Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH:16]([B-](F)(F)F)=[CH2:17].[K+].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([CH:16]=[CH2:17])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C=C[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2,6-dichloroisonicotinate (11.0 g, 44.3 mmol) in THF (200 mL) were added potassium vinyltrifluoroborate (7.1 g, 53.2 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.97 g, 1.33 mmol) and triethylamine (9.3 mL, 66.5 mmol). The mixture was heated to 65° C. After 1 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→90% hexanes/ethyl acetate) gave no separation of desired product. The mixture was carried onto next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.ClC1N=C(Cl)N=C(Cl)N=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: COc1c(Br)ccc(F)c1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: COc1c(Br)ccc(F)c1C#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromo-6-fluoro-2-methoxybenzamide (14 g, 61 mmol) in 100 mL of DMF was added 2,4,6-trichloro-[1,3,5]triazine (12.3 g, 67.0 mmol) portionwise at 0° C. and stirred for 2 hours before poured to ice/water. The white solid was collected by filtration and was washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 3-bromo-6-fluoro-2-methoxybenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.71˜7.74 (m, 1H), 6.84˜6.88 (m, 1H), 4.09 (s, 3H);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.ClCCl.[Br:17]N1C(=O)CCC1=O>CCCCCC>[Br:17][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)ncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
4-(4-Methylpyrimidin-2-yl)morpholine (300 mg) was mixed with dichloromethane (4 ml), and N-bromosuccinimide (357 mg) was added thereto at 0° C., followed by stirring at room temperature for 1 hour. Hexane was added to the reaction mixture, followed by purification by silica gel column chromatography (EtOAc/hexane), to obtain 4-(5-bromo-4-methylpyrimidin-2-yl) morpholine (372 mg).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:17].O>S1(CCCC1)(=O)=O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[NH2:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc2c(Cl)nccc2n1
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)(C)c1ccc2c(N)nccc2n1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
A mixture of 22.1 g (100 mmol) of 2-tert-butyl-5-chloro-1,6-naphthyridine (S36), 32.1 g (600 mmol) of ammonium chloride in 100 ml of sulfolane is stirred at 200° C. for 20 h. 300 ml of water are added to the cooled mixture, which is then stirred at room temperature for 2 h. The solid is filtered off with suction, washed twice with 50 ml of water each time and subsequently suspended in a mixture of 50 ml of methanol and 150 ml of conc. ammonia solution. The suspension is stirred at room temperature for 20 h. The solid is filtered off, washed three times with 50 ml of water each time, dried in vacuo and subjected to sublimation (p about 1×10−2 mbar, T=150° C.). Yield: 16.7 g (83 mmol), 83%. Purity: >97% according to 1H-NMR.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:24])[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:25]>>[ClH:25].[O:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[O:24])=[CH:12][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Product: O=C(c1ccc(Oc2ccccc2)cc1)C1CCNCC1

Procedure:
A sample of 48.8 g of 1-acetyl-4-(4-phenoxybenzoyl)piperidine is refluxed for 6 hours in 6N HCl. Upon cooling a white solid precipitates from solution, is collected, washed with water, then acetone, and dried. The filtrate is extracted with ether, the aqueous phase is basified with sodium hydroxide and extracted with benzene. The benzene is dried, and the solvent is removed under reduced pressure to give a solid which is converted to a hydrochloride. The salt is recrystallized from an ethanol-ether mixture to give a white solid, mp 219°-220° C., 4-(4-phenoxybenzoyl)piperidine hydrochloride.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:23]=2[N:24]=1)([OH:19])[CH2:17]Cl.C(OCC)(=O)C>CN(C)C=O.O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:23]=2[N:24]=1)([OH:19])[CH2:17][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Temperature: 60 °C
Yield: 71.8 %

