Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(Cl)Cl>[CH:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
To a solution of 4-(N-Boc amino)piperidine (2.61 g, 13 mmol) and triethylamine (3 mL, 21.5 mmol) in 25 mL of DCM, was added isopropyl chloroformate (1 M in toluene, 13.1 mL, 13.1 mmol). The mixture was stirred at room temperature for 20 h. It was then washed with a saturated solution of NaHCO3 (50 mL), followed by brine (50 mL). The solution was dried, filtered and evaporated to afford 3.26 g (87%) of 18a.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(Cl)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (342 mg, 0.87 mmol) is coupled to 1-bromo-4-chlorobenzene (200 mg, 1.05 mmol) using Method B to give the title compound.
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)([CH3:3])[CH3:2].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.O.CO>[CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2nccs2)c1
Temperature: 90 °C

Procedure:
A solution of 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (0.274 g, 0.46 mmol, based on presumed 45% yield of previous step), 2-bromo-1,3-thiazole (0.206 g, 1.2 mmol), potassium carbonate (0.1736, 1.2 mmol), tetrakis(triphenlyphosphine)palladium(0) (0.040 g, 0.035 mmol) in mixed solvent of benzene/water/methanol (10 mL/1 mL/1 mL), was degassed for 5 minutes, then refluxed at 90° C. for overnight. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]([CH:26]=1)[C:24]#[N:25]>CN(C)C=O.C1(C)C=CC=CC=1.O.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:24]([C:23]1[CH:26]=[C:19]([CH3:18])[CH:20]=[CH:21][C:22]=1[C:2]1[CH:11]=[C:10]([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1)#[N:25]
Reactant: COC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cc2C#N)cc(C(O)C(F)(F)F)c1

Procedure:
A mixture of methyl 3-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (300 mg, 0.96 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (280 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) in N,N-dimethylformamide (0.75 mL) and toluene (1.5 mL) under nitrogen was subjected to microwave irradiation at 110° C. for 1 h. After cooling, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone (6 parts), cyanuric chloride (1.8 parts) and 1-aminobenzene-4-β-sulfatoethylsulfone (2.8 parts) were subjected to condensation reactions one after another in an aqueous medium in a conventional manner, followed by successive condensation reaction with 3-aminobenzenesulfonic acid (1.7 parts) at 50° to 70° C. under a weak acid condition. Thereafter, salting out of the reaction mixture gave an anthraquinone compound of following formula (free acid form). ##STR117##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N+:15]=1[O-:23]>C1COCC1>[Cl:21][C:18]1[C:19]([CH3:20])=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N+:15]([O-:23])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1c(Cl)cc(C)[n+]([O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2c(C)c(Cl)cc(C)[n+]2[O-])c(C)c1
Yield: 90.1 %

Procedure:
To a solution of 2,4,6-trimethylphenol (415 mg, 3.05 mmol) in dry THF (20 ml) was treated with 60% sodium hydride in oil (122 mg, 3.05 mmol) at room temperature. After all H2 was evolved, 2,4-dichloro-3,6-dimethyl-pyridine 1-oxide (585.4 mg, 3.05 mmol) was added and the resulting mixture was heated at reflux for 2 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give solid. The solid was recrystallized from pet ether to give 802 mg (90%) of the title compound as white crystals, mp 106–107° C. 1H NMR (CDCl3) δ 7.04 (s, 1H), 6.78 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 2.06 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(O)=O.[CH:23]([NH2:25])=O>>[CH3:13][O:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:25][CH:23]=[N:1]2)=[CH:8][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: NC=O
Reactant: COCCOc1cc(C(=O)OC)c(N)cc1OC
Solvent: CC(=O)O
Product: COCCOc1cc2c(=O)[nH]cnc2cc1OC
Temperature: 140 °C
Yield: 69 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of methyl 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate (3.05 g, 11.9 mmol) and AcOH (5.4 mL) in formamide (15.25 mL) was heated at 140° C. overnight, to afford 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one as a solid (2.07 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 12.0 (br, 1H), 7.99 (s, 1H), 7.45 (s, 1H), 7.14 (s, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.71 (t, 2H), 3.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 80° C. for 16 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino4-chlorophenyl)-2-morpholinopyridine4-carboxamide. The reaction mixture was evaporated and the residue was triturated under water. The resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. The material so obtained was purified by column chromatography on an ion exchange column (isolute CBA column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using methanol as eluent. There was thus obtained the title compound (0.493 g) in 58% yield; NMR Spectrum: (DMSOd6) 3.51 (m, 4H), 3.71 (m, 4H), 7.09 (d, 1H), 7.23 (s, 1H), 7.55 (d, 1H), 7.71 (d, 2H), 8.06 (s, 1H), 8.27 (d, 1H), 8.35 (d, 1H), 8.96 (s, 1H), 10.39 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H+ 472.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([O:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17]C(=O)CC(C)CC)[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccsc1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccsc1

