Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23](O)([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23]([F:7])([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethylaminosulfur trifluoride (DAST, 0.65 mL) in dry methylene chloride (49 mL) at -78° C. under N2 is added a solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 1, 2.25 g) in dry methylene chloride (47 mL) over 2 mins. The resulting mixture is stirred at -78° C. for 1 hr and at ambient temperature for 30 mins and is then adjusted to pH 8 with saturated aqueous sodium bicarbonate (50 mL), diluted with water (50 mL), and the layers are separated. The organic phase is washed with water (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with methanol/methylene chloride (0.5/99.5). Those fractions with an Rf =0.27 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound (contaminated with approx. 15% of the elimination side product). An analytical sample is prepared by radial chromatography (1000μ silica gel rotor, ethyl acetate/hexane (20/80) eluent), mp 116-118° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.N1C=CC=CC=1>C(Cl)Cl>[S:1]([O:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Mesyl chloride (0.15 ml) was added dropwise to tert-butyl 3-hydroxycyclopentanoate (373 mg) dissolved in methylene chloride (2 ml) and pyridine (0.32 ml) at a temperature of 0° C. The mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into ice-water (10 ml). The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to obtained the title compound having the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(c2ccc(C(F)(F)F)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 4-fluorobenzotrifluoride
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]=[CH:8][C:7](=[O:13])[C:6]=2[NH:5][C:4](=[O:14])[CH:3]=1.CN(C)[N:17]=[CH:18][C:19]([CH2:21][CH3:22])=[CH2:20]>C(Cl)(Cl)Cl>[CH2:21]([C:19]1[CH:20]=[C:9]2[C:8](=[N:17][CH:18]=1)[C:7](=[O:13])[C:6]1[NH:5][C:4](=[O:14])[CH:3]=[C:2]([CH3:1])[C:11]=1[C:10]2=[O:12])[CH3:22]
Reactant: C=C(C=NN(C)C)CC
Reactant: Cc1cc(=O)[nH]c2c1C(=O)C=CC2=O
Solvent: ClC(Cl)Cl
Product: CCc1cnc2c(c1)C(=O)c1c(C)cc(=O)[nH]c1C2=O
Yield: 30.2 %

Procedure:
A solution of 150 mg (0.9 mmol) of 4-methyl-1H-quinoline-2,5,8-trione and 150 mg (0.79 mmol) of 2-ethylacrolein dimethylhydrazone in dry chloroform (130 ml) was stirred at room temperature for five minutes. After evaporation of the solvent, the residue was purified by silica gel chromatography using ethyl acetate as eluent to yield 29 mg of the starting hydrazone, 64 mg (30%) of 5 and 60 mg of 6-dimethylamino-4-methyl-1H-quinoline-2,5,8-trone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH3:27][O:28][C:29](=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Br>>[CH3:27][O:28][C:29](=[O:38])[CH:30]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)cc1)NCC2
Reactant: COC(=O)C(Br)c1ccccc1
Product: COC(=O)C(c1ccccc1)N1CCc2cc(OC)c(OC)cc2C1CCc1ccc(C(F)(F)F)cc1

Procedure:
This compound is prepared by reaction of 6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydroisoquinoline with α-bromo-phenyl-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([C:20]#[N:21])=[C:16]([C:18]#[N:19])[N:17]=1.[OH-:22].[Na+].Cl>O>[C:20]([C:15]1[NH:14][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])=[N:17][C:16]=1[C:18]([NH2:19])=[O:22])#[N:21]
Reactant: [OH-]
Reactant: N#Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(N)=O
Temperature: 40 °C
Yield: 17.5 %

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyanoimidazole (3.31 g, 0.01 mol) and sodium hydroxide (1.0 g, 0,025 mol) in water (10 ml) was stirred and heated at 40° C. overnight. Concentrated hydrochloric acid was added to the mixture and the precipitated solid was filtered off and purified by medium pressure liquid chromatography (mplc) on silica eluted with a mixture of ethyl acetate and dichloromethane (1:1). Recrystallization of the white solid from a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (1:1) gave 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole-4-carboxamide (0.61 g), m.p. 254°-255° C., as a white solid.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].O.[O:18]=[C:19]1[CH:26]2[CH:21]([CH2:22][CH:23]=[CH:24][CH2:25]2)[NH:20]1>C1C=CC=CC=1>[OH:4][CH:3]([N:20]1[C:19](=[O:18])[CH:26]2[CH:21]1[CH2:22][CH:23]=[CH:24][CH2:25]2)[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC2CC=CCC12
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3.5 h

