Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)[C@H]1CCCCN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To (R)-Piperidine-2-carboxylic acid (5.00 g, 38.73) in 150 ml of dry methanol at 0° C. was added thionyl chloride (5.2 ml, 71.28 mmol) under Ar. The mixture was stirred at 0° C. for 30 min, then at RT overnight, evaporated and crystallized with EtOH/hexane to afford 4.96 g (92%) of the title product. 1H NMR (CD3OD) 3.67 (s, 3H), 3.57 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.01 (m, 1H), 1.98 (m, 1H), 1.73 (m, 1H), 1.55-1.45 (m, 4H); 13C NMR 171.22, 62.50, 51.35, 45.35, 29.52, 28.41, 23.82; MS m/z+144.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: CCC(CC)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Temperature: 100 °C

Procedure:
191 mg of the product obtained in Stage 1 above, 2.5 ml of butanol and 0.115 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 90 to 110° C. for 5 hours. The reaction medium is then left to return to ambient temperature and left to crystallize, followed by separating, washing with 10 ml of isopropanol and drying under vacuum at approximately 50° C. In this way 148 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: BrC1C2N(N=C(Cl)N=2)C=CC=1.FC1C=CC=CC=1CN.[Cl:21][C:22]1[N:39]=[C:25]2[C:26]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=2)[NH2:50])[CH2:43][CH2:42]1>>[Cl:21][C:22]1[N:39]=[C:25]2[C:26]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1.[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][NH:30][C:26]1[C:25]2[N:24]([N:23]=[C:22]([NH:50][C:49]3[CH:51]=[CH:52][CH:53]=[C:47]([N:44]4[CH2:43][CH2:42][N:41]([CH3:40])[CH2:46][CH2:45]4)[CH:48]=3)[N:39]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: Clc1nc2c(Br)cccn2n1
Agent: Fc1ccccc1CNc1cccn2nc(Cl)nc12
Agent: NCc1ccccc1F
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccccc5F)cccn4n3)c2)CC1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-fluoro-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 2-fluorobenzylamine (1.11 mL, 9.72 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid, (1.45 g. 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.11 (d, J=6.9 Hz, 1H), 7.39-7.26 (m, 2H), 7.23-7.10 (m, 3H), 6.98 (t, J=14.0, 7.3 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 4.53 (d, J=6.1 Hz, 2H). 395b) N(8)-(2-Fluoro-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-fluoro-benzyl)-amine (0.3227 g, 1.166 mmol) and 3-(4-methylpiperazin-1-yl)aniline (223 mg, 1.17 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (102.96 mg, 20.5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.19 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.43-7.06 (m, 7H), 6.74 (t, J=14.3, 7.1 Hz, 1H), 6.46 (d, J=8.6 Hz, 1H), 6.35 (m, 2H), 4.59 (d, J=6.4 Hz, 2H), 3.11 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=432 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[S:18][C:11]=12)[NH2:5].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:40]([C:37]2[C:38](=[O:39])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:34]=[CH:35][CH:36]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[S:18][C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CN1CCN(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-(4-methylpiperazin-1-yl)thieno[3,2-b]pyridin-7-yloxy)aniline (40.0 mg, 0.112 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (39.2 mg, 0.167 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (64.2 mg, 0.335 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (45.2 mg, 0.335 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0996 ml, 0.558 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (48.3 mg, 75.3%). LRMS (APCI pos): >99% purity, 254 nm, m/e 575 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.80 (s, 1H), 8.40 (d, 1H), 8.28 (d, 1H), 8.23 (d, 1H), 7.92 (dd, 1H), 7.61 (m, 2H), 7.36 (m, 1H), 7.17-7.24 (m, 3H), 6.36 (s, 1H), 6.29 (d, 1H), 3.37 (m, 4H), 2.58 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO.[Pd].[C]>[CH3:20][C:14]1([CH3:19])[CH2:13][CH:12]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: CCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O

Procedure:
12 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-ethylmethanesulfonamide were dissolved in 250 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. After absorption of hydrogen was complete, the catalyst was filtered off with suction, the filtrate was concentrated and the residue was crystallized using diisopropyl ether, 7.7 g, m.p. 169-170° C.
Reaction SMILES: COCC([O:6][C:7]1([CH2:21][CH2:22][N:23]([CH2:25][CH2:26][CH2:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH3:24])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19])=O.FC1C=C2C(=CC=1)C(C(C)C)C(=[O:51])CC2.N1C2C=CC=CC=2N=C1CCCN(C)C(=O)C>>[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH2:27][CH2:26][CH2:25][N:23]([CH3:24])[C:22](=[O:51])[CH2:21][C:7]1([OH:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19]
Reactant: COCC(=O)OC1(CCN(C)CCCc2nc3ccccc3[nH]2)CCc2cc(F)ccc2C1C(C)C
Reactant: CC(C)C1C(=O)CCc2cc(F)ccc21
Agent: CC(=O)N(C)CCCc1nc2ccccc2[nH]1
Product: CC(C)C1c2ccc(F)cc2CCC1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1

