Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1)(O)=[O:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.N1C=CC=CC=1>[N:38]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=4)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]4[CH2:26][CH2:27][C@H:28]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH2:29][CH2:30]4)=[O:24])[C:8]=3[CH:37]=2)=[O:2])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=C(O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccc(C(=O)N3CCOCC3)cc2c1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (830 mg) obtained in Example 77 is suspended in N,N-dimethylformamide-pyridine (1:1, 30 ml), and thereto are added successively morpholine (196 mg), 1-hydroxybenzotriazole (406 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (576 mg) under ice-cooling, and the mixture is stirred at room temperature for 17 hours. To the reaction solution are poured ice-water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate, washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform). The resulting residue is suspended in ethyl acetate-n-hexane, and the precipitates are collected by filtration, and dried to give the title compound (805 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCNCC
Product: C[C@H](N[C@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1S)-6-Bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 17.5 min.) The oil obtained was converted to the HCl salt to give a white solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 9.85 (s, 1H), 9.30 (s, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.52-7.45 (m, 3H), 7.43 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.78 (m, J=6.4 Hz, 1H), 4.60 (m, 1H), 2.77-2.65 (m, 2H), 2.20-2.05 (m, 1H), 2.05-1.95 (m, 2H), 1.88-1.80 (m, 1H), 1.71 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90. Found: C, 59.36; H, 5.58; N, 6.97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[C:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[N:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1

Procedure:
9-(4-Chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purin-6-ol I-(1A-1)c (6.5 g, 17 mmol) was heated to reflux in POCl3 (3 ml) overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved into chloroform and poured onto ice. The organic layer was separated and washed with saturated aqueous NaHCO3; the organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was taken up in 1:1 methylene chloride/diethyl ether (200 ml) and was then filtered to remove residual starting material. Concentration of the organic layer gave the title compound I-(1A-1)d as a yellow foam (5.8 g, 85%): +ESI MS (M+1) 411.4; 1H NMR: (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 7.79–7.75 (m, 2H), 7.63–7.58 (m, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.42 (d, J=6.7 Hz, 2H).
Reaction SMILES: Cl[C:2]12[C:11]([O:14][CH3:15])([O:12][CH3:13])[C:6](Cl)([C:7](Cl)=[C:8]1Cl)[CH2:5][N:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:3]2.C(O)(C)(C)C.[Na]>O1CCOCC1>[CH3:15][O:14][C:11]1([O:12][CH3:13])[CH:2]2[CH:8]=[CH:7][CH:6]1[CH2:5][N:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:3]2
Reactant: COc1ccc(CN2CC3(Cl)C(Cl)=C(Cl)C(Cl)(C2)C3(OC)OC)cc1
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COc1ccc(CN2CC3C=CC(C2)C3(OC)OC)cc1
Temperature: 92 °C
Yield: 9.4 %

Procedure:
1,5,6,7-Tetrachloro-8,8-dimethoxy-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]oct-6-ene (6.23 g, 146 mmol) and t-butanol (25.13 mL, 263 mmol) were dissolved in dioxane (75 mL) in a flame dried 3N RB equipped with a water condenser and thermometer then heated to a gentle reflux (internal temp 92° C.). Sodium (5.36 g, 233 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 45 min The reaction was heated overnight and judged complete by GCMS. The reaction solution was decanted from the unreacted sodium, then washed with methanol to fully quench residual sodium. Solvent was removed in vacuo, diluted in water (100 mL), cooled in an ice bath, then acidified with 6 N HCl (100 mL). At room temperature, the acidic aqueous layers were washed with ether (2×100 mL) then made alkaline with 1N NaOH. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (1×100 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (3.97 g, 94%). (TLC 5% MeOH/CH2Cl2, (NH3) Rf 0.40); 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.3 Hz, 2H), 6.79 (d, J=8.3 Hz, 2H), 5.97 (s, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 3.20 (s, 3H), 3.13 (s, 3H), 2.59 (br s, 2H), 2.53 (d, J=10.6 Hz, 2H), 2.39 (d, J=10.6 Hz, 2H); GCMS m/z 287 (M)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[C:8]#[CH:9]>>[CH3:3][CH:2]([CH3:4])[C:1](=[O:5])[C:9]#[C:8][CH2:7][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C#CCOC1CCCCO1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)C#CCOC1CCCCO1

