Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[N:17]=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=[C:14]([Cl:19])[N:13]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (19.52 g, 136.3 mmol) was added to a solution of 2,4,6-trichloropyrimidine (25.0 g, 136 mmol) in CH2Cl2 (475 mL) at −78° C. with vigorous stirring. Diisopropylethylamine (26.4 g, 205 mmol) was added dropwise to the above mixture and stirred for 3 hours at −78° C. The resulting mixture was brought to 0° C. over a period of 3 hours and quenched with water (250 mL). The organic layer was separated, washed with aqueous citric acid (2×100 mL), brine (2×200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography [eluent: EtOAc/hexanes (1:9)], giving the desired product (7.40 g, 19%).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](F)[CH:16]=[C:15]([F:23])[C:14]=1[F:24].[C:25](OCC)(=[O:27])C>C1COCC1.CCCCCC>[F:24][C:14]1[C:15]([F:23])=[CH:16][C:17]([O:27][CH3:25])=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[NH:12][C:6]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=1[F:4]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of sodium methoxide (32.0 g, 600 mmol) in dry THF (500 mL) at −78° C. was added to (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (25 g, 60 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with 200 mL of water and concentrated. The concentrate was acidified with cold 2N HCl (pH=2) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1-5% ethyl acetate in hexane) afforded 18 g of the product (70.6% yield). H1NMR (CDCl3, 300 MHz): δ 7.42 (dd, 1H), 7.34 (d, 1H), 6.9 (s, 1H), 6.64-6.54 (m, 2H), 3.92 (s, 3H). LCMS: 94.1%, m/z=422.9 (M−1). HPLC: 98.8%.
Reaction SMILES: COC(C1C=C(O[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)C=C2OC(C)CC=12)=O.[CH3:26][O:27][C:28]([C:30]1[CH:40]=[C:39]([OH:41])[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[C:31]=1[F:42])=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:40]=[C:39]([O:41][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[C:31]=1[F:42])=[O:29]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: COC(=O)c1cc(O)c2c(c1F)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1F)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a). 1H NMR (400 MHz, CDCl3) δ 7.89-7.94 (m, 2 H) 7.10 (d, J=4.55 Hz, 1 H) 7.04-7.09 (m, 2 H) 3.92 (s, 3 H) 3.07 (s, 3 H) 2.92 (s, 2 H) 1.54 (s, 6 H); LCMS for C22H22FN3O5S m/z 395.00 (M+H)+.
Reaction SMILES: C([C@@H]1CO[C:10](=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16]C=O)C1C=CC=CC=1.N[C@H:38]1[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([C@H:38]3[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 10) (3.054 g, 5.8 mmol), trans-4-amino-cyclohexanol (1.35, 11.6 mmol), NaBH(OAc)3 (5.18 g, 23.21 mmol) and acetic acid (0.63 mL, 11.2 mmol) in 50 mL of 1,2-dichloroethane. Stir for 12 hours at room temperature. Quench with saturated solution of NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 1.39 g (54%) of the title compound: Mass spectrum (apci) m/z=448 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].Cl>C(Cl)(Cl)Cl>[C:15]([NH:19][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
To a solution of 4-methyl-3-nitrobenzenesulfonyl chloride (5.40 g, 22.9 mmol) in chloroform (50 ml) was added tert-butylamine (6.00 ml, 57.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and hexane was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide (5.89 g, yield 94.6%).
Reaction SMILES: NN.[C:3]1([C:9]([N:22]=[C:23]=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[OH:27]>C1COCC1>[CH3:23][N:22]1[CH2:9][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:7][OH:27]
Reactant: O=C=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: NN
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1CO
Reaction time: 8 h

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the procedure described above except 3 rounds of crystallization were performed. To a mixture of (±)-1-methyl-2-piperidinemethanol (95.6 g, 740 mmol) in EtOH (840 mL) was added dibenzoyl-L-tartaric acid (255 g, 711 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to provide 79.6 g. This process was repeated: (2) EtOH (335 mL) provided 50.4 g. (3) EtOH (345 mL) provided 35 g. The resulting salt was treated with 3M HCl (134 mL) which was heated to induce it to dissolve. The still warm solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 6 g of the alcohol. This alcohol (6 g, 46.7 mmol) was suspended in CH2Cl2 (100 mL) and SOCl2 (6.8 mL, 93.3 mmol) added dropwise. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt (5.98 g) was dissolved in EtOH (100 mL) and treated with NH2NH2 (19.5 mL, 405 mmol) and heated to reflux for 3 h. Half the solvent was removed, the residue extracted with ether and the extracts dried and concentrated to give 4.55 g of a crude oil. This crude hydrazine (2.01 g, 14.06 mmol) was dissolved in THF (100 mL) and triphenylmethylisocyanate (4.0 g, 14.1 mmol) was added slowly. The solution was then stirred overnight and the solvent removed under reduced pressure and the residue was purified by flash chromatography (CH2Cl2/MeOH/OH) to provide 350 mg of the desired product. 1H NMR (DMSO-d6) δ 1.10 (m, 2H), 1.30–1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71 (d, 1H), 3.25 (q, 1H), 3.55 (q, 1H), 4.80 (s, 2H), 7.12–7.32 (m, 15H), 8.02 (s, H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.CO[C:10](=[O:30])[CH2:11][CH:12]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>C1C=CC=CC=1>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH2:11][C:10]([NH:2][CH3:1])=[O:30])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: COC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Temperature: 5 °C
Yield: 94.3 %

