Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=3[Cl:20])[CH2:33][CH2:32]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1Br)CCC(=O)N2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(Br)c(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of 4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.43 g, approx. 1.37 mmol, crude from previous reaction) in DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (367 mg, 1.37 mmol) followed by Et3N (0.38 mL, 2.75 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (407 mg, 1.92 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as a white foam (497 mg, 0.941 mmol, 69%). MS: APCI: M+1: 527.0, 529.0, 531.0 (Exact Mass: 526.05).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2.0 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester are stirred in 90 ml of acetonitrile. 498 mg of potassium iodide are added and the suspension is heated to 80° C. After 7 h 20 min, the following reactants are successively added: 394 μl of morpholine, 1.24 g of potassium carbonate, 150 mg of potassium iodide. The suspension is heated at 80° C. overnight. The insoluble material is filtered off and the filtrate is concentrated under vacuum. The reaction crude is taken up in 50 ml of dichloromethane. The organic phase is washed with 2 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate and filtered. The solvent is evaporated off in a rotary evaporator to obtain 1.90 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:7][CH:8]=3)=[CH:13][CH:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: ClCCCOc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(-c2ccc(OCCCN3CCCC3)cc2)ccc1OCCCN1CCCCC1
Yield: 33 %

Procedure:
Following the procedure described in example 36, but starting from 1-{3-[4′-(3-chloropropoxy)biphenyl-4-yloxy]propyl}piperidine (250 mg), pyrrolidine (138 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (2 mL) affords 90 mg of 1-(3-{[4′-(3-piperidinopropoxy)biphenyl-4-yl]oxy}propyl)pyrrolidine as white crystals melting at 105-108° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)(=O)C>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[N:1][C:2]2[N:3]([N:4]=[C:5]([SH:7])[N:6]=2)[C:11]=1[OH:10])=[O:14])[CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1n[nH]c(S)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2nc(S)nn2c1O
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of 15 g 3-amino-5-mercapto-s-triazole, 28 g diethyl ethoxymethylenemalonate and 70 ml acetic acid was refluxed for 18 hours. After removing the solvent by distillation, the remaining brown oil was allowed to cool to room temperature, and the pH was adjusted to 10 with sodium hydroxide solution. After washing with 100 ml ethyl acetate, the brown aqueous solution was neutralized to pH 7.5 with 6N hydrochloric acid, and again washed with 100 ml ethyl acetate. The pH of the aqueous layer was lowered to 3.0 with 6N hydrochloric acid, and the separated crude product (12 g) was collected by filtration and recrystallized from 30 ml methanol, giving 9 g of the objective compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][C:28]1([CH3:34])[O:32][C:31](=[O:33])[NH:30][CH2:29]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH2:29][C:28]([CH3:34])([CH3:27])[O:32][C:31]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)cc2F)CC1
Yield: 22.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (480 mg) described in Preparation Example 86 and 5,5-dimethyloxazolidin-2-one (196 mg) described in Preparation Example 43, the title compound (119 mg) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[CH:15]=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (28.8 ml, 0.4 mol) was added dropwise to methanol (450 ml) at −10° C. temperature. To the obtained solution was added 3-(4-nitrophenyl)-acrylic acid (1) (38.63 g, 0.2 mol) and the reaction mixture was stirred at 0° C. for 3 hours, at ambient temperature for 24 hours and at 40° C. for 1 hour. The resulting precipitate was filtered, washed with methanol (2×10 ml) and dried affording the title compound in a form of yellow crystals (39.55 g, 96%). 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (2H, br s); 3.77 (3H, s); 6.87 (1H, d, J=16.0 Hz); 7.67-8.39 (5H, m).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@@H:32]([CH2:34][O:35]C(=O)C3C=CC=CC=3)[C@@H:22]([O:23]C(=O)C3C=CC=CC=3)[C@H:12]2[O:13]C(=O)C2C=CC=CC=2)=[C:4]([NH2:44])[N:3]=1.[OH-].[K+].C(O)(=O)C>C(O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]2[OH:13])=[C:4]([NH2:44])[N:3]=1
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O
Reaction time: 5 h

Procedure:
A suspension of 1a (108 mg, 0.18 mmol) in ethanol (10 ml) at room temperature is treated in one portion with 0.50 M KOH (anhydrous powder) in ethanol (180 μl). The mixture is stirred 5 h, neutralized with glacial acetic acid (6 μl), and evaporated to dryness. The resulting residue is crystallized from 1:1 acetonitrile/water to afford pure (1b) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)[CH2:13][CH2:14][CH2:15]C.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCOC(=O)c1ccccc1N
Reaction time: 8 h
Yield: 95 %

