Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#N.Cl.[C:26](=[O:29])(O)[O-:27].[Na+]>C(O)(=O)C>[C:26]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)([OH:27])=[O:29]
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(Cc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Cc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Temperature: 0 °C

Procedure:
A solution of 3-(4-cyanobenzyl)-2-(3-pyridyl)indole (5.8 g) in 100 ml of a 1:1 mixture of 20% aqueous hydrochloric acid and glacial acetic acid is heated at reflux for 20 hours. After cooling, the solution is poured into ice water (100 ml) and the pH is adjusted to 4.5-5 with saturated sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate, the ethyl acetate extract is washed with water and evaporated to dryness to give 3-(4-carboxybenzyl)-2-(3-pyridyl)indole.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:20][C:21]([NH2:23])=[O:22])=[C:17]([CH:19]=2)[NH2:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]([NH:30][C:31](=[N:34][C:35]([O:37][CH3:38])=[O:36])SC)=[O:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.CO>[CH3:38][O:37][C:35]([NH:34][C:31]([NH:30][C:28]([O:27][CH3:26])=[O:29])=[N:18][C:17]1[CH:19]=[C:13]([O:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)(=[O:11])=[O:10])[CH:14]=[CH:15][C:16]=1[NH:20][C:21]([NH2:23])=[O:22])=[O:36]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)NC(=Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(N)=O)NC(=O)OC

Procedure:
12.5 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidoaniline, 13.6 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 100 mg of p-toluenesulfonic acid in 90 ml of ethyl acetate and 45 ml of methanol are stirred under reflux for 20 minutes. After cooling down, the mixture is evaporated to dryness under reduced pressure, and the residue is stirred with diisopropyl ether and filtered off with suction. Recrystallization from ethyl acetate/diisopropyl ether, melting point 131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([C:40]#[N:41])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([C:40]#[N:41])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: N#CC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: N#CC1CCCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic 1-((2-bromophenyl)sulfonyl)piperidine-3-carbonitrile. MS (ESI): mass calcd. for C22H20FN5O2S, 437.13; m/z found, 438.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.29 (d, J=1.1, 1H), 8.11-8.07 (m, 1H), 7.98 (m, 1H), 7.74-7.68 (m, 1H), 7.65-7.60 (m, 1H), 7.44-7.40 (m, 1H), 7.36-7.30 (m, 2H), 3.06-3.02 (m, 2H), 2.90-2.86 (m, 2H), 2.80-2.74 (m, 1H), 1.89-1.80 (m, 1H), 1.77-1.61 (m, 2H), 1.53-1.42 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][C:10]=2[C:23]([F:26])([F:25])[F:24])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:23]([F:24])([F:25])[F:26])[CH2:4][CH2:3]1
Reactant: CN1CCC(Oc2ccc(NC(=O)OC(C)(C)C)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
t-Butyl 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)phenylcarbamate (82 mg, 0.299 mmol) was dissolved in methylene chloride (1 mL), and TFA (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The reaction mixture was diluted with ethylene chloride and washed with sat. NaHCO3 solution. The organic layer was dried with Na2SO4, filtered and concentrated to obtain the title compound (63 mg, 77%) without further purification.
Reaction SMILES: Cl.CO[C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C(O)C>[CH2:7]([N:6]1[CH2:5][C:4](=[O:14])[CH:24]([C:23](=[O:27])[CH3:22])[C:25]1=[O:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CNCc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)CN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
N-Benzylglycine methyl ester hydrochloride (23.0 g) is dissolved in ethanol (180 ml) and thereto is added triethylamine (11.1 g) under ice-cooling and further added dropwise diketene (9.2 g). The mixture is stirred at room temperature for 1 hour and distilled to remove the solvent. The residue is dissolved in chloroform, washed with water, 10% hydrochloric acid, and water in this order, dried and then distilled to remove the solvent. The residue is dissolved in xylene (360 ml) and the solution is added dropwise to a solution of sodium methoxide [which is prepared from metal sodium (2.6 g) and methanol (180 ml)], and the mixture is stirred at 80° C. for 2.5 hours while distilling off methanol. After cooling, the reaction mixture is extracted with water. The extract is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from n-hexane-isopropyl ether-diethyl ether to give 1-benzyl-3-acetyl-2,4-dioxopyrrolidine (20.33 g, 87.7%). m.p. 74°-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(Oc2cc(Br)cnc2Nc2nc(CCc3ccccc3)cs2)cc1
Yield: 102.2 %

