Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][OH:6])[CH3:2].[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([O:19]C)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:21])[CH:11]=[CH:12][C:13]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH3:10][N+:3]([CH2:1][CH3:2])([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][OH:6]
Reactant: CCN(CCO)CCO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: CC[N+](C)(CCO)CCO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 150 °C

Procedure:
Methyl-ethyl di (βhydroxyethyl) ammonium para-toluene sulfonate (C) is prepared by slowly adding ethyldiethanolamine to methyl para-toluene sulfonate in equal molecular quantity and by heating to 150°C for 2 hours.
Reaction SMILES: C1(CN2C3C=C(F)C(F)=CC=3N=C2C2C(OCC3CCCC3)=NC=CC=2)CCCCC1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:64]=[CH:65][CH:66]=1)[CH2:36][N:37]1[C:41]2[CH:42]=[C:43]([F:47])[C:44]([F:46])=[CH:45][C:40]=2[N:39]=[C:38]1[C:48]1[C:49]([O:54]CC2C=CC(OC)=CC=2)=[N:50][CH:51]=[CH:52][CH:53]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:64]=[CH:65][CH:66]=1)[CH2:36][N:37]1[C:41]2[CH:42]=[C:43]([F:47])[C:44]([F:46])=[CH:45][C:40]=2[N:39]=[C:38]1[C:48]1[C:49]([OH:54])=[N:50][CH:51]=[CH:52][CH:53]=1
Reactant: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1
Agent: Fc1cc2nc(-c3cccnc3OCC3CCCC3)n(CC3CCCCC3)c2cc1F
Product: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate b, from 1-(3-chloro-benzyl)-5,6-difluoro-2-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]-1H-benzoimidazole. Colorless powder (27%). MS (Turbo Spray): m/z=372.3 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([SH:38])[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([S:38][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:29]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>C(#N)C>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccnc1
Temperature: 4 °C
Yield: 68.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with nicotinic acid (3.7 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-chloro-1,8-naphthyridine (3.6 g). The product precipitated in the mixture is separated by filtration, washed with tetrahydrofuran (3×20 cc) and water (3×50 cc), and is then dried at 50° C. under reduced pressure (0.067 kPa). The product produced (4.75 g; m.p. 200° C.) is dissolved in boiling acetonitrile (435 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-pyridylcarboxamide (3.9 g) is produced, m.p. 200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH:10]([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](COCC1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.325 g (0.73 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one (Example 68, Step B) and iodomethane (0.055 mL, 0.874 mmol) in THF (7.0 mL) was added lithium bis(trimethylsilyl)amide (1M solution in THF, 0.8 mL, 0.8 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]=[O:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].S([CH2:44][N+:45]#[C-:46])(C1C=CC(C)=CC=1)(=O)=O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:25]3[O:26][CH:46]=[N:45][CH:44]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:25]3[O:26][CH:46]=[N:45][CH:44]=3)=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(-c3cnco3)cc21
Product: Fc1c(Nc2ccc(Br)cc2Cl)c(-c2cnco2)cc2[nH]cnc12
Temperature: 25 °C
Yield: 4 %
Yield: 18 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.025 g, 0.053 mmol) is suspended in MeOH (2 mL) and K2CO3 (0.015 g, 0.105 mmol) is added followed by tosylmethyl isocyanide (0.011 g, 0.058 mmol). The reaction mixture is heated to reflux under N2 for 16 hours. After cooling, additional tosylmethyl isocyanide (0.011 g, 0.058 mmol) is added and the reaction mixture heated to reflux under N2 for 16 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure and dissolved in ethyl acetate. The organic solution is washed with water and brine. The combined aqueous washes are extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 20:1 methylene chloride:MeOH gives 4 mg (18%) desired product 10x and 1 mg (4%) (4-bromo-2-chloro-phenyl)-[4-fluoro-1-(2-methanesulfonyl-ethyl)-6-oxazol-5-yl-1H-benzoimidazol-5-yl]-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]5[S:21][CH:22]=[CH:23][N:24]=5)=[O:18])[C:10]=4[N:9]=3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(N4CCOCC4)nc3)nc12
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 57.1 %

Procedure:
A mixture containing 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (7; 20 mg, 0.056 mmol) and morpholine (48; 49 mg, 0.56 mmol) in DMSO (1.5 mL) was stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solids were collected by filtration and dried. The solids were redissolved in EtOAc and enough petroleum ether was added to precipitate the product out again. The solids were collected by filtration, washed with MeOH and dried to afford 2-(6-morpholinopyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 247) as a pale yellow solid (13 mg, 57%). MS (ESI) calcd for C20H18N6O2S: 406.12; found: 407 [M+H].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[CH3:1])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Reactant: Cc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of toluene (20 ml), 2-methylbenzimidazole (0.55 g, 4.2 mmole), triethylamine (0.42 g, 4.2 mmole) and 4-(4-ethoxyphenoxy)benzyl chloride (1.00 g, 3.8 mmole) was heated under reflux for 5 hours and then cooled to room temperature. The resultant mixture was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (1.20 g) as colorless liquid. nD26.0 1.5984.