Procedure:
450 parts of anthranilic acid methyl ester, 500 parts of n-pentanol and 10 parts of potassium carbonate are reacted as described in Example 1. The reaction lasts for about 8 hours. There are obtained 588 parts of anthranilic acid n-pentyl ester (boiling point 132°-135° C. under 0.3-0.4 mm Hg; nD25 1.538; purity according to gas chromatography 99%, below 0.2% of anthranilic acid methyl ester). Yield: 95% of the theory.
Reaction SMILES: [CH:1]([CH:4]([CH:10]([CH3:13])[C:11]#[CH:12])[C:5]([O:7]CC)=[O:6])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C>O>[CH:1]([CH:4]([CH:10]([CH3:13])[C:11]#[CH:12])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: C#CC(C)C(C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CC(C)C(C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
A 250 milliliter flask was equipped with a magnetic stirrer, reflux condenser and nitrogen inlet. Into the flask was added 8.44 grams (0.05 mol) of ethyl 2-isopropyl-3-methyl-4-pentynoate prepared in Part B, 5.56 grams (0.14 mol) of sodium hydroxide, 20 milliliters of ethanol and 20 milliliters of water. Following three days of continuous refluxing and stirring under nitrogen, the reaction mixture was cooled to room temperature, diluted with three times its volume of water and extracted twice with ether. Ice was added to the aqueous phase and it was acidified with 3 N HCl, then extracted three times with ether. The ether was washed twice with water, dried (MgSO4) and removed under vacuum to give 5.87 grams (0.04 mol) of 2-isopropyl-3-methyl-4-pentynoic acid having the appearance of a light yellow oil.
Reaction SMILES: [CH:1]1([C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>C(#N)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9](=[O:11])[CH2:8][C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CC(=O)O)C1CCCCC1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)[C@H](CC(=O)Nc1ccc(Cl)cc1)C1CCCCC1
Yield: 94.5 %

Procedure:
To a suspension of (3R)-3-cyclohexyl-4-methoxy-4-oxobutanoic acid (0.21 g), 4-chloroaniline (0.13 g) and HOBt (0.23 g) in acetonitrile (10 ml) were added WSC (0.29 g) and N-methylmorpholine (0.10 g), and mixed at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed sequentially with an aqueous sodium hydrogen carbonate solution, water, a 5% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale brown solid (0.30 g, 93%).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[C:8]=1[CH:9]=O)(OCC)=[O:2].C([O-])(=O)C.[NH4+:22].[Cl-].[NH4+]>C(O)(=O)C.O>[CH2:16]1[O:15][C:12]2[C:11](=[C:8]3[C:7](=[CH:14][CH:13]=2)[NH:6][C:1](=[O:2])[N:22]=[CH:9]3)[O:17]1
Reactant: CCOC(=O)Nc1ccc2c(c1C=O)OCO2
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ncc2c3c(ccc2[nH]1)OCO3
Temperature: 90 °C
Reaction time: 15 h
Yield: 6.2 %

Procedure:
2-Carboethoxyamino-5,6-methylenedioxybenzaldehyde (5.0 g, 21.1 mmoles) was added to a suspension of ammonium acetate (1.63 g, 21.1 mmoles) and ammonium chloride (1.13 g, 21.1 mmoles) in 50 ml of acetic acid. The temperature was slowly raised to 90° C. and held there for 15 hours. The mixture was diluted with one volume of water and then extracted with ethyl acetate, after adjusting the pH to 9 with concentrated ammonium hydroxide. The ethyl acetate layers were evaporated to dryness and the residue was recrystallized first from 10% NH4OH then from methanol to give 250 mg of 5,6-methylenedioxy-2(1H)-quinazolinone (6%), mp >300° C., M+ 190. PG,10
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([C:14]([O:16]CC)=O)=[C:10]([OH:13])[C:11](=[O:12])[N:6]2[CH2:5][C:4](=[O:19])[N:3]1[CH3:20].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:9]2[N:8]=[C:7]3[N:6]([C:11](=[O:12])[C:10]=2[OH:13])[CH2:5][C:4](=[O:19])[N:3]([CH3:20])[N:2]3[CH3:1])=[O:16])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Reactant: NCc1ccc(F)cc1
Product: CN1C(=O)Cn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)N1C
Yield: 79.7 %

Procedure:
Reaction of intermediate 22, ethyl 1,2-dimethyl-7-hydroxy-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.050 g, 0.177 mmol) with 4-fluorobenzylamine (0.11 g, 0.87 mmol) as described in the preparation of example 1 gave 0.051 g (80% yield) of the title amide as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.27 (3H, s, NCH3), 3.30 (3H, s, NCH3), 4.61 (2H, d, J=6.3 Hz, NCH2), 4.67 (2H, s, CH2), 7.08 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.74 (1H, broad t, NH), 12.0 (1H, s, OH). MS (ESI+) m/z 362 [M+H+].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=1)(=O)=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([S:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:8][C:9]=1[CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24]
Reactant: COc1ccc(F)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC(C)(C)C)c1
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)cc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl trifluoromethanesulfonate (1.88 g) in toluene (22 mL) were added 4-methoxy-α-toluenethiol (748 μL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78 mg), N-ethyldiisopropylamine (1.56 mL) and tris(dibenzylideneacetone)dipalladium(0) (123 mg) at room temperature, and the mixture was stirred at 120° C. for 20 hr. The mixture was poured into ice water at room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.68 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N:22]=[C:23]=[O:24].CCOCC>C1COCC1>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:23]([NH:22][C:13]2[CH:14]=[C:15]([C:18]([F:19])([F:21])[F:20])[CH:16]=[CH:17][C:12]=2[F:11])=[O:24])=[C:4]([F:10])[CH:3]=1
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)cc1Br

