Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CC(C)=O.O>[CH:1]1([S:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][CH3:19])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of cyclopropanesulfonamide (Li, J. et al; Synlett 2006, 5, 725-728) (800 mg, 6.60 mmol) in acetone (25 ml) was added potassium carbonate (2.738 g, 3 eq, 19.81 mmol) and ethyl chloroformate (1.075 g, 1.5 eq, 9.90 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was poured into water and made acidic (pH 1) with cone HCl then extracted with EtOAc. The extract was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent 30% EtOAc in hexanes) afforded 374 as a colourless oil (800 mg, 63%). 1H NMR (DMSO, d6) 11.47 (s, 1H), 4.10 (q, J=10.27 Hz, 2H), 2.90 (m, 1H), 1.19 (t, J=7.24 Hz, 3H), 1.039 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1cnc2[nH]cc(C3CCNCC3)c2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5ncccc45)CC3)nn12
Temperature: 80 °C
Yield: 77.8 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (160 mg, 0.72 mmol), 3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (145 mg, 0.72 mmol) and DIPEA (0.14 mL, 0.79 mmol) in DMF (2.0 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was then cooled to ambient temperature and quenched in water (10 mL) to give a beige solid. The solid was collected by filtration, washed sequentially with water, acetonitrile and ether, and air dried to give 6-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (217 mg, 78%) as a colourless solid.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]3[CH:25]=[CH:24][N:23]=[C:14]3[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:8][CH2:7]1)(OCC)=O.[H-].[Li+].[OH-].[Na+]>O1CCCC1>[CH3:1][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]3[CH:25]=[CH:24][N:23]=[C:14]3[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Temperature: 25 °C

Procedure:
To the solution of 0.2 g of 5-(4-carboethoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium hydride are added at once and the mixture is refluxed under nitrogen for 48 hrs. The mixture is cooled to room temperature, stirred with 0.2 ml of pb 30% sodium hydroxide, and filtered. The filtrates were evaporated to dryness and the product is purified to give 5-(4-methylpiperazino]-imidazo[2,1-b][1,3,5]benzothiadiazepine, melting at 145°-147°, and identical to compound obtained in example 1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH2:33][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1cccc(N2CCN(CCNCc3cc(CC(C)C)n(-c4ccccc4)n3)CC2)c1C
Yield: 96.5 %

Procedure:
Compound 18 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18](Br)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:8][C:7]=1[CH3:22].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1(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)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)[CH:17]=[C:16]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: COC(=O)COc1ccc(OCc2cc(Br)cc(Br)c2)cc1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)cc(-c3ccc(C(F)(F)F)cc3)c2)cc1C

Procedure:
[4-(3,5-Dibromo-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester 13 (0.0375 g, 0.088 mmol) is dissolved in dioxane (1 mL). 4-Trifluoromethyl-phenylboronic acid (0.0514 g, 0.27 mmol) is added, followed by water (0.01 mL), ethanol (0.01 mL), potassium carbonate (0.0557 g, 0.4 mmol), and tetrakis-(triphenylphosphino)palladium (0.117 g, 0.01 mmol). The mixture is stirred under nitrogen and subjected to microwave (170° C. for 10 min). The resulting orange suspension is filtered, the solids are washed with more dioxane, and the resulting solution is concentrated and purified by silica gel chromatography (10% to 25% ethyl acetate in hexanes) to yield [4-(3,5-bis(4-trifluoromethylphenyl)-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester as an oil. 1H-NMR (400 MHz, CDCl3) δ=7.77-7.64 (m, 8H), 7.52 (s, 2H), 7.34 (s, 1H), 6.88 (d, J=2.8 Hz, 1H), 6.76 (dd, J=9.0, 2.8 Hz, 1H), 6.68 (d, J=9.2 Hz, 1H), 5.14 (s, 2H), 4.61 (s, 2H), 3.80 (s, 3H), 2.95 (s, 3H). 19F-NMR (376 MHz, CDCl3) δ=−62.4.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=5)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:46][C:47]([CH3:49])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=5)[CH2:31][CH2:32][N:33]([CH:47]([CH3:49])[CH3:46])[CH2:34][CH2:35]6)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(C)C)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added acetone (143 mg) and sodium triacetoxyborohydride (157 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1>[OH-].[K+].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1

