Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[O:6][CH:7]1[C:11]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:12][O:13][N:14]=[CH2:15])[O:10][CH:9]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[CH:8]1[OH:43])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>N1C=CC=CC=1>[C:1]([Si:5]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[O:6][CH:7]1[C:11]([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:12][O:13][N:14]=[CH2:15])[O:10][CH:9]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[CH:8]1[O:43][S:60]([CH3:59])(=[O:62])=[O:61])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(OS(C)(=O)=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
The mesylation of hydroxyl groups proceeds readily under these conditions (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 150-160 and references cited therein). Briefly, to a solution of Compound 17 in a 1:1 mixture of anhydrous dichloromethane and anhydrous pyridine is added methanesulfonyl chloride (1.2 eq.). After stirring at room temperature for several hours, this mixture is quenched with methanol, concentrated, diluted with dichloromethane, washed with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography will yield Compound 18.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([NH:38]C(=O)OC(C)(C)C)=[NH:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([NH2:38])=[NH:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=N)NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N=C(N)N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Reaction time: 0.02 h

Procedure:
To a solution of tert-butyl N—[N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamimidoyl]carbamate, 70c, (0.100 g, 0.156 mmol) in THF (20 mL) was added sodium methoxide (0.033 g, 0.156 mmol) at room temperature. After 1 minute, the reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 95 mg of the desired product. To 10 ml MeOH solution of the product was added hydrochloride/IPA (0.031 mL of 5 M solution, 0.156 mmol). The reaction mixture was stirred at room temperature for 1 hour after which the solvent was removed under reduced pressure to afford the product, as hydrochloride salt: 1H NMR (300 MHz, MeOD) δ 8.63 (s, 1H), 8.40 (dd, J=9.1, 2.7 Hz, 1H), 8.36 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 4.46 (d, J=11.7 Hz, 1H), 3.78-3.53 (m, 1H), 2.41 (d, J=11.7 Hz, 1H), 2.28 (d, J=12.0 Hz, 1H), 2.18-1.98 (m, 2H), 1.69 (dd, J=23.6, 11.8 Hz, 2H), 1.56-1.28 (m, 2H); LCMS RT=1.45 (M+H) 387.06.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[N:14]=1>>[NH:26]1[CH:27]=[CH:28][C:24]([NH:23][C:15]2[N:14]=[C:13]([O:1][C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:25]1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CC(=O)Nc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give N-{4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 360(MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6]([C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:30]
Reactant: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1cnc2ccccc2n1
Yield: 21.3 %

Procedure:
In 50 ml of chloroform was dissolved 1.47 g of 2-(2-dimethylaminobenzylthio)quinoxaline. To the chilled solution kept at -10° C. was portionwise added 1.54 g of m-chloroperbenzoic acid (purity: 80%). To the reaction liquid were washed successively with saturated aqueous NaHCO3 solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (hexane/acetone) to give 330 mg of 2-(2-dimethylaminobenzylsulfinyl)quinoxaline as a yellow powder, m.p. 114°-115° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=1[C:21](Cl)=[O:22]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:21](=[O:22])[C:20]1[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:19]=1[O:18][CH3:17]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Product: COc1cccc(OC)c1C(=O)Nc1ccc2oc3c(c2c1)CCCCCC3

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), 2,6-dimethoxybenzoyl chloride (0.15 mL, 0.77 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (12 mL) N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2,6-dimethoxybenzamide (0.15 g). MS (ESI) m/z 380 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:13](=[O:15])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1
Temperature: 25 °C
Yield: 161.8 %

Procedure:
To a suspension of 5-hydroxyanthranilic acid (15.3 g, 100 mmol) in THF (400 mL) at 0° C. was added triphosgene (10.1 g, 34 mmol). The resultant mixture was stirred for 5 min at 0° C. and then allowed to warm to room temperature over 6 h. The reaction mixture was cooled at 0° C. overnight and the resultant gray precipitate collected by filtration to afford 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (9.8 g, 55 mmol, 55%). The filtrate was concentrated in vacuo, the resultant solid triturated with diethyl ether and collected by filtration to afford additional product (7.3 g, 41 mmol, 41%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:33]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:33][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c(N)cc1OCc1ccccc1
Yield: 91.3 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-methoxyphenyl)piperazino]methanone (7a) (500 mg, 1.04 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (706 mg, 3.14 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8a) (425 mg, 91% yield). 1H NMR (CDCl3) δ 3.20-3.30 (m, 4H), 3.45-3.55 (m, 4H), 3.85 (s, 3H), 3.98 (s, 3H), 5.20 (s, 2H), 6.19 (s, broad NH2) 6.80-7.00 (m, 5H), 7.30-7.50 (m, 5H), 7.70 (s, 1H); FABMS: 447 (M+H)+.
Reaction SMILES: [C:1]([O:11]C)(=O)[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:13][NH2:14].CO>>[OH:3][C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([NH:14][CH3:13])=[O:11]
Reactant: CN
Reactant: COC(=O)[C@@H](O)c1ccccc1
Solvent: CO
Product: CNC(=O)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Methyl (S)-(+)-mandelate 36 (4.60 g, 27.7 mmol, 1.0 eq) was added to a 2M solution of methylamine in methanol, (70 mL, 140 mmol, 5.05 eq) and the mixture was stirred at rt for 24 h. The mixture was concentrated under reduced pressure to a semi-solid. Residual methanol was co-evaporated with toluene (2×50 mL) followed by 1:1 toluene/heptanes (50 mL) to give a white crystalline solid. The solid was triturated with heptanes (50 mL), filtered and dried to give 4.35 g (95%) of 37 as a white solid.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[N:15]=[C:9]2[CH:8]1[CH2:24][CH2:25][S:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:9]2[CH:8]([CH2:24][CH2:25][S:26][C:27]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:7][CH2:12][CH2:11][N:10]2[CH:13]=1
Reactant: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC2
Yield: 64 %

