Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1nnc(OCC2(O)CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OCC2(O)CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidin-4-ol dihydrochloride (0.1 mmol) aqueous formaldehyde (37%, 0.3 mmol) and molecular sieves in anhydrous DCM may be stirred for 20 minutes. To this suspension at room temperature may be added sodium triacetoxyborohydride (0.3 mmol). The reaction mixture may be monitored by LCMS until the reaction is complete. The reaction may be quenched with saturated NaHCO3 and the layers may be separated. The organic layer may be dried and the solvent may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N ammonia in MeOH) in DCM to give 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 463 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.32-7.49 (5H, m), 7.19-7.25 (2H, m), 7.02-7.09 (2H, m), 6.78 (1H, bs), 5.12 (2H, s), 4.58-4.83 (1H, m), 4.32 (2H, s), 2.54-2.69 (3H, m), 2.40-2.51 (2H, m), 2.27-2.36 (3H, m), 1.71-1.83 (2H, m), 1.59-1.70 (2H, m), 1.18-1.51 (5H, m), 0.81 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH3:14][NH2:15].[OH-].[Na+]>O>[CH3:14][NH:15][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
203.5 Parts of 99.5% 2,4-dinitrochlorobenzene are effectively stirred in 390 parts of water. The beige-coloured suspension is heated to 70° C in the course of 35 minutes, and at aprox. 46° C becomes a light brown emulsion. Then 120 parts by volume of a 41% aqueous solution of methylamine are added dropwise at 85° C bath temperature in the course of half an hour. During the dropwise addition the temperature rises to 88° C. The emulsion solidifies slowly and a thick yellow crust forms on the wall of the flask. Thereafter 103 parts by volume of 30% sodium hydroxide solution are added dropwise in the course of a further hour. The temperature falls to below 81° C. The crust gradually detaches itself from the wall of the flask and a yellow suspension forms. This suspension is heated to 90° C in the course of 15 minutes, stirred for 1 hour at 85° to 90° C, then cooled for 2 hours to 30° C and filtered by suction. As the filter cake still contains some lumps, it is stirred in 305 parts of water in a laboratory mixer, filtered by suction, washed with 1150 parts of water and dried at 60° C in vacuo, affording 193 parts of N-methyl-2,4-dinitro-aniline (97.8% of theory, referred to 2,4-dinitrochlorobenzene). The product has a melting point of 177°-178° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.C(N(CC)CC)C.C1(C(Cl)=O)C2C(=CC=CC=2)C=CC=1.[F:32][C:33]([F:62])([F:61])[C:34]1[CH:35]=[C:36]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=1)=[O:38]>ClCCl.O>[F:62][C:33]([F:32])([F:61])[C:34]1[CH:35]=[C:36]([CH:54]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:56]=1)[C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:41][C@@H:40]1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=1)=[O:38]
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: Cc1ccc(C[C@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2CN(C(=O)/C=C/c3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a stirred mixture of trans-3-(3-pyridyl)acrylic acid (100 mg) and triethylamine (0.19 ml) in dichloromethane (10 ml) was added 1-naphthoyl chloride (0.1 ml) at -15° C. After stirring for 30 minutes, a solution of (2S)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (300 mg) in dichloromethane (10 ml) was added at -15° C. and the resulting mixture was stirred for 30 minutes at the same temperature and then for 1 hour at room temperature. Dichloromethane and water were added to the reaction mixture and the organic layer was separated, washed successively with aqueous saturated sodium bicarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified on a silica gel column (20 g) eluting with a mixture of dichloromethane and methanol (100:2) to give (2S)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl benzyl)-4-[3-(3-pyridyl)-trans-acryloyl]piperazine (0.34 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:24]([NH:23][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:25])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc(N)n1
Reactant: O=C(N=C=S)c1ccccc1
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=S)NC(=O)c2ccccc2)n1
Reaction time: 0.08 h

