Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COP([CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)(=O)OC.[H-].[Na+].[N:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1>[N+:21]([C:17]1[CH:16]=[C:15]([C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:32][C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=Cc1ccncc1
Reactant: COP(=O)(OC)C(OC1CCCCO1)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C(=Cc2ccncc2)OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110 %

Procedure:
[(3-Nitro-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-phosphonic acid dimethyl ester (40.7 g, 0.105 mol) was dissolved in dry THF (1 L) under nitrogen. Sodium hydride (60% suspension in mineral oil)(6.3 g, 0.158 mol, 1.5 eq) was added and the mixture was stirred for 10 minutes at room temperature. Neat 4-picolinaldehyde (10 mL, 0.105 mol, 1 eq) was then added dropwise and the mixture was heated to 60° C. and stirred at this temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure to ⅓ of the original volume and then diluted with water (500 mL). pH was adjusted to 7-8 by adding a saturated solution of NaHCO3 and the mixture was extracted with ethyl acetate (4×300 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. An oil (37.7 g) was obtained, which was used without further purification in the following step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COCCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Agent: Cl
Solvent: CO
Product: COCCCN1CCCc2ccc(CO[C@H]3CNCC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine as a yellow oil; MS: 589 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][C:30]=3[F:38])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.C(O)C>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[C:30]([F:38])[CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])cc3F)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A suspension of 5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (420 mg, 0.77 mmol) and tin(II) chloride dihydrate (519 mg, 2.31 mmol) in ethyl acetate (15 mL) and ethanol (15 mL) was heated at 80° C. for 2 hours. The solution was cooled to room temperature and concentrated, diluted with ethyl acetate (50 mL) and washed with sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol, 91% yield) as a yellow solid. LCMS (m/z, ES+)=512 (M+H+).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH2:35][CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:38]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>CC#N>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:38])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH2:35][CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Solvent: CC#N
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile (compound 215) and using compound 11.2 HCl salt in place of compound 1.5. m/z (ES+) 502 [M+H]+, 543 [M+CH3CN+H]+. 1H-NMR (300 MHz, CD3OD): δ 7.73 (d, 2H), 7.64-7.58 (m, 2H), 7.39-7.26 (m, 2H), 4.89-4.82 (m, 1H), 4.35 (q, 2H), 4.10-3.95 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.27 (m, 1H), 2.75-2.65 (m, 2H), 2.22-1.86 (m, 10H), 1.41 (t, 3H), 1.35-1.20 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20](OS(C(F)(F)F)(=O)=O)=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([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)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:21][C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(-c4ccccc4)cc3O2)cc1
Temperature: 90 °C
Yield: 10.1 %

Procedure:
To a solution of (±)-(6-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.67 g, 27.2 mmol) in anhydrous dichloromethane (300 mL) at 0° C. was added diisopropylethylamine (4.22 g, 32.6 mmol) followed by trifluoromethanesulfonic anhydride (8.45 g, 29.9 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched with water (300 mL) and diluted with dichloromethane (400 mL), The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4→2:3) afforded 10.3 g (84%) of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan solid. To a solution of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.43 mmol) in dioxane (50 mL) was added phenylboronic acid (1.08 g, 8.86 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.884 mmol), and lithium chloride (0.787 g, 17.43 mmol) and the reaction mixture was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and washed with water (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.170 g (10%) of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as an oil. 1H NMR (DMSO d6) δH 7.75 (d, 2H); 7.56 (d, 2H); 7.42 (m, 4H); 7.28 (t, 1H); 7.21 (d, 1H); 7.08 (d, 1H); 6.92 (s, 1H); 4.98 (m, 1H); 4.24 (dd, 1H); 4.18 (q, 1H); 3.29 (dd, 1H); 2.88 (dd, 1H); 2.46 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]3)[CH:21]=2)[CH:16]=1)[CH2:9][CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:36].[Cl-].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:36][C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][C@H:26]3[CH2:27][CH2:28][C@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]3)[CH:21]=2)[CH:16]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCC(N)=O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
The mixture of 3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoic acid (483 mg, 1.0 mmol), NH4Cl (215 mg, 5.0 mmol, 5.0 equiv), Et3N (510 mg, 5.0 mmol, 5.0 equiv) and HATU (760 mg, 2.0 mmol, 2.0 equiv) in anhydrous THF (20 mL) was stirred at 45° C. for 15 min. The reaction mixture was concentrated in vacuum and the residue was purified by chromatography with silica gel (DCM/MeOH=20/1) to give compound the title compound as a white solid (337 mg, yield: 70%). ESI-MS (M+H+): 483.3. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (d, 2H), 7.60 (s, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 7.12 (dd, 1H) 4.49 (s, 2H), 4.38-4.31 (m, 1H), 3.30 (t, 2H), 2.30 (t, 2H), 2.19 (d, 2H), 1.81 (d, 2H), 1.45-1.33 (m, 11H), 1.23-1.16 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][C:15]1[S:16][C:17]2[C:26]3[C:25](=O)[CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:14][C:15]1[S:16][C:17]2[C:26]3[C:25](=[CH:3][C:1]#[N:2])[CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1nc2ccc3c(c2s1)C(=O)CC3
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2s1)C(=CC#N)CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a suspension of diethyl cyanomethylphosphonate (393 mg, 2.22 mmol) in tetrahydrofuran (6 mL) was added 65% sodium hydride (66.0 mg, 1.79 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Thereto was added a solution of 2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-one (300 mg, 1.48 mmol) in tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 2 hr. To the mixture were added diethyl cyanomethylphosphonate (131 mg, 0.74 mmol) and 65% sodium hydride (16.0 mg, 0.43 mmol), and the mixture was further stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was 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 (ethyl acetate) to give the title compound (181 mg, yield 54%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:5][C:6]=1C(O)=O>Cl>[Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[NH:5][CH:6]=1
Reactant: COc1ccc(-c2nc(Br)c(C(=O)O)[nH]2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(Br)c[nH]2)cc1
Yield: 78.6 %

