Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OS(C)(=O)=O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of 0.084 g (0.28 mmol) of the product (24) from Step 8 and 0.08 mL (0.56 mmol) of triethylamine in 2.5 mL of anhydrous DCM was cooled to 0° C. Then was added dropwise 0.03 mL (0.34 mmol) of methanesulfonyl chloride and the resulting mixture was allowed to warm to ambient temperature under nitrogen. Excess DCM was added and the reaction mixture was washed with water, saturated NaHCO3 and brine. The organic layer was then dried over MgSO4 and the solvent was removed in vacuo yielding 0.106 g (0.28 mmol, 100%) of 1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)propyl methanesulfonate (25) as a tan oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])[CH3:2].C([NH-])C.Cl[C:26](OC)=[O:27]>>[CH2:1]([N:3]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH2:17][CH2:18][CH3:19])[C:26]1=[O:27])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCCNc1c(C(=O)NCC)cnc2c(OC)cccc12
Agent: CC[NH-]
Product: CCCn1c(=O)n(CC)c(=O)c2cnc3c(OC)cccc3c21

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 1-aminopropane following general procedure B to afford 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethylamide (200 mg) following general procedure E. The above ethylamide (0.70 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg). LCMS: m/z 314 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:4](C(OCC2C=CC=CC=2)=O)[C:3]1=[O:24]>CO.[H][H].[Pd]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[NH:4][C:3]1=[O:24]
Reactant: [H][H]
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Yield: 98.2 %

Procedure:
8.5 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of methanol, and 0.1 g of palladium-black is added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After the reaction the catalyst is removed by filtration, and the filtrate is condensed under reduced pressure. The residue obtained is washed with n-hexane. 5.0 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 98.2% M.p. 135°-136° C.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1([C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5]1.Cl.C[OH:25]>>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([C:4]([C:12]2[C:7]([C:6]([OH:25])=[O:5])=[N:8][CH:9]=[CH:10][CH:11]=2)=[O:1])[N:14]=1
Reactant: [OH-]
Reactant: COc1cc(OC)nc(C2(Cl)OCc3ncccc32)n1
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1
Reaction time: 0.5 h

