Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
To a solution of the compound from Step F (457 mg, 1.63 mmol) in anhydrous pyridine (3.5 mL) was added tert-butyldimethylsilyl chloride (370 mg, 2.45 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted with ethyl acetate (40 mL) which was washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to an oil that was subjected to chromatography on silica gel eluting with 10% MeOH in CH2C2. The appropriate fractions were collected, evaporated, and dried under high vacuum to furnish the title compound as a colorless foam (516 mg).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].O>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-2-phenylethyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (2.33 g, 6.54 mmol, prepared in Synthetic Example 5) in DMF (50 ml) was added hydrazine monohydrate (80%, 970 μl, 24.21 mmol, 3.7 eq.) and the mixture was then stirred at 100 to 110° C. for 4 hours, admixed with water to precipitate crystals, and allowed to stand until it was cooled. Next, the cooled mixture was filtered, washed with water, and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (1.90 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: Nc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.49 g, 2.35 mmol) in DMF (10 mL) is added triethylamine (0.65 mL, 4.7 mmol), followed by 1-hydroxy-7-benzotriazole (0.32 g, 2.35 mmol) and 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol). After stirring 15 min at RT, 3-Piperidin-4-yl-phenylamine hydrochloride (0.50 g, 2.35 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1-[4-(3-amino-phenyl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone as a crude mixture of good enough purity for the next step (0.86 g, quantitative). 1H-NMR (400 MHz, MeOD): δ=1.52-1.63 (m, 1H), 1.64-1.73 (m, 1H), 1.80-1.93 (m, 2H), 2.33 (s, 3H), 2.68-2.81 (m, 2H), 2.99 (s, 2H), 3.21-3.27 (m, 1H), 4.02-4.09 (m, 1H), 4.55-4.62 (m, 1H), 5.12-5.28 (q, 2H), 6.41 (s, 1H), 6.55-6.60 (m, 1H), 6.61-6.62 (m, 1H), 7.00-7.07 (t, 1H), 7.99 (s, 1H). MS: m/z=367 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19](B(O)O)=[CH:20][C:15]=2[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(O)C.O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[NH:4][N:3]=3)=[CH:20][C:15]=2[CH2:14][CH2:13]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1ncnc2[nH]nc(-c3ccc4c(c3)CCO4)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.70 g, 2.68 mmoles) in DMF (10 ml), ethanol (6 ml) and water (6 ml), 2,3-dihydrobenzofuran-5-boronic acid (0.527 g, 3.21 mmoles) and sodium carbonate (0.852 g, 8.04 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.610 g, 0.528 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.198 g, 29% yield 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.42(s,1H), 8.18(s,1H), 7.48(s,1H), 7.36(d, J=8.1Hz, 1H), 6.90(d, J=8.2Hz, 1H), 4.61(d, J=8.7Hz, 2H),3.27(d, J=8.7Hz, 2H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[ClH:16].S(=O)(O)O>O>[ClH:16].[NH:5]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[NH2:1]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(NN)c1
Reaction time: 0.08 h

Procedure:
A solution of 5.75 g of sodium nitrite in 30 ml of water was dropwise added to a solution of 11.7 g of methyl 3-aminobenzoate and 20 ml of concentrated hydrochloric acid in 200 ml of water, at about 0° C. with cooling with ice-methanol. The mixture was stirred at the same temperature for 5 minutes. The mixture was then added to 650 ml of a 6% aqueous sulfurous acid solution being ice-cooled. The resulting mixture was stirred at 50-60° C. for 2 days. The reaction mixture was allowed to cool and then extracted with ethyl acetate. The aqueous layer was made basic with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and an aqueous sodium chloride solution in this order, then dried with anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added ethanol. The mixture was made acidic with concentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added a slight amount of ethanol. The resulting insolubles were collected by filtration, washed with ethanol, and dried to obtain 3.1 g of methyl 3-hydrazinobenzoate hydrochloride as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.O1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19]CC1>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][C:20](=[O:19])[CH2:21][CH2:22]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCN(c2cncc(Cl)n2)CC1
