ice bath for 10 minutes. The Grignard was slowly dripped in over the course of 30 minutes while stirring at 0° C. under nitrogen. After addition, the ice bath was removed and the reaction mixture was stirred for 4 hours at room temperature under nitrogen. Excess Grignard was quenched by slowly adding water to the reaction mixture cooled to 0° C., and the product was extracted three times with diethyl ether. The organic layer was dried over Na2SO4 and solvent was removed under vacuum to obtain the homoallylic alcohol that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:37]([O:36][C:34](=[O:35])[O:23][C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:1])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=2)[CH3:38]
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Oc1nc2c(N)nc(OCCOC)nc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxy-ethoxy)-9H-purin-8-ol, 29 (11.75 mg, 0.027 mmol, prepared according to the procedure described by Kurimota, et al., Bioorg. Med. Chem., 12, 1091-109 (2004) was suspended in CH2Cl2 (0.6 mL) and cooled to 0° C. DIEA (11.96 μL, 0.068 mmol) and ethyl chloroformate (3.86 mg, 0.036 mmol, added as a 10% by volume solution in dichloromethane) were then added to the suspension. The reaction mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature for 15 minutes. TLC of the reaction mixture shows that starting material remained. The reaction mixture was heated to 35° C., DMAP (cat.), methanol (60 μL portions) was added to dissolve 29, and additional aliquots of ethyl chloroformate (3.86 mg, 0.036 mmol, added as a 10% by volume solution in dichloromethane) were added until the reactions was complete. The crude mixture was purified by flash chromatography using a 0 to 100% gradient of ethyl acetate in hexane. The desired peaks were collected and concentrated in-vacuo to yield 8.5 mg (80%) of compound 51 as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=Hz, 2H), 7.27 (m, 3H), 4.98 (s, 2H), 4.46 (m, 4H), 3.74 (m, 2H), 3.42 (s, 2H), 1.46 (t, 3H); MS [M+H]+ m/z 388.3.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([CH:8]([OH:10])[CH3:9])[C:4]=1[O:11][C:12]1[CH:13]=[C:14]([C:20]#[N:21])[CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18])[CH3:2].Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=[C:5]([CH:8]([OH:10])[CH3:9])[C:4]=1[O:11][C:12]1[CH:19]=[C:16]([C:17]#[N:18])[CH:15]=[C:14]([CH:13]=1)[C:20]#[N:21])[CH3:2]
Reactant: CCc1[nH]nc(C(C)O)c1Oc1cc(C#N)cc(C#N)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)O)nn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 60 h
Yield: 29.2 %

Procedure:
To a stirred solution of the pyrazole from Example 263 (197 mg, 0.70 mmol) in dimethylformamide (3 ml) at 0° C. was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (105 μl, 0.70 mmol) followed by sodium hydride (31 mg, 0.77 mmol). After 15 minutes the cooling bath was removed and the mixture was stirred at room temperature for 60 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (0.5 ml) and then concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (a gradient from 100:0 to 95:5, by volume) to provide the title compound (84 mg) as a white foam which reverts to an oil on standing.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:4]2[N:5]([CH2:11][CH:12]([CH3:14])[N:13]=2)[C:6](=[O:10])[C:7]=1[N:8]=O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].N1C=CC=[CH:35][CH:34]=1.C(OC(=O)C)(=O)C>C(O)=O.C(#N)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:3]2[C:2]3[NH:1][C:34]([CH3:35])=[N:8][C:7]=3[C:6](=[O:10])[N:5]3[CH2:11][CH:12]([CH3:14])[N:13]=[C:4]23)=[CH:17][CH:18]=1
Reactant: c1ccncc1
Reactant: CC1CN2C(=O)C(N=O)=C(N)N(Cc3ccc(Cl)cc3)C2=N1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: Cc1nc2c([nH]1)N(Cc1ccc(Cl)cc1)C1=NC(C)CN1C2=O
Temperature: 25 °C