Procedure:
0.208 g of 50% NaOH is added at 55° to a solution of 0.551 g of 5-chloro-5-(4,6- dimethoxy-2-pyrimidinyl )-furo[3,4,b]pyridine (Table B, cpd. no. 68) in 50 ml methanol. The mixture stirred for a further 1/2 hr at 55°, cooled in an ice-bath, acidified with 1 ml of concentrated HCl and the solvent evaporated. The residue is partitioned between 50 ml of CH2Cl2 and 50 ml H2O and the CH2Cl2 layer concentrated to give 0.39 g of the title product as a white solid, m.p. 71°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1>O1CCCC1>[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:37])=[O:36])[CH:34]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 14, 40.6 g, 0.1619 mol) in anhydrous tetrahydrofuran (600 mL), cooled to −70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 161.9 mL, 0.161.9 mol) drop wise. The reaction mixture was warmed to room temperature and stirred for 1 hour before cooling to −70° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (40 g, 0.1619 mol) in tetrahydrofuran (200.0 mL) was added dropwise. After complete addition, the reaction mixture was gradually warmed to room temperature and stirred for 1 hour. Reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and saturated aqueous sodium chloride solution. Crude residue was purified by column chromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to afford the title compound as a white solid, 46 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([NH2:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][CH:7]=1.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.FC(F)(F)C(O)=O.CO>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH3:18])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=3)[NH:8][C:7]=2[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([OH:21])[CH:23]=2)[NH:19]1)=[O:20]
Reactant: CCOc1ccc2[nH]cc(CC(C)(N)C(=O)OC)c2c1
Reactant: O=Cc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of (+/−)-2-amino-3-(5-ethoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (829 mg, 3 mmol), 3-hydroxybenzaldehyde (439 mg, 3.6 mmol) and trifluoroacetic acid (223 μl, 3 mmol) in dry dichloromethane (40 ml) is stirred for 6 h under argon. Methanol (2 ml) is added to dissolve the precipitated product and the mixture is diluted with dichloromethane (150 ml). It is washed with saturated aqueous NaHCO3 (2×50 ml) and water (2×50 ml), is dried, and the solvent is removed under reduced pressure. The residue is purified by column chromatography (dichloromethane-ethyl acetate, 7:1→4:1) to provide (1RS,3SR)-1-(3-hydroxy-phenyl)-6-ethoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (1.05 g, 93%). M.p. 173-175° C. (from ethyl acetate-hexane).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.O[CH2:14][C:15]1[O:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+].C(OC(=O)C)(=O)C>O>[C:22]([O:21][CH2:20][C:18]1[O:19][C:15]([CH:14]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:16][CH:17]=1)(=[O:24])[CH3:23]
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc(CO)o1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc(C=C2N=C(c3cccs3)OC2=O)o1
Temperature: 90 °C
Yield: 18.1 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (100 mg, 0.54 mmol), 5-hydroxymethylfuran-2-aldehyde (61 μL, 0.6 mmol), sodium acetate (45 mg, 0.54 mmol) and acetic anhydride (0.32 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The reaction mixture was extracted with ethyl acetate (5 mL) twice, and organic layers were then gathered. The thus obtained organic layer was washed with water (5 mL) twice, and then with a saturated saline (5 mL) once. Thereafter, the resultant was dried over anhydrous sodium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was purified by medium-pressure silica gel chromatography (hexane:ethyl acetate=9:1→4:6) and was then dried under reduced pressure, so as to obtain 31 mg of the above-captioned compound.
Reaction SMILES: [CH2:1]([C:15]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:18]([NH2:19])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=1)[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O>C(O)C.C(O)=O>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[N:19][C:18]1[C:20]([CH:22]([CH3:24])[CH3:23])=[CH:21][C:15]([CH2:1][C:2]2[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([N:6]=[CH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)=[CH:16][C:17]=1[CH:25]([CH3:27])[CH3:26]
Reactant: O=Cc1ccccn1
Reactant: CC(C)c1cc(Cc2cc(C(C)C)c(N)c(C(C)C)c2)cc(C(C)C)c1N
Solvent: CCO
Solvent: O=CO
Product: CC(C)c1cc(Cc2cc(C(C)C)c(N=Cc3ccccn3)c(C(C)C)c2)cc(C(C)C)c1N=Cc1ccccn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a suspension of 2b (1.60 g, 4.37 mmol) in absolute ethanol (10 ml) was added 2-pyridinecarboxaldehyde (1.24 ml, 13.11 mmol, 3 eq.) and two drops of formic acid. The mixture was stirred at 45° C. overnight. On cooling to room temperature the suspension was filtered, washed with cold ethanol and dried under reduced pressure to afford 18a as a yellow solid (1.68 g, 49%).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]1[CH2:34][CH2:33][CH2:32][C@@H:24]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1C=CC2N(O)N=NC=2C=1.O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]1[CH2:34][CH2:33][CH2:32][C@@H:24]1[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 62 %

Procedure:
Z-L-Phe-OH (2.25 g, 7.5 mmol) and H-D-Pro-OtBu (0.862 g, 5.0 mmol) were dissolved in DMF (10 ml), mixed with HOBt H2O (766 mg, 5.0 mmol), BOP (3.3 g, 7.5 mmol) and triethylamine (1.75 ml, 12.5 mmol) under ice cooling, and then stirred for 2 hours. After the reaction mixture was concentrated, it was re-dissolved in ethyl acetate and washed sequentially with 10% citric acid, 4% NaHCO3 and brine. After drying over anhydrous MgSO4 and concentrating, the oily residue was purified by flash chromatography on silica gel (CHCl3/MeOH=99/1) to yield 1.403 g (62%) of the titled compound as an oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[C:39](=[O:40])([O:41][CH3:42])[O:35][CH:34]([C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:37][CH:36]=1)[Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCC[Sn](CCCC)(CCCC)C(OC(=O)OC)c1ccc(OCc2ccccc2)cc1
Yield: 41 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethylbenzene, 10.5 mL, 21 mmol), tri-n-butyltin hydride (5.55 mL, 21 mmol), 4-benzyloxybenzaldehyde (4.24 g, 20 mmol), and methyl chloroformate (1.86 mL, 24 mmol) were processed using the method described in Example 1B to afford 4.6 g (41%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]([C:9]#[N:10])[CH2:8][C:5]=2[CH:4]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][CH:12]=1)[CH:7]([C:9]#[N:10])[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[CH2:20][CH2:8]2
Reactant: C=Cc1ccc(OC)cc1
Reactant: COc1ccc2c(c1)CC2C#N
Product: COc1ccc(C2CCc3cc(OC)ccc3C2C#N)cc1

