Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([NH:22][NH2:23])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:21][C:34](=[O:36])[NH:23][N:22]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)NN)c3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
To a solution of 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carbohydrazide (1 g, 3.2 mmol) in DCM (100 mL) and DIPEA (1.19 mL, 19 mmol) was added a solution triphosgene (1.1 g, 3.7 mmol) in DCM (3 mL) dropwise. The reaction was stirred at RT for 2 h, then the solution was concentrated in vacuo. The residue was purified with silica gel chromatography (eluting with 0-10% MeOH in DCM) to give 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (50 mg, 5%) as a white solid. MS (ESI, pos. ion) m/z: 338.0 (M+1); 1H NMR (DMSO-d6) δ ppm: 12.32 (s, 1H), 12.1 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.00-8.17 (m, 3H), 7.6 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 1.49 (d, J=6.0 Hz, 6H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][OH:12]
Reactant: O=C(O)[C@H]1COc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1COc2ccccc2O1

Procedure:
(R)-2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid (27.9 mmol, 5.02 g) was dissolved in dry THF (30 ml). LiAlH4 (56.9 mmol, 2.16 g) was added. The mixture was refluxed for 70 minutes. After cooling, the reaction was quenched with water and 1 M NaOH. The mixture was filtrated through Celite and evaporated to dryness. This gave 4.3 g of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH2:19]([C:21]1[CH:22]=[C:23]([CH3:33])[C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1)[CH3:20]>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[C:9]([CH3:17])[C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[C:23]([CH3:33])=[CH:22][C:21]([CH2:19][CH3:20])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:15][CH:16]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)c(C)c1
Yield: 5.1 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (251 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Example 109, the title compound (25 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](=[O:25])[CH3:24].O>O1CCCC1>[C:23]([CH:22]([C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14])[C:10](=[S:11])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(N=C=S)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C(=S)Nc1ccc(F)cc1F)c1ccc(Cl)cc1Cl
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
2,4-Difluorophenyl isothiocyanate (0.27 mL, 2.0 mmol) was added to a stirred suspension of sodium hydride (60% in mineral oil) (112 mg, 2.8 mmol) in anhydrous tetrahydrofuran (4 mL) cooled in an ice-water bath under a nitrogen atmosphere. A solution of (2,4-dichlorophenyl)-2-propanone (570 mg, 2.8 mmol) in tetrahydrofuran (4 mL) was added dropwise over 5 min. The resultant yellow solution was stirred at 5-10° C. for 1 h. Water (10 mL) was carefully added, and the reaction mixture was extracted with ethyl acetate (10 mL). The aqueous phase was acidified to pH 3 with 1 N aqueous HCl, then extracted with ethyl acetate (20 mL). The organic extract was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a solid. The solid was triturated with hexanes/ethyl acetate (2:1), collected on a glass frit, and air-dried to give the title compound as a white solid (240 mg). MS: 373 amu (AP+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]1=[O:20].[Cl-].[NH4+].C(=O)(O)[O-].[Na+].CCOC(C)=O>CO.[Zn]>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]2=[O:20])[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: CN1CCN(c2cc(C#N)cc([N+](=O)[O-])c2Cl)C(=O)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(C#N)cc(N)c2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 4-chloro-3-(4-methyl-2-oxopiperazin-1-yl)-5-nitrobenzonitrile (40 mg, 0.136 mmol) in MeOH (4 mL) was added ammonium chloride (218 mg, 4.07 mmol) and zinc (133 mg, 2.036 mmol) (in two portions, after the first portion, reaction was not complete). After stirring at room temperature for 12 h. LC-MS indicated completion. Then 5 mL of saturated aqueous sodium bicarbonate solution was added followed by 10 mL of EtOAc. The mixture was filtered through a pad of Celite and the filter cake was washed EtOAc. The solvent from the filtrate was evaporated. Purification via flash chromatography (0-10% MeOH in DCM, 24 g) gave 3-amino-4-chloro-5-(4-methyl-2-oxopiperazin-1-yl)benzonitrile (28 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][O:13][C:14]3=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[C:16]3[C:10]([CH:11]=[CH:12][O:13][C:14]3=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1OCCc2ccc(Oc3ccc(Cl)cc3)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1occc2ccc(Oc3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of 500 mg of 7-(4-chlorophenoxy)-3,4-dihydroisocoumarin, 325 mg of N-bromosuccinimide and 20 mg of benzoyl peroxide in 20 ml of carbon tetrachloride was refluxed under heating for 2 hours. After finishing the reaction, the mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was mixed with 10 ml of toluene and 490 mg of 1,8-diazabicyclo[5, 4, 0]undec-7-ene and stirred at room temperature for 1 hour. The toluene was evaporated in vacuo, and the resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate and hexane (1:1) to give 367 mg of the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=2)=[C:13]([F:18])[CH:12]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: Cc1cc(Br)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)cc2F)cc(C)n1
Temperature: 150 °C
Yield: 80 %

Procedure:
A mixture of 4-bromo-2,6-dimethyl-pyridine (1 g, 5.4 mmol), 4-bromo-2-fluoro-phenol (0.59 g, 5.4 mmol), and potassium carbonate (0.89 g, 6.4 mmol) in xylenes (2 ml) was heated at 150° C. (oil bath temperature) in a sealed tube for 48 hours. After cooling to room temperature the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated vacuo to yield intermediate 19 (1.28 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH2:23][CH3:24])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:23][CH3:24])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCn1c2ccccc2c2cc(Nc3ccnc(Cl)n3)ccc21

