Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.O.Cl.[Cl-].[Na+].O>[Cl:15][CH2:16][CH2:17][CH2:18][S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: COC(=O)C(OC)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(OC)c1ccc(NS(=O)(=O)CCCCl)cc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-2-methoxyacetate (0.6 g, 3.07 mmol) in anhydrous pyridine (6 mL) under argon was added 3-chloropropane-1-sulfonyl chloride (0.5 mL, 4.11 mmol) dropwise. The exothermic reaction was cooled briefly over a cold H2O bath. After stirring for 1 hr, the reaction was diluted with H2O, 1 M HCl and brine and extracted with EtOAc. The combined organics were washed with 1 M HCl, H2O and brine then dried over Na2SO4 and concentrated in vacuo to give methyl 2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate as an orange oil (1.03 g, quant. yield). The product was used without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]1[CH2:41][CH2:40][CH2:39][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(=O)=O>CO>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:41][CH2:40][CH2:39][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: O=C=O
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
2.5 g of Z-Arg-Pro-Phe-His-OMe are dissolved in 25 ml of 95% strength methanol and, after the addition of 250 mg of Pd-on-carbon, hydrogenated with CO2 -absorption until saturation. The catalyst is filtered off and the filtrate is concentrated to dryness, yielding H-Arg-Pro-Phe-His-OMe in the form of an amorphous powder; Rf (E)=0.05; Rf (C)=0.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(OCC)C>[NH+:1]1([O-:18])[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCOCC
Product: [O-][NH+]1C=Cc2cccnc21
Yield: 125 %

Procedure:
To 1H-pyrrolo[2,3-b]pyridine (94, 3.0 g, 25.3 mmol) dissolved in 175 mL of diethyl ether was added m-CPBA (1.5 equiv) in portions over 30 minutes with vigorous stirring. The solution turned yellow, and precipitates formed. After two hours the solid was collected, washed with 2×50 mL of ether, and recrystallized from acetone:ether. Yield was approximately 125% due to contaminating acid. This crude material was carried through to the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCCP(=O)(CCC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCP(=O)(CCC)Cc1ccc(N)cc1
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A mixture of 4-nitrobenzyldipropylphosphine oxide (3.0 g) and 5% Pd—C (0.3 g) in ethanol (50 ml) was vigorously stirred under hydrogen atmosphere for 16 hours, and the Pd—C was filtered off. The filtrate was concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:5→1:4) and recrystallized from ethanol-ethyl acetate to give 4-aminobenzyldipropylphosphine oxide (1.78 g) as colorless crystals.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[C:20]([CH2:22][CH:23]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][C:25](OCC)=[O:26])#[N:21]>C1COCC1.O.CO>[C:20]([CH2:22][CH:23]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][C:25](=[O:26])[CH2:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[N:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(CC#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)CC(CC#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -7.5 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium in hexane (14.4 ml, 0.21 mol) was added to a chilled solution (−5 to −10° C.) of diisopropylamlie (23.2 g, 0.23 mol) in THF (100 ml) and the resulting mixture was stirred at −5 to −10° C. for 30 minutes. After chilling the reaction to about −45° C., tert-butyl acetate (26 g, 0.21 mol) was added and the resulting reaction mixture was stirred at −20-30° C. for 1 hour. A solution of ethyl 4-cyano-3-(tert-butyldiphenylsilyloxy)-butanoate (20 g, 0.050 mol) in THF (20 ml) was added to the reaction mixture at about −75° C. and further stirred −70-−75° C. for 2 hours. Methanol (15 ml) was added to the reaction mixture followed by water (200 ml) and layers were separated. The organic layer was preserved. The aqueous layer was extracted with ethyl acetate (2×200 ml) and combined with the organic layer. The combined organic layer was evaporated to give the title compound.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:18][C:17]=1[Cl:26])=[N:5]/[O:6][CH3:7].[CH3:28][NH2:29]>CO>[Cl:26][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[Cl:24])[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1/[C:4](=[N:5]\[O:6][CH3:7])/[C:3]([NH:29][CH3:28])=[O:2]
Reactant: CN
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1Cl
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
Methyl-(E)-2-(2-((2-chloro-4-(2,2-dichlorovinyl)phenoxy)methyl)phenyl)-2-methoxyiminoacetate (0.428 g, 1 mmol) obtained in Example 39 was added to 10 ml of methanol. 40% methylamine solution (0.39 g, 5 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 6 hours. The solvent was removed therefrom under a reduced pressure. After adding water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (0.38 g, 89%).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=S)[CH3:2].[CH3:6][C:7]1([CH3:31])[CH2:16][CH2:15][C:14]2[N:13]=[CH:12][N:11]=[C:10]([N:17]3[CH2:23][C:22]4[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:21]=4[O:20][CH2:19][CH2:18]3)[C:9]=2[CH2:8]1>>[CH3:6][C:7]1([CH3:31])[CH2:16][CH2:15][C:14]2[N:13]=[CH:12][N:11]=[C:10]([N:17]3[CH2:23][C:22]4[CH:24]=[C:25]([C:8]5[CH:7]=[CH:2][C:1]6[N:3]=[C:4]([NH:13][CH2:14][CH3:15])[NH:11][C:10]=6[CH:9]=5)[CH:26]=[CH:27][C:21]=4[O:20][CH2:19][CH2:18]3)[C:9]=2[CH2:8]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CCN=C=S