Procedure:
Following General Procedure I above, and using 3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure 3 above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]1([C:11]2([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:30])C>ClCCl.CCCCCC>[C:1]1([C:11]2([CH:16]=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2cccc3ccccc23)CCCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
To a solution of 1-naphthalen-1-yl-cyclopentanecarbonitrile (338) (10.5 g, 47.4 mmol) in dichloromethane (150 mL) was added dropwise diisobutylaluminium hydride (25% in toluene, 67.5 mL, 118.6 mmol) at −78° C. and stirred for 2 h at the same temperature (silica TLC, 5% ethyl acetate in hexane; Rf=0.6). The reaction mixture was quenched with a saturated aqueous solution of potassium sodium tarterate (35 mL) and stirred for 17 h at room temperature. The reaction mixture was filtered and the residue was washed with dichloromethane. The organic phase was separated and the aqueous part was back extracted with dichloromethane (100 mL). The combined organic part was dried, filtered and concentrated in vacuo to get a crude mass which was purified by CombiFlash using gradient eluent mixture of ethyl acetate and hexane to obtain pure 1-naphthalen-1-yl-cyclopentanecarbaldehyde (339) (10.4 g, 98%) as a colorless sticky liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:25]2[CH2:26][CH2:27][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]2)=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
5-(4-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1483.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:36])[CH2:32][C:31]([F:34])([F:33])[CH2:30][N:29]([NH2:35])[CH2:28]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:35][N:29]3[CH2:28][C:27]([F:26])([F:36])[CH2:32][C:31]([F:33])([F:34])[CH2:30]3)=[O:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: NN1CC(F)(F)CC(F)(F)C1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Product: Cc1c(C(=O)NN2CC(F)(F)CC(F)(F)C2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Form the acid chloride from 2.0 mmol of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid and react it with 1.4 mmol of the product of Example 33 using the general procedure set forth in Example 39, to yield the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:28])=[C:19]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH:22]([CH3:27])[CH2:21]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:30])[CH2:10][C:11]3=[O:29])[CH:7]=1)=[O:5])C.[OH-].[Na+].[ClH:33]>C(O)C>[OH2:3].[ClH:33].[F:28][C:18]1[CH:17]=[C:14]2[C:13]3[N:8]([CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16])[CH:9]([CH3:30])[CH2:10][C:11](=[O:29])[C:12]=3[C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH:22]([CH3:27])[CH2:21]1
Reactant: CCOC(=O)c1cn2c3c(c(N4CCN(C)C(C)C4)c(F)cc3c1=O)C(=O)CC2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2C(=O)CC4C)CCN1C
Product: O
Reaction time: 3 h
Yield: 73.2 %