Procedure:
The product from Step 13.f. (2.50 g, 3.96 mmol) was dissolved in CH2Cl2 (16.0 ml) and treated with Tfa (4.0 ml) at room temperature under N2 for about 3.5 hours. The reaction was then poured cautiously into a saturated NaHCO3 solution (150 ml) and the product was extracted with CH2Cl2 (2×50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 9:1/hexanes:EtOAc and then 100% EtOAc as eluants. Product fractions were combined and concentrated under reduced pressure to obtain a white foam (1.35 g, 64%) which was used without further purification. Mass spec. 532.4 MH+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCN)c(C)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reaction time: 1.67 h
Yield: 87.2 %

Procedure:
To a solution of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)ethanamine (1.0 g, 2.65 mmol) in dioxane (6.6 mL) was added di-tert-butyldicarbonate (730 μL, 3.19 mmol), followed by aqueous sodium hydroxide (2.5 M solution, 1.28 mL, 3.19 mmol). The reaction mixture was stirred for 100 min, At this time, HPLC analysis indicated complete conversion to product. The mixture was then diluted in ethyl acetate (25 mL), transferred to a separatory funnel, and washed with 1 M aqueous sodium bicarbonate (2×10 mL), saturated ammonium chloride (10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The carbamate product was then dissolved in THF (13 mL), and the solution was treated with lithium aluminum hydride (800 mg). The resulting slurry was warmed to reflux and stirred for 90 min, after which HPLC analysis indicated consumption of starting material. The mixture was subsequently added slowly to 75 mL 2.5 M aqueous sodium hydroxide stirred over ice. The resulting grey suspension was stirred for 10 min, during which time the solids became white. To the suspension was added 100 mL isopropyl acetate, and the resulting mixture was filtered, and transferred to a separatory funnel. The organics were removed and the aqueous layer washed with 50 mL isopropyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 900 mg of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine. 1H-NMR (400 MHz, CD3OD) 7.51-7.30 (m, 10H), 4.72 (s, 3H), 2.84 (s, 2H), 2.42 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([Sn](C)(C)C)=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46](I)[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:41]=2[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.[Cu]I.[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>[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([C:16]3[C:15]4[C:19](=[CH:20][C:12]([C:4]5[CH:5]=[C:6]([F:11])[C:7]([O:9][CH3:10])=[CH:8][C:3]=5[CH2:1][CH3:2])=[CH:13][CH:14]=4)[N:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:17]=3)[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:41]=2[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c([Sn](C)(C)C)nn(C3CCCCO3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(I)n(COCC[Si](C)(C)C)c2CC1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c(n3COCC[Si](C)(C)C)CCN(C(=O)OC(C)(C)C)CC4)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-trimethylstannanyl-1H-indazole (Preparation 18, 735 mg, 1.53 mmol) in toluene (6 mL) was added 2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 29, 829 mg, 1.68 mmol), copper (I) iodide (60 mg, 310 μmol) and tetrakis(triphenylphosphine) palladium(0) (173 mg, 150 μmol). The reaction mixture was degassed with nitrogen, heated at 100° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% EtOAc in toluene to give the title compound as a foam (633 mg) in a 57% yield.
Reaction SMILES: O[CH2:2]CCC1CCN(CC2C=CC=CC=2)C(N)C1.[C:19]([C:22]1[CH:23]=[C:24]([N:28]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:33]2)=[O:30])[CH:25]=[CH:26][CH:27]=1)(=[NH:21])[NH2:20]>>[C:19]([C:22]1[CH:23]=[C:24]([N:28]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:2]2)[C:29]([NH:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:36][CH2:37]2)=[O:30])[CH:25]=[CH:26][CH:27]=1)(=[NH:21])[NH2:20]
Reactant: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCC2)c1
Reactant: NC1CC(CCCO)CCN1Cc1ccccc1
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCC2)c1