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 15 by using ethyl isothiocyanate in step 1 and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 3. 1H NMR (400 MHz, d6-DMSO): 8.37 (s, 1H), 7.56 (d, 1), 7.43 (dd, 1H), 7.38 (s, 1H), 7.20 (s, 2H), 7.00 (d, 1H), 4.62 (s, 2H), 4.29 (m, 2H), 3.83 (m, 2H), 3.35 (q, 2H), 2.70 (t, 2H), 2.47 (s, 2H), 1.60 (t, 2H), 1.19 (t, 3H), 0.86 (s, 6H); MS (EI) for C28H32N6O: 469 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[CH2:9]2)[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:16])=[C:6]([N:8]2[CH2:9][C@@H:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[N:7]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: CC1(C)CN(c2nc(Cl)nc(NN)c2F)C[C@H]1O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C[C@H]1O
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of (3S)-1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-4,4-dimethyl-3-pyrrolidinol (0.131 g, 0.475 mmol) in DMF (3 mL) was added added (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.1181 g, 0.395 mmol), N-methylmorpholine (0.220 ml, 2.001 mmol), 1-hydroxy-7-azabenzotriazole (64 mg, 0.470 mmol), and EDC (91 mg, 0.475 mmol). The solution was stirred overnight and then purified directly by Gilson RPLC to afford [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1294 g, 59% yield) as an orange oil. LCMS: (M+H)+: 557.3.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CCCCCC.O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH:9]=[CH:8]2)#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Sodium hydride (8.4 g, 210 mmol) was washed twice with hexane and then suspended in tetrahydrofuran (500 ml). 5-Cyanoindole (20 g, 140 mmol) in tetrahydrofuran (200 ml) was added dropwise. The resulting mixture was stirred at ambient temperature for 1 hour and then p-toluenesulfonyl chloride (26.7 g, 140 mmol) in tetrahydrofuran (200 ml) was added. The reaction was stirred 3 hours more followed by addition of water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried over calcium sulfate and concentrated. The residue was recrystallized from ether to afford 29.97 g, 72% of title product; m.p. 129°-131° C.; NMR 8.04 (d, J=8.5 Hz, 1H), 7.85 (d, J=1 Hz, 1H), 7.75 (d, J=9 Hz, 2H), 7.67 (d, J=3.5 Hz, 1H), 7.53 (m, 1H), 7.23 (m, 2H), 6.68 (d, J=3.5 Hz, 1H), 2.34 (s, 3H). IR(CHCl3 solution) 2225, 1597, 1453, 1380, 1289, 1266, 1169, 1138, 1123, 1089 (shoulder), 990. FAB HRMS calcd for C16H13N2O2S(MH+): 297.0669. Observed m/e: 297.0685.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([CH2:32][CH2:33][CH2:34]O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59].N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCOC(C)=O.C1COCC1>[C:58]([O:62][C:63](=[O:64])[N:65]=[C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:67][CH2:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:9])[CH3:10])=[CH:12][N:13]=2)=[C:30]([F:31])[CH:29]=1)([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(CCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 8 h
Yield: 126.3 %

Procedure:
To a solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)propan-1-ol (407 mg, 0.73 mmol) in anhyd THF (0.97 mL) were added PPh3 (285 mg, 1.08 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (384 mg, 1.45 mmol) and diisopropyl azodicarboxylate (DIAD) (225 μL, 1.08 mmol) sequentially. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (80% EtOAc/hexanes) to yield tert-butyl(tert-butoxycarbonylamino)(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)propylamino)methylenecarbamate (740 mg), which was taken to the next step without further purification. MS (EI) m/z 802.50 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].O1CCCC1.C(Cl)(=O)C([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:21])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A stirred solution of 0.22 gram (0.0012 mole) of 3-chloro-4-methoxybenzoic acid in a small amount of tetrahydrofuran and chloroform was cooled to 0° C., and 0.12 mL (0.0014 mole) of oxalyl chloride was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about 3.5 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding 3-chloro-4-methoxybenzoyl chloride, which was dissolved in a small amount of tetrahydrofuran for later use.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=O)=[CH:10][CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[CH:1][CH3:2])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=C1CCc2ccc(Br)cc21
Reaction time: 1 h
Yield: 74 %

Procedure:
(Ethyl)triphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran followed by addition of potassium tert-butoxide (5.29 g, 47.3 mmol) at room temperature. Upon completion of the addition, the reaction mixture was stirred for 1 hour. A solution of 6-bromo-indan-1-one 38b (3.39 g, 18.6 mmol) in 25 mL of tetrahydrofuran was added to above mixture and the mixture was stirred for another 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was quenched with 150 mL of water and then the mixture was extracted with dichloromethane (50 mL×4). The combined organic extracts were washed with saturated brine (45 mL×2), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-ethylidene-indan 41a (3.07 g, 74%) as a yellow oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:27].C(OCC)C>O1CCOCC1>[ClH:27].[ClH:27].[NH2:8][C@H:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (R)—(R)-quinuclidin-3-yl 2-((tert-butoxycarbonyl)amino)-2-phenylacetate (0.608 g, 1.687 mmol) in anhydrous dioxane (6 mL) was added 2M HCl in diethyl ether (5.2 mL, 10.4 mmol). The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo to afford the title compound as a white solid (0.564 g, quantitative yield).