Procedure:
Sodium hydride (440 mg) was suspended in dimethylformamide (10 ml), and 1,2,4-triazole (948 mg) was added to the suspension, to which a solution of 1-(2,4-difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-chloroethanol (1.49 g) in dimethylformamide (10 ml) was added. The mixture was heated at 60° C. for 4 hours. After the liquid reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto. An organic layer separated was washed three times with water and then dried over magnesium sulfate, and the solvent was distilled out. The residue was recrystallized from dichloromethanediisopropyl ether to obtain the intended compound (1.17 g). Melting point: 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 15 (1.25 g, 1.94 mmol) in dry methanol (100 mL) was added sodium methoxide powder until the pH reached 10. The solution was stirred overnight and then neutralized with Dowex H+ resin and filtered. After evaporation of the filtrate, the residue was washed with ether to remove methyl benzoate and the crude material was crystallized from water: yield 520 mg, 81%: mp 220° C. dec.: UV λmax 1H NMR (DMSO-d6) δ6.48 (d, J=3.00 Hz, 1H, C1, H), 6.99 (s, 2H, NH2), 11.47 (s, 1H, NH), and other sugar protons. Anal. Calcd. for C10H12N4O5S2.H2O: C, z34.28: H, 4.03: N, 15.99: S, 18.30. Found: C, 33.99: H, 3.92: N, 15.68: S, 18.22.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1>C(O)(=O)C.CO.[Fe]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(Cl)c(N)c(Cl)n1
Temperature: 65 °C

Procedure:
Add iron powder (6.0 g) to a solution of 4,6 dichloro-2-methyl-5-nitro-pyrimidine (6.50 g, 31 mmol) in acetic acid (11 mL) and MeOH (50 mL). Heat the resulting mixture at 65° C. for 1 h. After cooling, to ambient temperature, filter the mixture through a pad of celite, and evaporate the filtrate to dryness under reduced pressure. Treat the residue with 1N aq NaOH, and extract with EtOAc. Wash the EtOAc extract with water and saturated aq NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain the title compound as a solid.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:16][CH2:15][C:12]2[N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[O:14][N:13]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCc1noc(-c2cc3cnccc3o2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNCc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 72 h

Procedure:
A solution of C-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)methylamine (Preparation 14, 50 mg, 0.23 mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (59 mg, 0.27 mmol) in anhydrous CH2Cl2 (5 mL) was stirred for 45 min. Na(AcO)3BH (78 mg, 0.37 mmol) was added, then the mixture was stirred for 3 d. Standard aqueous work-up, followed by column chromatography (EtOAc), gave the title compound: RT=2.18 min; m/z (ES+)=414.1 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[N:8]=[C:7]([CH3:20])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O.[O:28]1CCO[CH2:30][CH2:29]1>>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]2[C:5]([OH:4])=[C:6]([C:29](=[O:28])[CH3:30])[C:7]([CH3:20])=[N:8]2)=[CH:15][CH:14]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: C1COCCO1
Reactant: CC(=O)Oc1cc(C)nn1-c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 66 %

Procedure:
5-Acetyloxy-1-(4-t-butylphenyl)-3-methyl-1H-pyrazole (4.21 g, 15.5 mmol) in 1,4-dioxane (150 mL) was stirred with potassium carbonate (2.14 g, 15.5 mmol) at 110° C. for 3.5 hours, and after addition of water (50 mL), the organic solvent was removed by distillation. Then, ethyl acetate, water and 6 M hydrochloric acid were added to adjust the aqueous layer to pH 2, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted with ethyl acetate twice, and the organic layer was combined with the extract, washed with saturated aqueous ammonium chloride three times and with saturated aqueous sodium chloride once and dried over anhydrous sodium sulfate and filtered. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1→3/1→1/1) to give 2.77 g of the desired product (66% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6]O.CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][Br:35]
Reactant: COC(CCCO)OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCCBr)OC

Procedure:
A solution of 0.1 moles of 4,4-dimethoxybutanol in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is allowed to react for 18 hours with 0.1 moles of carbon tetrabromide. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated to a crude product which is purified by distillation to yield 4,4-dimethoxybutylbromide. This bromide is then converted into the diethyl phosphonate using the procedure described in Example 2.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]2[C:44]3[C:43]4[CH2:42][CH2:41][NH:40][CH2:39][C:38]=4[S:37][C:36]=3[N:35]=[CH:34][N:33]=2)[CH:27]=[CH:28][C:29]=1[F:30]>ClCCl.CO.C(Cl)Cl>[Br:1][CH2:2][CH:3]=[CH:4][C:5]([N:40]1[CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]([NH:31][C:26]4[CH:27]=[CH:28][C:29]([F:30])=[C:24]([Cl:23])[CH:25]=4)[C:44]=3[C:43]=2[CH2:42][CH2:41]1)=[O:7]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Reactant: O=C(O)/C=C/CBr
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(C=CCBr)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reaction time: 1 h

