Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18](OC3CCOCC3)[C:19]=2[N:20]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:41][CH:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Hunig's base (6.53 mL, 37.5 mmol) was added to a suspension of 4,6-dichloropyrido[3,2-d]pyrimidine (intermediate 1, 5.00 g, 25.0 mmol) and tert-butyl-4-aminopiperidine-1-carboxylate (6.00 g, 30.0 mmol) in 1,4-dioxane (250 mL) at room temperature. The reaction mixture was refluxed for 1 h, and cooled to room temperature. The solvent was removed under reduced pressure, EtOAc and water were poured into the residue, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give a pale yellow solid which was washed with MeOH afforded tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (8.72 g, 96%) as a off white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.50-1.62 (2H, m), 2.10-2.15 (2H, m), 2.98-3.01 (2H, m), 4.01-4.25 (2H, m), 4.25-4.40 (1H, m), 6.86 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=8.8 Hz), 8.04 (1H, d, J=8.8 Hz), 8.62 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])=[O:18]>CS(C)=O.O>[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[C:24]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])=[O:18]
Reactant: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4-dichlorophenol (1.2 g, 7.6 mmol) and potassium carbonate (2.1 g, 15.2 mmol) is stirred together in dimethylsulfoxide (20 ml). N-methylcarbonyl 2-nitro-5-fluoroaniline (1.5 g, 7.6 mmol) is added in portions. After 1 hour, the reaction is heated to 100° for 1.5 hours. The reaction is then cooled to RT and diluted with water. A solid is collected, dissolved in chloroform, washed with water, dried and stripped to give N-methylcarbonyl 2-nitro-5-(2,4-dichlorophenoxy)aniline.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:14]=2[CH:30]=1.CN1CCOCC1>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:14]=2[CH:30]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1cccc(CN2CCOc3ccc(N)cc32)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1cccc(C(=O)OC)c1)CCO2
Reaction time: 0.5 h

Procedure:
Hexanoyl chloride (0.135 g.) was added dropwise to a stirred solution of methyl 3-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (X) (0.3 g.), and N-methylmorpholine (0.101 g.) in dichloromethane (30 ml.). After 0.5 hours, the mixture was diluted with dichloromethane, washed with water, dried (MgSO4) and evaporated to give an oil which was filtered through a short column of silica gel using 35:65 v/v ethyl acetate:hexane to give the title compound as a syrup; partial NMR (80 MHz, CDCl3): 0.8-1.9[complex m,9H, CH3 (CH2)3 ]; 2.2(m,2H, CH2CONH); 3.3(m,2H, N.CH2.CH2.O); 3.9(s,3H, OMe); 4.2(m,2H, N.CH2.CH2O); 4.5(s,2H, N.CH2Ar).
Reaction SMILES: [C:1]1([C@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:30][N:20]([CH2:19][C@@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:8]1[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 1,1-dimethylethyl [((1S,2R)-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (39.2 g, 92 mmol), accessed via the method of 11A, and methyl iodide (39.2 g, 276 mmol, 3 eq) in 300 mL THF cooled to 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (138 mL, 138 mmol, 1.5 eq). The reaction mixture was stirred 2 h at 0° C. followed by 16 h at ambient temperature. The reaction mixture was partitioned between EtOAc and water, the phases separated, the aqueous phase extracted twice with EtOAc, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to an amber oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM/hexanes (1:1), DCM, and EtOAc/hexanes (1:4)) to give the title compound (22.25 g, 58 mmol, 63%) as a pale yellow oil. ES-LCMS m/z 404.30(M+Na).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[CH2:6]1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[CH2:6]1
Reactant: CNc1ccccc1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Agent: Cl
Product: CN1CC(CCN(C)c2ccccc2)Cc2ncccc2C1=O

Procedure:
A solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one hydrochloride in excess N-methylaniline is heated to about 95° C. for 2 days. Excess N-methylaniline is removed at reduced pressure and the residue is taken up in chloroform. The chloroform layer is washed with dilute aqeuous base, decolorized with activated carbon and dried over sodium sulfate, filtered and concentrated. The residue is dissolved in a suitable solvent and purified by high pressure liquid chromatography using a silica gel column and ethyl acetate. The product is recrystallized from ethyl acetate.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][N:16]([C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>O.C(O)C.[Pd]>[ClH:1].[O:25]([C:23]([N:16]([CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccccc1)N(CC1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Oc1ccccc1)N(CC1CNCCO1)c1ccccc1

