Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O1CCCC1.[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37](Cl)=[O:38]>>[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:38]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: c1ccc2c(c1)CCCN2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cc2c(s1)-c1ccccc1OCC2)N1CCCc2ccccc21

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride (0.100 g, 0.378 mmol) portionwise as a solid. Reaction was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. After aqueous workup, the crude was taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 218 (yield 80% of theoretical). MS: (ESI+) 362.2
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[N:11]1>C(O)C.CO>[CH:15]1[CH:14]=[C:13]2[C:12]([NH:11][NH:10][C:18]2=[CH:17][CH:16]=1)=[C:19]([N:2]=[O:3])[NH2:20]
Reactant: N#Cc1n[nH]c2ccccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: NC(N=O)=C1NNc2ccccc21
Temperature: 25 °C
Yield: 36.6 %

Procedure:
Hydroxylamine hydrochloride (1.5 g) and potassium carbonate (3.83 g) were stirred together in absolute ethanol (100 ml) for 15 minutes. Indazole-3-carbonitrile (2 g) was added and the solution heated at reflux for 4 hours, cooled to room temperature and diluted with methanol (5 ml). The solution was filtered and the solvent evaporated. The residue was extraced with anhydrous either, the extracts were dried over MgSO4, filtered and the solvent removed to afford a white solid, which was recrystallised from acetone/dichloromethane to afford the title compound (900 mg), m.p. 155°-158° C. δH (360 MHz, CDCl3) 6.46 (1 H, brm, N--OH), 7.17 (1 H, t, J=1 Hz, H-6), 7.41 (1 H, t, J=2 Hz, H-5), 7.55 (1 H, d, J=2 Hz, H-4), 8.03 (1 H, t, J=2 Hz, H-7 ); m/z (M+, 100%), 176 (100), 144 (80), 119 (25), 92 (15).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH:45]1[CH2:50][CH2:49]C[CH2:47][CH2:46]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH:15]3[CH2:49][CH2:50][CH2:45][CH2:46][CH2:47]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: BrCC1CCCCC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC3CCCCC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (bromomethyl)cyclohexane and isolated as white solid (4.2 mg, 27%). MS (m/e): 379.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCC(NC(C)=O)c1ccc(CCl)cc1
Product: CCC(NC(C)=O)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)propyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as pale-brown crystals, m.p.=113-114° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN(C1C=CC=CN=1)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.C(OCC)(=O)C>[C:20]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2ccccc2N1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2CC1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a mixture of 2-methylindoline (20.0 g, 0.15 mol) and dimethylaminopyridine (500 mg, 5 mmol) in pyridine (50 mL) at room temperature is added acetic anhydride (20 mL). The mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 26.3 g (100%) of the title compound as an amber oil. MS (ESI+) m/z 176.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.N1C=CC=CC=1.[CH:59]1([C:62](Cl)=[O:63])[CH2:61][CH2:60]1>ClCCl>[Br:13][C:11]1[C:10]([CH2:14][O:15][CH:16]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][CH2:2][NH:1][C:62]([CH:59]1[CH2:61][CH2:60]1)=[O:63])[CH:5]=[C:6]2[CH3:52]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCNC(=O)C4CC4)c3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of 0.400 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 76b) in 2.5 ml of dichloromethane is admixed successively with 0.74 ml of pyridine and 0.43 ml of cyclopropanecarbonyl chloride, and stirred at room temperature over 30 minutes. The reaction mixture is poured onto water (50 ml) and extracted with dichloromethane (2×40 ml). The organic phases are washed successively with 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([C:35]2[CH:36]=[C:31]([NH2:30])[CH:32]=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 60 °C
Yield: 92.6 %

Procedure:
Twenty-five grams of 2,4-dichloro-6,7-dimethoxyquinazoline was suspended in 2.25 L of a mixed solution consisting of toluene:tetrahydrofuran:a 2 N sodium carbonate solution=1:1:1. To the reaction mixture was added 21.5 g of 3-aminophenyl boronic acid ½ sulfate, and the mixture was degassed, the atmosphere in the reaction vessel was replaced with nitrogen. To the reaction mixture was added 2.23 g of tetrakis(triphenylphosphine)palladium(0), followed by stirring at 60° C. under a nitrogen atmosphere. Eighteen hours after initiation of the reaction, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture, and the stirring was continued. Thirty hours later, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was further added to the reaction mixture, and stirring was further continued. Forty-eight hours after initiation of the reaction, the reaction mixture was cooled, and it was then transferred into a separatory funnel, so as to separate an organic layer. The obtained organic layer was washed with 300 mL of brine, and was then dried over anhydrous magnesium sulfate. The desiccant was removed by passing it through 250 g of silica gel. The silica gel was washed with 1.5 L of ethyl acetate, and the obtained organic layers were combined and concentrated to dryness. The residue was triturated with 200 mL of ethyl acetate, and the obtained solid was then filtrated. The solid was washed with 100 mL of diethyl ether and 200 mL of a mixed solution consisting of n-heptane:ethyl acetate=1:1, and dried under aeration to give 28.2 g of a target product. Yield: 92.5%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12]([CH3:13])=[O:49])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: Cc1cc(F)ccc1C(c1ccc(F)cc1)c1c[nH]c2c(CS(C)=O)cc(F)cc12