Procedure:
A mixture of 4-methoxybenzocyclobutane-1-carbonitrile (16 g) and 4-methoxystyrene (23.5 g) was stirred and heated at 175° for 45 minutes. The mixture was cooled, and purified by flash column chromatography on silica (K60), eluting with a mixture of ethyl acetate and petroleum ether (b.p. 40°-60°), 1:9 by volume, to give 1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)naphthalene-1-carbonitrile, m.p. 127°.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH:14]([Cl:16])[CH:13]2[O:17][CH2:18][C:19]([O:22][CH3:23])([O:20][CH3:21])[CH:12]12)=[O:10])C1C=CC=CC=1.[H][H].[C:26]([NH:33][C@H:34](C(O)=O)[CH2:35][CH:36]([CH3:38])[CH3:37])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[Pd]>[C:29]([O:28][C:26](=[O:27])[NH:33][CH2:34][CH:35]([C:9]([N:11]1[CH2:15][CH:14]([Cl:16])[CH:13]2[O:17][CH2:18][C:19]([O:20][CH3:21])([O:22][CH3:23])[CH:12]12)=[O:10])[CH:36]([CH3:37])[CH3:38])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC1(OC)COC2C(Cl)CN(C(=O)OCc3ccccc3)C21
Reactant: [H][H]
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC1(OC)COC2C(Cl)CN(C(=O)C(CNC(=O)OC(C)(C)C)C(C)C)C21
Reaction time: 2 h
Yield: 93 %

Procedure:
6-Chloro-3,3-dimethoxy-hexahydro-furo[3,2-b]pyrrole-4-carboxylic acid benzyl ester (68 mg, 0.20 mmol) was deprotected by catalytic hydrogenation using 10% palladium on charcoal and hydrogen under atmospheric pressure. After stirring for 2 hours, the suspension was filtered through Celite and the filtrate evaporated on rotavapor to give the crude 6-chloro-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole, which was coupled with N-Boc-leucine using HATU in the same way as the method described in Example 2, which gave the title compound (78 mg, 93%). MS m/z 421.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[ClH:22].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Solvent: CN(C)C=O
Product: Cl
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 2013.6 %

Procedure:
A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (800 mg, 3.17 mmol) and DMF (100 μl) in thionyl chloride (20 ml, 0.27 mmol) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene and dried under vacuum to give 7-benzyloxy-4-chloroquinazoline hydrochloride (835 mg, 86%) as a cream solid. m.p. 131-132° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:28])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[F:28][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (8.35 g, 14.7 mmol) prepared in Example 124b and triethylsilane (11.75 mL, 73.6 mmol) in dichloromethane (147 mL), trifluoroacetic acid (14.7 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound as a colorless solid. A suspension of this title compound in a hexane/dichloromethane mixed solvent was further irradiated with ultrasonic wave for 1 hour. The suspension was filtered, and crystals collected by filtration were washed with hexane and dried at 40° C. for 24 hours to yield the title compound (5.95 g, 97%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][N:26]([CH3:33])[C:27]2=[O:32].B(Br)(Br)Br>>[OH:18][C:11]1([C:14]([F:16])([F:15])[F:17])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][N:26]([CH3:33])[C:27]2=[O:32].[OH:18][C:11]1([C:14]([F:15])([F:16])[F:17])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][N:26]([CH3:33])[C:27]2=[O:32]
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: BrB(Br)Br
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Product: Cn1ncc2c(NC3c4cccc(O)c4C(C)(C)CC3(O)C(F)(F)F)cccc2c1=O

