Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cnccn1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCCCNC(=O)OC(C)(C)C)c1cnccn1
Yield: 91 %

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester and 2-acetyl pyrazine in MeOH with NaBH4 gave [4-(1-pyrazin-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester (294 mg, 91%) as a colorless oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.57 (m, 4H), 1.59 (d, 3H, J=6.6 Hz), 2.38-2.43 (m, 1H), 2.51-2.59 (m, 1H), 3.08-3.14 (m, 2H), 3.08 (m, 2H), 3.91 (d, 1H, J=6.7 Hz), 4.72 (bs, 1H), 8.45 (d, 1H, J=2.5 Hz), 8.53 (d, 1H, J=2.6 Hz), 8.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][CH:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.CO.O1CCCC1.[Li]>O.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:9]([OH:11])=[O:10])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CC(C)C)OCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(OCc1ccc(Br)cc1)C(=O)O

Procedure:
Methyl 2-[(4-bromobenzyl)oxy]-4-methylpentanoate in a mixture of water (3 mL), methanol (3 mL) and tetrahydrofuran (6 mL) was treated with lithium hydroxyde monohydrate (560 mg, 13.3 mmoles) until disappearance of the starting material was observed by TLC. The reaction was diluted with 1.2 N hydrochloric acid until pH 1. The aqueous phase was extracted 3 times with dichloromethane. The organic phase was concentrated under reduced pressure to afford 2-[(4-bromobenzyl)oxy]-4-methylpentanoic acid which was used as such in the next reaction.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[O:18])[CH3:17])[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH2:7]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]([OH:18])[CH3:17])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1cccc1C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCn1cccc1C(C)O
Temperature: 0 °C

Procedure:
To a stirred suspension of 4 g (130 mmol) of lithium aluminum hydride in 300 ml of anhydrous tetrahydrofuran was added dropwise, at room temperature, a solution of 27 g (160 mmol) of 1-butyl-2-acetylpyrrole in 200 ml of anhydrous tetrahydrofuran. The reaction mixture was refluxed for 30 minutes, cooled to 0° C. and the excess reagent destroyed by carefully adding ethyl acetate, saturated sodium sulfate solution and solid anhydrous sodium sulfate. The insoluble material was separated by filtration and the filtrate evaporated under reduced pressure, to produce 1-butyl-2-α-hydroxyethylpyrrole. This unstable crude alcohol 26 g (150 mmol) was dissolved in 250 ml of methanol, cooled to -10° C. and thereafter 101 ml of glacial acetic acid and 22.8 g (360 mmol) of sodium cyanoborohydride were added thereto. The reaction mixture was allowed to attain room temperature and stirred for 1 hour. It was then poured into 600 ml of saturated sodium carbonate solution and the product extracted with ethyl acetate (5×300 ml). The combined extracts were washed with water (2×300 ml), dried and evaporated in vacuo. Purification of the residue by column chromatography on 500 g of silica gel, using hexane-acetone (90:10) as eluant, provided 20 g (81%) of the title compound, 1-butyl-2-ethylpyrrole, as an oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccccc3)c12