Procedure:
This material was prepared from 4-(3-hydroxypropyl)-amino-1-benzylpiperidine by the same route employed in the synthesis of N-(3-amidinophenyl)-N′-(1-benzylpiperidin-4-yl)cyclopentylurea. There was obtained 26 mg of the desired product as the bis-tifluoroacetic acid salt after purification by reverse phase HPLC. LRMS (M+2H)2+ m/z 196.7, (M+H)+ m/z 392;1H NMR (CD3OD): d 2.23 (m, 6H), 3.21 (bt, 2H), 3.58 (t, 2H, J=5.12 Hz), 3.62 (m, 2H), 4.39 (m, 3H), 4.53 (t, 2H, J=5.12 Hz), 7.51 (m, 5H), 7.62-7.78 (m, 3H), 7.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:16][CH:15]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1,3-bis(4-chlorophenyl)-prop-2-en-1-one and diethyl malonate, diethyl 2-[1,3-bis(4-chlorophenyl)-3-oxopropyl]-malonate was obtained as colourless solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCc1ccccc1Br
Product: Clc1ccc(-c2nn(Cc3ccccc3Br)c3c2CCNCC3)cc1
Yield: 42 %

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05; found, m/z 418.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69 (d, J=7.8 Hz, 1H), 7.53-7.27 (m, 6H), 6.78 (d, J=7.8 Hz, 1H), 5.58 (s, 2H), 3.50-3.48 (br m, 4H), 3.19-3.17 (br m, 4H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[CH3:30][C@@H:31]1[C@@H:36]([O:37]C(=O)C(C)(C)C)[CH2:35][CH2:34][NH:33][CH2:32]1>>[OH:37][C@H:36]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:6][CH2:5]2)[CH2:32][C@@H:31]1[CH3:30]
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCO)CC4)cc23)cn1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cn1

Procedure:
This compound is synthesized from 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (184, preparation see below) and 2,2-Dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-yl ester (17) analogously to the method described in example 150, followed by cleavage of the protecting group.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1

Procedure:
107 mgm of 6-(4-phenylsulfonyl-butoxy)-carbostyril were suspended in 15 ml of methanol, the suspension was admixed with 40 mgm of palladium-on-charcoal, and the mixture was hydrogenated at 50° C. and a hydrogen pressure of 2.5 bar for 14 hours. After filtering off the catalyst and evaporating the clear solution, a colorless crystalline residue was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([C:33](=[O:43])[CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([CH2:34][C:33]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:43])=[CH:36][CH:37]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(CC(=O)C2CCCCC2)cc1
Product: O=C(Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Yield: 46.1 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (137 mg, 0.325 mmol) and 4-(2-cyclohexyl-2-oxo-ethyl)-benzylamine (150 mg, 0.65 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) to obtain 7-chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (76 mg, 46%). MS (ES+) m/z: 507 (M+H)+.
Reaction SMILES: C1[C:5]2([CH2:10][CH2:9][N:8](C(=O)[C@H](NC(=O)C3C=C(Cl)C=C(Cl)C=3)CCC(O)=O)[CH2:7][CH2:6]2)CCC1.Cl[C:31]([O:33]CC)=[O:32].C(N(CC)CC)C>C1COCC1>[NH:8]1[CH2:7][CH2:6][CH2:5][CH:10]([C:31]([OH:33])=[O:32])[CH2:9]1
Reactant: O=C(O)CC[C@@H](NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)N1CCC2(CCCC2)CC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)C1CCCNC1
Yield: 123.9 %

Procedure:
The method described in Example 1 was again used in this case, first of all by reacting 60 g (0.136 moles) of (R)-5-(8-azaspiro[4.5]decan-8-yl)-4-(3,5-dichloro-benzoylamino)-5-oxopentanoic acid (CR 2194) with 14 ml of ethyl chloroformate (0.1469 moles) in the presence of 20 ml of triethylamine (0.1435 moles) in THF and then by reacting the mixed anhydride thus formed with 19.2 g (0.1685 moles) of piperidine-3-carboxylic acid dissolved in THF/H2O. Upon completion of the reaction the reaction mixture was treated as described in Example 1. The crude oily residue thus obtained was precipitated by treatment with ligroin. The crude product was crystallized by acetonitrile. After cooling, the precipitate was filtered and dried at 60° C. under vacuum, producing 47.3 g (0.086 moles) of the pure product with a yield of 63% (C27H35Cl2N3O5).