Procedure:
The product of Procedure 99 was reduced with sodium dithionate in formic acid according to the method of Procedure 21. The resulting 7-amino-4-[(4-chlorophenyl)methyl]-2,3-dihydro-6-formylamino-2-methylimidazo[1,2-a]pyrimidin-5-(8H)-one, 3.5 g. (0.0104 mole) in 7 ml. of pyridine and 7 ml. of acetic anhydride was refluxed for three 3 hrs. during which the mixture foamed and turned dark. The mixture was allowed to cool to room temperature and diluted with acetonitrile resulting in the formation of a white precipitate which was collected. Recrystallized from iPROH/MeOH, yield 800 mg., m.p. 290°-291° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:3]=1.[OH:20][CH:21]([CH2:24][OH:25])[CH2:22][NH2:23]>CN(C)C=O.O>[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:23][CH2:22][CH:21]([OH:20])[CH2:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: NCC(O)CO
Reactant: Clc1ccc(-c2nc(Cl)c3ccccc3n2)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: OCC(O)CNc1nc(-c2ccc(Cl)c(Cl)c2)nc2ccccc12
Reaction time: 4 h

Procedure:
A mixture of 46.5 g. (0.15 mole) of 4-chloro-2-(3,4-dichlorophenyl)quinazoline in 500 ml of dimethylformamide and 29 g (0.31 mole) of 2,3-dihydroxypropylamine was heated on a steam bath with stirring for 4 hrs. Diluted the mixture with water until turbid and cooled in an ice bath. The colorless solid was filtered and recrystallized from methyl alcohol (Darco). The product was collected as colorless needles melting at 155°-160° (with previous softening) in a yield of 49 g. (90%). Further recrystallization from nitromethane gave 39 g. melting at 162°-164°. Anal. Calcd. for C17H15Cl2N3O2 : C, 56.06; H, 4.15; N, 11.54 Found: C, 55.63; H, 4.04; N, 11.49.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.C([C@@:35]1([C:44]([OH:46])=[O:45])[CH2:39][CH2:38][CH2:37][N:36]1[C:40](=[O:43])[CH2:41]Br)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:41][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:44]([OH:46])=[O:45])=[O:43])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: O=C(CBr)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.24 g, 0.0011 mole) in chloroform (10 ml) was added triethylamine (0.34 ml, 0.002 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (0.29 ml, 0.0023 mole) was added to the above solution dropwise, followed by benzyl bromoacetyl-L-proline (0.25 g, 0.0011 mole). The ice bath was removed and the mixture stirred at room temperature for 4 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil was vacuum dried to get 0.23 g (57%) of title compound, TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot at Rf =0.23.
Reaction SMILES: O1CCCOC1C1N(C)C(C2SC3C(=NC=CC=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])C=2)=NC=1.[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[C:38]1[CH:39]=[CH:40][C:41]([C:44]2[S:52][C:51]3[C:46](=[N:47][CH:48]=[CH:49][C:50]=3Cl)[CH:45]=2)=[N:42][CH:43]=1>>[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[C:38]1[CH:39]=[CH:40][C:41]([C:44]2[S:52][C:51]3[C:46](=[N:47][CH:48]=[CH:49][C:50]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:45]=2)=[N:42][CH:43]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Reactant: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 72 %

Procedure:
Following the procedure described above for the synthesis of compound 41 (scheme 1) but substituting compound 40 for compound 137, title compound 138 was obtained in 72% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.49 (dd, J=10.4, 2.5 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23-8.21 (m, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.73 (t, J=8.5 Hz, 1H), 6.99 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H). MS (m/z): 440.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:26][CH3:27]>O>[CH2:26]([N:11]1[C:10](=[O:15])[C:9](=[CH:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:13][C:12]1=[O:14])[CH3:27]
Reactant: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)S1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)SC(=Cc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a mixture of 5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (3.50 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60% in oil, 0.62 g) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and iodoethane (6.55 g) was added to the reaction mixture. The mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 3-ethyl-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione as yellow crystals (3.81 g, yield 98%). Recrystallization thereof from acetone-hexane gave yellow prism crystals. melting point: 217-218° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]4([C:34]([NH:36][C:37]5[CH:42]=[CH:41][C:40](/[CH:43]=[CH:44]/[C:45]([O:47]CC)=[O:46])=[CH:39][CH:38]=5)=[O:35])[CH2:33][CH2:32][CH2:31]4)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]4([C:34]([NH:36][C:37]5[CH:42]=[CH:41][C:40](/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46])=[CH:39][CH:38]=5)=[O:35])[CH2:31][CH2:32][CH2:33]4)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)c3ccc4c(C5CCCCC5)c5n(c4c3)CCOc3cc(OC)ccc3-5)CCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC3(C(=O)Nc4ccc(/C=C/C(=O)O)cc4)CCC3)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.1 %

