Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:21][C@@H:22]([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[CH2:23][CH2:24][OH:25])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Reactant: N[C@H](CCO)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(N[C@H](CCO)c3ccc(C(F)(F)F)nc3)c2C1

Procedure:
A reaction mixture of 2-(4-bromo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (35 mg, 0.10 mmol) and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (22 mg, 0.10 μmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) was subjected to microwave irradiation at 200° C. for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-70% CH3CN-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(Cl)(Cl)Cl.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:36](O)=[O:37])[CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:36](=[O:37])[C@H:30]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
L-Histidine methyl ester dihydrochloride (1.21 g) is suspended into chloroform (20 ml), and therto are added triethylamine (1.40 ml) and further N-benzyloxycarbonyl-L-glutamine (1.40 g) and triethylamine (0.70 ml). After stirring for a while, to the mixture is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.07 g) and the mixture is stirred for 1 hour. After allowing to stand overnight, the solvent is distilled off. To the residue are added water and 1 N aqueous sodium hydrogen carbonate and the mixture is cooled. The precipitated gelling product is separated by filtration and washed with water. The product is heated together with a small amount of water and cooled. The precipitated by filtration to give N-(N-benzyloxycarbonyl-L-glutaminyl)-L-histidine methyl ester (1.25 g), melting point: 186°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cc(F)cc(F)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′,5′-difluoroacetophenone (prepared according to the method of S. Kajigaeshi et al., Bull.Chem.Soc.Jpn., 1987, 60, 1159-1160).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.I[C:20]1[CH:21]=[N:22][N:23]([CH3:32])[C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[Cl-].[Li+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][N:23]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[C:20]([C:6](=[O:8])[CH3:7])[CH:21]=[N:22]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(-c2c(I)cnn2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnn(C)c1-c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Tributyl(1-ethoxyvinyl)stannane (95%, 1.39 mL, 3.88 mmol) was added to a mixture of 4-iodo-1-methyl-5-(4-methylphenyl)-1H-pyrazole (768 mg, 2.58 mmol), tetrakis(triphenylphosphine)palladium(0) (298 mg, 0.258 mmol) and lithium chloride (98%, 279 mg, 6.45 mmol) in N,N-dimethylformamide (20 mL), and the reaction was stirred at 90° C. for 18 hours. After cooling, the mixture was filtered through Celite, and concentrated in vacuo; silica gel chromatography (Gradient: 10% to 50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 460 mg, 2.15 mmol, 83%. LCMS m/z 215.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H), 2.45 (br s, 3H), 3.69 (s, 3H), 7.28 (br AB quartet, JAB=8 Hz, ΔvAB=28 Hz, 4H), 7.99 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CCO.O>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH2:6][C:5]2([C:3]([OH:4])=[O:2])[CH3:17])=[CH:10][CH:11]=1
Reactant: COC(=O)C1(C)CCCc2ccc(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(C)(C(=O)O)CCC2
Reaction time: 8 h