Procedure:
A method of preparing 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting 6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with the dianion of N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide to form N-[3-(1H-benzirnidazol-2-yl) propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-[2-{[3-(1H-benzirnidazol-2-yl)propyl]methylarnino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-[3-(1H-Benzimidazol-2-yl)propyl]-N-methylacetamide, and the acetic acid solvate of 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol dioxalate, are new.
Reaction SMILES: [CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5].[BH4-].[Na+].Cl>CO.CCOCC>[CH2:3]([O:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]34[CH2:8][CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([CH2:11][CH2:10]3)[CH2:13][CH2:12]4)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)/[CH:2]=[CH:1]/[CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC12CCC(c3ccc(C4CCC(=O)CC4)cc3)(CC1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCC/C=C/CO[C@H]1CC[C@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(4-pentylbicyclo[2.2.2]octyl)penyl]cyclohexanone (1.5 g, 4.3 mmol) and a mixture of 9:1 methanol/ether (25 cm3) is added dropwise to a freshly prepared mixture of sodium borohydride (1.2 g, 8.5 mmol) and a mixture of 9:1 methanol/ether (25 cm3) at 0° C. When the addition is complete, the reaction mixture is stirred overnight at room temperature. A 25 per cent hydrochloric acid solution is added carefully to the reaction mixture, which was extracted into ethyl acetate (3×50 cm3). The combined organic extracts are washed with water (2×500 ml) and dilute sodium carbonate solution (2×500 ml), dried (MgSO4), filtered and then evaporated down. The residue is purified by column chromatography on silica gel using a 7:3 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield the pure 1-[4-(trans-4-hydroxycyclohexyl)phenyl]-4-pentylbicyclo[2.2.2]octane (1.2 g, 80 per cent).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:26]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:26][N:53]2[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {4-ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.17 g, 0.44 mmol) that was obtained in Example 13 (13a), carbon tetrabromide (0.19 g, 0.57 mmol), triphenylphosphine (0.15 g, 0.57 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.66 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:2) as the eluent to afford the title compound (0.19 g) in a yield of 89% as a pale yellow oily product.
Reaction SMILES: F[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[O:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:31]>CN(C=O)C.C(Cl)Cl.CO>[ClH:31].[O:24]([C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[O:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)NC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N=C(N)NC(=O)c1ccc(Oc2ccccc2)c(C(F)(F)F)c1

Procedure:
Colorless crystals, m.p. 162°-65° C. from 4-fluoro-3-trifluoromethylbenzoylguanidine (30 base) by reaction with phenol in the presence of potassium carbonate in DMF at 120° C., aqueous work-up, column chromatography, methylene chloride/methanol 9:1, followed by hydrochloride formation
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]3[CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:23]([F:33])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([F:33])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:36][CH:37]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and 2-amino-5-methyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 9.01 (br. s., 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.62 (dd, J=8.59, 1.77 Hz, 1 H) 7.53 (t, J=8.08 Hz, 1 H) 7.15 (s, 1 H) 7.11 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.63-6.73 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.15 (t, J=7.71 Hz, 2 H) 3.74 (d, 1 H) 3.61 (d, J=111.87 Hz, 1 H) 3.18 (d, J=16.67 Hz, 1 H) 2.79 (d, J=16.67 Hz, 1 H) 2.28-2.38 (m, H) 1.46 (s, 3 H); LCMS for C27H26FN3O5 m/z 492.00 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)nc(N2CCOCC2)n1

Procedure:
Reaction of the above amine with methanesulfonyl chloride as in previous examples gave trans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide in 90% yield: mp (CH2Cl2/MeOH) 269-272° C.; 1H NMR (DMSO-d6) δ 8.10 and 7.97 (d, J=8.3 Hz, 1H), 7.88 and 7.73 (2t, JHF=53.2, 53.9 Hz, 1H) 7.86 and 7.80 (d, J=7.6, 8.0 Hz, 1H), 7.38 (q, J=8.1 Hz, 1H), 7.02-6.92 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.77-3.69 (m, 9H), 3.13 (br, 1H), 2.93 and 2.92 (2s, 3H), 1.98-1.96 (m, 4H), 1.42-1.32 (m, 4H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0; H, 5.5; N, 20.3. Found: C, 50.0; H, 5.4; N, 20.5%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:40]=[CH:39][C:27]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])=[O:8].[ClH:41].C(OCC)C>C(OCC)(=O)C>[ClH:41].[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])=[CH:39][CH:40]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])=[O:8]
Reactant: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 1 h