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylaniline (500 mg, 2.45 mmoL) in THF (3 mL) was added the 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (625 mg, 3.0 mmol). The reaction generated a white solid within 10 min. An additional portion of THF (3 mL) was added and the mixture dissolved. TLC analysis (1:1 Et2O:Hex) indicated that the reaction was complete. The product was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O). 1H-NMR (DMSO-d6) δ 9.37 (d, J=2.8 Hz, 1H), 9.17 (d, J=2.4 Hz, 1H), 8.61 (dd, J=7.2, 2 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.49 (dd, J=10.8, 8.8 Hz, 2H), 7.39 (m, 1H), 2.29 (s, 3H); MS [M+H]+=409.3, LCMS RT=3.91 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[S:14])[NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[S:14][CH:19]=[C:17]([CH2:16][Cl:15])[N:13]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=S)C1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nc(CCl)cs2)C1

Procedure:
To a solution of 3-Thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl ester (0.800 g, 3.7 mmol) in acetone (15 mL) was added 1,3-dichloroacetone (0.611 g, 4.81 mmol), MgSO4 (0.67 g, 5.6 mmol) and MgCO3 (3.12 g, 3.7 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (20 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product which was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31].O>CN(C)C=O>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:15]1[C:6]2[C:5]3[N:4]=[C:3]([S:2][CH3:1])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14]1
Reactant: CN(C)CCBr
Reactant: CCOC(=O)c1n[nH]c2c1ccc1cnc(SC)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(CCN(C)C)c2c1ccc1cnc(SC)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (150 mg, 0.52 mmol) in dry dimethylformamide (4 ml) was added cesium carbonate (339 mg 1.04 mmol) followed by 2-bromo-N,N-dimethylethanamine (135 mg 0.88 mmol). The heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with water and extracted with EtOAc. The organic layer washed with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography eluting with EtOAc/Ethanol 85/15 to give ethyl 1-[2-(dimethylamino)ethyl]-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate as the major isomer (60 mg 32%) 1H NMR (401 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.16 (d, J=8.67 Hz, 1H), 7.83 (d, J=8.79 Hz, 1H), 5.29 (t, J=6.59 Hz, 1H), 4.32-4.49 (m, 2H), 2.94 (br. s., 2H), 2.71 (s, 3H), 2.24 (br. s., 6H), 1.41 (t, J=7.08 Hz, 3H); and
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH2:31]>CN(C)C=O>[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH:31][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: COC(=O)CN
Reactant: O=C(O)CN1CCCC1=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)CN1CCCC1=O
Temperature: -8 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
55 g of (2-oxo-1-pyrrolidinyl)acetic acid was dissolved in 1 l of dimethylformamide and 39.3 g of triethylamine was added thereto. After the solution was cooled to -8° C., 55.1 g of isobutyl chloroformate was added at -8° to -1° C. Then the reaction liquid was stirred at 0° to -7° C. for 10 minutes, 50.7 g of glycine methyl ester hydrochloride was added at -7° to -4° C. and stirred at -4° to -8° C. for 6 minutes. Next, 40.8 g of triethylamine was added at -8° to -3° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours and triethylamine hydrochloride was filtered off. Dimethylformamide was distilled off under reduced pressure and the residue was purified through the chromatography on silica gel (silica gel 1200 g, chloroform-1 to 3% of methanol as the eluent) to obtain 70.5 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]glycine methyl ester as the oily substance. This was dissolved in 120 ml of methanol and 21.7 g of potassium hydroxide dissolved in 150 ml of methanol was added thereto. After reacting at room temperature for 5 hours, 40 g of acetic acid was added. The solvent was distilled off under reduced pressure and the residue was purified through the chromatography on silica gel (silica gel 1 kg, chloroform-5 to 20% of methanol-1% of formic acid as the eluent) and crystallized from tetrahydrofuran to obtain the titled compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH2:27][CH2:26]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@H](N)CC2)c2ccccc2c1=O
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (200 mg, 0.60 mmol), trans-4-aminocyclohexan-1-ol (278 mg, 2.42 mmol) and Cs2CO3 (591 mg, 1.81 mmol) in DMSO (4 mL) was stirred at 120° C. for 12 hrs. Water (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound (103.15 mg, 36.9%) as its hydrochloride salt. 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, J=8.0 Hz, 1H), 8.10 (s, 3H), 7.95 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.51-7.49 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 4.50-4.44 (m, 1H), 3.56 (s, 3H), 3.22 (s, 3H), 2.95-2.85 (m, 1H), 2.00-1.94 (m, 2H), 1.84 (d, J=11.2 Hz, 2H), 1.47-1.41 (m, 2H), 1.20-1.12 (m, 2H). LCMS (M+H)+=427.1 (M+H)+