Procedure:
8-Chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (prepare as described in Schumacher, D. P.; et.al., J. Org. Chem. 1989, 54, 2242-4) (2 mmols) in 13% aq. KOH (20 mL) and ethanol (20 mL) is stirred and heated at reflux temperature under argon for 24 hours. The reaction mixture is cooled and extracted with ether. The ether extracts are dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Pure 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 8 is obtained by chromatography of the crude product.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:29]4[CH:25]([CH3:24])[CH2:26][CH2:27][C:28]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)CCC4C)cn3)CC2)c(C)c1
Yield: 32.1 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (113 mg) described in Preparation Example 232 and 5-methylpyrrolidin-2-one (36 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (38 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Al](Cl)(C)C.[CH3:14][N:15]([CH3:42])[S:16]([C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:21][C:20]=1[F:41])(=[O:18])=[O:17]>ClCCCl.C(Cl)Cl>[CH3:42][N:15]([CH3:14])[S:16]([C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34]([NH:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=3)=[O:35])[CH:25]=2)=[CH:21][C:20]=1[F:41])(=[O:17])=[O:18]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)N(C)C)c(F)c2)c2cc(C)oc2c1
Reactant: COc1ccnc(N)c1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccnc(NC(=O)c2cc(Oc3ccc(S(=O)(=O)N(C)C)c(F)c3)c3cc(C)oc3c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
To a solution of 4-methoxypyridin-2-amine (295 mg, 2.37 mmol) in DCE at 0° C. was added Al(CH3)2Cl (3.0 mL, 1.0M) drop wise, and the reaction was stirred for 20 minutes at room temperature. Ethyl 4-{4-[(dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-1-benzofuran-6-carboxylate (100 mg, 0.24 mmol) was then added and the reaction was stirred at room temperature for an additional 14 hours. The sample was diluted with CH2Cl2 and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl3 (5/95-10/90) to provide the product (110 mg, 93% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.49 (s, 3 H) 2.84 (d, J=1.51 Hz, 6 H) 3.91 (s, 3 H) 6.26 (s, 1 H) 6.64 (dd, J=5.75, 2.35 Hz, 1 H) 6.71-6.91 (m, 2 H) 7.52 (s, 1 H) 7.81 (t, J=8.29 Hz, 1 H) 7.91 (s, 1 H) 8.01 (s, 1 H) 8.09 (d, J=5.84 Hz, 1 H) 8.59 (s, 1 H); MS (ESI, pos): 500.
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([CH3:28])=[C:23]([C:25](O)=[O:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([N:4]([CH:32]2[CH2:33][CH2:34]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([CH3:28])=[C:23]([C:25]([N:36]([CH3:37])[CH3:35])=[O:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)O)c(C)s3)nc21
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)N(C)C)c(C)s3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylic acid (43A, 30 mg, 0.063 mmol), dimethylamine, 40% aqueous (0.016 mL, 0.125 mmol) and HATU (35.7 mg, 0.094 mmol) in DMF (1 mL) was stirred at room temperature for 3 h. The solvent was evaporated off and the residue purified by silica gel chromatography (2-10% MeOH/dichloromethane). The material was further purified by preparative HPLC to give of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N,5-trimethylthiazole-4-carboxamide (20 mg, 62.5% yield) as off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:16][CH2:17]1)=[O:29])[C:7]([N:44]1[CH2:43][CH2:42][N:41]([CH:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[CH2:46][CH2:45]1)=[O:8]
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Reactant: CN1CCC(N2CCNCC2)CC1
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-(1-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH2:30][OH:31])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:21][C:22]2[N:26]([CH:27]([CH3:28])[CH3:29])[N:25]=[C:24]([CH2:30][OH:31])[CH:23]=2)=[N:3][CH:4]=1
Reactant: CC(C)n1nc(CO)cc1N
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cc(CO)nn2C(C)C)ncc1Cl
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (188 mg, 0.602 mmol), [5-amino-1-(1-methylethyl)-1H-pyrazol-3-yl]methanol (140 mg, 0.90 mmol), cesium carbonate (589 mg, 1.81 mmol) and DMF (5 ml). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (6.8 mg, 0.03 mmol) and BINAP (37.5 mg, 0.06 mmol) were added. The reaction mixture was heated in an oil bath at 90° C. for 5 hrs and then in a microwave at 150° C. for 40 min. It was evaporated and the residue was dissolved in MeOH, filtered thru celite and thru an Acrodisc and purified further using preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. EtOAc was added to the brown oil residue. Then the mixture was heated and hexane was added dropwise. A light yellow precipitate crashed out upon sonication. It was filtered off and dried under vacuum at 40° C. for 12 hrs. LC-MS [M+H]+=431.2. 1H NMR (400 MHz, DMSO-d6) ppm 11.93 (br. s., 1 H) 9.54 (br. s., 1 H) 8.54 (s, 1 H) 7.96-8.01 (m, 1 H) 7.52-7.62 (m, 3 H) 7.11-7.16 (m, 1 H) 6.70 (s, 1 H) 6.10 (s, 1 H) 4.95 (t, J=5.81 Hz, 1 H) 4.43 (dt, J=13.14, 6.57 Hz, 1 H) 4.33 (d, J=5.56 Hz, 2 H) 3.71 (s, 3 H) 1.29 (d, J=6.57 Hz, 6 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][C:15]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCOCC1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C1CCOCC1C(=O)Cc1ccccc1
Yield: 49.4 %