Procedure:
The title compound, light grey solid (62 mg, 84%), MS (ISP) m/z=295.2 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:16][CH:17]([CH3:19])[CH3:18])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[C:33]([O:37][C:38]([NH:40][C@@H:41]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:16][CH:17]([CH3:19])[CH3:18])[CH2:11][N:10]([C:42](=[O:43])[C@@H:41]([NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To an iced slurry of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-(isopropylthio)pyrrolidine-2-carboxylate, TFA (255 mg, 0.543 mmol), (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (138 mg, 0.597 mmol), and HATU (309 mg, 0.814 mmol) in DCM (8 mL) was added N,N-diisopropylethylamine (0.285 mL, 1.629 mmol). The formed colorless slurry was stirred at room temperature overnight. Diluted with DCM, quenched with 5% citric acid. The organic layer was washed with 0.1 M NaOH and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with 5˜35% EtOAc-hexane to yield the desired product (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylate (240 mg, 0.380 mmol, 69.9% yield) as a white foam. 1H NMR (500 MHz, MeOD) ppm 1.06 (d, 3H), 1.09-1.13 (m, 12H), 1.48 (s, 9H), 2.48 (dd, J=12.82, 8.24 Hz, 1H), 2.53-2.62 (m, 1H), 2.97 (dd, J=12.51, 7.63 Hz, 1H), 3.73 (s, 3H), 4.03 (d, J=11.29 Hz, 1H), 4.25 (t, J=7.93 Hz, 1H), 4.45 (s, 1H), 4.88-4.91 (m, 1H), 7.36 (t, J=7.32 Hz, 1H), 7.45 (t, J=7.78 Hz, 2H), 7.58-7.73 (m, 6H). LC-MS (retention time: 3.50 min, method B), MS m/z 569 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35].O>CC(N(C)C)=O>[Br:35][CH2:11]/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: OC/C=C/c1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(/C=C/CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of the alcohol obtained in step 2 (10 g) in dimethylacetamide (100 ml) at room temperature were added triphenylphosphine (23 g) and carbon tetrabromide (29 g). The resulting solution was stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and filtered over silica gel to give 13 g of the desired product as a white solid (95%) which was characterized by its mass and NMR spectra.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]2([C:46]#[N:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:42]=[CH:41][C:40]([C:43]4([C:46]#[N:47])[CH2:45][CH2:44]4)=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#CC1(c2ccc(Cl)nc2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C#N)CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 48 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridin-3-yl)-cyclopropanecarbonitrile following a procedure analogous to that described in Example 1. Yield: 48% of theory; LC (method 3): tR=3.52 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2C=N[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1[S:19]C=CN=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:19][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: Brc1nccs1
Product: Cc1ccc(-c2nccs2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-bromothiazole. ESI-MS (m/z): 220 [M+1]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:18]([O:20]CC)=[O:19])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(NC(C)C)nncc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of ethyl 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoate (4 g, 11 mmol) (obtained by method D below) in ethanol/water (4:1) (50 mL) at RT was treated with potassium hydroxide (1 g, 23 mmol). The mixture was warmed to reflux and stirred for 2 h (M+1=322). The mixture was cooled to RT, then concentrated to remove the organic solvent. The mixture was diluted with 1 N aq. sodium hydroxide (20 mL), extracted with ether (2×50 mL). The combined ether extract was washed with 1N aq. sodium hydroxide (20 mL). The combined water layer was neutralized to pH 7 with conc. HCl. The white precipitate was collected and washed with water (20 mL), azotropically dried with toluene and placed under high vacuum to give 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoic acid as pale yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:32][N:31]=[N:30][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2cccc(C)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2cccc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 84 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-methylbenzimidazole (0,5 g), sodium azide (1.3 g) and ammonium chloride (1.1 g) in DMF (5 ml) was stirred for 3.5 days at 110-120° C. To the reaction mixture was added water, which was made acidic (pH 3-4) with 1N-HCl, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-methanol afforded colorless crystals (0.36 g, 62%),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[N:34]1([CH2:39][CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:38]=[CH:37][N:36]=[N:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][N:34]4[CH:38]=[CH:37][N:36]=[N:35]4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1ccnn1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCn4ccnn4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 66.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.25 g, 0.54 mmol), 4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.31 g, 0.54 mmol) to give the title compound: Rf=0.41 (silica gel, 10% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C1C=CC=CC=1>[O:6]=[S:5]1(=[O:7])[CH2:4][C:3]2[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1
Reactant: NS(=O)(=O)Cc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)c1ccccc1
Product: O=S1(=O)Cc2c(Cl)cccc2N1
Temperature: 170 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
The 2,6-dichlorobenzylsulfonamide (8 g, 33.47 mmol) was added to potassium carbonate (4.62 g, 33.47 mmol), copper powder (560 milligram (hereinafter “mg”)) and N,N-dimethylaniline (10 ml) in a round bottom flask. The reaction mixture was stirred at 170° C. for about 4 hours. then was cooled to room temperature and partitioned between ethyl acetate and 10% aqueous HCl. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% Ethyl acetate/Hexane) gave desired product (4 g, 59%). EI-MS m/z 204.5 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])C.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1.CNC1CCCCC1NC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I.O>[CH3:19][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(-n2cc(C(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A solution of 1H-pyrazole-4-carboxylic acid ethyl ester (1.65 g), 5-iodo-m-xylene (1.65 g), copper (I) iodide (68 mg), N,N′-dimethyl-1,2-cyclohexanediamine (222 mg) and potassium carbonate (2.06 g) in toluene (2 ml) was stirred at 110° C. for 48 hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in ethanol (10 ml), 1N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated by an evaporator, the aqueous solution was acidified by the addition of 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the titled compound (438 mg) as a dark brown solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:28]=[C:13]3[CH:14]=[C:15]([C:18]4[CH:26]=[C:25]5[C:21]([CH2:22][CH2:23][C:24]5=[O:27])=[CH:20][CH:19]=4)[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.CO.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:28]=[C:13]3[CH:14]=[C:15]([C:18]4[CH:26]=[C:25]5[C:21]([CH2:22][CH2:23][CH:24]5[OH:27])=[CH:20][CH:19]=4)[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc(-c3ccn4nc(-c5ccc(Cl)cc5)cc4c3)cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC1CCc2ccc(-c3ccn4nc(-c5ccc(Cl)cc5)cc4c3)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
0.040 g (1.06 mmol) of sodium borohydride is added portionwise to a solution, cooled to approximately 5° C., of 0.12 g (0.33 mmol) of 6-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]indanone in 16 ml of a 1/1 mixture of methanol and tetrahydrofuran. The medium is stirred at 70° C. for 2 hours, then cooled to 0° C. and then hydrolysed by dropwise addition of 10 ml of a saturated aqueous ammonium chloride solution. The medium is subsequently diluted with 50 ml of ethyl acetate and 30 ml of water. The organic phase is recovered and the aqueous phase is extracted with 30 ml of ethyl acetate. The organic phases are combined, dried over sodium sulphate and then concentrated under reduced pressure. The residue obtained by solid deposition is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2). 0.080 g (66%) of the expected product is obtained in the form of a white powder.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[F:17]C1C=C(NN)C=CC=1C>>[ClH:1].[F:17][C:14]1[C:3]([CH3:2])=[CH:4][CH:5]=[C:6]2[C:13]=1[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1ccc(NN)cc1F
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1ccc2[nH]cc(CCN)c2c1F