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 302 mg of 5-amino-2-methylphthalazin-1-one. As in Example 2, 158 mg of 5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one as fraction 1, 66 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, diastereomer A as fraction 4, and 77 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, diastereomer A as fraction 5 are obtained by reaction of 570 mg of imine with 6.4 ml of BBr3 (1 M in dichloromethane).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:35]1[CH2:38][CH:37]([C:39]2[C:40]([C:45]3[CH:54]=[CH:53][C:48]([C:49]([NH:51][CH3:52])=[O:50])=[C:47]([F:55])[CH:46]=3)=[N:41][CH:42]=[CH:43][N:44]=2)[CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[N:11][C:2]([N:35]3[CH2:36][CH:37]([C:39]4[C:40]([C:45]5[CH:54]=[CH:53][C:48]([C:49]([NH:51][CH3:52])=[O:50])=[C:47]([F:55])[CH:46]=5)=[N:41][CH:42]=[CH:43][N:44]=4)[CH2:38]3)=[N:3]2)=[CH:8][C:7]=1[F:12]
Reactant: Fc1cc2cnc(Cl)nc2cc1Cl
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ncc4cc(F)c(Cl)cc4n3)C2)cc1F
Temperature: 100 °C
Yield: 70.4 %

Procedure:
A mixture of 2,7-dichloro-6-fluoroquinazoline (46 mg, 0.21 mmol), 4-(3-(azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.15 g, 0.23 mmol), and potassium carbonate (0.15 g, 1.06 mmol) in DMSO (1 mL) was heated to 100° C. for 1 h, then cooled to RT. Water was added, then the product was extracted into EtOAc. The combined extracts were washed with water (2×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromtography to give 4-(3-(1-(7-Chloro-6-fluoroquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide as a light yellow solid (69 mg, 70% yield). m/z=467 (M+1). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.70 Hz, 3 H) 4.28-4.38 (m, 1 H) 4.45-4.54 (m, 4 H) 6.80 (br. s., 1 H) 7.32-7.42 (m, 3 H) 7.71 (d, J=6.65 Hz, 1 H) 8.27 (t, J=7.92 Hz, 1 H) 8.58 (d, J=1.76 Hz, 1 H) 8.65 (s, 1 H) 8.94 (s, 1 H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1.Cl.[C:18]1([O:24]C2C=CC=CC=2)C=CC=C[CH:19]=1>O1CCOCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:13]([C:18]([OH:24])=[CH:19][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:16]2)=[CH:14][CH:15]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1ccccc1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a stirred round bottled flask with toluene (100 mL) ethyl benzoyl acetate (18.7 g, 97 mmol) and m-anisidine (12 g, 97 mmol) was added. 4 M HCl in dioxane (0.5 mL) was added and the reaction mixture was refluxed for 6 h (140° C.). The mixture was co-evaporated with toluene. To the crude mixture diphenyl ether (50 mL) was added and the mixture was heated to 280° C. for 2 h. When the theoretical amount ethanol (6 mL) was collected in a Dean Stark trap the heating was stopped and the mixture was cooled to rt. The crude mixture was dissolved in CH2Cl2 (100 mL) and stirred for 30 min. The formed precipitate was filtered off and dried which gave 1 (4.12 g, 16.4 mmol, 17%): pale yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:26][C@@H:25]([OH:27])[CH2:24]2)[C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.F[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:29][C:2]([CH3:28])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:24][C@@H:25]([O:27][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:26]2)[CH:6]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2C[C@@H](O)C2)CC1
Reactant: Fc1cccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2C[C@@H](Oc3cccnc3)C2)c(C(=O)O)s1

Procedure:
The title compound was synthesized in a manner analogous to Example 1, using 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid in place of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid and 3-fluoro-pyridine in place of 2-fluoro-pyridine: MS (m/z): 492.8 [M−H]−; HPLC retention time: 3.44 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).