Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[CH:3]=2)[N:8]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (0.75 mmol), and dichlorobis(triphenylphosphine)palladium (II) (35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2 M K3PO4 aq. solution (5.0 mL, 1.0 mmol) and heated at 60° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic phase was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with one equivalent of L-tartaric acid in IPA:ethanol to give the tartrate salt. mp 164° C.; MS (ESI) 342 (M+H)+; 1H NMR (DMSO-d6) δ 8.40 (1H, d), 8.38 (1H, d), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d), 7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m), 3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m), 1.55 (1H, m), 1.29 (3H, d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([NH:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](=O)[CH2:20][CH:21]([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][NH:13][C:12]2=[O:16])[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCNC12CCN(Cc1ccccc1)CC2
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCN1CNC(=O)C12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg (0.408 mmol) 8-benzyl-1,3,8-triaza-spiro[4,5]decan-4-one (m.p. 164–166° C.) and 0.062 ml (49.2 mg, 0.571 mmol) isovaleraldehyde in 3 ml 1,2-dichloroethane were added 130 mg (0.611 mmol) sodium triacetoxyborohydride and the mixture stirred at ambient temperature for 16 h. Then the reaction mixture was quenched with 10 ml saturated aqueous NaHCO3-solution and extracted with dichloromethane. The organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated: 128 mg 8-benzyl-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one as colorless crystals: m.p. 139–140° C., MS (ISP): 316.4 MH+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:46])=[C:41]([CH:45]=1)[C:42](O)=[O:43])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:46])=[C:41]([C:42]([N:23]2[CH2:24][CH2:25][CH:20]([N:18]3[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]4[C:8]5[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)=[N:19]3)[CH2:21][CH2:22]2)=[O:43])[CH:45]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4ccccc4OC(F)(F)F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][C@@H:28]2[C:34](=[O:35])[NH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[S:30][CH2:29]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[S:30][CH2:29]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
A mixture of 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (1.0 g), tert-butyl chloroacetate (0.27 g), potassium iodide (0.3 g), potassium carbonate (0.24 g) and N,N-dimethylformamide (10 ml) is stirred for 15 hours at room temperature. The mixture is poured into water (50 ml) and extracted with ethyl acetate (40 ml). The extract is washed with diluted hydrochloric acid, sodium bicarbonate solution and water successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give firstly tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.45 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[N:6][CH:7]=1.[O:14]1[CH2:16][CH:15]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:16][CH:15]([OH:14])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(OC2CCNC2)nc1
Reactant: O=C(Nc1ccccc1OCC1CO1)c1ccccc1
Product: O=C(Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cn2)C1)c1ccccc1

Procedure:
A solution of 5-chloro-2-(3-pyrrolidinyloxy) pyridine (100 μL, 0.2M/DMSO), N-[2-(2-oxiranylmethoxy)phenyl]benzamide (100 μL, 0.2 M/DMSO) was refluxed for 3 h.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)(=O)C>CC(O)C>[C:13]([C@@:10]1([CH2:15][CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:27][CH:28]=3)[N:7]=2)[C:9]1=[O:17])#[N:14]
Reactant: CNC(=O)c1ccc(N)cc1
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)NC)cc3)n2)C1=O
Yield: 41.8 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (51 mg), 4-amino-N-methylbenzamide (32 mg) and acetic acid (12 μL) in 2-propanol (1 mL) was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (31 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)([CH3:10])[CH3:9])=[CH:6][N:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=1[OH:37])[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=1[O:37][CH2:2][C:3]1[N:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)([CH3:9])[CH3:10])=[CH:6][N:7]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(F)c(O)c(Cl)c1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CCl)n1-c1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(F)c(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)c(Cl)c1
Temperature: 60 °C
Yield: 68 %

