Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(C)(O)CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)CC(C)C)c21

Procedure:
Using Method C above, 3,5-dimethyl-1-hexyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3,5-dimethyl-3-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 87 mg, 60%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([O:13]C(=O)C)[C@H:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>C1COCC1.CO>[C:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (3R,4R)—N-Boc-3-azido-4-acetoxypyrrolidine (1.0 g, 3.4 mmol) in THF-MeOH (3:1, 8 mL) at 0° C. was added 1N LiOH (4 mL) dropwise. The reaction mixture was stirred at room temperature overnight, then it was evaporated under reduced pressure. Ethyl acetate (20 mL) was added to the residue and the solution was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash column (50% ethyl acetate in hexane) to give (3R,4R)—N-Boc-3-azido-4-hydroxypyrrolidine: 1H NMR (300 MHz, CDCl3) identical to that of the (3S,4S) isomer; [α]20D=−26.8° (c=1.0, CHCl3).
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC(=O)[CH:14]([C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22](F)[C:21]=1[F:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.CS(C)=O.[Cl:35][C:36]1[CH:37]=[C:38]([C:42]([F:46])([F:45])[CH2:43][NH2:44])[CH:39]=[CH:40][CH:41]=1>C([O-])(O)=O.[Na+]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:44][CH2:43][C:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([Cl:35])[CH:37]=2)([F:45])[F:46])[C:21]=1[F:29])[CH3:19]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C#N)ccc(F)c1F
Reactant: NCC(F)(F)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(Cl)c2)c1F
Temperature: 110 °C
Reaction time: 69 h
Yield: 64.1 %

Procedure:
To a solution of DIPEA (1.38 mL, 7.9 mmol), 2-(6-cyano-2,3-difluorophenyl)malonic acid diethyl ester (1.35 g, 6.00 mmol), as prepared in the preceding step, and DMSO (1.7 mL) was added 2-(3-chlorophenyl)-2,2-difluoroethylamine (1.44 g, 7.51 mmol), as prepared in Example 2d. The reaction was stirred under argon at 110° C. for 69 h and then allowed to cool to room temperature. The mixture was diluted with saturated NaHCO3 (15 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to afford the title compound (1.525 g, 64%) as a tan crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.41 (m, 2H), 7.40-7.36 (m, 2H), 7.30 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.63 (t, J=8.2 Hz, 1H), 4.67 (br, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.84 (d, J=2.0 Hz, 2H), 3.81 (dt, J=13.3 Hz, 6.9 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (ESI) calcd for C21H20ClF3N3O2 (MH+.MeCN) 438.1. found 438.2.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:5]=1[CH2:6][N:7]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:8](=[O:28])[CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=1>O.C1COCC1>[F:3][C:4]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:5]=1[CH2:6][N:7]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:8](=[O:28])[CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Reaction time: 0.12 h
Yield: 66.6 %

Procedure:
Lithium hydroxide (13.3 mg, 0.554 mmol) in water (1.5 ml) was added into 70335 methyl 2-[(4-{2-[(2,4-difluorobenzyl)(heptyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (145 mg, 0.277 mmol) dissolved in THF (3 ml). The mixture was then in microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4 and then extracted with ethyl acetate (×2). The organic portions were combined, washed with brine, dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM then MeOH/DCM (0.5:99.5, then 1:99) as eluant gave 94 mg desired product, yield 67%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccc(F)cc3F)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1Br
Temperature: 100 °C

Procedure:
2-Bromo-5-methylbenzoic acid (9.3 g, 43.4 mmol) was dissolved in MeOH (100 mL) and then cat. conc. H2SO4 was added. The mixture was refluxed at 100° C. overnight. The mixture was cooled to rt and the solvent was removed at reduced pressure. The crude residue was dissolved with EtOAc, and washed with water twice, followed by saturated NaHCO3 and brine, dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the title compound with no further purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[O:5]CC1C=CC(Cl)=CC=1Cl.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C@@H:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[OH:5]
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Reaction time: 27 h