Procedure:
(3-Amino-pyrazol-1-yl)-acetic acid tert-butyl ester (1.05 g, 5.33 mmol) is added dropwise under argon to a stirred solution of benzoyl isothiocyanate (0.754 ml, 5.4 mmol). After stirring for 5 minutes the reaction mixture is poured onto water and the titled compound, a yellow precipitate, is collected and dried.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14](=[O:16])[CH3:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Reaction time: 3 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 1H-indol-3-yl acetate (8 g, 45.69 mmol) in tetrahydrofuran (150 mL). To this was added acetic anhydride (46.6 g, 456.86 mmol). Addition of triethylamine (9.25 g, 91.49 mmol) was next. To the mixture was added DMAP (1.11 g, 9.10 mmol). The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 300 mL of ethyl acetate The resulting mixture was washed 2 times with 150 mL of NaCl(aq.). The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 20:1 petroleum ether/ethyl acetate solvent system. This resulted in 6.6 g (67%) of 1-acetyl-1H-indol-3-yl acetate as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC.C(OCC)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1)=[CH2:22]
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Br)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1cncc(OC(CC)C(=O)NC(C)(C)C#CC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-(5-Bromo-3-pyridyloxy)-N-(4-methylpent-2-yn-4-yl)butyramide (0.34 g), tetrakis(triphenylphosphine) palladium (0) (0.0.02 g) and tributylvinyl tin(0.38 g) in dry toluene (5 ml) were stirred and heated to reflux for 9 hours under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, stored for 72 hours then evaporated under reduced pressure to give a gum that was fractionated by chromatography (silica; diethyl ether) to give the required product, 0.16 g, as a colourless gum.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:51])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][O:43]C3CCCCO3)[N:41]=2)[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[S:38][CH:39]=[C:40]([CH2:42][OH:43])[N:41]=4)[CH:32]=3)[CH2:29][C:28](=[O:51])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.32 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]>C(OCC)(=O)C.O.C(OCC)C.Cl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]
Reactant: O=C(O)/C=C/C(=O)c1cc(Br)c(O)c(Br)c1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C(O)CCC(=O)c1cc(Br)c(O)c(Br)c1
Yield: 35.7 %

Procedure:
To a stirred solution of (E)-4-(3,5-dibromo-4-hydroxyphenyl)-4-oxobut-2-enoic acid (G) (2.852 g, 8.149 mmol) in ethyl acetate (27 mL) and water (3 mL) was added zinc power (5.7 g) portion wise until no further gas evolution was observed. At this point, the reaction mixture was diluted with diethyl ether (50 mL) and HCl (2 M solution, 8 mL) and the resulting mixture was filtered through a pad of Celite. After filtration, the organic solution was washed with HCl (2 M solution, 10 mL), followed by water (3×10 mL). The organic layer was then dried (MgSO4) and concentrated in vacuo to give a brown solid. This was then triturated with cold ethanol to give the title compound as a pale brown solid (1.025 g, 36%). 1H NMR δ (ppm) (DMSO-d6): 2.58 (2 H, t, J=6.12 Hz), 3.17-3.27 (2 H, m), 8.15 (2 H, s), 10.99 (1 H, s), 12.19 (1H, s)
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:15]2[N:14]=[CH:13][N:12]3[CH:16]=[N:17][C:18]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=5)[CH2:21][CH2:20]4)=[C:11]3[C:10]=2[CH:9]=[CH:8]1.C[Si](C)(C)CCOCN1C2N=CN3C=NC(C4CCCN(C(OCC5C=CC=CC=5)=O)C4)=C3C=2C=C1>>[C:18]1([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[N:17]=[CH:16][N:12]2[C:11]=1[C:10]1[CH:9]=[CH:8][NH:7][C:15]=1[N:14]=[CH:13]2
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCN(Cc4ccc(C#N)cc4)CC3)c21
Agent: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCCN(C(=O)OCc4ccccc4)C3)c21
Product: N#Cc1ccc(CN2CCC(c3ncn4cnc5[nH]ccc5c34)CC2)cc1
Yield: 4 %

Procedure:
The reactions in Synthetic Examplea 3 were carried out in substantially the same manners except that 4-{[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile obtained in Reference Synthetic Examplea 97 was used instead of benzyl 3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate to give the title compound as a brown solid (1.3 mg, yield 4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CCOCC.O>[CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)OCn1c(SCc2nccc3ccsc23)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)OCn1c(S(=O)Cc2nccc3ccsc23)nc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 279.6 mg (0.700 mmol) of 1-ethoxycarbonyloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-11) in 30 ml of CHCl, was mixed with 226.5 mg (1.05 mmol) of 80% m-CPBA at -10° to -15° C., and stirred for 1 hr. The mixture was treated with 3 ml of saturated aqueous NaHCO3 and 0.6 ml of 10% aqueous sodium sulfite, and after bringing back to room temperature, the solution was mixed with water and extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby brown viscous liquid was obtained. After silica gel column chromatography, the crystals were dispersed with 3 ml of ether, followed by filtration and washed with ether, whereby 158.0 mg (Yield : 54.3%) of the objective compound (Ic-17), 1-ethoxycarbonyloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl]methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)[CH3:15])[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:37])[F:38])=[CH:27][CH:26]=3)[CH2:32]2)[CH2:35][CH2:34]1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(4-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 716 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.60-7.71 (m, 1H), 7.10-7.15 (m, 2H), 6.56-6.59 (m, 2H), 4.24-4.32 (m, 1H), 3.47 (dd, J=9.9, 3.6 Hz, 1H), 3.31 (dd, J=9.8, 7.9 Hz, 1H), 3.19 (dd, J=9.5, 7.9 Hz, 1H), 3.10 (dd, J=6.9, 5.8 Hz, 1H), 3.01 (dd, J=9.6, 4.0 Hz, 1H), 2.71-2.83 (m, 1H), 2.56-2.70 (m, 1H), 2.40 (s, 3H), 2.09 (dq, J=12.6, 6.3 Hz, 1H), 1.92-2.01 (m, 1H), 1.74-1.83 (m, 1H), 1.58-1.70 (m, 2H), 1.38-1.53 (m, 3H), 0.88 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>CO>[C:13]12([CH:11]([OH:12])[CH2:10][S:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: O=C(CSc1ccc(Cl)c(Cl)c1)C12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CSc1ccc(Cl)c(Cl)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantyl 3,4-dichlorophenylthiomethyl ketone (1.2 g.) in 250 ml. of methanol is treated with excess sodium borohydride with stirring and ice cooling. When reduction is complete, the solvent is removed, 50 ml. of water is added and the product is extracted with ether. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness to yield 1-(1-adamantyl)-2-(3,4-dichlorophenylthio)ethanol.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:10][P:9]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: Cc1cc(CCl)on1
Reactant: CCOP(OCC)OCC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1cc(C)no1)OCC
Reaction time: 4 h