Procedure:
To a solution of 4-Bromo crotonic acid (2.07 g, 0.012 mol) in dichloromethane (48 ml) at 0-5° C. was added isobutyl chloroformate (1.70 ml, 0.013 mol) followed by 4-methylmorpholine (1.40 ml, 0.013 mol) under nitrogen. This mixture was stirred at this temp. for one hour. The resulting suspension was added to a cooled solution of (3-Chloro-4-fluoro-phenyl)-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)-amine (4.0 g, 0.012 mol) in dichloromethane (200 ml) over a period of 10 min. This mixture was stirred at RT for 1.5 hours. TLC (10% MeOH/DCM) shows no starting material present. The mixture was used as such in further reaction. LCMS RT=3.55 min, [M+H]+=483.04.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Product: c1ccc(CN2CCC(Oc3ccncc3)CC2)cc1
Yield: 52 %

Procedure:
The title compound was prepared from 1-benzyl-4-hydroxypiperidine and 4-chloropyridine (979 mg, 8.62 mmol), using the same method as that described for preparation 25, as an oil in 52% yield. 1H NMR (CDCl3, 400 MHz) □: 1.81-1.96 (m, 2H), 1.98-2.18 (m, 2H), 2.30-2.48 (m, 2H), 2.70-2.83 (m, 2H), 3.52-3.70 (m, 2H), 4.40-4.50 (m, 1H), 6.72-6.80 (m, 2H), 7.22-7.39 (m, 5H), 8.40 (m, 2H); LRMS APCI m/z 269 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29]Br)=[CH:25][CH:24]=1>CN(C)C=O>[F:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][O:8][C:4]2[C:3]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: Fc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2N)cc1
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (5 g) in dimethylformamide (30 ml) at room temperature was added potassium carbonate (24.8 g) and 4-fluorophenoxyethylbromide (5.6 g), the mixture was stirred for 16 hrs. The reaction was partitioned between water (100 ml) and diethyl ether (100 ml). The aqueous layer was separated and extracted with further diethyl ether (4×100 ml). The organic fractions were combined, washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure azeotroping with xylene. The residue was purified by column chromatography on silica gel eluting with a solvent gradient, pentane:ethylacetate (7:3 to 0:1, by volume) to yield the title compound as a white solid (4.95 g).
Reaction SMILES: Cl[S:2][N:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[P:4](=[S:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[CH3:18][NH:19][C:20](=[O:32])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([CH3:31])[CH3:30].CN(C)C=O>C(OCC)C.O>[CH2:6]([O:5][P:4]([N:3]([S:2][CH2:18][NH:19][C:20](=[O:32])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([CH3:30])[CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:8][CH2:9][CH3:10])=[S:11])[CH3:7]
Reactant: CNC(=O)Oc1ccccc1OC(C)C
Reactant: CCOP(=S)(OCC)N(SCl)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=S)(OCC)N(SCNC(=O)Oc1ccccc1OC(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The O,O-diethyl N-(chlorothio)phenylphosphoramidothioate as a yellow oil obtained in Part A, above, is dissolved in a minimal amount of diethyl ether (about 5 ml) and the ether solution is added to a cooled (0° C.) solution consisting of 6.34 gm (0.030 mole) of 2-isopropoxyphenyl methylcarbamate and 20 ml dimethylformamide. This reaction mixture is stirred as it is permitted to warm to 25° C., and stirring is continued for four hours. The mixture is then diluted with 100 ml water and extracted with diethyl ether. The ether phase is recovered, washed with water, and dried over anhydrous sodium sulfate. The ether is removed by evaporation under reduced pressure. The oily residue thus obtained is chromatographed through a column of silica gel. Development is with methylene chloride. After removing the methylene chloride by evaporation under reduced pressure, there is obtained 1.02 gm. of the crude product as an amber oil which is crystallized from petroleum ether having a boiling range between 30° and 60° C. to give 2-isopropoxyphenyl [[(diethoxyphosphinothioyl)anilino]thio]methylcarbamate as colorless crystals having a melting point at 69° to 70.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[NH:11]1[CH2:10][CH:9]([O:8][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nccnc2Cl)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1nccnc1OC1CNC1
Reaction time: 72 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (see PREPARATION P20.2; 4.3 g, 15.05 mmol) and DCM (50 mL) was added 4M HCl in dioxane (3.76 mL, 15.05 mmol). After 72 hours, a precipitate coated the walls of the flask. The liquid was carefully decanted off and the rinsed with DCM (20 mL) and again carefully decanted off. The precipitate coated round bottomed flask was treated with DCM:saturated NaHCO3 (1:1, 150 mL). The aqueous layer was extracted with 10% MeOH in DCM (4×25 mL). The combined organic layers were concentrated in vacuo to give crude product. The aqueous layer still contained the majority of the product. The aqueous layer was concentrated in vacuo and the solids stirred with 10% MeOH in DCM (200 mL) for 2 hours, then filtered. The filtrate was concentrated in vacuo to give more crude product. The separate lots of crude product were combined to give crude 2-(azetidin-3-yloxy)-3-chloropyrazine (1.75 g, 62.6% yield), as a tan solid. The product was carried forward in the next step without further purification. MS (ESI) m/z 186.1 (MH+).
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[N:17]1([C:23]2[C:24]3[CH2:32][CH2:31][NH:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>COC(O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([N:30]1[CH2:31][CH2:32][C:24]3[C:23]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:28][CH:27]=[N:26][C:25]=3[CH2:29]1)[NH:11][C:10]2=[O:12]
Reactant: c1nc2c(c(N3CCOCC3)n1)CCNC2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(ncnc4N4CCOCC4)C3)[nH]c(=O)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (0.28 g, 1.18 mmol) and 4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 6a (0.26 g, 1.20 mmol) in methoxyethanol (10 mL) was heated to 100° C. with stirring for 18 h. After cooling to room temperature, the precipitated solid was separated by filtration, washed with methoxyethanol and dried to give 0.31 g of 6,7-dimethoxy-2-(4-morpholin-4-yl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-3H-quinazolin-4-one 201, mp. 287.7–290.4° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17])(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=2)=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Yield: 71 %