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][Si:8]([O:14][Si:15]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.Br[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[C:36]#[N:37]>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].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>[C:36]([C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][Si:8]([O:14][Si:15]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:33]4[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=4)=[CH:25][CH:24]=3)([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:9])=[CH:30][CH:31]=2)[CH:40]=[CH:39][CH:38]=1)#[N:37]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(CCc1ccc(Br)cc1)O[Si](C)(CCc1ccc(Br)cc1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(CCc1ccc(-c2cccc(C#N)c2)cc1)O[Si](C)(CCc1ccc(-c2cccc(C#N)c2)cc1)C(C)(C)C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a cooled (−78° C.) solution of 4-bromo-benzyl-(t-butyldimethylsilyl)-ether (2.73 g, 9 mmol) (reference example 10) in THF (40 mL) was added, dropwise, n-buLi (4.4 mL, 2.5M in hexanes). On complete addition, the resulting solution was stirred for 10 min then ZnCl2 (10 mL, 0.5M in THF) was added. The cold bath was removed and stirring continued for 10 min. To this solution was added a solution comprised of 3-bromo-benzonitrile (1.82 g, 10 mmol) (Aldrich), (Ph3P)4Pd (410 mg, 0.35 mmol) in THF (5 mL). The resulting mixture was heated to 65° C. and stirred at this temperature for 20 min. The reaction mixture was allowed to cool to room temperature then diluted with ether, washed, sequentially, with sat. ammonium chloride solution and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (eluting with 5% EtOAc in hexanes) to give 2.0 g of the title compound. 1H NMR (CDCl3) d 0.15 (s, 6H), 1.00 (s, 9H), 4.80 (s, 2H), 7.43 (d, J=8 Hz, 2H), 7.45-7.65 (m, 4H), 7.80 (m, 1H), 7.85 (bs, 1). MS (ion spray) m/z 324 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([NH2:17])[CH2:15][NH2:16]>>[CH2:15]([NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:14]([NH:17][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:13]
Reactant: CCCCCCCCCC1CO1
Reactant: CC(N)CN
Product: CCCCCCCCCC(O)CNCC(C)NCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1-methyl-1,2-ethanediamine affords N,N'-(1,2-propylene)-bis[2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R'= H, X= CH(CH3)CH2, Z= H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH2:23])[CH:22]=2)[CH:12]=[N:13][CH:14]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:23][C:5](=[O:7])[CH3:6])[CH:22]=2)[CH:12]=[N:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Add acetic anhydride (113 mg, 1.11 mmol) to a solution of 5-(5-chloropyridin-3-ylethynyl)-2-fluorophenylamine, (prepared as described in EXAMPLE 190) (0.275 g, 1.11 mmol) in pyridine (4 mL). Stir the mixture at room temperature under nitrogen for 18 h then concentrate. Purify by silica gel chromatography, eluting with a gradient of 75:25 to 50:50 with hexanes:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (240 mg, 75%).
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[C:6]([O:12][CH2:13][CH3:14])(=O)[O:7]COC.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>CCO>[CH:1]1([N:4]2[C:20]([C:6]([O:12][CH2:13][CH3:14])=[O:7])=[CH:15][C:16]([CH3:17])=[N:5]2)[CH2:3][CH2:2]1
Reactant: NNC1CC1
Reactant: CCOC(=O)OCOC
Reactant: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)nn1C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred solution of cyclopropylhydrazine (Step 17.2) (4.90 g, 45.1 mmol) in toluene (30 mL) and EtOH (30 mL) was added ethyl 2,4-dioxavalerate (6.34 mL, 45.1 mmol). The reaction mixture was stirred for 1 hr at 100° C., quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%) to afford the title product (3.01 g, 15.50 mmol, 34% yield). tR: 4.70 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 195 [M+H]+ (LC-MS 2); Rf=0.33 (hexane/EtOAc 9:1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:14]C([N-]C(C)C)C.CI.[Br:23][CH2:24][CH2:25][CH2:26]Br.[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:11]([O:10][C:8](=[O:9])[C:7]([CH3:14])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:26][CH2:25][CH2:24][Br:23])[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: BrCCCBr
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(CCCBr)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
Under Ar atmosphere, to a solution of ethyl phenylacetate (42.4 g, 0.257 mol) and DMPU (5 mL) in THF (250 mL) was added drop-wise LDA (2.0 M solution in heptane/THF/ethylbenzene, 135 mL, 270 mmol) at −78° C. After 2 h, methyl iodide (41.40 g, 0.292 mol) was added and the mixture was allowed to warn to rt overnight. This solution was cooled to −78° C. and 1,3-dibromopropane (72.7 g, 0.36 mol) was added. The reaction mixture was allowed to stir overnight, gradually warming to rt. After careful addition of ice (200 g), sat. NH4Cl solution (400 mL), and concd. HCl (100 mL), the mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over MgSO4, concentrated in vacuo, and distilled under reduced pressure to give 5-bromo-2-methyl-2-phenyl-pentanoic acid ethyl ester (88.6 g, 59%) as a colorless oil (bp.: 122-128° C./0.25 mmHg). 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 7.34-7.21 (m, 5H), 4.12 (q, 2H, J=6.9 Hz), 3.35 (t, 2H, J=6.6 Hz), 2.20-1.95 (m, 2H), 1.77-1.71 (m, 2H), 1.56 (s, 3H), 1.18 (t, 3H, J=6.9 Hz). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 175.88, 143.40, 128.54, 126.90, 125.99, 60.96, 49.83, 38.18, 34.01, 28.45, 22.81, 14.17.