Procedure:
The desired compound was prepared from isobutyryl chloride and 3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran by analogy to the procedure of Tohda, et. al. (Synthesis, 777 (1977)).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:22][CH3:23])=[C:7]([CH:21]=1)[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15].[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([OH:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([O:41][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:8][CH2:9][C:10]3[N:11]=[C:12]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[O:13][C:14]=3[CH3:15])[CH:21]=2)=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(CCl)cc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OC)c(OCc2nc(-c3ccco3)oc2C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
A mixture of 4-(5-chloromethyl-2-methoxyphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.24 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.51 g, yield 76%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]2)=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)ccc1N1CCN(C(=O)C(=O)O)CC1
Yield: 92.6 %

Procedure:
To a stirred solution of ethyl [4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl](oxo)acetate (Example 66, 0.280 g, 0.705 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 2 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide [4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl](oxo)acetic acid (0.241 g, 92%) as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:12])[C:6](=[N:10][OH:11])[C:7]([CH3:9])=[O:8].Cl[CH2:14][O:15][CH3:16].C(OCC)(=O)C>O1CCCC1>[CH3:3][O:4][C:5](=[O:12])[C:6](=[N:10][O:11][CH2:14][O:15][CH3:16])[C:7]([CH3:9])=[O:8]
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCON=C(C(C)=O)C(=O)OC
Reaction time: 0.5 h

Procedure:
To a suspension of 4.13 g of 80% NaH in 50 ml of dry tetrahydrofuran are added successively at 0° 18.14 g of 2-hydroxyiminoacetoacetic acid methyl ester and 9 g of chloromethylmethylether. After 30 minutes at room temperature, the mixture is divided between 200 ml of ethyl acetate and aqueous buffer (pH 5.5). The contents of the ethyl acetate phase are bulb distilled to obtain the heading compound, m.p. 115°-120°/0.1 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(Cl)c1
Reactant: ClCCN1CCCCC1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCN(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 26 %

Procedure:
A mixture of 0.035 g (0.10 mmol) of 3-chloro-N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-benzamide and 0.055 g (0.30 mmol) of 1-(2-chloroethyl)piperidine in acetonitrile (2 mL) is heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to give 0.012 g (26%) of the title compound (107) as a brown oil. [M+H]+=464.2.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH:9]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: O=C(c1c(Cl)cccc1Cl)c1c[nH]c2cnc(NC(=O)C3CC3)cc12

Procedure:
N-[3-(2,6-Dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2,6-dichloro benzoyl chloride (Compound No. 18).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[OH2:21]>>[CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:21])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 57.2 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-isopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.3 g, 4.15 mmol), NaH (60%, 500 mg, 12.45 mmol) and water (89 mg, 4.98 mmol) were reacted to form the desired product (0.7 g, 57%). EI- MS m/z 293.5 (M-H)−.
Reaction SMILES: CS[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:22][NH2:23]>CO>[CH3:22][NH:23][C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CN
Reactant: COC(=O)C/C=C/c1ccc(NC(=C[N+](=O)[O-])SC)cc1
Solvent: CO
Product: CNC(=C[N+](=O)[O-])Nc1ccc(/C=C/CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
1.00 g of methyl (E)-4-{4-((1-methylthio-2-nitroethen-1-yl)amino)phenyl}-3-butenoate was suspended in 5 ml of methanol, followed by the addition of 1.25 ml of a 40% solution of methylamine in methanol. The obtained mixture was stirred at a room temperature for 4 hours and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1)] to obtain 0.5 g of the title compound as a pale yellow solid (yield: 54%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12](F)[C:9]=1[CH:10]=O>CN(C)C=O>[Cl:7][C:8]1[C:9]2[CH:10]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[S:3][C:12]=2[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)ccc(Cl)c1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)c(Cl)ccc2s1

Procedure:
In a similar manner to Example 18, methyl thioglycolate (9.3 ml) was reacted with 2,3-dichloro-6-fluorobenzaldehyde (15.46 g) in dimethylformamide to give methyl 4,5-dichlorobenzo[b]thiophene-2-carboxylate (7.28 g) as an off-white solid which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 4,5-dichloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.96 g) as a colourless solid. Reaction of this amide with ethylmagnesium bromide gave 1-(4,5-dichlorobenzo[b]thiophen-2-yl)propan-1-one (1.09 g) as an oil which was used without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.I[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH3:1][C@@H:2]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: CC(C)=CCC[C@H](C)CCc1ccc(B(O)O)cc1
Reactant: Nc1ccc(I)cc1
Product: CC(C)=CCC[C@H](C)CCc1ccc(-c2ccc(N)cc2)cc1
Yield: 67.4 %