Procedure:
A solution of 4-benzyl-2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride (9 g.) in water (75 ml.) and ethanol (200 ml.) is shaken in an atmosphere of hydrogen in the presence of palladium on charcoal catalyst (0.5 g.; 5%) until no further hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is then evaporated to give a white residue which is recrystallised from methanol/ether to give 2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride, m.p. 179°-181°C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CNCc1ccccc1)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: CCCCCBr
Product: CCCCCN(Cc1ccccc1)CC(C)c1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Using a method similar to example 3, using 6-[4-(2-benzylamino-1-methyl-ethyl)-phenoxy]-nicotinamide (example 190 step 2), and 1-bromopentane gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.52 minutes, Purity: 97.4%; mass spectrum (ion spray): m/z=432.3 (M+1).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH:18]([C:12]1[CH:17]=[CH:16][C:15]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and cumene (0.56 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 4 hours. Using the same procedure as in Example 1, 4'-iso-propylbenzoin was obtained as crystal (300.6 mg, 59.6% yield).
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[C:1]([Cl:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCCCCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCCCCC(=O)Cl
Reaction time: 1 h

Procedure:
To a solution of 6-heptenoic acid (251 μL, 1.85 mmol) in CH2Cl2 (5 mL) at rt was added oxalyl chloride (476 μL, 5.55 mmol) and DMF (1 drop). After stirring for 1 hr, the reaction mixture was concentrated under reduced pressure and put under high vacuum for 15 min. The residual yellow oil was dissolved in CH2Cl2 (3 mL) and used as a stock solution (0.62M) for the subsequent acylation reactions.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:7][O:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:8]2[CH2:7][O:6][CH2:5][C@H:4]2[NH2:1])=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A solution of cis-3-azido-4-(4-bromophenoxy)tetrahydrofuran (286.7 g, 1.01 mol) in tetrahydrofuran (1.25 L) was cooled to 0° C. and treated with triphenylphosphine (278 g, 1.06 mol). The reaction was allowed to warm to room temperature and stirred for 18 hours. Water (53 mL) was added and the reaction was stirred at room temperature for 66 hours. Solvent was removed under reduced pressure and the residue was mixed with diethyl ether. The supernatant was decanted and concentrated in vacuo, providing a residue, which was filtered through a short plug of silica gel (Gradient: 0% to 5% methanol in methylene chloride) to afford cis-4-(4-bromophenoxy)tetrahydrofuran-3-amine (155 g) and 366 grams of impure product. An acid/base extraction was carried out on the impure material, providing additional product (48.5 g). Total yield: 203.5 g, 0.788 mol, 68% over four steps. 1H NMR (300 MHz, CDCl3) δ 3.6 (m, 1H), 3.7 (m, 1H), 3.9 (m, 1H), 4.0 (m, 1H), 4.1 (m, 1H), 4.6 (m, 1H), 6.8 (m, 2H), 7.3 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][CH2:3][OH:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 12 h
Yield: 73.1 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester (Example 57) (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treated with a 1 N THF solution of lithium aluminum hydride (750 μL, 0.75 mmol) and allowed to stir for 12 h. The reaction mixture was quenched with an aqueous 15% NaOH solution (250 μL) followed by water (250 μL) and THF (2 mL). the reaction mixture was then treated with MgSO4, filtered, and evaporated. The residue was then dissolved in EtOAc (3 mL), retreated with MgSO4, filtered, and evaporated to afford product as an oil (75 mg, 73%). 1H NMR (CDCl3) 1.58-1.62 (m, 2H), 1.67-1.88 (m, 6H), 2.74-3.22 (m, 12H), 3.65-3.76 (m, 2H), 3.78 (s, 3H), 4.64-4.67 (m, 1H), 6.34 (dd, J=8.6, 2.9, 1H), 6.40 (d, J=2.6, 1H), 6.75 (d, J=8.6, 1H), 7.20-7.33 (m, 5H). 13C NMR 24.2 (CH2), 33.0 (CH2), 33.0 (CH2), 48.4 (CH2), 49.7 (CH2), 53.9 (CH2), 55.5 (CH2), 56.9 (CH3), 58.1 (CH2), 61.6 (CH), 80.5 (CH), 106.5 (CH), 108.1 (CH), 113.4 (CH), 126.5 (CH) 128.8 (CH), 129.5 (CH), 139.6, 144.7, 146.5, 148.5. LC/MS 4.81 min, [M+1]+ 411.
Reaction SMILES: Br[C:2]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])=[CH:20][CH:19]=1)=[C:3]([NH:8][C:9]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.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>[Cl:17][C:12]1[C:11]([C:9]([NH:8][C:3](=[C:2]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)C(NC(=O)c1cccnc1Cl)=C(Br)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Reactant: OB(O)c1ccccc1
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: ClCCl
Solvent: COCCOC
Product: COC(=O)C(NC(=O)c1cccnc1Cl)=C(c1ccccc1)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium (O) (10 mol %, 58 mg) was added to a mixture of the compound of Example 13, Isomer A (288 mg, 0.493 mmol) and phenyl boronic acid (90 mg, 0.74 mmol) in DME (10 ml) and sodium carbonate (2M, 0.986 mmol, 0.493 ml). The mixture was heated at 80° overnight, dlute with CH2Cl2 (200 ml), washed with diluted HCl and sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; CH2Cl2/MeOH, 93:7) gave the title compound as a white solid (133 mg). δH (DMSO-d6), 11.04 (1H, s, CONH), 10.40 (1H, s, CONH), 8.79 (2H, s, Cl2PyH), 8.48 (1H, dd, J 4.9, 1.9 Hz, PyH), 7.85 (1H, dd, J 7.5, 1.9 Hz, PyH), 7.66 (2H, d, J 8.7 Hz, ArH), 7.51 (1H, dd, J 7.5, 4.9 Hz, PyH), 7.39-7.35 (3H, m, ArH), 7.23 (2H, d, J 8.7 Hz, ArH), 7.07 (2H, m, ArH) and 3.45 (3H, s, CO2Me); m/z (ESI, 60V) 581 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([CH:21]2[CH2:22][CH2:23][N:24]([CH:31]3[CH2:32][CH2:33][CH2:34][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH2:25][CH2:26]2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCC(=O)CC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCCC(N2CCC(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)CC1