Procedure:
The title compound was prepared starting from 75 mg (0.18 mmol) of the compound from Example 292 in analogy to the synthesis of the compound from Example 296. 75 mg (96% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].S(=O)(=O)(O)O.[H][H]>[Pd].CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][NH2:25])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: [H][H]
Reactant: CC(CN1C(=O)c2ccccc2C1=O)c1c[nH]c2ccc(C#N)cc12
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(CN1C(=O)c2ccccc2C1=O)c1c[nH]c2ccc(CN)cc12
Yield: 232.9 %

Procedure:
A suspension of 3-[2-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl]1-methylethyl]-1H-indole-5-carbonitrile (1.4 g) and pre-reduced 10% palladium on charcoal (1.4 g) in methanol (100 ml) containing concentrated sulphuric acid (0.5 ml) was hydrogenated at room temperature and pressure until hydrogen uptake ceased. The catalyst was filtered off and the filtrate was evaporated to dryness to give a red oil (3.3 g) which was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5](F)=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[C:7]([N:9]([CH2:11][CH2:12][OH:13])[CH3:10])=[O:8].O>CN(C=O)C>[Cl:3][C:4]1[C:5]2[O:13][CH2:12][CH2:11][N:9]([CH3:10])[C:7](=[O:8])[C:6]=2[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCOc2c(ccc(F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
Sodium hydride (28 mg, 0.723 mmol, 60% dispersion in mineral oil) was added slowly to a solution of 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (180 mg, 0.723 mmol) in DMF (4 mL) and the reaction stirred at room temperature for 16 hours. Water was added to the reaction and the mixture was subsequently extracted with DCM (3×30 mL). The combined organic phases were washed with water (5×25 mL) and saturated brine solution then dried (MgSO4), filtered and evaporated to give the desired product as an oil (140 mg). 1H NMR δ (CDCl3): 3.21 (s, 3H), 3.54 (t, 2H), 4.52 (t, 2H), 6.97 (dd, 1H), 7.72 (dd, 1H). m/z 230 (M+H)+
Reaction SMILES: [I-:1].[Na+].[CH:3]1([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(#N)C>[CH:3]1([C:9]([I:1])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(I)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
In 80 ml of acetonitrile is dissolved 6 g of sodium iodide and, then, 5 g of cyclohexanecarbonyl chloride is added dropwise to the solution under ice-cooling. This mixture is stirred at 0° C. for 30 minutes. Then, insoluble matters are removed by filtration and the filtrate is concentrated under reduced pressure. To the residue is added 20 ml of petroleum ether and insoluble matters are removed by filtration and the filtrate is subjected to distillation under reduced pressure to obtain 5.0 g of cyclohexanecarbonyl iodide. Yield: 61%. B.p. 75°-80° C./5 mmHg [b.p. 103°-105° C./11 mmHg according to "Bull. Chem. Soc. Japan" 34, 480 (1961)].
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: CNCCCN(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)CCCN(C)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)pyridin-2-ol (500 mg, 2.4 mmol), CHCl3 (25 mL), oxalyl chloride (0.42 mL, 4.8 mmol) and DMF (1 drop) was allowed to reflux for 16 h. Once consumption of starting material was complete the reaction was concentrated under reduced pressure. A portion of the crude material (182 mg, 0.8 mmol) was removed and added to a mixture of N1,N1,N3-trimethylpropane-1,3-diamine (0.13 mL, 0.88 mmol), K2CO3 (221 mg, 1.6 mmol) and heated at 90° C. for 10 min. The mixture was concentrated under reduced pressure and reconstituted in CH2Cl2 (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine. MS m/z=307 [M+H]+. Calc'd for C12H17F3N4O2: 306.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Product: O=C(c1ccccc1)c1[nH]c2cc(Cl)ccc2c1CC(=O)N1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and morpholine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[CH3:27][Si:28]([CH3:38])([CH3:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>O>[O:1]=[C:2]1[C@H:7]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Si:28]([CH3:27])([CH3:38])[CH3:37])[CH:30]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc([Si](C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