Procedure:
2.08 g (0.005 mole) of 9-fluoro-5-methyl-8-(3,4-dimethyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in 5 ml of ethanol, 30 ml of a 2N aqueous solution of sodium hydroxide was added thereto, and this mixture was stirred at 15°-20° C. for 3 hours to hydrolyze the starting material. The resulting reaction solution was adjusted to pH 1 by the addition of concentrated hydrochloric acid under cooling with ice. The crystals which separated out were collected by filtration and successively washed with small volumes of water and ethanol. These crystals were recrystallized from water to obtain 1.62 g (73.2% yield) of 9-fluoro-5-methyl-8-(3,4-dimethyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride monohydrate in the form of yellow crystals. These crystals had a melting point of 226°-228° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[CH:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C([O-])([O-])=[O:33].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C(#N)C.[OH2:53]>>[O:53]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:5])=[O:4])=[N:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: O
Reactant: CN(c1cccc2cc(-c3ncc(CN4CCSCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: CN(c1cccc2cc(-c3ncc(CN4CCS(=O)(=O)CC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A mixture of N-methyl-N-{2-[5-(thiomorpholinomethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.35 g), sodium percarbonate (0.33 g), acetonitrile (6 ml) and water (2 ml) was stirred at 40° C. for 30 min. Sodium percarbonate (0.15 g) was added, and the mixture was further stirred at 40° C. for 1 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were subjected to silica gel short column to give the title compound (0.28 g, yield 76%) as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 225-226° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)=[CH2:25].C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([CH:24]=[CH2:25])=[CH:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-vinylbenzyl chloride (9.9mg, 0.065 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) was stirred at 50° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]-1-(4-vinylbenzyl)pyrrolidine (Compound No. 1701) (19.6 mg, 88%): The purity was determined by RPLC/MS (92%); ESI/MS m/e 547.2 (M++H, C23H25ClF3N4O2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([S:25]([CH3:24])(=[O:27])=[O:26])[S:25]([CH3:24])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(Benzyloxy)-3-nitropyridine (14 g, 69.8 mmol, 1 eq) was dissolved in dichloromethane and cooled to 0° C. Then added TEA (29.2 ml, 209.6 mmol, 3 eq), followed by the addition of potassium carbonate (9.96 g, 69.8 mmol, 1 eq) at 0° C. and stirred for 15 minutes. Methane sulfonyl chloride (20 g, 174 mmol, 2.5 eq) was added slowly at 0° C. to the above mixture and stirred for 14 h. After the completion of reaction, monitored by TLC, the reaction mixture was diluted with water and organic layer was separated. Water layer was extracted twice with 200 ml of dichloromethane, and the combined dichloromethane mixture was washed with water (500 ml) and brine (500 ml). The organic solution was concentrated under vacuum to yield the pure product. Yield: 19.5 g (78%). 1HNMR (400 MHz, DMSO-d6): δ 3.47 (S, 6H), 5.35 (s, 2H), 7.32 (d, J=5.76 Hz, 1H), 7.40-7.49 (m, 3H), 7.51 (t, J=4.12 Hz, 2H), 8.52 (d, J=5.68 Hz, 1H), 8.57 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N1C=CN=C1)([N:15]1[CH:19]=[CH:18]N=C1)=O.Cl.N1C=CN=C1.[Cl:31][C:32]1(NCC)[CH:36]=[CH:35][N:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[NH:33]1>C(#N)C>[Cl:31][C:32]1[C:36]([N:15]([CH2:19][CH3:18])[C:8](=[O:10])[CH2:7][CH2:6][S:5][CH2:4][CH2:3][C:2]([F:1])([F:12])[F:11])=[CH:35][N:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[N:33]=1
Reactant: CCNC1(Cl)C=CN(c2cccnc2)N1
Reactant: O=C(O)CCSCCC(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
A 20 mL vial was charged with 3-((3,3,3-trifluropropyl)thio)propanoic acid (0.999 g, 4.94 mmol) and acetonitrile (5 mL). Carbonyldiimidazole (0.947 g, 5.84 mmol) (off-gassing) and 1H-imidazole hydrochloride (0.563 g, 5.39 mmol) were added and the reaction was stirred at 20° C. for 4 hours. 3-Chloro-N-ethyl-1-(pyridine-3-yl)-1H-pyrazol-amine (1.00 g, 4.49 mmol) was added and the reaction was stirred at 75° C. for 42 hours, at which point HPLC analysis indicated that the conversion was 96%. The reaction was cooled to 20° C. and concentrated to dryness. The residue was purified by flash column chromatography using 80% ethyl acetate/hexanes as eluent. Pure fractions were combined and concentrated to afford a light yellow solid (1.58 g, 86%).
Reaction SMILES: ClC1C(C2C=CC=CC=2)=NN=C2N(CCI)N=C(C3C=CC=CC=3)C=12.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]=12.Cl.N1CCNCC1=[O:64].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][N:53]([CH3:56])[C:54](=[O:64])[CH2:55]3)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]=12
Reactant: CN1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Reactant: O=C1CNCCN1
Agent: Cl
Agent: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1=O
Reaction time: 48 h

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (example 74 step 1 (Compound 81)) (100 mg, 0.21 mmol) in CH2Cl2 (1 ml) was added to piperazinone hydrochloride (160 mg, 1.05 mmol) and diisopropylethylamine (DIPEA) (220 μl, 12.6 mmol) in CH2Cl2 (0.5 ml) and the reaction stirred at ambient for 2 days. Further piperazinone hydrochloride (160 mg, 1.05 mmol) and diisopropylethylamine (DIPEA) (220 μl, 12.6 mmol) were added and the reaction stirred for a further 24 h. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC to give Compound 84 as a yellow glass solid (17 mg).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(O)CC(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Agent: Cl
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(N2CCN(c3cccc(Cl)c3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (118.8 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 51 mg (29%), crystals;