Procedure:
445 g of 5-chloromethyl-3-methylisoxazole and 674 g of triethyl phosphite are slowly heated to 150° C. and left at this temperature for 4 hours. After distillation, 546 g (69% of theory) of (3-methylisoxazol-5-yl)-methanephosphonic acid diethyl ester of boiling point 118°-121° C./0.3 mm Hg are obtained. 1H-NMR spectrum (CHCl3, with TMS as internal standard): τ=3.85 (d, J=3 Hz, 1H), 4.17 (m, J=8 Hz, 4H), 6.67 (d, J=22 Hz, 2H), 7.72 (s, 3H), 8.67 (t, J=8 Hz, 6H)
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:29])[N:14]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1[C:13](=[O:29])[N:14]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=1
Reactant: CC(C)c1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
3-(Benzyloxycarbonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.35, 3.37 mmol), as prepared in the preceding step, and 10% palladium (0) on activated carbon (0.12 g) were dissolved in methanol (50 mL), degassed, backfilled with nitrogen, and stirred under hydrogen gas at ambient pressure and temperature for 2 hours. The reaction mixture was then filtered through Celite and the filtrate evaporated giving the title compound as a golden oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[CH3:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=4[CH3:30])[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CC2)CC1

Procedure:
Example 89 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.40–7.32 (m, 7H), 7.08 (d, 1H, J=8.4 Hz), 5.70 (br s, 1H), 3.27 (dd, 2H, J=6.4, 12.4 Hz), 2.88 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.53 (m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.28 (s, 3H), 1.99 (dt, 2H, J=2.8, 11.2 Hz), 1.67–1.60 (m, 8H), 1.27 (d, 6H, J=6.8 Hz), 1.03 (dd, 2H, J=4.0, 6.8 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[NH:11][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:17]=2[N:18]=1)(C(C)(C)C)(C)C.[H-].[Na+].[CH3:21]I.Cl.N>CN(C)C=O>[OH:8][CH2:9][C:10]1[N:11]([CH3:21])[C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:17]=2[N:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1nc2cncnc2[nH]1
Reactant: CI
Agent: Cl
Agent: N
Agent: [H-]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cncnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 1.89 g of 2-t-butyl-dimethylsilyloxymethyl-3H-imidazo[5,4-d]pyrimidine (prepared as described in Preparation 49), 0.37 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 490 μl of methyl iodide and 30 ml of dimethylformamide were used. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness, and the resulting residue was purified by column chromatography through silica gel, using a 6:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 0.37 g of the title compound, melting at 122-125° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>O1CCOCC1>[Cl:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH2:21])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2cccnc2n1-c1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1c(Cl)c2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
4.0 M Hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added to a solution of tert-butyl {1-[3-chloro-1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (26 mg, 0.067 mmol) in 1,4-dioxane (1.0 mL). The reaction was stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The aqueous layer was adjusted to pH 9 with saturated NaHCO3 solution and then extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give the desired amine (7 mg, 40%). LCMS calculated for C15H14ClFN3(M+H)+: m/z=290.1. Found: 290.0.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.19 g, 146 mmole), 5-chloroindole (5.0 g, 33 mmole) and piperidine-4-one hydrochloride (10.22 g, 85.7 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 6.4 g (90%) as a yellow solid with an m.p. of 166°-168° C.