Procedure:
p-Nitrobenzyl glyoxylate hydrate (9.08 g) was refluxed in benzene (150 ml) with provision for the removal of water. After 1 hour 8-oxo-7-azabicyclo[4.2.0]oct-3-ene (1) (2.46 g) was added and refluxing continued for 3.5 hours. The cooled solution was washed with water (x 2), then brine. After back extraction of the first aqueous extract with ethyl acetate, the organic solutions were dried over magnesium sulphate, filtered combined, and evaporated. Chromatography on silica, eluting with ethyl acetate-petroleum ether mixtures gave two separate isomers of the alcohol (54) (43%). Less polar isomer I m.p. 153-5° (crystalline plates ex ethyl acetate/ether), νmax (CHCl3) 3400 (broad), 1760, 1745, 1520, 1350 cm-1. δ ppm (CDCl3) 1.90-2.83 (4H, m, 2-CH2), 3.23-3.55 (1H, m, β-lactam proton), 4.00-4.20 (1H, m, β-lactam proton), 4.27 (1H, d, J 8 Hz, exchangeable with D2O, OH), 5.33 (2H, s, CH2Ar)-obscuring 1H, CHOH; 5.67-5.88 (2H, m, CH=CH), 7.55 (2H, d, J 8.5 Hz, Ar), 8.23 (2H, d, J 8.5 Hz, Ar) (Found: C, 58.07; H, 5.15; N, 8.51%, C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%). More polar isomer II m.p. 118°-120° (fine crystalline needles ex ethyl acetate/ether). νmax (CHCl3) 3400 (broad), 1760-1745, 1520, 1350 cm-1. δ ppm (CDCl3) 1.83-2.77 (4H, m, 2-CH2), 3.25-3.55 (1H, m, β-lactam proton), 4.02-4.37 (2H, m, β-lactam proton and CHOH, -OH exchangeable with D2O), 5.31-5.98 [5H, 5.35 (2H, s, CH2Ar), obscuring, 1H, which sharpens to s, at δ 5.40 on D2O exchange, CHOH, and 2H, m, CH=CH], 7.56 (2H, d, J 8 Hz, Ar), 8.23 (2H, d, J 8 Hz, Ar) (Found: C, 57.95; H, 4.95; N, 8.50%. C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH:24](S)([SH:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:25]1[O:23][C:13]2([CH2:14][C@H:15]([CH3:22])[C@@:16]3([CH2:17][OH:18])[C:11]([CH2:10][CH2:9][C@@H:8]4[C@@H:19]3[CH2:20][CH2:21][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])=[CH:12]2)[S:26][CH2:24]1
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Reactant: CC(S)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: C[C@H]1CC2(C=C3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31CO)OCCS2
Reaction time: 4 h

Procedure:
17β,19-Dihydroxy-1α-methyl-4-androsten-3-one in acetic acid is treated with ethanedithiol and p-toluenesulfonic acid. After standing about 4 hours at room temperature, the solution is poured onto water and the mixture extracted with methylenechloride. The methylenechloride extract is washed well with water, sodium hydroxide solution, water, dried over sodium sulfate and evaporated under reduced pressure to leave 17β,19-dihydroxy-1α-methyl-4-androsten-3-one 3-ethylenethioketal which is recrystallized once from acetone-hexane.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[C:13]1([CH:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(CN2CCCC(c3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCCC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 100 %

Procedure:
100 mg of 1-(4-Bromo-benzyl)-3-phenyl-piperidine was combined with 862 mg of 2-(Trifluoromethyl)phenyl boronic acid, 35 mg of tetrakis(triphenylphosphine)palladium(0), 1.015 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 396, 100% yield
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1cc(F)c(N)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(F)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane and N-methyl-N-[2-(4-amino-3-chloro-5-fluoro-phenyl)-ethyl]-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:25]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[S:25]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:10][C:11]=23)=[O:23])[CH:32]=[CH:33][CH:34]=1)(=[O:27])(=[O:28])[NH2:26]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(F)c3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.21) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 498.2 [(M+H)+]; mp 275° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH:10][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:9])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)CCCCC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Yield: 49.5 %

Procedure:
24 mg of (1S,2S)-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine obtained in Example 115, 14 mg of monoethyl adipate and 10 mg of 4-dimethylaminopyridine were dissolved in 2 ml of methylene chloride, and 15 mg of 1-ethyl-3-(3-dimethyaminopropyl)carbodiimide hydrochloride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, then sequentially washed with a 10% citric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel™ C-200, 1 g, hexane/ethyl acetate=2/1), and 28 mg of the obtained amide compound was dissolved in 1 ml of methanol. Then, 0.5 ml of a 2N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and then subjected to liquid separation by an addition of ethyl ether and water. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off. The residue was treated with a liquid mixture of isopropyl ether and ethyl ether to obtain 16 mg (yield: 49%) of the above-identified compound as white crystalline powder having a melting point of from 123° to 124° C. and
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH2:15][C:14]2[CH:26]=[CH:27][CH:28]=[C:12]([F:11])[CH:13]=2)[N:17]=[CH:18]3)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: Nc1ncnc(Cl)c1C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1ncnc(Nc2ccc3c(cnn3Cc3cccc(F)c3)c2)c1C=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-6-chloro-pyrimidine-5-carbaldehyde (95.5 mg, 0.61 mmol) and 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine (147 mg, 0.61 mmol) in DMSO (1.5 mL) was added diisopropylethylamine (DIEA, 79 mg, 0.61 mmol). The mixture was stirred at 100° C. for 2 h, cooled to room temperature, then partitioned between ethyl acetate and H2O. The combined ethyl acetate extracts were dried over Na2SO4 and evaporated to afford a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[C:6]([CH3:12])=[N:7][C:8](F)=[CH:9][CH:10]=1.O>CS(C)=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:1]#[N:2])=[N:7][C:6]=1[CH3:12]
Reactant: [C-]#N
Reactant: Cc1nc(F)ccc1Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C#N)ccc1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100° C., poured into H2O (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 10 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.6 g, 15%) as white solid; MS (D): m/e=197.0 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[H][H]>C(O)(=O)C.O=[Pt]=O>[N:1]1([C:6]([CH:8]2[CH:13]([OH:14])[CH2:12][CH2:11][CH2:10][NH:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ncccc1O)N1CCCC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1NCCCC1O)N1CCCC1
Yield: 82.4 %