Temperature: 10 °C
Yield: 70.9 %

Procedure:
A solution of 3.0 g (20 mmol) 2,6-dichloropyrazine, 2.0 g (20 mmol) triethylamine, and 2.9 g (20 mmol) 1,4-dioxa-8-azaspiro[4.5]decane in 60 ml acetonitrile is refluxed 17 hours. The solvent is removed in vacuo, and the residue is dissolved in ethylacetate. After washing with water and brine, the organic fraction is dried (MgSO4) and evaporated to an oil. The oil is dissolved in 30 ml acetone and mixed with 30 ml 1N HCl. After heating this solution on the steam bath 30 minutes, the acetone is evaporated, and the concentrate is cooled to 10° C. A solid separates which is filtered and dried to afford 3 g (71%) of the desired product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:8])[CH2:23][C:22]([O:28][CH2:29][CH3:30])=[O:27])=[CH:2]1
Reactant: O=C(O)c1ccoc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccoc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 184.4 %

Procedure:
To a solution of 3-furancarboxylic acid (25.5 g, 227 mmol) in tetrahydrofuran (200 ml) was added 1,1′-carbonylbis-1H-imidazole (40.5 g, 250 mmol) and the mixture was stirred at 60° C. for 2 hrs. To the reaction solution was added monoethyl malonate magnesium salt (35.8 g, 125 mmol) and the mixture was heated under reflux for 30 min. Ethyl acetate (50 ml) and water (50 ml) were added the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(3-furanyl)-3-oxopropionate (42 g, 100%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[H-].[Na+].B(OCC)(OCC)OCC.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1F)([O-:24])=[O:23]>CN(C)C=O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])([O-:24])=[O:23]
Reactant: Oc1cccc(O)c1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1cccc(O)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
18.9 g of pyrogallol, 380 ml of anhydrous dimethylformamide and 13.6 g of sodium hydride in suspension at 53% in oil were mixed together under an inert gas atmosphere and then stirred for 45 minutes at ambient temperature. 29 ml of triethyl borate were added, and the mixture was stirred for 30 minutes. Then, 17.6 ml of 2-nitro fluorobenzene were added over one hour at 0° C. followed by stirring for 20 hours at ambient temperature. The mixture was poured into a water-ice-N hydrochloric acid mixture and the precipitate was separated, washed with petroleum ether, taken up in ethyl ether and washed with N hydrochloric ac:id to obtain about 27 g of the expected product (Yield approx.: 76%) in the form of beige crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:23])=[CH:11][C:12]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2].N1C=CC=CC=1.[CH:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH:23][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH:33]([CH3:34])[CH3:35])=[CH:37][CH:38]=2)=[CH:11][C:12]([O:15][Si:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c(N)c1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-4-(dimethyl-t-butylsiloxy)-1,2-benzenediamine (2.63 g, 7.17 mmol) and CH2Cl2 (45 mL) at 0° C. was added pyridine (0.65 mL, 8.0 mmol) followed by a solution of the 4-isopropyl benzoyl chloride (10.1 mmol) in CH2Cl2 (90 mL). The reaction was allowed to warm to room temperature and stirred for 10 m. The reaction was diluted with CH2Cl2 (200 mL) and washed with sat. aq. NH4Cl (2×50 mL). The organic layer was MgSO4 dried filtered, and concentrated. The residue was chromatographed (10% EtOAc/hexanes to 20% EtOAc/hexanes) to give the title compound as a solid (3.04 g, 83%); IR(CHCl3): 2962, 1656, 1610, 1513, 1473, 1295 cm−1; NMR(300 MHz, CDCl3): δ0.16 (s, 6H), 0.95 (s, 9H), 1.29 (s, 3H), 1.31 (s, 3H), 3.00 (m, 1H), 6.68 (d, 1H, J=9.0), 6.86 (s, 1H), 7.38 (d, 2H, J=8.1), 7.50 (d, 1H, J=9.0), 7.61 (m, 1H), 7.81 (d, 1H, J=6.3), 7.89 (d, 2H, J=7.1), 8.16 (d, 1H, J=9.3), 8.29 (s, 1H), 8.58 (br s, 1H), 9.40 (br s, 1H); MS(FD): 513.1.