A dry 250 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet was charged with 2.08 g of t-butyl (2R, 3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (Aldrich), 1.43 g of 3-(trimethylsilyl)benzyl bromide (Yamakawa, T., et al, J. Med. Chem., 1990, 33, 1430), and 45 mL of anhydrous THF. The solution was cooled to -78° C. and was treated with 6.17 mL of 1 M sodium bis(trimethylsilyl)amide/THF (Aldrich) via syringe through a rubber septum. The solution was stirred at -78° C. for 3.5 h and was then poured into 150 mL of water. The resulting mixture was extracted with EtOAc (4×50 mL). The combined EtOAc extracts were washed with saturated brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a light yellow oil. The crude material was purified by flash chromatography on silica gel (9:1 hexane:EtOAc) to afford 2.6 g (88%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(trimethylsilyl)benzyl)-4-morpholinecarboxylate as a white powder, m.p. 88-90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18]O)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][O:10][C:9]2[C:8]([CH3:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[CH3:1])[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzonitrile (5.0 g, 34.0 mmol) in THF (40 mL), rac-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (4.49 g, 34.0 mmol) followed by triphenylphosphine (13.4 g, 50.9 mmol) is added. The mixture is cooled with an ice-bath before DEAD (8.87 g, 50.9 mmol, 23.4 mL of a 40% solution in toluene) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 99:1 to 92:8 to give rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g) as a pale yellow oil; LC-MS: tR=0.99 min, [M+1]+=not detected. b) To a solution of potassium tert.-butylate (6.18 g, 55.1 mmol) in methanol (125 mL), hydroxylamine hydrochloride (5.74 g, 82.7 mmol) is added. To this solution, a solution of rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g, 27.6 mmol) in methanol (40 mL) is added. The mixture is refluxed for 72 h before the solvent is removed in vacuo. The residue is purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% sat. aq. NH3) to give the title compound (4.85 g) as a pale yellow solid; LC-MS: tR=0.67 min, [M+1]+=295.06; 1H NMR (CDCl3): δ1.43 (s, 3H), 1.48 (s, 3H), 2.29 (s, 6H), 3.76-3.81 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.99 (m, 1H), 4.17-4.23 (m, 1H), 4.47-4.54 (m, 1H), 5.02 (s br, 1H), 7.28 (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(CO)CCC1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Benzylamino-3-methyl-cyclohexyl)-methanol (0.1 g, 3.00 mmol) in DCM (30 mL) and pyridine (3 mL) is treated with TsCl (0.86 g, 4.50 mmol) and the resulting mixture is stirred at RT overnight. The reaction mixture is partitioned between DCM and water and the organic portion is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (1:2 increasing to 1:4) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2H, d), 7.50 (2H, d), 7.30 (4H, m), 7.20 (1H, m), 3.80 (2H, d), 3.63 (2H, q), 2.41 (4H, m), 2.01 (1H, m), 1.72 (2H, m), 1.58 (1H, m), 1.49 (2H, m), 1.20 (1H, m), 1.02 (1H, m), 0.85 (1H, m), 0.81 (3H, d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][Br:23])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccccc2)CC1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Temperature: -1.7999999523162842 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of (4-phenylcyclohexyl)-acetic acid ethyl ester (10.0 g, 40.6 mmol) (patent WO2004 047755) in DCM (100 mL) at 0° C. is added AlCl3 (9.94 g, 74 mmol) portionwise. After it is stirred at −1.8° C. for 10 min, bromoacetyl bromide (3.59 mL, 40.6 mmol) is added dropwise over 2 min. The reaction mixture is allowed to stir at −1.8° C. for 2 h. It is then poured slowly to water/ice mixture (200 mL) and stirred for 30 min. The mixture is extracted with DCM (2×50 mL). The organic phase is separated and washed with NaHCO3 (3×100 mL), and brine (3×100 mL), dried with Na2SO4, concentrated and dried under high vacuum to give the title compound (12.8 g) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.17 (m, 2H) 1.20 (t, J=8.00 Hz, 3H) 1.39-1.51 (m, 2H) 1.56-1.68 (m, 1H) 1.76-1.87 (m, 4H) 2.18 (d, J=4.29 Hz, 2H) 2.48 (td, J=12.32, 2.65 Hz, 1H) 4.08 (q, J=7.24 Hz, 2H) 4.35 (s, 2H) 7.25 (d, J=8.34 Hz, 2H) 7.85 (d, J=8.59 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: C[C@@H](N)c1ccccn1
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 0.4 g, 1.2 mmol) and (1R)-1-(2-pyridinyl)ethanamine (2 eq, 0.293 g) in CH3CN (20 ml) was heated at 60° C. for 2 h. The mixture was extracted with DCM. The organic phase washed with saturated aqueous Sodium hydrogen carbonate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue taken up in diethyl ether. The precipitate was filtered off and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-N-[(1R)-1-(2-pyridinyl)ethyl]-4-quinolinamine (0.4 g) which was used without purification in the next step.