Reaction SMILES: C([O-])(=O)C(C)(C)C.[C:8]([CH2:10][CH2:11][Zn+])#[N:9].Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[C:8]([CH2:10][CH2:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:9]
Reactant: N#CCC[Zn+]
Reactant: N#Cc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#CCCc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, (2-cyanoethyl)zinc pivalate (1t) (2.35 g, 2150 mg/mmol, 1.09 mmol) was dissolved in a mixture of THF (3.0 mL) and NMP (1.0 mL). 4-Bromobenzonitrile (168 mg, 0.92 mmol) was added followed by PEPPSI-iPr (14 mg, 0.02 mmol) and the mixture was stirred for 12 h at 50° C. Then sat. aq. NH4Cl (10 mL) was added and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4). Evaporation of the solvents in vacuo and purification by flash chromatography (silica gel, ihexane/Et2O=3:1) afforded 4-(2-cyanoethyl)benzonitrile (entry 26) (113 mg, 80%) as a pale yellow oil.
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)[CH:6]=CC=C[CH:2]=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:40]1([CH:17]([C:16]2[CH:46]=[CH:6][CH:1]=[CH:2][CH:15]=2)[C:18]([NH:20][C@@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by substituting 2,2-diphenylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 7.71 (d, J=7.5, 2H), 7.63 (d, J=7.2, 2H), 7.45 (d, J=7.4, 2H), 7.39-7.28 (m, 5H), 7.25 (dd, J=5.8, 8.9, 3H), 4.51-4.42 (m, 1H), 3.44 (d, J=13.3, 1H), 3.25 (d, J=13.3, 1H), 2.85 (qd, J=3.2, 7.9, 1H), 2.59 (dd, J=3.4, 9.5, 1H), 2.47-2.37 (m, 1H), 2.26 (t, J=8.3, 1H), 2.21-2.13 (m, 2H), 1.85-1.76 (m, 1H), 1.67-1.52 (m, 3H), 1.27-1.18 (m, 1H); MS (ESI+) m/z 479 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)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>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=4[CH:18]=3)=[CH:22][CH:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: [O-]B([O-])Oc1ccc(N2CCCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-(1-pyrrolidinyl)phenyl borate (508 mg) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 17 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with diisopropylether to give yellow crystals of methyl 7-[4-(1-pyrrolidinyl)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (323 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:21])[CH2:19][CH3:20]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([CH2:19][CH3:20])=[N:21][N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: CCOc1ccc(N/C(C)=C\C(=O)OC)cc1
Reactant: CCC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOc1ccc(-n2nc(CC)c(C(=O)OC)c2C)cc1
Yield: 88 %

Procedure:
According to AVV A, (Z-3-(4-ethoxyphenylamino)-but-2-enoic acid methylester (235.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. The bluish-brown raw product (307.8 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→70:30→0:100), whereby the pure product was obtained in the form of a weak-yellow oil (254.7 mg, 0.88 mmol, 88%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12]N1C(=O)CCC1=O>C(#N)C.C(Cl)(Cl)Cl>[Br:12][C:4]1[NH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c(Br)nc1C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
To a stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (2.00 g, 13.0 mmol) in acetonitrile (25 mL) and chloroform (25 mL) was added N-bromosuccinimide (2.31 g, 13.0 mmol). The reaction mixture was stirred under nitrogen atmosphere for 20 h, then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate as a light yellow solid (1.88 g, 62%): 1H NMR (300 MHz, CDCl3) δ 4.35 (q, J=7.1 Hz, 2H), 2.51 (s, 3H), 1.37 (t, J=7.1 Hz, 3H); MS (ES+) m/z 233.1 (M+1), 235.1 (M+1).