Procedure:
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in 1.8 L CH2Cl2 that was cooled to 0° C., was added dropwise a solution of stannous chloride (31.522 mL, 0.2676 mol) in 134 mL CH2Cl2 while stirring. After the solution was kept at 3° C. for 27 hours, another 5.031 ml of SnCl4 (0.04282 mol) was added and the solution was kept at 3° C. overnight. After 43 hours the reaction was quenched by carefully adding the solution to 1.9 L saturated NaHCO3 solution. Tin salts were removed via filtration through celite after which the organic phage was isolated, dried with MgSO4 and evaporated in vacuo. The yield of raw, dark yellow oil was 173.6 g, which contains 2,4-dibenzoyl chloride. The crude oil was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:25]1([CH2:24][NH:31][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]3[CH:13]=[N:12][C:11]4[N:10]([N:9]=[CH:8][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:15]=3)=[CH:17][CH:18]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNCc2ccc(-c3cnc4c(-c5ccccc5)cnn4c3)cc2)cc1

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5, 75 mg, 0.25 mmol), benzylamine (0.056 mL, 0.50 mmol), acetic acid (14 TL, 0.25 mmol), and sodium triacetoxyborohydride(106 mg, 0.50 mmol) in 1,2-dichloro-ethane (6 mL) was stirred under ambient conditions overnight. The residue was partitioned between sat. NaHCO3 solution (4 mL) and ethyl acetate (3×4 mL). The organic layer was washed with brine and dried over MgSO4 and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 1-phenyl-N-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzyl]methanamine (1-6) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ9.21 (d, 1H, J=2.4 Hz), 8.96 (d, 1H, J=2.4 Hz), 8.61 (s, 1H), 8.12 (br d, 2H, J=7.8 Hz), 7.91 (d, 2H, J=8.2 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.49 (m, 5H), 7.44 (br t, 2H, J=7.8 Hz), 7.27 (t, 1H, J=7.5 Hz), 4.34 (s, 2H), 4.29 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CCC[C@H](Cl)C2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sixty-percent sodium hydride (470 mg, 12 mmols) was washed with petroleum ether, and then suspended in 50 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.5 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 3.2 g (11 mmols) of (S)-(+)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine[[α]D25=+20.3 ° (c=0.9, ethano 1)] in 30 ml of dimethyl sulfoxide, and the mixed solution was stirred at 50° C. for 5 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:3. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 300:1. The mixed solvent was then distilled off under reduced pressure to give 2.8 g of (R)-(+)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 85%.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([N:33]3[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:35][CH2:34]3)=[O:3])[C:5]=12
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: C1CCN(CCCCC2CCNCC2)CC1
Solvent: CCOC(C)=O
Product: Cc1scc2c1N(C(=O)N1CCC(CCCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 31 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[4-(1-piperidinyl)butyl]piperidine in a yield of 31% of theory. Colourless crystals, m.p. 209°-210° C. (ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[Li+:45].[OH-].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:23][CH:24]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[Li+:45]
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)[O-])c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1

Procedure:
3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid (1 eq.) is added to a reactor containing ethanol and stirred. A LiOH solution in water (1.05 eq.) is added to the reactor and stirred at ambient temperature. After removal of the solvent, lithium 3-[5-(pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionate is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(CC(=O)OC)[C@@H]1c1ccc(C#N)cc1

Procedure:
500 mg (1.164 mmol) of the compound from Example 5A were stirred together with 220 mg (1.397 mmol) of methyl bromoacetate and 322 mg (2.329 mmol) of potassium carbonate in 20 ml of DMF at 60° C. overnight. The solid was then filtered off, the filtrate was concentrated on a rotary evaporator, the residue was dissolved in dichloromethane and this solution was washed three times with water. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated. The crude product was purified by chromatography on silica gel (mobile phase toluene/ethyl acetate 3:1). This gave 419 mg (72% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]3[OH:23])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].IC.[C:30]([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH:11]3[O:23][CH3:30])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: Cc1nc2cc(F)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC1CN(C(=O)OC(C)(C)C)CCC1n1c(C)nc2cc(F)ccc21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
4-(5-fluoro-2-methylbenzimidazol-1-yl)-3-hydroxy-Boc-piperidine (205 mg, 0.59 mmol) mmol) in THF (5 mL) and cooled to 0° C. under Ar. NaH (60% oil dispersion; 32 mg, 0.8 mmol) was added and the reaction mixture was stirred for 15 minutes. Iodomethane (0.8 mmol) was then added. After stirring for 3 hours at rt the reaction mixture was poured into saturated NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure yielded crude product from which 4-(5-fluoro-2-methylbenzimidazol-1-yl)-3-methoxy-Boc-piperidine (191 mg, 89%) was isolated as a waxy solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14]C(OC(C)(C)C)=O)[CH2:8]2)(=[O:3])[CH3:2].[ClH:22].O1CCOCC1>C(O)(=O)C>[ClH:22].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH2:14])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)Oc1ccc2c(c1)CC(N)C2

