Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:32])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:32][N:8]([CH3:7])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: Cc1ccc(NC(=O)CC2CCC(c3ccccc3)(N(C)C)CC2)cc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl

Procedure:
Chlorotrimethylsilane (0.477 ml) and water (34 μl) were added to a solution of the more polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-p-tolyl-acetamide (1.2 g, 3.4 mmol) in ethyl methyl ketone (10 ml). The hydrochloride was extracted as an oil with hexane and isolated in a yield of 78% (1.04 g; 2.7 mmol) (Example 60).
Reaction SMILES: FC1C=CC(CN2C3=CN=C(C(OCC)=O)C=C3C=C2)=CC=1.N1C2=CN=C(C(OCC)=O)C=C2C=C1.FC1C=CC(CBr)=CC=1.FC1C=C(F)C=CC=1CN1C2=CN=C(C(O)=O)C=C2C=C1.F[C:68]1[CH:87]=[C:86]([F:88])[CH:85]=[CH:84][C:69]=1[CH2:70][N:71]1[C:75]2=[CH:76][N:77]=[C:78]([C:80]([NH:82][OH:83])=[O:81])[CH:79]=[C:74]2[CH:73]=[CH:72]1.FC1C=CC(CN2C3=CN=C(C(O)=O)C=C3C=C2)=CC=1.Cl.NO>>[F:88][C:86]1[CH:87]=[CH:68][C:69]([CH2:70][N:71]2[C:75]3=[CH:76][N:77]=[C:78]([C:80]([NH:82][OH:83])=[O:81])[CH:79]=[C:74]3[CH:73]=[CH:72]2)=[CH:84][CH:85]=1
Reactant: O=C(NO)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2cc[nH]c2cn1
Agent: CCOC(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(NO)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
Ethyl 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. The title compound was prepared by alkylation of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate with 4-fluorobenzyl bromide in a manner similar to step (a) of example 1. 1H NMR (CD3OD) δ: 8.91 (s, 1H), 8.62 (s, 1H), 7.90 (d, 1H, J=3.0 Hz), 7.42 (m, 2H), 7.20 (m, 2H), 6.90 (d, 1H, J=3.0 Hz), 5.75 (s, 2H), 4.60 (q, 2H, J=7.0 Hz), 1.60 (t, 3H, J=7.0 Hz). LCMS (API-ES, M+H+): 299.1. (b) 1-(4-Fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6): δ: 8.97 (s, 1H), 8.35 (s, 1H), 7.90 (d, 1H, J=3.0 Hz), 7.35 (m, 2 H), 7.15 (m, 2H), 6.76 (d, 1H, J=3.0 Hz), 5.67 (s, 2H). LCMS (API-ES, M+H+): 271.1. (c) 1-(4-Fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 11.12 (s, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 8.21 (s, 1H), 7.85 (d, 1H, J=3 Hz), 7.36 (d, 2H, J=8.3 Hz), 7.17 (d, 2H, J=8.4 Hz), 6.71 (d, 1H, J=3.0 Hz), 5.59 (s, 2H). LCMS (API-ES, M+H+): 286.1. HRMS calcd for C15H13FN3O2 (M+H) 286.0992, found 286.0978. Anal. (C15H12FN3O2) C, H, N. HPLC: 96.6% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH2:9][CH2:10][NH:11][C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)NCCC=C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)NC=CC=C2
Reaction time: 16 h
Yield: 169.6 %

Procedure:
To a solution of the 8-methoxydihydrobenzazepine (0.45 g, 1.6 mmol) from step F above in ethanol (60 mL) were added trifluoroacetic acid (0.8 mL) and palladium(II) hydroxide (0.15 g, 0.21 mmol). The reaction solution was shaken under hydrogen (35 psi) for 16 hours. The resultant reaction mixture was filtered through a pad of Celite and the filtrate obtained was concentrated in vacuo to give the desired 8-methoxybenzazepine (0.47 g, quantitative), which was used in the next step without purification: ESI MS m/z 282 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:26]=4[F:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(F)cc1F
Yield: 81.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.194 g (1.1 mmol) of 2,4-difluorobenzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from ethyl acetate-hexane to give 0.37 g of crystals, m.p. 215°-217° C.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25]C(C(O)=O)=[CH:20][N:19]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25][C:6]([C:7]([Cl:9])=[O:8])=[CH:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCOCC2)nc1
Reaction time: 0.25 h