Procedure:
Following the procedure in Example 7 Step E, 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (740 mg, 2.163 mmol), 1-bromo-4-phenylbutan-2-one (687.6 mg, 3.028 mmol) and triethylamine (0.5014 mL, 3.676 mmol) afforded 5-bromo-3-(4-fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1040 mg, 102.2% yield) as a white solid after drying. 1H NMR (CDCl3) δ 8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.13 (m, 2H), 7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H). Mass spectrum (apci) m/z=470.2, 472.2 (M+H).
Reaction SMILES: [Br:1][CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[CH2:9][CH2:8]2)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(#N)C>[BrH:1].[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[CH2:9][CH2:8]2
Reactant: Nc1ccccn1
Reactant: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2C
Solvent: CC#N
Product: Br
Product: Cc1c(-c2ccc3c(c2)CCC(=O)N3C)nc2ccccn12
Temperature: 0 °C
Yield: 90.4 %

Procedure:
6-(α-Bromopropionyl)-1-methyl-3,4-dihydrocarbostyril (5 g), 2-aminopyridine (4.77 g) and acetonitrile (20 ml) were refluxed for 1.5 hours. The reaction mixture was cooled with ice water and crystals which precipitated were collected by filtration. The crystals were dissolved in acetone and the solution was adjusted to pH of about 1 by the addition of 48% hydrobromic acid. Crystals which formed were collected by filtration and recrystallized from water to give 5.68 g of 6-(3-methylimidazo[1,2-a]pyridine-2-yl)-1-methyl-3,4-dihydrocarbostyril monohydrobromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([N:37]1[CH2:38][CH2:39][N:34]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][CH2:36]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To solution (15 ml) of 2,4-dibenzyloxyphenyl acetic acid (760 mg) and 1-benzylpiperazine (440 mg) in N,N-dimethylformamide are added triethylamine (0.6 ml) and diethyl cyanophosphate (420 mg) at 5° C. under stirring and stirring is continued for 15 minutes. To the reaction solution is added water and the product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried. The solvent is distilled off to yield 1-(2,4-dibenzyloxyphenylacetyl)-4-benzylpiperazine (968 mg).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:40]2[N:41]=[C:42]([NH:45][CH:46]=[O:47])[S:43][CH:44]=2)[C:9]([NH:11][C@@H:12]2[C:38](=[O:39])[N:14]3[C:15]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:16]([CH2:20][I:21])[CH2:17][S:18](=[O:19])[C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:48][N:49]1[CH:53]=[CH:52][CH:51]=[N:50]1>C(OCC)(=O)C>[I-:21].[CH:1]1([O:6][N:7]=[C:8]([C:40]2[N:41]=[C:42]([NH:45][CH:46]=[O:47])[S:43][CH:44]=2)[C:9]([NH:11][C@@H:12]2[C:38](=[O:39])[N:14]3[C:15]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:16]([CH2:20][N+:50]4[N:49]([CH3:48])[CH:53]=[CH:52][CH:51]=4)[CH2:17][S:18](=[O:19])[C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Cn1cccn1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS(=O)[C@H]23)cs1
Solvent: CCOC(C)=O
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2S(=O)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of benzhydryl 7β-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate 1-oxide (syn isomer, 7 g) and N-methylpyrazole (17.5 ml) was stirred at ambient temperature for 4.5 hours. The reaction mixture was poured into ethyl acetate (500 ml). Precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether to give benzhydryl 7β-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem -4-carboxylate 1-oxide iodide (syn isomer, 5.4 g).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].O>C(OCC)C>[C:18]1([C:15]([C:10]2[S:9][CH:8]=[N:12][CH:11]=2)([OH:17])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(O)(c1ccccc1)c1cncs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 7ml) in diethyl ether (30ml) was stirred at -70° C. under a nitrogen atmosphere and 2-trimethylsilylthiazole (2.5g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, acetophenone (2.3g) in diethyl ether (10 ml) was added dropwise. After a further 45 minutes the mixture was allowed to warm to room temperature and was then left overnight. Water was added and the mixture was extracted with diethyl ether. The material thus obtained was purified by flash chromatography to give the title compound.
Reaction SMILES: [CH:1]([F:10])([C:6]([Cl:9])([Cl:8])[F:7])[C:2]([F:5])([F:4])[F:3].[F:11][CH:12]=[C:13]([F:15])[F:14].[Cl:16][C:17](Cl)([F:19])[F:18]>>[Cl:16][C:17]([F:19])([F:18])[CH:12]([F:11])[C:13]([Cl:8])([F:15])[F:14].[Cl:8][C:6]([Cl:9])([F:7])[CH:1]([F:10])[C:2]([F:5])([F:4])[F:3]
Reactant: FC(F)(Cl)Cl
Reactant: FC=C(F)F
Agent: FC(C(F)(F)F)C(F)(Cl)Cl
Product: FC(C(F)(F)Cl)C(F)(F)Cl