Procedure:
A suspension of 9 (2.6 g, 0.0088 mol) in 8N HCl (100 ml) was heated at reflux for 20 hours. The solution was then cooled and filtered to yield 1.75 g (70%) of 10.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][CH2:7][O:6]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:2]([CH2:3][CH2:4][CH:5]1[O:6][CH2:7][CH2:8][CH2:9][O:10]1)=[O:1]
Reactant: OC(CCC1OCCCO1)c1ccc(Cl)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC1OCCCO1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.4 %

Procedure:
A mixture of 2-[3-hydroxy-3-(2,4-dichlorophenyl)prop-1-yl]-1,3-dioxane (2.91 g) and pyridinium dichromate (6.96 g) in dry dimethylformamide (DMF: 20 ml) was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (100 ml) and extracted with diethyl ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated under reduced pressure to give 2-[2-(2,4-dichlorobenzoyl)ethyl]-1,3-dioxane (2.7 g, 93%) as an orange oil, IR (film): 1700 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[Si:9]([O:8][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][CH:5]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cccc(I)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1cccc(I)c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3-iodophenol (3.36 g, 15.3 mmol), tert-butyldiphenylsilylchloride (4.17 mL, 16.0 mmol), and imidazole (1.48 g, 21.7 mmol) in DMF (30 mL) was heated to 60° C. for 72 hours. The solvent was removed in vacuo and the residue partitioned between saturated sodium bicarbonate (50 mL) and methylene chloride (50 mL). The layers were separated and the aqueous layer washed with methylene chloride (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (0→20% ethyl acetate/hexane) to provide the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc(CCC(=O)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (0.80 g), 5% palladium-carbon (0.30 g), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 6 hrs. in a hydrogen atmosphere at atmospheric pressure. Palladium-carbon was filtered off and the filtrate was concentrated to give 3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]propionic acid (0.78 g, yield 97%) as a colorless solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C@@H:12]2[C@H:7]([O:8][CH2:9][CH2:10][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:11]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][O:8][CH:7]2[CH2:6][NH:5][CH2:14][CH2:13][CH:12]12
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(C(=O)C(F)(F)F)CC[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC2CNCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-tert-butyl 6-(trifluoroacetyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (70 g, 0.20 mol) in MeOH (160 mL) and water (600 mL) was added K2CO3 (34.2 g, 0.24 mol) in one portion at room temperature. The mixture was stirred for 2 h at room temperature, and then extracted with DCM (200 mL×5). The combined organic layers were concentrated to give tert-butyl octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate as a mixture of trans diastereomers. SFC purification afforded the pure S,S diastereomer tert-butyl (4aS,8aS)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (peak 1) 1H NMR: (CDCl3) δ 3.88-3.80 (m, 2H), 3.77-3.67 (m, 1H), 3.35-3.34 (m, 2H), 3.29-3.27 (m, 2H), 3.10-3.11 (d, 1H), 2.54-2.42 (m, 3H), 1.76 (s, 1H), 1.70-1.60 (m, 1H), 1.45 (s, 9H) LCMS (M+H)=243 and R,R diastereomer tert-butyl (4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (peak 2)1H NMR: (CDCl3) δ 3.89-3.80 (m, 2H), 3.77-3.67 (m, 1H), 3.35-3.34 (m, 2H), 3.29-3.27 (m, 2H), 3.10-3.11 (d, 1H), 2.54-2.42 (m, 3H), 1.76 (s, 1H), 1.70-1.60 (m, 1H), 1.44 (s, 9H) LCMS (M+H)=243.
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2C=CC=[CH:10][C:9]=2[C:14]2C=CC=CC=2N(C)C)CCCCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:39]([O-:42])(=[O:41])[CH3:40].Br[C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=1[CH3:51]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:40][C:39]([O:42][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:41])=[C:45]([CH3:51])[CH:46]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(F)ccc1Br
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a 2 L flask containing 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.(3.76 g) and Pd(OAc)2 (1.02 g) were added 396 mL of 1 N LHMDS in hexanes, then 400 mL of toluene under N2. The solution was cooled to −10° C. and tButyl acetate (49 mL was added. The solution was stirred at −10° C. for 10 min and was added 2-bromo-5-fluoro toluene. The mixture was heated at 80° C. for 15 min and was washed with NH4Cl and NaCl, dried with Na2SO4, filtered and concentrated. The crude was purified by flash chromatorghy with EtOAc/hexanes=1:30 to give tert-butyl (4-fluoro-2-methylphenyl)acetate (21.85 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.O.[CH3:22]O>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14][CH3:22])=[O:13])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C=CC(=O)O)c(C)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Temperature: 25 °C