Procedure:
N,N-Dimethylformamide (1 mL) was slowly added to a solution of oxalyl chloride (0.13 g, 1 mmol) in chloroform (5 mL). 6-Morpholinonicotinic acid (0.21 g, 1 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was concentrated under vacuum, diluted with toluene and then concentrated under vacuum to provide 6-morpholinonicotinoyl chloride. This material was kept under vacuum at ambient temperature overnight and then used in the next step.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:29])[C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:14]C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)([O-:4])=[O:3].CCOCC>O1CCCC1>[ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:29])[C@H:13]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
250 ml of 5 N ethereal hydrogen chloride were added to a solution of 21 g of tert.-butoxycarbonyl-L-phenylalanine p-nitrophenyl ester in 50 ml of anhydrous tetrahydrofurane and the reaction mixture was stirred for 1 hour at 22° C., with exclusion of moisture. 250 ml of absolute ether were added to the precipitate formed and the yellowish crystals were isolated by filtration; 15.9 g (99% of theory) of melting point 191°-193° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)C1CC=NN1C(=O)[C@@H](CC(=O)OC(C)(C)C)CC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)C1CC=NN1C(=O)[C@@H](CC(=O)O)CC1CCCC1
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-{5-[(dimethylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobutanoate (315 mg, 0.83 mmol) in 1,4-dioxane (5.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (10.4 mL, 42 mmol) at room temperature. The reaction mixture was stirred for 4 hours. The solvent was then removed by reduced pressure to afford the crude product, (3R)-3-(cyclopentylmethyl)-4-{5-[(dimethylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobutanoic acid (269 mg, 100% yield), which was used directly in the next step. MS: 324 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=3)[N:36]=2)[CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:42][CH2:41][C:39]2[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:51])[F:52])=[CH:45][CH:44]=3)[N:36]=[C:35]([N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)[CH:40]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.1 %

Procedure:
A solution of acid 4C (0.40 g, 1.45 mmol) in THF (25 mL) was added with DEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27D (0.56 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc and washed with water and brine. After drying over Na2SO4, the separated organic phase was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale yellow solid (0.24 g) after crystallization from a mixture of diethyl ether/petroleum ether. Yield=36%, 1HNMR (DMSO, 200 MHz) δ 2.95 (s, 3H), 3.55 (m, 4H), 3.70 (m, 4H), 4.40 (d, 2H, J=6), 5.12 (s, 1H), 5.87 (s, 1H), 6.82 (s, 1H), 7.29 (s, 1H), 7.43 (d, 2H, J=8.2), 7.83-7.74 (m, 4H), 8.17 (d, 2H, J=8), 8.86 (t, 1H); [M+1] 611.03 (C27H26ClF3N4O5S requires 610.13).
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(C)=O.O>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[NH:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Reaction time: 1 h
Yield: 113.9 %

Procedure:
To a solution of 11.3 g of diphenylmethyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 230 ml of acetone is added a solution of 900 mg of sodium hydroxide in 36 ml of water under ice-cooling, and the mixture stirred for 1 hour, then diluted with water, acidified with hydrochloric acid, and then extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield 12.54 g of diphenylmethyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: C([O:8][C:9](=[O:35])[C@@H:10]([NH:31][C:32](=[O:34])[CH3:33])[CH2:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:16]1)=[O:14])C1C=CC=CC=1>C(O)C.Cl.C(OCC)(=O)C.O=[Pt]=O>[NH:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:13]([NH:12][CH2:11][C@H:10]([NH:31][C:32](=[O:34])[CH3:33])[C:9]([OH:35])=[O:8])=[O:14])[CH2:16]2)=[O:30])[CH2:25][CH2:26]1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)C=Cc2ccncc2)C1)C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O
Reaction time: 3.5 h
Yield: 79.8 %