Procedure:
10 g (0.052 moles) of 2-(pyrrolidin-1-yl)carbonyl-3-hydroxy pyridine, dissolved in 100 ml of acetic acid and 8 mml of trifluoroacetic acid, were hydrogenated at 40 psi over 1 g of PtO2 at room temperature, until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue was taken up in 20% NaOH and extracted with CH2Cl2, which was dried and evaporated in vacuo to dryness. 8.5 g of the title compound were obtained as a 80/20 diastereoisomeric mixture, which was used for the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccc(O)cc2)s1
Temperature: 100 °C

Procedure:
A flame-dried test tube under N2 was charged with 1-(5-bromothiophen-2-yl)ethanone (250 mg, 1.22 mmol), p-hydroxyphenylboronic acid (1.2 equiv, 1.40 mmol, 202 mg), and 2.0 mL 1,4-dioxane. To the yellow solution, tetrakistriphenylphosphinepalladium(0) (6 mol %, 0.0731 mmol, 84 mg) and 2 M aqueous sodium carbonate (2.0 equiv, 2.44 mmol, 2.0 mL) were added. The yellow mixture was heated to 100° C. for 18 h. The resulting yellow-brown mixture was cooled to rt, adsorbed onto Celite in vacuo, and purified by silica gel chromatography to afford the desired product as an analytically pure yellow solid (51 mg, 19% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:19](OC(OCC)OCC)C>COCCO>[CH2:17]1[O:16][C:14]2[CH:15]=[C:2]3[C:3]([C:4](=[O:5])[N:6]([C:7]4[NH:8][N:9]=[N:10][N:11]=4)[CH:19]=[N:1]3)=[CH:12][C:13]=2[O:18]1
Reactant: Nc1cc2c(cc1C(=O)Nc1nnn[nH]1)OCO2
Reactant: CCOC(OCC)OCC
Solvent: COCCO
Product: O=c1c2cc3c(cc2ncn1-c1nnn[nH]1)OCO3

Procedure:
A slurry of 11.6 g of 2-amino-4,5-methylenedioxy-N-(1H-tetrazol-5-yl)benzamide and 25 g of triethoxymethane in 150 ml of 2-methoxyethanol was heated at reflux for 1 hour. A complete solution was not obtained at any time but the final mixture was filtered and the separated solid was air dried and recrystallized from a mixture of dimethylformamide and methanol to give 6,7-methylenedioxy-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 280° C. (dec).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:33]([CH3:35])[CH3:34]>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH:33]([CH3:35])[CH3:34])[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)Br
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: CC(C)N1Cc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc2C1=O
Yield: 58.1 %

Procedure:
In the same manner as in Example 51, the title compound (32 mg) was prepared from the compound (50 mg) obtained in Example 50 and 2-bromopropane (148 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[NH2:16][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(O)c(N)c1C(=O)OC
Yield: 52 %

Procedure:
A mixture of the crude dimethyl 4-hydroxy-3-nitrophthalate C1-3 (25 g, 98 mmol) and Pd/C (1.0 g) in CH3OH (400 mL) was stirred at room temperature overnight under H2 atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered through a celite pad and the filtrate was evaporated in vacuo. The residue was purified by chromatography (silica gel, PE:EA (1:1, v:v)) to yield compound C1-4 as a yellow solid (11.5 g, yield: 52%). 1H NMR (DMSO-d6, 400 MHz) δ: 10.45 (s, 1H), 6.89 (d, J=8 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 5.19 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H); MS (ESI+): m/z 226 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccccc1F
Product: O=c1[nH]c2nccc(Nc3ccccc3F)c2c2ccccc12
Yield: 74.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-fluoroaniline (96 mg, 0.87 mmol) to provide 189 (98 mg, 74% yield) as a white solid. LC-MS (M+H=306, obsd.=306).