Procedure:
Until HCFC-225eb becomes available in commercial quantities, HCFC-225eb may be prepared by a standard and well-known organic synthesis technique. For example, 1,1-dichloro-1,2,3,3,3-pentafluoropropane may be prepared by reacting trifluoroethylene with dichlorodifluoromethane to produce 1,3-dichloro-1,1,2,3,3-pentafluoropropane and 1,1-dichloro-1,2,3,3,3-pentafluoropropane. The 1,1-dichloro-1,2,3,3,3-pentafluoropropane is separated from its isomer using fractional distillation and/or preparative gas chromatography. Alternatively, 225eb may be prepared by a synthesis disclosed by O. Paleta et al., Bull. Soc. Chim. Fr., (6) 920-4 (1986). The 1,1-dichloro-1,2,3,3,3-pentafluoropropane can be separated from its two isomers using fractional distillation and/or preparative gas chromatography.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C(N(CC)CC)C.Cl[Si:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][Si:18](Cl)([CH3:20])[CH3:19]>ClCCl>[CH3:5][C:2]([N:1]1[Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][Si:15]1([CH3:23])[CH3:22])([CH3:6])[C:3]#[CH:4]
Reactant: C#CC(C)(C)N
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: 15 °C
Reaction time: 3 h

Procedure:
3-Amino-3-methylbutyne (commercially available as 90% aqueous solution; 16.6 g) was dissolved in dichloromethane (150 ml), dried over sodium sulphate and filtered to give a solution containing 14.9 g of amine. To the stirred solution of amine under an atmosphere of nitrogen at ambient temperature was added dry triethylamine (48.4 ml). 1,2-Bis-(chlorodimethylsilyl)ethane (38.98 g) in dichloromethane (100 ml) was then added dropwise, maintaining the reaction temperature at 15° C. by cooling. The mixture was stirred for 3 hours, the colourless solid, which had formed during the reaction, was filtered from solution and the filtrate was evaporated under reduced pressure to give a paste. The paste was extracted into hexane and refiltered. The filtrate was evaporated under reduced pressure and the oil obtained was distilled to give 1-(1,1-dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane, 21.5 g, b.p. 41° C. at 0.06 mm Hg pressure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:32]#CBr.O>CS(C)=O>[C:20]1([S:17]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([N:5]3[CH2:4][CH2:3][N:2]([C:1]#[N:32])[CH2:7][CH2:6]3)=[N:9]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CBr
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (237 g, 0.67 mole), K2CO3 (102 g, 0.74 mole) and dimethylsulfoxide (DMSO, 2000 ml), under nitrogen, was added cyanogen bromide (72 g, 0.68 mmol) dissolved in DMSO (525 ml). The reaction was stirred at ambient temperature for 5.5 hours and was then poured into H2O (7 l). The solid, which precipitated from solution, was collected by filtration and was washed well with H2O affording 168 g (68%) of product. A 5.2 g sample was recrystallized twice from ethanol-H2O yielding 4.0 g of 4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile, m.p.=178°-180° C.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[F:18][C:19]([F:34])([F:33])[C:20]([N:22]1[C:27]2[CH:28]=[C:29](I)[CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1)=[O:21]>>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]4[O:25][CH2:24][CH2:23][N:22]([C:20](=[O:21])[C:19]([F:33])([F:18])[F:34])[C:27]=4[CH:28]=3)([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: O=C(N1CCOc2ccc(I)cc21)C(F)(F)F
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)N(C(=O)C(F)(F)F)CCO3)O2