Procedure:
The obtained 3-(4-acetyl-2-methylphenyl)acrylic acid (657 mg, 3.22 mmol) was dissolved in methanol (20 mL). Concentrated sulfuric acid (250 μL) was added to the solution. The mixture was refluxed for 2 hours, and cooled to room temperature. Water (50 mL) was added to the solution. Methanol was removed under reduced pressure. The solution was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (9:1, v/v) to give the desired compound (665 mg) as yellow crystalline product (yield 95%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:15][NH:16][CH3:17].[CH2:18]=O>C(O)C>[CH3:15][N:16]([CH2:18][C:5]1[CH:4]=[C:3]([CH2:12][CH2:13][CH3:14])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH3:17]
Reactant: C=O
Reactant: CNC
Reactant: CCCc1ccc2cccnc2c1O
Solvent: CCO
Product: CCCc1cc(CN(C)C)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a cold (0°) solution of 8-hydroxy-7-propylquinoline (5.7 g, 30.4 mmol) and 26% aqueous dimethylamine (15 g, 83 mmol) in 30 mL of ethanol was added dropwise 37% aqueous formaldehyde (4.5 g, 55.4 mmol). After stirring at room temperature for 1 hr, the mixture was refluxed for 2 hr, cooled and evaporated to dryness. The residue was diluted with water, extracted twice with ether and the extracts combined and dried (MgSO4). Evaporation gave 5-dimethylaminomethyl-8-hydroxy-7-propylquinoline as a syrup (7.00 g, 94%), structure confirmed by NMR. A portion of this syrup (2.44 g, 10 mmol) was heated under nitrogen with 2,4-diamino-6-methylthiopyrimidine (1.56 g, 10 mmol) in ethylene glycol (20 mL) at 120°-160° for 1 hr, then cooled. The solid that separated was collected, and washed with ether and hexanes to give the title compound (3.20 g, 90%). An analytical sample was obtained by recrystallization from 95% ethanol, mp 204°-206° dec. Anal. Calcd for C18H21N5SO: C, 60.82; H, 5.95; N, 19.70; S, 9.02. Found: C, 60.81; H, 5.98; N, 19.67; S, 9.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[ClH:19].[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][N:21]=[C:20]2[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(S(=O)(=O)Nc4ccccc4)cc3)c2cc1OC
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-N-phenylbenzenesulphonamide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 6,7-dimethoxy-4-[4-(N-phenylsulphamoyl)anilino]quinazoline hydrochloride salt in 95% yield,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N=C2CCCNC2=O)[CH:5]=[CH:6][CH:7]=1.[C:17](=[O:20])([O-])[O-].[Na+].[Na+]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:2]3[CH2:3][CH2:4][NH:8][C:17](=[O:20])[C:7]=3[NH:8]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCCC1=NNc1cccc(Br)c1
Agent: [Na+]
Solvent: O=CO
Product: O=C1NCCc2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 2,3-piperidinedione 3-(3-bromophenyl) hydrazone (2.5 g, 22.3 mmol) in formic acid (40 mL) is refluxed for 1 h then cooled to room temperature. The reaction mixture is neutralized with sodium carbonate to basic condition. The resulting precipitate is filtered and collected. Recrystallization with ethanol provides 1.0 g (56%) of the title compound as a yellow solid.