Procedure:
0.4 g (0.78 mmol) of the compound from Example 3-7 are dissolved in 4 ml of ethyl acetate. At 40° C., first 8 ml of 1N hydrochloric acid (in diethyl ether) and then 12 ml of diethyl ether are added. The mixture is allowed to stand at 4° C. for one hour. The precipitated crystals are filtered off with suction, washed with a mixture of ethyl acetate and diethyl ether (ratio 1: 1) and then dried at 40° C. under reduced pressure for 20 hours. This gives 0.362 g (84.5% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][CH:9]=1.[CH3:19]I>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH3:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][CH:9]=1
Reactant: Brc1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cncc(Br)c2)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
60% NaH (84 mg, 2.1 mmol) is added to a solution of 2-(5-bromo-pyridin-3-yl)-1H-indole (192 mg, 0.70 mmol) in THF (20 mL) and the temperature is kept below 0° C. After the addition, the mixture is stirred at room temperature for 30 min. MeI (125 mg, 0.88 mmol) is added to the mixture at 0° C. and the mixture is stirred at room temperature for 3 hrs. Then the solvent is removed and the residue is dissolved in EtOAc and washed with water. The organic layer is separated, dried and concentrated. The crude product is purified by flash column chromatography to give 173 mg of 2-(5-bromo-pyridin-3-yl)-1-methyl-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:12]([CH3:11])[CH2:13][CH2:14][OH:15]
Reactant: COc1ccccc1CBr
Reactant: CNCCO
Product: COc1ccccc1CN(C)CCO

Procedure:
2-Methoxybenzyl bromide [J.Med. Chem., 32, 1761 (1989)] was reacted with N-methylethanolamine as described in the three previous examples to give N-(2-methoxybenzyl)-N-methylethanolamine which was reacted with 3-chloro-2-(dimethylaminomethyl)phenol in a similar manner to Example 1 (except that conversion into the dihydrochloride salt was omitted) to give the title compound b.p. 100° C. at 0.01 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(Cc2cc(F)ccc2O)c1

Procedure:
Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3′-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [H][H].[O:3]=[C:4]1[CH:16](C(OC(C)(C)C)=O)[N:8]2[C:9]3[C:14]([CH:15]=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3>C1(C)C=CC=CC=1>[CH:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[C:7]1[CH2:6][CH2:5][C:4](=[O:3])[CH2:16][N:8]12
Reactant: CC(C)(C)OC(=O)C1C(=O)CCc2cc3ccccc3n21
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc3ccccc3n2C1

Procedure:
Compounds of formula (I) wherein R3 represents hydrogen may be prepared from the respective tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6-carboxylate derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene gives the corresponding 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivatives (9). Reductive amination with ammonium acetate in the presence of a reducing agent such as NaBH3CN in a mixture of AcOH and EtOH and subsequent Boc protection yields the corresponding tert-butyl (6,7,8,9-tetrahydropyrido[1,2-a]indol-7-yl)carbamate derivatives (10). Friedel-Craft acylation by reaction with oxalyl chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and subsequent reduction with triethylsilane in the presence of TFA gives the corresponding methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate (11). Reaction with an appropriate heteroaryl halide like R4—Cl in the presence of a base such as K2CO3 in an aprotic solvent such as DMA and subsequent saponification with a base such as NaOH furnished the compounds of formula (I).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].O.[OH-].[Li+].CO.O>O1CCCC1>[C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cccc(C(=O)O)c2)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of methyl 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate (0.62 g, 2.5 mmol) in tetrahydrofuran (6.0 mL) were added lithium hydroxide-monohydrate (0.18 g, 4.3 mmol), methanol (2.0 mL) and water (2.0 mL), and the mixture was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (5.0 mL). The mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (0.48 g, 83%) as a white powder.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH3:20]
Reactant: CCOC(=O)CI
Reactant: O=C1NCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCc2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 3,4-dihydro-2H-isoquinolin-1-one (0.250 g, 1.70 mmol) in toluene (5 mL) was added sodium hydride (60% in mineral oil, 0.049 g, 2.04 mmol) and the resulting suspension was heated at about reflux for about 1 h. The reaction mixture was cooled at room temperature and ethyl 2-iodoacetate (0.364 g, 1.70 mmol) was added dropwise and the mixture was again heated at about reflux for about 12 h. The reaction mixture was cooled at room temperature and filtered, rinsed with toluene. The filtrate was concentrated in vacuo to provide (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid ethyl ester as a peach oil (0.336 g, 1.44 mmol). The crude material was used in subsequent reactions without further purification.