Procedure:
A mixture of 4-[(3S)-3,7-dimethyl-6-octenyl]phenylboronic acid (5.00 g, 19.2 mmol), 4-iodoaniline (2.79 g, 12.75 mmol), and a quaternary ammonium salt (Aliquat 336, 1.3 g) was degased three times with nitrogen before 100 mL of dry toluene was added. This step was followed by addition of tetrakis(triphenylphosphine)palladium (1.46 g) and aqueous sodium carbonate (1 M, 60 mL, deaerated for 2 hours) under nitrogen. The mixture was stirred vigorously and heated under reflux for 20 hours. The organic phase of the resulting reaction mixture was filtered through a thin layer of Celite® and evaporated to dryness to give 3.09 g of crude material. The crude material was purified by chromatography on silica gel (ethyl acetate:hexanes) to yield 4-[(3S)-3,7-dimethyl-6-octenyl]-4′-aminobiphenyl as a yellow oil (2.64 g, 8.59 mmol, 67.4% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[CH:36]([NH:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33])([CH3:38])[CH3:37]
Reactant: CC(C)NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
64.3 mg (0.46 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 65.1 mg (0.31 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 45.0 mg (0.15 mmol) of 4′-amino-N-isopropylbiphenyl-4-sulfonamide (Example 12A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., the reaction mixture is concentrated in vacuo. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 21 mg (29.2% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]>CC#N.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[NH:8][C:5]3=[N:6][CH:7]=2)[CH:15]=[C:14]([O:13][CH3:12])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: O=C1Cc2cc(Br)cnc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3c(c2)CC(=O)N3)cc(OC)c1OC
Temperature: 150 °C
Yield: 30.1 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (200 mg, 0.939 mmol), 3,4,5-trimethoxyphenylboronic acid (239 mg, 1.127 mmol) and dichlorobis(triphenylphosphine)palladium (II) (33 mg, 0.047 mmol) in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) was heated in a microwave reactor for 10 min at 150° C. The reaction mixture was filtered, evaporated, partitioned between water and DCM and purified by silica gel chromatography with 0-10% MeOH:DCM to obtain 85 mg (30%) of compound #. 1H NMR (CDCl3/DMSO-d6, 300 MHz): δ 10.19 (bs, 1H), 8.18 (d, J=1.1 Hz, 1H), 7.54 (s, 1H), 6.57 (s, 2H), 3.80 (s, 6H), 3.75 (s, 3H), 3.47 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1ccncc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccncc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4-bromopyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCC(F)(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (200 mg) in anhydrous DMF were added 2-(2,2,2-trifluoroethoxy)ethyl 4-methylbenzenesulfonate (intermediate BS) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 12 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative-HPLC to obtain compound BT (117 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.62 (s, 2H), 4.08˜4.12 (m, 3H), 4.02˜4.05 (m, 3H), 4.00˜3.94 (m, 2H), 3.90˜3.87 (m, 1H), 3.72˜3.68 (m, 1H), 3.46˜3.39 (m, 3H), 3.30˜3.27 (m, 1H); MS ESI (m/z) 507 (M+H)+, calc. 506.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30](C(=O)CBr)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:1][O:8][C:9]2[CH:18]=[C:17]3[C:12](=[CH:11][CH:10]=2)[CH:13]=[CH:14][C:15]([OH:19])=[CH:16]3)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)N1CCC(Cc2ccccc2)CC1
Reactant: Oc1ccc2ccc(OCc3ccccc3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1ccc2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2c1

Procedure:
The title compound was prepared from 7-benzyloxy-naphthalen-2-ol (1.00 g, 4.00 mmol), 1-(4-benzyl-piperidin-1-yl)-2-bromo-ethanone (1.20 g, 4.05 mmol) and potassium carbonate (1.10 g, 7.96 mmol) in tetrahydofuran (40 ml) in three steps as a solid, mp 159-160° C. Analysis calculated for C24H27NO2 ·0.16H2O: C, 79.11; H, 7.56; N, 3.85. Found: C, 79.11; H. 7.63; N, 3.83.