Procedure:
Add trifluoroacetic acid (2.0 mL, 26.0 mmol) to a stirred solution of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (0.5000 g, 1.297 mmol) in dichloromethane (8 mL). Stir the reaction at room temperature under nitrogen for 2.5 h. Load the reaction contents directly onto a 10 g prepacked SCX cartridge, flush with methanol (200 mL), and elute the product with 2 M ammonia in methanol (75 mL). Concentrate the eluant on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 1.5% concentrated ammonium hydroxide/15% ethanol/chloroform to yield 0.2626 g (71%) of 6-[4-(2-amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=286.1 (M+1); 1H NMR (DMSO-d6): 8.59 (d, 1H), 8.23 (dd, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 7.40-7.36 (m, 2H), 7.08-7.02 (m, 3H), 3.32 (br s, 2H), 2.64 (s, 2H), 1.22 (s, 6H).
Reaction SMILES: [C:1](OC)(=O)[C:2]1[C:3](=[CH:8][C:9](=[CH:14][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])[C:4](OC)=O.[C:19]([O:27][CH3:28])(=[O:26])[C:20]1C=CC=C[CH:21]=1>>[CH:1]1[C:2]2[C:3](=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)[CH:4]=[CH:21][C:20]=1[C:19]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(C(=O)OC)c1
Product: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1

Procedure:
The procedure in Example 1 was repeated to carry out esterification except that mixed solvent containing 10.0 g of trimethyl trimellitate and 2.0 g of methyl benzoate was fed into the reactor. The results of analysis for the reaction product indicated 91.2 mol % yield of-the objective dimethyl 2,6-naphthalene-dicarboxylate based on 2,6-naphthalene-dicarboxylic acid; 96.0% efficiency of equilibrium achievement; and at most 1.0 mol % by-produced dimethyl ether based on methanol that was fed into the reaction system.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1.[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([CH:38]4[CH2:40][CH2:39]4)(=[O:43])=[O:42])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CCc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CCc4ccccc43)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 89.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.08 mmol) obtained in step 2 and cyclopropanesulfonamide (0.049 g, 0.40 mmol), the title compound (0.043 g, 88%) was obtained.