Procedure:
To a solution of ethyl (E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate (102 mg, 0.154 mmol) in tetrahydrofuran (3 ml) and methanol (2 ml), was added 2N aqueous sodium hydroxide solution (1.2 ml), and the mixture was stirred at room temperature for 17 hr. 2N Hydrochloric acid (1.3 ml) was added and the mixture was extracted with ethyl acetat. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane:diethyl ether (1:1) solution was added to the obtained residue, and the precipitated solid was collected by filtration and washed with hexane:diethyl ether (1:1) solution. The obtained solid was dried in vacuo to give (E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic acid (84 mg, yield 86%).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: C=Cc1ccccc1
Reactant: N#Cc1ccc(I)cc1
Product: N#Cc1ccc(/C=C/c2ccccc2)cc1

Procedure:
4-Iodobenzonitrile (57 mg, 0.25 mmol) and styrene (43 μL, 0.375 mmol) were coupled using the procedure described above to give 63% conversion to (E)-4-cyanostilbene by GC analysis.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](OC(=O)C(C)=O)([C:14]2[C:22]3[O:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH:10]([CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C@H:10]([CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)OC1(c2cccc3cc(C)oc23)CCN(Cc2ccccc2)CC1C
Agent: CCCC[SnH](CCCC)CCCC
Product: Cc1cc2cccc([C@H]3CCN(Cc4ccccc4)C[C@H]3C)c2o1

Procedure:
Beginning with 1.06 gm (3.16 mMol) cis-1-benzyl-3-methyl-4-hydroxy-4-(2-methylbenzofur-7-yl)piperidine, 1-benzyl-3-methyl-4-(methyl oxoacetoxy)-4-(2-methylbenzofur-7-yl)piperidine was prepared essentially as described in EXAMPLE 16. This material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to provide the desired compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O>C(O)CC>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ncccn1
Yield: 134.3 %

Procedure:
N-(Boc)ethylenediamine (0.80 g, 5.0 mmol) (Syn. Commun. 1990, 20, 255-264) was dissolved in 1-propanol (12 mL) and treated with K2CO3 (1.2 g, 9.0 mmol), followed by 2-chloropyrimidine (0.91 g, 8.0 mmol), and the mixture was heated to reflux for 24 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic fractions were dried (MgSO4) and concentrated to give the title compound as a yellow solid (1.6 g): MS (ES) m/e 238.9 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[S:20][C:19]([CH2:21][CH3:22])=[N:18][C:17]=1[CH:23]([CH3:25])[CH3:24])=O)C.C(=O)=O.CO>C1(C)C=CC=CC=1>[CH2:21]([C:19]1[S:20][C:16]([CH2:14][OH:13])=[C:17]([CH:23]([CH3:24])[CH3:25])[N:18]=1)[CH3:22]
Reactant: CCOC(=O)c1sc(CC)nc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1nc(C(C)C)c(CO)s1
Temperature: -78 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
Diisobutylaluminum hydride (1M in toluene; 15 mL, 15 mmol) was added dropwise to a solution of 2-ethyl-4-(1-methylethyl)thiazole-5-carboxylic acid ethyl ester (Example 7; 1.7 g, 7.5 mmol) in toluene (20 mL) at −78° C. The solution was stirred in a dry ice-acetone bath overnight and as the dry ice dissipated the reaction temperature rose to −10° C.. Examination of the reaction by TLC showed a mixture of starting material and product. After the reaction was again cooled to −78° C., a second portion of diisobutylaluminum hydride (1M in toluene; 15 mL, 15 mmol) was added with stirring and the cooled reaction was allowed to proceed overnight. As before, the reaction temperature rose slowly from −78° C. to −10° C. The reaction temperature was re-adjusted to −50° C., then methanol was added dropwise and the mixture was stirred for 30 min. The resulting gel was filtered through Celite® and the filter cake was washed with ethyl acetate. Evaporation of the combined filtrates in vacuo yielded 1.5 g of 2-ethyl-4-(1-methylethyl)thiazole-5-methanol (108% of theory). This material was used without further purification in a subsequent reaction.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([O:9][CH3:10])=[O:8].[N:11]1([CH2:20][CH2:21][C:22](OC)=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>C1COCC1>[OH:23]/[CH:22]=[C:21](/[CH2:20][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)\[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC=O
Reactant: COC(=O)CCn1ccc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C\O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.3 %