Procedure:
A mixture of N-[(R)-1-[3-(4-pyridyl)-2-propenoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester (233 mg), PtO2 (60 mg) in ethanol (10 ml), 4N HCl in ethyl acetate (121 μl) and PtO2 (50% wet, 1.2 g) was stirred vigorously under hydrogen (1 atm) atmosphere. After 3.5 hours, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in water (10 ml). The solution was adjusted to pH 6.5 with aqueous NaHCO3, then evaporated in vacuo. The residue was purified by ODS-chromatography (Disogel SP-120®) eluting with 4% CH3CN/water. The eluent was concentrated in vacuo and freeze-dried to give N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine (154 mg) as a white powder, which is the compound obtained in Example 8.
Reaction SMILES: [C:1]([CH:8]([NH2:16])[CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:17]1[C:26]2[N:25]=[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]3=[CH:22][C:21]=2[CH:20]=[CH:19][C:18]1=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:17]1[C:26]2[N:25]=[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]3=[CH:22][C:21]=2[CH:20]=[C:19]([N:10]([CH2:9][CH:8]([NH2:16])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:18]1=[O:31]
Reactant: COC(=O)CNCC(N)C(=O)OC(C)(C)C
Reactant: O=c1ccc2cc3ccccc3nc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CN(CC(N)C(=O)OC(C)(C)C)c1cc2cc3ccccc3nc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.1 %

Procedure:
Methyl N-(2-Boc-aminoethyl)glycinate (0.812 g, 3.5 mmol) was dissolved in DMF (10 mL) and benzo[b][1,8]napthyridin-2(1H)-one 3 acetic acid (883 mg, 3.5 mmol) was added. The mixture was cooled in an ice bath and HBTU (1.52 g, 4.0 mmol) was added. After 1 hour the ice bath was removed and the mixture was stirred overnight at room temperature. The mixture was evaporated in vacuo, redissolved in dichloromethane (100 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4) and evaporated in vacuo. The crude product was purified on a silica column eluted with dichloromethane/methanol (97:3, v/v). Fractions containing the product were pooled and evaporated in vacuo to give 345 mg (21%) of the title compound as a tan solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:16][C:15]3([CH2:28][CH2:27][CH:26]([C:29]([O-])=[O:30])[CH2:25][CH2:24]3)[O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C1COCC1>[C:7]1([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:15]3([CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]3)[O:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C([O-])C1CCC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a mixed solution of lithium aluminum hydride (3.36 g) in THF (215 mL) was added a solution of (2S,3S)-2,3-diphenyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (43.3 g) in THF (215 mL) at an internal temperature of 10° C. or lower over 30 minutes in a methanol-ice bath, followed by stirring at an internal temperature of 10° C. or lower for 1 hour and then stirring in an ice bath for 2 hours. To the reaction mixture were sequentially added water (8.6 mL), 10% aqueous sodium hydroxide solution (8.6 mL), and water (27.5 mL) in an ice bath, followed by stirring at room temperature for 30 minutes. The solid was removed by filtration through Celite and the filtrate was concentrated to obtain [(2S,3S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-8-yl]methanol (38.4 g) as a pale peach pink oily substance.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:41])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]4[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=3)[N:21]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:20]=2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:8][N:9]([CH3:41])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]4[CH:29]=[C:30]([NH:34][C:1](=[O:3])[CH3:2])[CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=3)[N:21]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)[CH:20]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc(N)c4)ccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc3c(-c4ccc(OCCN(C)C)cc4)cn(-c4ccncc4)c3c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic anhydride (4.8 μL, 0.5.1 μmol) was added to a mixture solution of 3-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)benzenamine (2.2 mg, 4.9 μmol) in pyridine (0.4 mL) at room temperature. After stirring for 15 hours at room temperature, the reaction solution was added to saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative TLC, DCM:MeOH=10:1). The target compound (1.5 mg) was obtained as white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[CH:13].C([Mg]Br)C.I[CH2:19][C:20]#[C:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1.CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[C:13][CH2:19][C:20]#[C:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICC#CCOc1ccccc1
Reactant: C#CCC#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C(#CCC#CCOC1CCCCO1)CC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a cold (-20° C.) solution of 2.879 g (0.0161 mol) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 30 ml of tetrahydrofuran, there were added dropwise, under argon atmosphere, 4.0 ml (2.15 g, 0.016 mol) of a 4.05N solution of ethylmagnesium bromide in ether, maintaining the temperature at -20° C. After the addition was finished, the reaction mixture was stirred for 2 hours further at -20° C. Then, 52.8 mg (0.53 mmol) of cuprous chloride was added. The mixture was stirred for 20 additional minutes, warmed to room temperature and 2.2 g (0.008 mol) of 1-iodo-4-phenoxybut-2-yne were added. The reaction mixture was then stirred at room temperature for 3 hours, poured into 50 ml of saturated ammonium chloride solution and extracted with ether. The combined extracts were dried and evaporated in vacuo. The residue was purified by column chromatography on 80 g of silica gel, using hexane-ether (90:10) as eluant, thus obtaining 10-phenoxydeca-2,5,8-triyn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: F.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[C:10](OC)(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]2[C:4]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][C:10]2=[O:19]
Reactant: Cc1ccc(C)cc1
Reactant: COC(=O)/C=C/c1ccccc1
Agent: F
Product: Cc1ccc(C)c2c1C(=O)CC2c1ccccc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 90 %