Procedure:
4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 3-fluoro-4-methyl-phenylhydrazine hydrochloride (6.00 g) as starting material.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(CC1CCNCC1)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
3-[2-(1-t-Butoxycarbonylpiperidin-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.34 g) obtained in Example 212 is suspended in ethyl acetate (30 ml), and thereto is added 2.6N hydrogen chloride in ethyl acetate (30 ml), and the mixture is stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure, and to the resulting residue are added chloroform and an aqueous sodium hydrogen carbonate solution. The precipitates are collected by filtration to give the title compound (1.47 g).
Reaction SMILES: [NH3:1].[CH2:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>>[CH2:2]([N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N
Reactant: CCCCCCCCO
Product: CCCCCCCCN(CCCCCCCC)CCCCCCCC

Procedure:
Reacting n-octanol with ammonia in a molar ratio of 7:1 under the same reaction conditions gave tri-n-octylamine in a yield of over 95 mol%. The 2.5% by weight of di-n-octylamine formed at the same time were separated quantitatively from the reaction product, added to fresh feed and alkylated with octanol. The resulting reaction mixture likewise contained the secondary amine in amount of about 2% by weight, so that in the steady state where the secondary amine formed is being returned again and again the reaction to the tertiary amine was virtually quantitative.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:26]([O:28][CH:29]([O:32][CH2:33][CH3:34])[C:30]#[CH:31])[CH3:27]>C(N(CC)CC)C.O1CCCC1.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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:31]#[C:30][CH:29]([O:32][CH2:33][CH3:34])[O:28][CH2:26][CH3:27])=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C#CC(OCC)OCC
Reactant: C=C(c1ccccc1I)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(c1ccc(C#CC(OCC)OCC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)-3-(iodophenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (4.0 g, 8.8 mmol-see Preparation 20), 3,3-diethyloxyprop-1-yne (1.52 ml, 10.6 mmol), copper(l)iodide (0.02 g) and bis(triphenylphosphine)palladium dichloride (0.12 g) In triethylamine (40 ml) and tetrahydrofuran (13 ml) was stirred at room temperature for 18 hours. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was flash chromatographed on silica by elution with ethyl acetate. Fractions containing the desired product were combined and evaporated under reduced pressure to yield 2-(2,4-difluorophenyl)-3-(4-[3,3-diethoxyprop-1-yn-1-yl]phenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol as a yellow gum (2,4 g, 60%). Trituration with cyclohexane gave an off-white solid which was characterised by NMR.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][C:11]=1[C:26](=[S:28])C)(=[S:9])C.Cl.O>C1COCC1>[SH:9][CH2:7][C:10]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][C:11]=1[CH2:26][SH:28]
Reactant: CCCCCc1cc(C(C)=S)c(C(C)=S)cc1CCCCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1cc(CS)c(CS)cc1CCCCC
Temperature: 25 °C
Yield: 80 %

Procedure:
A 250 mL two necked round bottom flask equipped with a magnetic stir bar and a reflux condenser was charged with 0.28 g (7.5 mmol) of lithium aluminum hydride (LAH) and 10 mL of dry THF. The apparatus was purged with argon and a solution of 5e (0.98 g; 2.5 mmol) in dry THF was transferred via cannula to the LAH suspension under argon. The mixture was refluxed under argon for 2 h. After cooling the flask to rt, ice cold water was added dropwise carefully. Upon observation of a white precipitate, conc. HCl was rapidly added, followed by more cold water. The aqueous layer was extracted with a mixture of hexanes/Et2 0 (3×50 mL). The organic extracts were combined together, washed with saturated NaHCO3 (2×50 mL), brine (1×50 mL), dried over MgSO4 and concentrated by rotary evaporation. The residual oil was chromatographed on silica gel using a mixture of hexanes/Et2O (60/1) and gave 0.61 g (2.0 mmol, 80% yield) of 5f as a colorless liquid. 1H NMR (300 MHz, CDCl3): δ 0.91 (6H, t, J=7 Hz, CH3), 1.36-1.57 (12H, m), 1.85 (1H, t, SH), 2.53 (4H, t, J=8 Hz, CH2Ar), 3.79 (4H, d, SCH2), 7.04 (2H, s, Ar--H). 13C NMR (75 MHz, CDCl3): δ 14.0, 22.5, 25.8, 30.9, 31.9, 32.2, 130.32, 130.38, 135.7 and 140.3.