Procedure:
To the suspension of potassium tert-butoxide (1.0 g, 8.91 mmol) in dry THF (10 mL) was added dropwise solution of methyl formate (1.0 ml, 16.22 mmol) and methyl 3-(1H-indol-1-yl)propanoate (1.0 g, 4.92 mmol) in dry THF over 30 min. The mixture was stirred at room temperature for 1 h. Concentration in vacuo then afforded the crude title compound (1.3 g). LCMS: rt=2.59 min, [M+H+]=232
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:5]#[N:6]
Reactant: Clc1ncccn1
Reactant: N#CCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ncccn1)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of 2-chlorobenzyl cyanide (4.50 g, 0.297 mol), potassium carbonate (6.84 g, 0.0495 mol) and dimethylformamide is stirred 30 minutes at 100° C. and treated dropwise with a solution of 2-chloropyrimidine (2.30 g, 0.0201 mol) in dimethylformamide. The resultant mixture is stirred overnight at 100° C. and treated with additional 2-chlorobenzyl cyanide (1.54 g, 0.0102 mol). The mixture is stirred several more hours at 100° C., cooled and diluted with water. The mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant brown oil is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a brown oil (3.25 g, 70.8%) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:19]2[CH:24]=[C:23]([O:25][CH2:26][CH3:27])[C:22]([O:28][CH2:29][CH3:30])=[CH:21][C:20]=2[OH:31])[CH2:11][NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:31][C:20]1[CH:21]=[C:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:19]=1[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:11][NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OCC)c(OCC)cc1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OCC)c(OCC)cc1OCC(=O)OCC
Reaction time: 67 h
Yield: 65.5 %

Procedure:
Propane-1-sulfonic acid [2-(4-cyano-phenylamino)-2-(4,5-diethoxy-2-hydroxy-phenyl)-ethyl]-amide (100 mg, 0.223 mmoles) was dissolved in dimethylformamide (1.5 ml) and treated with solid potassium bicarbonate (22 mg, 0.223 mmoles) followed by ethyl bromoacetate (0.37 ml, 0.223 mmoles). The reaction was stirred under N2, for 67 hours. Thin-layer chromatography showed presence of a new product with a higher Rf. The reaction was quenched in water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue was submitted to flash chromatography (ethyl acetate:methylene chloride 1:9) to yield 78 mg of {2-[1-(4-cyano-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxy-phenoxy}-acetic acid ethyl ester. 1HNMR (CHCl3): 7.35 (d, 2H), 6.81 (s, 1H), 6.57 (d, 2H), 6.43 (s, 1H), 4.81 (t, 1H), 4.68 (ABq, 2H), 4.56 (t, 1H), 4.26 (q, 2H), 4.05 (q, 2H), 3.95 (m, 2H), 3.54 (t, 2H), 2.98 (m, 2H) 1.80 (m, 2H) 1.42 (t, 3H), 1.32 (t, 6H), 1.02 (t, 3H). MS (M+H): 534.
Reaction SMILES: O.[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][CH2:14][S:13]1(=[O:18])=[O:17]>O1CCCC1>[CH3:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][CH2:14][S:13]1(=[O:18])=[O:17]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCS1(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1N1CCCS1(=O)=O

Procedure:
1.0 g of water-moist Raney nickel is added to a solution of 2.50 g (9.76 mmol) of 2-(2-methyl-4-nitrophenyl)isothiazolidine 1,1-dioxide in 50 ml of tetrahydrofuran, and the mixture is hydrogenated at room temperature. The catalyst is filtered off, and the filtrate is evaporated, giving 2-(2-methyl-4-aminophenyl)isothiazolidine 1,1-dioxide as a yellowish solid; ESI 227.