Procedure:
A mixture of 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (154 mg, 0.39 mmol), methyl 3-chloro-5-fluoro-4-hydroxybenzoate (118 mg 0.57 mmol), potassium carbonate (79 mg, 0.57 mmol), and 18-crown-6 (11 mg, 0.04 mmol) in CH3CN (4 mL) was heated 8 h at 60° C. After cooling, the reaction mixture was filtered, combined with water and DCM, and then extracted further with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The material was purified by chromatography (silica, 0-70% EtOAc/Hex) to give methyl 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)-5-fluorobenzoate as a white solid (150 mg, 68% yield). MS (EI) m/z 567.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[NH2:12])C.[ClH:14]>CCOCC>[ClH:14].[NH:12]1[C:7]2[C:6](=[CH:11][CH:10]=[N:9][CH:8]=2)[CH2:5][C:4]1=[O:3]
Reactant: CCOC(=O)Cc1ccncc1N
Agent: Cl
Solvent: CCOCC
Product: O=C1Cc2ccncc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 50-ml round-bottom flask was added 0.36 g (2.0 mmol) of 3-amino-4-pyridineacetic acid ethyl ester, 15 mL of ether and 10 mL of 10% hydrochloric acid. The resulting biphasic solution was stirred for 16 hours at room temperature. The two phases were separated, and the ether phase was washed with 5 mL of water. The combined aqueous phases were evaporated to dryness to yield 0.285 g of the title compound as a brown solid. 1H NMR (DMSO-d6): δ5.93 (s, 1H), 7.59 (d, J=5.6 Hz, 1H), 8.02 (s,1H), 8.49 (d, J=5.6 Hz, 1H), 12.54 (s, 1H), 14.0 (bs, 1H); C8H6N2O: APCI+MS: m/z 135 (M+H).
Reaction SMILES: Br.ClC1C=CC(CN[C:9](=[O:29])[C:10]([F:28])([F:27])[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-:40].[Na+].[Na+]>O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:11]([OH:18])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:10]([F:27])([F:28])[C:9]([OH:29])=[O:40]
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Br
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To 4 ml of 47% hydrobromic acid was added 500 mg of N-(4-chlorobenzyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. The resulting mixture was refluxed for 6 hours. Thereto were added 20 ml of toluene and 20 ml of water. The resulting solution was adjusted to pH 8.5 with sodium carbonate. The aqueous layer was separated and 20 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 230 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:9])[C:6](Cl)=[O:7])[CH:2]=[CH2:3].[F-:10].[Cs+]>>[CH2:1]([O:4][C:5](=[O:9])[C:6]([F:10])=[O:7])[CH:2]=[CH2:3]
Reactant: [F-]
Reactant: C=CCOC(=O)C(=O)Cl
Agent: [Cs+]
Product: C=CCOC(=O)C(=O)F

Procedure:
By the procedure of the preceding Preparation, allyl oxalochloride (252.5 g, 1.70 mol) and cesium fluoride (284 g, 1.87 mol) were converted to twice distilled title product, b.p. 48°-50° C./35 mm; 124°-126° C. (atmospheric pressure).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=1.[OH-].[NH4+:18]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:18])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: CN(C)CCn1cc(Br)c2c(Cl)ncnc21
Reactant: [NH4+]
Agent: [OH-]
Product: CN(C)CCn1cc(Br)c2c(N)ncnc21
Temperature: 100 °C
Yield: 116.1 %

Procedure:
To [2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]dimethylamine (175 mg, 0.576 mmol) was added ammonium hydroxide (22.45 μl, 0.576 mmol) in to a 5 ml sealable vial. The vial was then capped and heated at 100° C. overnight. The reaction was cooled to room temperature and concentrated to a light brown oil of 5-bromo-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (190 mg, 0.669 mmol, 116% yield), which was used without further purification. LC/MS (ES) m/z=284.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ8.14 (s, 1H), 7.53 (s, 1H), 6.82 (br. s., 2H), 4.48 (t, J=6.32 Hz, 2H), 3.41 (br. s., 2H), 2.71 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH:19]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:28])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[CH:7]1[C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10](=[O:28])[C:9]=2[CH:19]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1CC2

Procedure:
540 Mg. methyl-10,11-dihydrodibenzo[b,f]-thiepin-3-carboxylate is dissolved in 40 cc methylene chloride and m-chloroperbenzoic acid is added in small portions until TLC shows very little starting material left. Excess calcium hydroxide powder is added and the mixture filtered through celite. The organic layer is evaporated and the residue chromatographed on silica gel to afford 570 mg. (94.7%).
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19](=[O:23])[CH2:20][CH2:21][CH3:22].CN(C=[O:28])C>>[C:19]([N:5]1[CH2:6][C:7]2[C:8](=[O:28])[C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[NH:15][C:16]=2[C:4]1=[CH2:3])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)CCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=C1c2[nH]c3ccc(OC)cc3c(=O)c2CN1C(=O)CCC
Reaction time: 6 h
Yield: 40 %