Procedure:
A mixture of 7-methoxy-1-methyltetralin-1-yl-carboxylic acid, methyl ester (0.67 g; 2.9 mmol; from step (ii) above) and KOH (4 g) in EtOH:H20 (1:1; 50 mL) was stirred overnight. The resultant mixture was diluted with water and extracted with ether. The aqueous layer was acidified (HCl) and extracted 3 times with ether. The combined organic layer was washed with water, dried (Na2SO4), and concentrated. Yield 0.58 g (81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:25][C:24]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38])(=[O:22])=[O:21]>C(#N)C>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:35])[C:31]([F:32])([F:33])[F:34])=[CH:25][C:24]=3[CH2:36][C:37]([O:39][CH3:40])=[O:38])(=[O:21])=[O:22])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirred solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (3.5 g, 0.024 mol, 0.9 eq) and NMM (7.9 g, 0.079 mol, 3 eq) in acetonitrile (50 mL) was added a solution of methyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido) phenyl)acetate (9.4 g, 0.026 mol) in anhydrous acetonitrile (50 mL) at 0-5° C. Then the mixture was stirred at r.t overnight, the mixture was concentrated and dissolved in DCM and then washed with brine, dried and concentrated, purified by column chromatography (PE:EA 10:1˜1.5:1) to give the title compound (7.4 g, yield 60%). 1H NMR DMSO-d6 400 MHz δ11.54 (s, 1H), 10.36 (s, 1H), 9.21 (s, 1H), 7.87-7.10 (m, 6H), 4.87 (s, 2H), 4.08 (s, 2H), 3.58 (s, 3H). ESI-MS m/z 495 (M+Na+, positive); HPLC purity: 98.23% (220 nm), 99.55% (254 nm).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:34])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][C:27]([F:31])=[CH:28]2)[C:24]([CH3:33])([CH3:32])[CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[CH3:32][C:24]1([CH3:33])[C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:34])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22][CH2:23]1)[CH:28]=[C:27]([F:31])[CH:26]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c3cc(F)cc1c32

Procedure:
Beginning with (indol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=O)[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:33][O:34][NH2:35]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[N:35][O:34][CH3:33])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=NOC
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained by the method described in Example (28a) (100 mg, 0.21 mmol) was dissolved in pyridine (3 mL). Methoxyamine hydrochloride (28 mg, 0.34 mmol) was added, and the mixture was stirred at 60° C. for two hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, ethyl acetate) to obtain 107 mg of the title compound (100%).
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[Cu][C:34]#[N:35]>CN1CCCC1=O.O.C(OCC)(=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[S:21][C:20]([CH3:30])=[N:19][C:18]=2[C:16]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH2:9][C:7]2[NH:6][C:5]3[CH:31]=[CH:32][C:2]([C:34]#[N:35])=[CH:3][C:4]=3[N:8]=2)=[O:17])=[CH:28][CH:27]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(Br)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(C#N)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 200 °C
Yield: 1 %

Procedure:
A stirring mixture of (RS)-1-[2-(5-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E34 (25 mg, 0.44 mmol) and copper(I)cyanide (79 mg, 0.88 mmol) in N-methylpyrrolidinone (7 ml) under argon was heated at 200° C. for 5 h. The cooled reaction mixture was diluted with water/ethyl acetate and filtered through Kieselghur. The organic phase was washed with water (2×), brine (2×), dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-4% methanol (containing 10%.0.880 ammonia)-dichloromethane). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown gum (2 mg, 1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].Cl.[NH2:16][C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:14])[NH:16][C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: N#CC1(N)CC1
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester and 1-amino-cyclopropanecarbonitrile hydrochloride performed in analogy to example 1, step 8 yielded the title compound as a colorless solid. MS: 265.1 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.OC[CH2:40][N:41]1[CH2:46][CH2:45]OC[CH2:42]1.Cl[CH2:48]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][CH2:48][CH2:45][CH2:46][N:41]([CH3:42])[CH3:40])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCCl
Reactant: OCCN1CCOCC1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Product: COc1ccc(C2(OCCCN(C)C)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 125 mL dichloromethane was added 3-Benzo[1,3]-dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 6.06 g (11.96 mmol), giving a suspension. 4-(2-Hydroxyethyl)morpholine 3 g (22.86 imol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After 3 hours at room temperature, additional 4-(2-hydroxyethyl)-morphline 3 g (22.86 mmol) was added, followed by stirring for 24 hours at room temperature. The mixture was evaporated in vacuo, and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 4 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a crude foam, 2.86 g. The crude material was purified by chromatography on 200 g silica gel eluted with 5% methanol in chloroform. The appropriate fractions were evaporated to a glassy solid, 2.0 g. The product was identified by 1H NMR, MS [M--H]+ =620 Da.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1)[O:16][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(COc2cc(F)cc(C3(OC)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (1.5 g, 6.6 mmol), methyl 4-(bromomethyl)benzoate (1.7 g, 7.4 mmol), K2CO3 (0.6 g, 4.3 mmol), 18-crown-6 (0.05 g) and KI (0.05 g) in dimethylacetamide (5.00 mL) was stirred at room temperature for 16 h, and at 80° C. for 2 h. The reaction mixture was poured into cold water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 20% EtOAc in hexane, to furnish 2.2 g (88%) of methyl 4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate as a white solid: m.p. 88–89° C. 1H NMR (CDCl3/300 Hz) δ 8.07 (d, 2H, J=7.8 Hz), 7.5 (d, 2H, J=7.8 Hz), 6.81 (s, 1H), 6.72 (d, 1H, J=9.9 Hz), 6.6 (d, 1H, J=9.9 Hz), 5.12 (s, 2H), 3.93 (s, 3H), 3.82 (m, 4H), 2.97 (s, 3H), 1.92 (m, 4H). FABMS m/z 375 (M+H).
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH:18]=[CH2:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.C(OCC)(=O)C>C1COCC1>[CH2:15]([C:14]1[CH:13]=[C:12]([CH:18]=[CH2:19])[CH:11]=[C:10]([CH2:20][CH2:21][CH3:22])[C:9]=1[OH:8])[CH2:16][CH3:17]
Reactant: C=Cc1cc(CCC)c(O[Si](C)(C)C(C)(C)C)c(CCC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1cc(CCC)c(O)c(CCC)c1