Procedure:
The title compound is prepared from 5-chloro-2-(piperidin-4-ylcarbonylamino)-N-(5-chloropyridin-2-yl)-benzamide and 1-methyl-hexahydro-4H-azepin-4-one by reductive alkylation using NaCNBH3 and 5%-acetic acid in methanol, for example using a procedure similar to that of Example 25-F.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:22]=[CH:21][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]2[CH2:51][O:50]2)=[CH:43][CH:42]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:50][C@H:49]([CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([OH:40])=[CH:42][CH:43]=1)[CH2:51][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]2)=[CH:21][CH:22]=1
Reactant: NCCc1ccc(NC2CCN(C(N)=O)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: NC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 12.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-1-piperidinecarboxamide formate (0.76 g, 2.37 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.817 g, 2.02 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.175 g, 0.26 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CN(C)c1cccc(C=O)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(N(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(dimethylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 380.2 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([F:24])=[C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[N:21]=[C:20](F)[C:19]=1[F:37]>C(OCC)C>[F:24][C:23]1[C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[N:21][C:20]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[C:19]([F:37])[C:18]=1[CH3:17]
Reactant: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(F)c(Oc2cccc(C(F)(F)F)c2)nc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Butyl lithium (2.6 ml, 6.6 mmol, 2.5 M solution in hexane) is added to a solution of 1-bromo-4-trifluoromethyl benzene (0.84 ml, 6 mmol) in anhydrous diethyl ether (5 ml) at −30° C. The mixture is stirred for 60 min at −20° C. and for 60 min at 10° C. The solution is allowed to warm to ambient temperature. This solution is then added to a mixture of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine 2A (1.5 g, 5 mmol) in anhydrous diethyl ether (100 ml) at −50° C. during 2.5 hours. The mixture is further stirred for 7 hours at −50° C. and washed with saturated aqueous ammonium chloride and water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains colorless crystals (0.37 g, 0.85 mmol, bp. 130° C. at 0.01-0.02 mbar) of mp. 87° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([O:28]CC)=O)=[CH:9]2)[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:26]([C:10]2[C:11](=[O:25])[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:13]=3)[N:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=2)=[O:28])=[CH:34][CH:33]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C2CCN(C)CC2)c2ccc(CN3CCOCC3)cc2c1=O
Product: CN1CCC(n2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(CN4CCOCC4)ccc32)CC1
Temperature: 165 °C

Procedure:
A flask containing crude ethyl 1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.31 g) is treated with 4-chlorobenzylarnine (2.0 mL). The reaction is tightly capped and heated to 165° C. overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 2% to 10% methanol saturated with ammonia in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.11 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([C@@H:28]([NH2:30])[CH3:29])[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@H:28]([CH:25]4[CH2:27][CH2:26]4)[CH3:29])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: C[C@H](N)C1CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@@H](C)C3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.26 (m, 1H) 0.28-0.36 (m, 1H) 0.36-0.44 (m, 1H) 0.44-0.53 (m, 1H) 0.92-1.08 (m, 1H) 1.25 (d, J=6.82 Hz, 3H) 2.43 (s, 3H) 3.39-3.60 (m, 1H) 7.66 (dd, J=8.08, 1.52 Hz, 1H) 7.73 (s, 1H) 7.78 (d, J=6.57 Hz, 1H) 8.17 (br. s., 1H) 8.43 (d, J=6.57 Hz, 2H) 8.59 (d, J=8.08 Hz, 1H) 8.79-9.05 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 388.2.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[C:7]([O:8][CH2:9][CH:10]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[O:12][CH2:11]3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Clc1nccnc1OCC1COc2ccccc2O1
Reactant: C1CNCCNC1
Product: c1ccc2c(c1)OCC(COc1nccnc1N1CCCNCC1)O2

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and homopiperazine (266 mg, 2.66 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 105 mg (57%) of the title product. Anal. (C18H24N4O3) H, N; C: calcd, 63.14; found, 62.70.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].Br[C:10]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:10]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(Cl)c1cccs1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(C(=O)c2cccs2)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting thiophene-2-carboxylic acid chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.