Procedure:
This compound was prepared by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6ol (1,15 g or 5 mmol) with 4-(trifluoroacetyl)-3,4-dihydro-6-iodo 2H1,4-benzoxazine (1.95 g or 5.5 mmol) under the conditions described in Example 15. The product was isolated by chromatography over the 40 fold amount of silica gel methylene chloride. It was crystallized from ether/hexane and recrystallized twice from methanol to give colorless crystals with m.p. 153°-155°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[N+:2]=[N-:3].[S:40]1[CH2:44][C:43](=[O:45])[NH:42][C:41]1=[O:46].N1CCCCC1>CCO>[N:1]([CH2:4][CH2:5][C:6]1[N:7]([CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:44]3[S:40][C:41](=[O:46])[NH:42][C:43]3=[O:45])=[CH:20][CH:19]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[N+:2]=[N-:3]
Reactant: O=C1CSC(=O)N1
Reactant: [N-]=[N+]=NCCc1c(CCOc2ccc(C=O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: [N-]=[N+]=NCCc1c(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 87 %

Procedure:
The mixture of 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehyde (1.29 g, 2.41 mmole, 1.0 equiv.), 2,4-thiazolidine dione (0.41 g, 3.13 mmole, 1.3 equiv.) and piperidine (0.12 ml, 1.21 mmole, 0.5 equiv.) in EtOH (125 ml) was refluxed overnight. EtOH was removed on vacuo. The residue was diluted in EtOAc and washed with water, then brine. The organic layer was dried over MgSO4 and concentrated, and the residue was chromatographed with 30-35% EtOAc/hexane to obtain 5-(4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione (1.33 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13](=[O:14])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of the product of Example 364B (27.5 g, 0.0618 mol) and pyridine (7.73 g, 7.50 mL, 0.0927 mol, 1.5 equiv.) in dichloromethane (500 mL) was stirred at room temperature. To this mixture was added slowly, dropwise 2,2,2-trichloroethyl chloroformate (17.0 g, 10.8 mL, 0.0803 mol, 1.3 equiv.) over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours, during which time the product precipitated as a yellow solid. The mixture was filtered and the filter cake was rinsed with dichloromethane (100 mL) and dried in vacuo to give the title compound (35.3 g, 92%) as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([O:12][C:13](OCC)=[CH2:14])[CH3:11].CCO>[O-]CC.[Na+].CCOC(C)=O>[C:3]([C:2](=[C:10]([O:12][CH2:13][CH3:14])[CH3:11])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=C(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(C)=O)=C(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A 5 L 4-neck flask equipped with a mechanical stirrer, condenser, thermowell, addition funnel and N2 inlet was charged with ethyl acetoacetate (493.1 g, 483 mL, 3.7931 mol, 1.0 equiv) and sodium ethoxide (3.1 g, 0.046 mol, 1.2 mol %). Ketene diethylacetal (880.0 g, 1000 mL, 7.5862 mol, 2.0 equiv) was added over 1 hr maintaining the reaction temperature at <22° C. by external cooling. When addition was complete, the reaction mixture was heated at 85° C.±5° C. for 7.5 hr. The yellow brown reaction mixture was cooled to room temperature and stirred overnight. Much of the lower boiling components [EtOH, EtOAc, Me(OEt)3] were stripped on a roto-evaporator (bath temperature 65° C.). The residual yellow-orange oil was distilled, collecting the fraction with bp 100-107° C. (1.8-2.1 Torr) to give 675.2 g (89%) of product as a yellow liquid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].S(O[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30])(=O)(=O)C>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][CH2:19][O:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: COc1cccc(OC)c1OCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(OC)c1OCCOC1CCN(C(C)=O)CC1
Reaction time: 20 h
Yield: 61.8 %

Procedure:
N-Acetyl-4-hydroxypiperidine (4.3 g.) in D.M.F. (50 ml.) was added dropwise to a stirred suspension of sodium hydride (3.0 g., 50% dispersion in mineral oil) in D.M.F. (50 ml.) under an atmosphere of nitrogen. After stirring for 3 hours at room temperature 2-[2,6-dimethoxyphenoxy]ethyl mesylate (9.0 g.) in D.M.F. (50 ml.) was added dropwise and stirring continued for 20 hours at room temperature. The solvent was evaporated in vacuo, the residue taken up in water, extracted with chloroform (3×100 ml.), the organic layer dried (Na2SO4) and the solvent evaporated. Distillation gave N-acetyl-4-(2-[2,6-dimethoxyphenoxy]ethoxy)piperidine (6.0 g.), b.p. 200° C. @ 1 mm.