Procedure:
3-(2-Phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.538 g, 49.4%) was synthesised from tetrahydro-4H-pyran-4-one (0.923 mL, 9.99 mmol) and phenylacetyl chloride (0.660 mL, 4.99 mmol) by the general procedure for the preparation of ketones.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])C.[CH2:36]([NH2:38])[CH3:37]>CO>[CH2:36]([NH:38][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:18])[CH3:19])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])[CH3:37]
Reactant: CCOC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 120 °C

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester was dissolved in excess 2M ethylamine in methanol and heated in the Smith Synthesiser microwave at 120° C. for 600 seconds. The solution was concentrated in vacuo to give a solid which was purified by hexane trituration, to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)isoxazole-3-carboxylic acid ethylamide.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH2:21][CH3:22])[C:14]1=[O:23])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([N:17]1[C:18](=[O:19])[N:13]([C:9]([CH3:11])([CH3:12])[CH3:10])[C:14](=[O:23])[N:15]([CH2:21][CH3:22])[C:16]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)[nH]c(=O)n(C(C)(C)C)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCn1c(=O)n(Cc2ccccc2)c(=O)n(C(C)(C)C)c1=O
Yield: 62.3 %

Procedure:
7.7 g (45 mmol) of benzyl bromide are added dropwise at room temperature to a solution of 10 g (46.9 mmol) of 1-tert.-butyl-3-ethyl-1,3,5-triazine-2,4,6-trione and 9.9 g (93 mmol) of sodium carbonate. The reaction mixture is refluxed for 6 hours. After it has cooled, the solid constituents are separated off, and the reaction solution is concentrated. The residue is taken up in methylene chloride and washed twice with water. After the organic phase has been dried over sodium sulphate, it is concentrated and distilled in vacuo. 8.5 g (60% of theory) of 5-benzyl-1-tert.-butyl-3-ethyl-1,3,5-triazine-2,4,6-trione are obtained as a highly viscous oil having a boiling point of 170° C./0.03 mbar.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]3)=[N:23]2)=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([CH2:36][NH:37][CH2:12][C:10]4[CH:9]=[CH:8][C:5]5[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=5[N:11]=4)[CH2:34][CH2:35]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(OCCCN3CCC(CN)CC3)nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc(OCCCN3CCC(CNCc4ccc5c(n4)NC(=O)CO5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.5 %

Procedure:
3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (22 mg, 0.12 mmol 1.0 eq) is added at room temperature to a stirred solution of C-{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-methylamine (40 mg, 0.12 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) and methanol (0.5 mL), followed by acetic acid (9 μL, 0.15 mmol, 1.3 eq) and sodium cyanoborohydride (11 mg, 0.15 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×5 mL) and a saturated sodium hydrogen carbonate aqueous solution (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one as a white viscous oil (18 mg, 29% yield).
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3CC3C=CC(OC)=CC=3OC)=[C:7]([CH3:30])[C:6]=2[F:31])[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:31][C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[N:14][C:5]=1[NH:1][CH2:2][CH2:3][CH2:4][O:36][C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[NH:12][CH:11]=[C:10]([C:26]([OH:28])=[O:27])[C:9]2=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CCC4)nc32)c(OC)c1
Product: Cc1c(F)c(NCCCOC(=O)C(F)(F)F)nc2[nH]cc(C(=O)O)c(=O)c12

Procedure:
A solution of Example 62A (0.55 mmol) in trifluoroacetic acid (15 mL) was heated to 80° C. for 16 hours and concentrated. The concentrate was dissolved in dichloromethane, washed with water, and filtered; and the filtrate was concentrated to provide the desired product and a small amount of 6-fluoro-5-methyl-4-oxo-7-(azetidin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 7-azetidin-1-yl compound. NMR (300 MHz, DMSO-d6) δ 8.4 (s, 1H), 8.15 (m, 1H), 4.5 (m, 2H), 3.55 (m, 2H), 2.7 (m, 3H), 2.1 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:9])([CH3:12])([CH3:16])[CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Oc1ccccc1)N1C=CC(Cl)=CC1C1CCCC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C=CC(Cl)=CC1C1CCCC1
Temperature: -42 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-cyclopentyl-1,2-dihydropyridine (5.52 g, 17.3 mmol) in 200 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (50 mL, 50 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 3.71 g (75.7%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ6.89-6.67 (dd, 1 H), 5.58 (br s, 1 H), 5.27-5.23 (m, 1 H), 4.92-4.62 (m, 1 H), 2.21 (m, 1 H), 1.892-1.25 (m, 17 H).