Reaction SMILES: [CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[NH:10][C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH2:34](I)[CH3:35]>>[CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[N:10]([CH2:34][CH3:35])[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Reactant: CCI
Solvent: CI
Product: CCOc1cc2c(cc1OCC)N(CC)C(=O)C(Cc1ccccc1)N=C2c1ccccc1
Yield: 36 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 3-benzyl-7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaj), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 36%. M: 128–130° C. 1H-NMR (CDCl3, 200 MHz): d 1.10 (t, 3H, CH3), 1.40 (t, 3H, CH3), 1.55 (t, 3H, CH3), 3.66 (m, 3H, CH2Ph+CH), 3.94 (q, 2H, —OCH2), 4.15 (AB system, ? d=0.52, JAB=13.2, 2H, —NCH2), 4.19 (q, 2H, —OCH2), 6.67 (s, 1H Ar), 6.85 (s, 1H Ar), 7.33–7.63 (m, 10H Ar).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@H:28]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:27][C@H:28]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29]3)=[O:22])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](N)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3S,4R)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[CH2:21][CH2:20][CH2:19]2.[CH2:27]=O>C(O)(C)C.C1(C)C=CC=CC=1>[ClH:1].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[CH:21]([CH2:27][N:11]1[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]1)[CH2:20][CH2:19]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(CN1CCC(c3ccccc3)CC1)C2=O

Procedure:
Concentrated hydrochloric acid (4.9 mL) was added to a solution of 4-phenylpiperidine (9.38 g, 58.2 mmol) in isopropanol (60 mL) at 10-15° C. followed by the sequential addition of 6-methoxy-1-tetralone (9.76 g, 55.4 mmol), 37% aqueous formaldehyde (5.72 g) and 60 mL isopropanol. The mixture was refluxed for 1 hour, diluted with toluene, concentrated and the residue recrystallized sequentially from acetone and ethanol to afford the title compound as a white solid (5 g), mp 177-8° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)[CH3:4].[NH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>C(#N)C>[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:12]2[C:13]([F:15])=[C:14]3[C:9]([C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][N:5]3[CH:3]([CH3:4])[CH2:2][Cl:1])=[CH:10][C:11]=2[F:17])[CH2:26]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(N3CCC(N)C3)c(F)cc2c1=O
Yield: 83.1 %

Procedure:
174 mg (0.5 mmol) of ethyl 1-(1-chloroprop-2-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was dissolved into 20 ml of acetonitrile. To this was added 215 mg (2.5 mmol) of 3-aminopyrrolidine and the mixture was reacted with heating under refluxing for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-20:1) to obtain 172 mg of light yellow crystals of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (Compound No. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37].CCOC(C)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[N:12]=2)[CH:7]=1
Reactant: CC(C)=CCBr
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CC=C(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a suspension of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (114.0 mg, 0.31 mmol) and cesium carbonate (201.4 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL), was added 4-bromo-2-methyl-2-butene (53 μL, 0.46 mmol). The reaction mixture was stirred for 3 hours at room temperature, then EtOAc was added. The organic layer was washed 1× each with water and saturated brine solution. The organic layer was separated, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (20-100% EtOAc:Hex) to afford N-(3-(5-chloro-2-methoxyphenyl)-1-(3-methylbut-2-enyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow foam (67 mg, 0.15 mmol). Acetone and water (1 mL each) were then added, followed by osmium tetraoxide (1.89 mg, 0.0074 mmol), and N-methylmorpholine-N-oxide in water (1:1, N-methylmorpholine-N-oxide:Water, 37 mg). The reaction mixture was stirred for 3 hours