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Yield: 95.9 %

Procedure:
A solution of 4-(4-benzylaminosulfonylmethylbenzyl)-nitrobenzene (44 mg) was dissolved in ethyl acetate and hydrogenated at 40 psi with 10% palladium on carbon catalyst for 2 hours. The mixture was filtered, and the solvent was evaported to give 4-(4-benzylaminosulfonylmethylbenzyl)-phenylamine (39 mg) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7]S[N:9]=2)[C:5]([Br:11])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:10]([NH2:9])=[C:6]([NH2:7])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1c(Br)ccc(Br)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The specific preparation is described as follows: dissolving 4,7-dibromo-2,1,3-benzothiadiazole in organic solvent such as ethanol, adding appropriate sodium borohydride at 0° C., then raising the temperature to room temperature, stirring for 12-24 hours, distilling organic solvent of reaction product, after adding water, washing with saline water, then extracting with diethyl ether, drying with anhydrous sodium sulfate. 3,6-dibromo-1,2-diaminobenzene is obtained after solvent is rotary dried.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].C(N(CC)CC)C>CN(C)C=O.ClCCl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:8]2[NH:13][N:12]=[C:11]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][Cl:27])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCCCl
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(I)c2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
A nitrogen degassed stirred mixture of 5-butyl-N-(3,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (4.58 g, 9.7 mmol), copper(I) iodide (278 mg, 1.46 mmol) and bis(triphenylphosphine)palladium(II)dichloride (515 mg, 0.734 mmol) in anhydrous N,N-dimethylformamide (105 mL) was warmed to 60° C. under a nitrogen atmosphere before addition of a solution of 6-chloro-1-hexyne (1.712 g, 14.69 mmol) and triethylamine (2.047 mL, 14.69 mmol) in anhydrous nitrogen degassed N,N-dimethylformamide (15 mL), dropwise over 5 minutes. The reaction was stirred at 60° C. for 6 hours. The cooled reaction mixture was evaporated in-vacuo and the resultant oil partitioned between 1:1 water/brine and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield an orange oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 330 g silica pre-conditioned cartridge and purified by chromatography using cyclohexane over 1 column volume followed by 0-100% ethyl acetate in cyclohexane gradient over 14 column volumes followed by ethyl acetate over 2 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a yellow foam (3.334 g)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O>ClCCl>[CH:2]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:1]
Reactant: COC(=O)CC/C(C)=C/Cc1c(CO)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(C=O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
Methyl (E) 6-(1,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.2 g) is dissolved in dichloromethane (10 ml) and pyridinium chlorochromate (0.15 g) is added. After one hour water (25 ml) is added. The organic solution is dried and evaporated and the residue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6-(1,3-dihydro-6-formyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[CH:31][CH:30]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)=[CH:33][CH:34]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ncco2)cc1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)[C@@H]1CCCCC[C@H]1CO
Yield: 87.6 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (80 mg, 0.25 mmol), cesium carbonate (164 mg, 0.50 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (72 mg, 0.30 mmol) according to the procedure described for 4-Chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (Example 40) to give 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (104 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.31 Hz), 7.73-7.75 (1H, m), 7.71-7.73 (1H, m), 7.69 (1H, s), 7.51 (1H, s), 7.48 (2H, s), 7.44-7.47 (1H, m), 7.21 (1H, s), 4.69 (1H, d, J=15.86 Hz), 3.99 (1H, d, J=15.61 Hz), 3.74-3.85 (1H, m), 3.67 (1H, dd, J=11.58, 4.28 Hz), 3.28 (1H, dd, J=11.58, 2.27 Hz), 2.27 (1H, br. s.), 1.42-1.65 (6H, m), 1.12-1.39 (5H, m). LC/MS R.T.=2.25 min; [M+H]+=475.22. HRMS [M+H]+ calc'd 475.1458, found 475.1459.