Procedure:
To a 5° C. stirring suspension of MeNH2—HCl (160 mg, 2.4 mmol) in benzene (2 ml) under N2, in a sealed tube was added dropwise Me3Al (2M in toluene, 1.2 ml, 2.4 mmol). The mixture was stirred at room temperature for 1 hour and a solution of 3-(1H-Indol-6-yl)-3-(2-methoxy-phenyl)-propionic acid methyl ester XXXVII (340 mg, 1.1 mmol) in benzene (10 ml) was added. The resulting mixture was stirred at 90° C. for about 4.5 hours, cooled to room temperature, and the reaction was quenched by slowly adding HCl (1M, 25 ml). The resulting mixture was stirred for 10 minutes, diluted with H2O, and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and evaporated to provide 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide XXXVIII (320 mg, 94% yield).
Reaction SMILES: [CH2:1]([N:8]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][C:22]=2[CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42].N1C=CN=C1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([N:8]([CH2:9][C@H:10]([O:19][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:30][C:22]=2[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1

Procedure:
Under nitrogen, a solution of (2S)-1-[N-benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (20 g), chlorotriethylsilane (7.4 ml), imidazole (3.2 g) and 4-dimethylaminopyridine (0.48 g) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 12 hours. The resulting mixture was poured into water, and extracted with ethyl acetate-hexane (1:1). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amine (25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27][CH2:28]Cl)[CH3:25].O>CN(C)C=O>[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][CH2:28][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under cooling with stirring 1,2 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 20 minutes. To the mixture is added dropwise 7.6 g of N,N-dimethyl-3-chloropropylamine and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured into iced water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with a benzenechloroform mixture. The eluate is treated according to usual procedure to obtain an oily 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from anhydrous ethanol and acetone to obtain 4.3 g of 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 154°- 156° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9][C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([O-:18])=[O:17].[Na+]>S(=O)(=O)(O)O>[N+:16]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:11](=[O:12])[C:10]([CH3:13])([CH3:14])[NH:9][C:8]2=[O:15])=[CH:6][CH:5]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)NC(=O)N(c2ccccc2)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
17.0 g (83 mmol) of 3-phenyl-5,5-dimethylhydantoin were dissolved in 160 ml of concentrated sulphuric acid and 7.07 g (83 mmol) of sodium nitrate were slowly added with stirring, at 0° C. over a 40 minute period. After the addition was completed, maintained stirring at 0° C. was continued for 20 minutes with the reaction mixture. The mixture was allowed to warm to room temperature and stirring was continued for 4 hours. The mixture was then poured onto ice water and then extracted with methylene chloride. The extract was dried over sodium sulphate. The methylene chloride was evaporated and the resulting product was crystallized from methylene chloride/petroleum ether. The recrystallized product was dried for 16 hours, under greatly reduced pressure, to yield 3-(4-nitrophenyl)-5,5-dimethylhydantoin, m.p. 176°-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: COc1cc(Br)c(O)cc1F
Product: COc1cc(Br)c(OCC2CC2)cc1F