at room temperature. Celite was added and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (50-100% EtOAc*:Hex, *EtOAc also contained 10% MeOH), and then by chiral SFC to separate enantiomers to give 11.2 mg and 15.8 mg of the title compounds as white solids. LCMS (ESI) m+H=471.1; 1H NMR (500 MHz, DMSO) δ 9.69 (s, 1H), 9.34 (d, J=6.9, 1H), 8.78 (d, J=4.0, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 7.49 (dd, J=8.8, 2.6, 1H), 7.42 (d, J=2.6, 1H), 7.29 (dd, J=10.0, 4.6, 2H), 5.05 (d, J=6.3, 1H), 4.53 (s, 1H), 4.43 (d, J=13.5, 1H), 3.95 (dd, J=13.5, 10.1, 1H), 3.85 (s, 3H), 3.60 (s, 1H), 1.16 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([OH:17])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].Br[CH2:19][C:20]([NH2:22])=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:4]1[N:5]([O:17][CH2:19][C:20]([NH2:22])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: NC(=O)CBr
Reactant: CCCc1nc2cnc3ccccc3c2n1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1nc2cnc3ccccc3c2n1OCC(N)=O
Yield: 83.9 %

Procedure:
A solution of 2-propyl-1H-imidazo[4,5-c]quinolin-1-ol (2.0 g, 8.8 mmol), bromoacetamide (1.9 g, 14 mmol), and triethylamine (2.8 mL, 0.020 mol) in THF (100 mL) was heated at reflux overnight. The solvent was removed under reduced pressure, and dichloromethane (75 mL) and saturated aqueous sodium bicarbonate (25 mL) were added to the residue. The resulting mixture was filtered to provide 2.1 g of 2-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]acetamide as a solid. The organic layer was separated, and methanol was added until all solids were dissolved. The solution was then dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide an additional 0.13 g of material.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1.[CH3:14][C:15]1[N:16]=[CH:17][O:18][C:19]=1[CH:20]=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:14][C:15]1[N:16]=[CH:17][O:18][C:19]=1[CH:20]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[OH:21]
Reactant: Cc1cccc(Br)c1
Reactant: Cc1ncoc1C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2ocnc2C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (2.5 solution in hexanes, 3.9 ml) was added dropwise to a stirred solution of 3-bromotoluene (1.1 ml) in dry tetrahydrofuran (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 20 minutes, 4-methyl-5-oxazolecarbaldehyde (1.15 g) in tetrahydrofuran (10 ml) was added. After 1 hour the mixture was allowed to warm to room temperature and was then heated under reflux for 1 hour. The cooled solution was poured into saturated aqueous sodium hydrogen carbonate. Extraction with ethyl acetate and flash chromatography then gave the title compound. M.p. 76.5°-77.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)(=[O:8])=[O:7])=[O:4].[CH3:28][C:29]([CH3:45])([CH3:44])[C:30]([O:32][NH:33][C:34]([CH:36]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:37](O)=[O:38])=[O:35])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:24]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:37](=[O:38])[CH:36]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:34]([NH:33][O:32][C:30](=[O:31])[C:29]([CH3:44])([CH3:45])[CH3:28])=[O:35])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CN)cc1
Reactant: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)C(CC(C)C)C(=O)NOC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2-Aminoacetyl)-4-(2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide (770 mg, 1.2 mmol, 1.0 eq) and 2-(2,2-Dimethylpropionyloxycarbamoyl)-4-methylpentanoic acid (360 mg, 1.2 mmol, 1.0 eq) were dissolved in 13 mL DMF. HATU (460 mg, 1.2 mmol, 1.0 eq) was then added followed by DIPEA (630 μL, 3.6 mmol, 3.0 eq) and the mixture was stirred at room temperature. After 3 hours, the mixture was diluted with 30 mL EtOAc, washed with 20 mL 10% aq. LiCl solution, water, saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to yield crude intermediate 3a. MS m/z: [M+H+] calcd for C29H40ClN5O8S, 654.2. found 654.4.