Procedure:
NaH (1.5 eq; 60% suspension in oil) is added to a solution of 1-methylene-2-butyryl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (160 mg; 0.6 mmol) in DMF (3 ml). The mixture is stirred under an oxygen atmosphere for 6 hours. The DMF is then distilled off under reduced pressure. The crude product is washed several times with ethyl acetate. After filtration and drying, 2-butyryl-7-methoxy-3-methylene-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (yield=40%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
Into a 5 mL microwave tube was charged 4-fluoro-2-methoxy-1-nitrobenzene (1 g, 0.584 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.321 g, 1.753 mmol), triethylamine (0.244 mL, 1.753 mmol), and acetonitrile (1.948 mL). The reaction was heated in Biotage microwave reactor at 130° C. for 40 minutes. The solvent was removed under reduced pressure, and the reaction purified by flash chromatography using a gradient 100% CH2Cl2 to 1:1 CH2Cl2/methanol to provide the title compound. MS (ESI) m/e 335 (M+H)+.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([N:21]([C:25](=[O:27])[CH3:26])[CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH:12]1[CH3:28])=O)C1C=CC=CC=1>CO.[Pd]>[CH:22]1([N:21]([CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][CH:12]([CH3:28])[CH2:13]2)[C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]1
Reactant: CC(=O)N(C1CC1)C1CC(C)N(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C1CC1)C1CC(C)Nc2ccccc21
Reaction time: 8 h

Procedure:
Benzyl-4-[acetyl(cyclopropyl)amino]-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was dissolved in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The round bottom flask in which resided the resulting solution was evacuated and backfilled with hydrogen. The reaction was stirred under the hydrogen atomosphere overnight. The mixture was carefully filtered through a Celite® plug and concentrated to afford crude product. The crude residue was purified by silica gel chromatography (hexanes/ethyl acetate system) to afford N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetamide.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[C:22]([O:28][CH3:29])[CH:21]=1.C[O-].[Na+].Cl>CO.O>[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
A mixture of 1-(2-phenylamino-pyridin-3-yl)-ethanone (833 mg, 3.92 mmol) in methanol (16.5 mL) at 25° C. was treated with 4-formyl-3-methoxy-benzoic acid methyl ester (508 mg, 2.61 mmol) and sodium methoxide in methanol (4.37M, 1.2 mL, 5.23 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction was diluted with water (100 mL), neutralized with a 1N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate filtered and concentrated in vacuo. Flash chromatography (40 g silica column, 10-50% ethyl acetate/hexanes) afforded 3-methoxy-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (880 mg, 86.8%) as a red solid. ES+-HRMS m/e calcd for C23H20N2O4 [M+H+] 389.1496. Found 389.1494.
Reaction SMILES: [CH:1]1([C:7]2([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH:17]1([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:11]3[CH2:12][N:13]([C:32]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:40])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(C3CCCCC3)(C3CCCCC3)C2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.1 %

Procedure:
To a solution of 1,1-dicyclohexyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.13 g, 0.42 mmol) in tetrahydrofuran (1 mL) were sequentially added diisopropylethylamine (0.5 mL) and phenyl chlorocarbonate (0.10 g, 0.64 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=7:3), crystallized from diisopropyl ether and dried to obtain the title compound (88 mg, yield 49%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:39]([O:44][CH2:45][C@@H:46]1[O:48]C1)(=[O:43])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][C@H:45]([CH2:46][OH:48])[O:44][C:39]4=[O:43])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at -78° C. under N2 is treated with n-butyllithium (0.73 mL, 1.6M in hexanes) dropwise over five minutes. The resulting mixture is stirred at -78° C. for 45 minutes and is then treated with (R)-(-)-glycidyl butyrate dropwise. The resulting solution is allowed to warm to ambient temperature over approximately 45 minutes and is stirred for an additional 20 hours, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g), eluting with methanol/methylene chloride (1/99). Pooling and concentration of those fractions with an Rf =0.37 by TLC (methanol/chloroform, 5/95) gives the title compound, mp 131.5-133.5° C.