Procedure:
Starting from 2-bromo-5-fluoro-4-methoxy-phenol (example B.a1) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:20][CH:21]1[NH:26][CH:25]([CH3:27])[CH2:24][N:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22]1.C(N(CC)CC)C>C(#N)C>[CH3:20][C@H:21]1[CH2:22][N:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@@H:25]([CH3:27])[N:26]1[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: CC1CN(S(C)(=O)=O)CC(C)N1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1Cc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
4-[5-(Chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 86 mg, 0.3 mmol) and 3,5-dimethyl-1-(methylsulfonyl)piperazine (Intermediate 36, 78 mg, 0.41 mmol) were weighed into a vial and suspended in acetonitrile (1.2 mL). Triethylamine (84 μL, 0.60 mmol) was added, and the mixture was heated at 140° C. in a microwave with stirring for 3 h. The reaction mixture was applied to a 10 g SCX cartridge, pre-washed with MeOH (50 mL). This was eluted with MeOH (100 mL) and 10% aq NH3 in MeOH (100 mL). The basic fractions were concentrated to give an off-white solid (137 mg). This was purified by MDAP to give the title compound as a colourless solid (38 mg), confirmed by NMR to be the pure cis-isomer.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH:4]1[CH2:13][C:12]2[CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:41]([N:44]=[C:45]=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH:41]([NH:44][C:45]([N:31]1[CH2:30][CH2:29][CH:28]([CH2:27][N:3]([CH2:1][CH3:2])[CH:4]2[CH2:5][CH2:6][C:7]3[C:12](=[CH:11][C:10]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=4)=[CH:9][CH:8]=3)[CH2:13]2)[CH2:33][CH2:32]1)=[O:46])([CH3:43])[CH3:42]
Reactant: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
To an ice-cold solution of N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-methanesulfonyl-benzamide (1.3 g, 2.3 mmol) in methylene chloride (40 mL) under a nitrogen atmosphere was added the triethylamine (1.3 mL, 9.2 mmol, 4 eq.) in a single portion followed by the isopropylisocyanate (0.33 mL, 3.3 mmol, 1.4 eq). The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 10% aq. sodium hydroxide (40 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined EtOAc layers were dried over MgSO4, filtered, and concentrated. Trituration with ether afforded 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide 1 as a light pink solid (1.1 g). [M+H]+=555.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:4][CH2:3][CH:2]([NH2:1])[CH3:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 67.1 %

Procedure:
A mixture of (S)-(+) 2-amino-1-propanol (1.04 g, 13.85 mmol), tert butyldimethylsilyl chloride (2.09 g, 13.85 mmol) and triethylamine (2 ml, 1.05 eq) was stirred in DCM overnight ca 16 h. The reaction was diluted with DCM, washed with water, satd. NH4Cl, brine, dried and evaporated to an oil. Silica gel purification of the crude using 3% MeOH/CH2Cl2 as eluent provided 2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (1.76 g, 80%); 1H NMR (300 MHz, CDCl3) 0.0 (s, 6H), 0.82 (s, 9H), 0.99 (d, J=6.5 Hz, 3H), 2.22 (bs, 2H), 2.98 (bs, 1H), 3.30 (dd, J=10 Hz, J=17.0 Hz, 1H), 3.48 (dd, J=10.0 Hz, J=4.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8].C(O)=O.[Cl-].[Na+]>O>[Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=C(Cl)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=C(Cl)CN(CC=O)C(=O)OCC

Procedure:
151 g (0.6 mol) of ethyl N-(2-chloroallyl)-N -(2,2-dimethoxyethyl)-carbamate are heated under reflux for 3 hours with 60 ml of formic acid in 1.2 1 of water. The mixture is saturated with sodium chloride, and the aqueous phase is separated off and extracted twice with 300 ml of methylene chloride each time. The organic phases are washed with saturated sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.O>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][N:13]2[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: BrC1CCCC1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in one portion to a room temperature solution of 5.7 g (27.9 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester in 125 mL anhydrous DMF. After 20 minutes, 3.89 mL (36.6 mmol, 1.3 equiv) cyclopentyl bromide were added dropwise, and the reaction was mixture allowed to stir overnight at room temperature. The mixture was then poured into 1 L H2O and extracted 3×450 mL ethyl acetate. The organic extracts were combined, washed 3×400 mL H2O, 1×200 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave an amber oil, which was purified on a silica gel column (10% ethyl acetate/hexanes, gravity) to give 5.48 g (72%) of a clear oil: 1H NMR (300 MHz, CDCl3) d 8.16 (d, 1H, J=1.0 Hz), 7.7 (m, 2H), 5.00 (quintet, 1H, J=7.5 Hz), 3.97 (s, 3H), 3.01 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H), 1.39 (t, 3H, J=7.6 Hz); HRMS calcd for C16H20N2O2; 272.1526. Found: 272.15078.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1cccnc1CBr
Product: O=[N+]([O-])c1cccnc1COc1ccccc1Cl
Yield: 85 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2-chlorophenol, the titled compound was obtained as yellow oil. (Yield: 85%)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COc1ccc(-n2cnc3c(Cl)nc4ccccc4c32)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2cnc3c(OC)nc4ccccc4c32)cc1

Procedure:
A mixture of 3.6 g (0.0116 mole) of 4-chloro-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline (from Example 109), 25.1 g (0.116 mole) of 25% sodium methoxide in methanol and 50 ml of methanol was heated its reflux temperature for one hour. Evaporation provided a residue which was diluted with 75 ml of water. The precipitate was separated by filtration, washed with water and recrystallized from ethanol to provide 4-methoxy-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline, m.p. 180°-182° C. Analysis: Calculated for C18H15N3O2 : %C, 70.8; %H, 5.0; %N, 13.8; Found: %C, 70.6; %H, 5.0; %N, 13.9.