Procedure:
Using 5-acetoxy-2-(tert-butoxycarbonylamino)indan (120 mg, 0.40 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6 ml), a similar procedure to Example 24 was carried out to obtain 5-acetoxy-2-aminoindan hydrochloride (86 mg, 0.38 mmol) having the following physical properties:
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]1([C:28]2[S:29][CH:30]=[C:31]([CH2:33]O)[N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][CH2:33][C:31]1[N:32]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:29][CH:30]=1
Reactant: BrBr
Reactant: OCc1csc(-c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1csc(-c2ccccc2)n1
Temperature: -6 °C
Yield: 93.8 %

Procedure:
Bromine (177 mg, 1.1 mmol) was added directly into a solution of triphenylphosphine (288 mg, 1.1 mmol) in DCM (2 mL) to give a kind of white precipitate. The temperature was cooled to −6° C. A solution of commercially available (2-phenylthiazol-4-yl)methanol (200 mg, 1.04 mmol) in DCM (1 mL) was added dropwise. The resulting mixture was maintained at −6° C. for 15 min and then warmed to room temperature for 1 h. A white precipitate was formed. The solution was filtered and the white precipitate was washed with DCM. The white precipitate was collected and dissolved in NaHCO3 0.5M After 30 min of stirring, the aqueous layer was extracted with DCM and the organic phase was washed with water, dried over MgSO4, filtered and evaporated to afford 248 mg of 4-(bromomethyl)-2-phenylthiazole (Yield 71%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:18][CH2:19][C:20]3[S:24][C:23]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:22][CH:21]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: C=CCOC(=O)c1ccc(CO)s1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
In a manner similar to Example 1(d), by reaction of 2.5 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride with 1.98 g (10 mmol) of allyl 5-hydroxymethyl-2-thiophene carboxylate, 3.7 g (90%) of allyl ester are obtained in the form of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[O:16].Cl>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[OH:16])=[CH:3][CH:4]=1
Reactant: O=Cc1cccs1
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccs1
Yield: 108 %

Procedure:
To a stirred Grignard complex, previously prepared from 17.5 g (0.10 mol) 1-bromo-4-fluorobenzene and 2.43 g (0.10 mol) magnesium turnings in 50 ml tetrahydrofuran, 8.97 g (0.080 mol) thiophene-2-carboxaldehyde, dissolved in 30 ml tetrahydrofuran, was added dropwise. Upon complete addition the reaction mixture was refluxed for 1 h and then poured on a mixture of ice and 6N hydrochloric acid. Subsequent extraction with toluene, washing of the organic layer and evaporation in vacuo, gave 18 g of the desired (4-fluorophenyl)(2-thienyl)methanol as a brown oil. This was directly converted to the corresponding (4-fluorophenyl)(2-thienyl)methyl chloride with thionyl chloride by a procedure known to the art.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:13]1[C@@H:14]([CH2:16][CH2:17][CH3:18])[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: CCC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of (3S,4S) -1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-propylpyrrolidine (4.02 g, 11.09 mmol) and a 10% palladium carbon catalyst (1.0 g) in ethanol (100 mL) was stirred hard for 20 hours under an ordinary pressure in a hydrogen atmosphere. Insoluble matter was removed through filtration by use of Celite, and then ethanol was removed under reduced pressure. The residue was dissolved in diethyl ether (200 mL), and the solution was washed by a 1 mol/L aqueous sodium hydroxide solution (100 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (2.34 g, 92.4%).