Procedure:
The title compound was prepared from t-butyldimethyl-silyloxy-2,6-dipropyl-4-vinylbenzene (Step B, Example 14) by treatment with tetrabutylammonium fluoride in THF for a few hours. It was poured into ether/ethyl acetate mixture and washed with brine. After removal of the solvent the crude product was purified by flash column chromatography using ethyl acetate/hexane as eluent.
Reaction SMILES: [S:1](=[O:3])=[O:2].[CH2:4]([C:6]1[CH:11]=[CH:10][C:9](N)=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])[CH3:5].N([O-])=O.[Na+].[ClH:21]>C(O)(=O)C.O.[Cu]Cl>[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([S:1]([Cl:21])(=[O:3])=[O:2])=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])[CH3:5]
Reactant: CCc1ccc(N)cc1C(F)(F)F
Reactant: O=S=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F

Procedure:
Amounts used: 8 mL of acetic acid was saturated with sulfur dioxide, 190 mg of copper(I) chloride, 1.45 g (7.67 mmol) of 4-ethyl-3-trifluoromethyl-phenylamine dissolved in a mixture of 3 mL of acetic acid and 3 mL of concentrated hydrochloric acid, 0.635 g of sodium nitrite in 3 mL of water. Flash chromatography on silica using 0-20% ethyl acetate in hexanes afforded 0.9 g of the product as a white solid. LC-MSD spectrum not observed; HPLC retention time: 2.9 min.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl.O>[F:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:16][CH2:17][OH:18])[CH2:4]1.[F:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:4]1
Reactant: F[C@@H]1CCNC1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CC[C@@H](F)C1
Product: OCCN1CC[C@@H](F)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-[(3R)-3-fluoropyrrolidin-1-yl]ethanol was synthesized as followed: a suspension of (3R)-3-fluoropyrrolidine hydrochloride (1 g, 8 mmol) in CH2Cl2 was cooled to 0° C. Triethylamine (2.79 mL, 20 mmol) and methyl bromoacetate (0.83 mL, 8.8 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and water. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo, yielding methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]acetate, which was used in the next step without further purification (1.29 g). A solution of lithium aluminium hydride in THF (2 M, 8 mL, 6 mmol) was slowly added to a solution of methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]acetate (1.29 g, 8 mmol) in THF (72 mL). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to 0° C. and ice-cold 10% KOH aqueous solution was added slowly. The reaction mixture was filtered and the solid was washed with 10% KOH aqueous solution and hot ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo, yielding 2-[(3R)-3-fluoropyrrolidin-1-yl]ethanol as an oil (779 mg).
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][C:26]=5[CH:27]=[CH:28][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.[CH3:29]I.O>CS(C)=O>[CH3:29][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][C:26]=5[CH:27]=[CH:28][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:5]1.[CH3:29][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][C:26]=5[CH:27]=[CH:28][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:2][N:3]=[N:4]1
Reactant: O=C1CC(=O)N(c2cccc(-c3nnn[nH]3)c2)c2ccc3c(c2N1)CCC3
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nnc(-c2cccc(N3C(=O)CC(=O)Nc4c3ccc3c4CCC3)c2)n1
Product: Cn1nnnc1-c1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %
Yield: 11 %