Procedure:
100 g (5 mol) of anhydrous hydrogen fluoride were added to 10.6 g (100 mmol) of p-xylene (99% purity) and 17 g (105 mmol) of methyl trans-cinnamate, and the mixture was stirred at 70° C. for 17 hours. Work-up carried out analogously to Example A gave 23.6 g of a yellowish solid. The purity of the product is 96% (GC). (96% of theory). After recrystallization once from an ethyl acetate/hexane mixture (1:1), a virtually white solid was obtained in a yield of 90%. The purity after this step is greater than 98% (GC).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(C(N)=O)=C2CN(S(C3SC(C4C=CC=CN=4)=CC=3)(=O)=[O:36])CCN2C=1C1C=CC=CC=1.[OH-].[Na+].OO>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[CH:15][C:16]([C:17](=[O:36])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1-c1cc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(S(=O)(=O)c1ccc(-c3ccccn3)s1)CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccncc1-c1cc(C(N)=O)c2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of a 2:3 mixture of 8-cyano-6-(4-methylpyridin-3-yl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester and 7-cyano-6-(4-methylpyridin-3-yl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (18.30 g, Reference Example 31) in methanol (538 mL) at 10° C. was treated with a solution of sodium hydroxide (21.35 g) in water (4 mL) dropwise. The reaction mixture was then treated with a 27.5% w/w aqueous solution of hydrogen peroxide (9 mL). After stirring at 50° C. for 2 hours the reaction mixture was allowed to cool to room temperature. The insoluble material collected was washed with ethyl acetate to give the title compound (3.47 g) as a white solid, Rf 0.09 (ethyl acetate). 1H NMR [(CD3)2SO]: δ 8.51 (s, 1H), 7.77 (d, 1H), 7.40–7.25 (bs and d overlapping, 2H), 6.85–6.74 (bs and s overlapping, 2H), 4.83 (s, 2H), 3.98 (t, 2H), 3.66 (t, 2H), 2.50 (s, 3H) and 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: OCc1ccc(O)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(CO)cc1

Procedure:
A mixture (50 ml) of 4-hydroxybenzyl alcohol (1.5 g), 1-bromopropane (1.3 ml), potassium carbonate (2.5 g) and acetone (50 ml) was stirred at 60° C. for 8 hours. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 4-propoxybenzyl alcohol (1.37 g) as a yellow oily substance.