Procedure:
5-[3-(1H-Tetrazol-5-yl)phenyl]-5,8,9,10-tetrahydroindeno[5,4-b][1,4]diazepine-2,4(1H,3H)-dione sodium salt (46 mg, 0.12 mmol) was dissolved in dry dimethylsulfoxide (2 mL). To the solution was added methyl iodide (37 μL, 0.60 mmol). The mixture was stirred at room temperature for 72 hours. To the mixture was added water. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1-3/1) to give 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-5,8,9,10-tetrahydroindeno[5,4-b][1,4]diazepine-2,4(1H,3H)-dione (17 mg, yield 38%) and 5-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-5,8,9,10-tetrahydroindeno[5,4-b][1,4]diazepine-2,4(1H,3H)-dione (5 mg, yield 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([CH2:19]O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C(Cl)Cl>[Br:22][CH2:19][CH:11]1[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10]1
Reactant: OCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(C2CC(CBr)Cc3ccccc32)cc1Cl
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of compound 11 (1.25 g, 4.07 mmol) and CBr4 (2.33 G, 7.04 mmol) in CH2Cl2 (15 ml) was added Ph3P (1.82 g, 6.92 mmol) in CH2Cl2 (15 ml) at 0° C. The reaction was allowed to warm to room temperature overnight, was then poured into water ((40 ml), extracted with CH2Cl2 (75 ml), dried over Na2SO4, and the solvent was evaporated. The residue was purified by chromatography, CombiFlash silica gel column, EtOAC hexanes, EtOAc from 0% to 15%, to give compound 12 as a clear oil (mixture of cis and trans diastereomers, 1.50 g, 99%). 1H NMR. (CDCl3) δ 1.52-1.62 (m) and 1.97-2.15 (m, total 2H), 2.25-2.30 (m, 1H), 2.64-2.77 (m, 1H), 3.02-3.12 (m, 1H), 3.34-3.47 (m, 2H), 4.08 (dd, J=12 Hz, 5.2 Hz) and 4.26 (t, J=3.6 Hz, total 1H), 6.72-7.39 (m, 7H). 13C NMR (CDCl3) δ 31.8, 34.6, 35.6, 36.8, 37.2, 39.2, 39.3, 39.4, 43.3, 46.4, 126.5, 126.8, 126.9, 127.2, 128.3, 128.4, 128.6, 129.0, 129.4, 129.5, 129.7, 130.2, 130.5, 130.7, 130.9, 132.5, 132.8, 136.1, 136.3, 138.3, 147.0, 147.5.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1cc[nH]c1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cccc2)cc1

Procedure:
Using pyrrole and 4-(bromomethyl)benzonitrile and the method of Example 83A, except using DMF as the solvent, provided N-(4-cyanobenzyl)pyrrole. 1H NMR (CDCl3) δ7.62 (m, 2H), 7.14 (m, 2H), 6.69 (m, 2H), 6.24 (m, 2H), 5.15 (s, 2H). MS (DCl/NH3) (M+H)+ 183 and (M+H+NH3)+ 200.