Procedure:
Briefly, 2,4-dichloropyrimidine (1) was reacted with 3-amino-9-ethylcarbazole (2) by heating in iso-propanol in the presence of N,N-diisopropylethylamine. Separation of the regioisomers provided the pure 4-substituted pyrimidine derivative (3), which was reacted with 4-(3-Aminopropyl)morpholine (4) in sec-butanol under microwave heating in the presence of N,N-diisopropylethylamine to provide EHop-016 (5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)c(Cl)c3)[C@@H](N(C)C(=O)Oc3ccc(F)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-acetyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using methoxyacetyl chloride instead of propionyl chloride and was obtained as a white foam. MS m/e: 566.3 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13]([O:15][CH3:16])=[N:12][C:11]([CH2:17][CH3:18])=[C:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:36]([O:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:37])[C:13]([O:15][CH3:16])=[N:12][C:11]([CH2:17][CH3:18])=[C:10]2[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 4 h

Procedure:
Into a well-stirred solution of benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate (27.5 g, 68.75 mmol) and pyridine (9.2 mL) in CH2Cl2 (300 mL) was added 4-nitrophenyl chloroformate (14.49 g, 82.5 mmol) at room temperature. The reaction mixture was stirred for 4 h and then washed with 10% aqueous KOH solution (2×150 mL). The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the residue was used in the next step without further purification: 1H NMR (CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:24][CH2:23][C:22]3[N:21]=[C:20]([CH2:25][CH3:26])[C:19]([C:27]([O:29][CH3:30])=[O:28])=[CH:18][C:17]=3[C:16]2=[O:31])[CH2:11][CH2:10]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[CH2:25]([C:20]1[C:19]([C:27]([O:29][CH3:30])=[O:28])=[CH:18][C:17]2[C:16](=[O:31])[N:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:24][CH2:23][C:22]=2[N:21]=1)[CH3:26]
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Product: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2M hydrogen chloride (methanol solution, 236 mL) and methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (19.7 g) was stirred at room temperature under nitrogen atmosphere for 4 hours and concentrated in vacuo. The residue was crystallized with methanol and ethyl acetate. After filtration, the crystals were washed with ethyl acetate to give the title compound (18.5 g).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]>O>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C=O
Solvent: O
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reaction time: 9.5 h
Yield: 52 %

Procedure:
MoO3 (600 mg) was added to a mixture of 6-deoxy-L-talose (100 g) in water (1.5 l). The reaction mixture was stirred for 9.5 h at reflux. At 80° C. resin IRA-67 (SUPELCO, 50 g) was added and the mixture was stirred for further 30 min, filtered and distilled off. The residue was dissolved in isopropanol (400 ml) and directly evaporated. Isobutanol (400 ml) was then added and the mixture was heated under reflux for 10 min and allowed to cool. Crystallization spontaneously occurs or it was promoted by adding seed crystals. After one night at room temperature the suspension was filtered to give L-fucose (52 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22]1>C(O)C.N1CCCCC1>[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:27])[CH2:22]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)N2CC[C@H](N(C)C)C2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3S)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.C([O-])(O)=O.[Na+].[CH2:21]([O:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:27][CH:26]=1)[CH3:22]>CCO>[CH2:21]([O:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([N:32]2[CH2:37][CH2:36][N:35]([C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:34][CH2:33]2)=[N:27][CH:26]=1)[CH3:22]
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Reactant: CCOC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (2.82 g, 0.12 mol) and NaHCO3 (1.95 g, 0.023 mol) in EtOH at 0° C., add 5-chloro-6-piperazin-1-yl-nicotinic acid ethyl ester (3.44 g, 0.013 mol). Remove the ice bath and stir at room temperature for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13](O)=[O:14])=[CH:8][O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([Cl:19])=[O:14])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2c(O)c(O)ccc2c1=O
Product: O=C(Cl)c1coc2c(O)c(O)ccc2c1=O

Procedure:
A mixture of 7,8-dihydroxychromone-3-carboxylic acid (6.6 g, 30 mmol) and thionyl chloride (25 ml) was refluxed for 1 hour, and the thionyl chloride was removed. After the addition of benzene to the residue, the mixture was evaporated to dryness and the residue was triturated with n-hexane to give the desired compound (7.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]([CH3:16])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]([CH3:16])=[N:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C(C)C
Solvent: CC(=O)O
Product: Cc1ncc(-c2nc(N)ncc2Cl)n1C(C)C
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Method 39 of WO 03/076436; 0.5 g, 2.3 mmol) and N-chlorosuccinimide (0.4 g, 3 mmol) in acetic acid (5 ml) was stirred at 65° C. under nitrogen for 2 hours. Then the reaction mixture was allowed to cool down to room temperature and the solvent was removed under vacuum. The crude was taken up in EtOAc and water then portions of solid potassium carbonate were added to this stirred biphasic solution until pH 8-9 was reached. The two layers were separated, the aqueous layer was extracted once with EtOAc then the organics were combined, washed with brine and dried. Removal of the solvent left a residue, which was purified on silica (MeOH/DCM/EtOAc, from 0/50/50 to 6/47/47). Triturating the foam in ether gave a white solid, which was filtered off. (0.49 g, 85%). NMR (CDCl3): 1.51 (d, 6H), 2.55 (s, 3H), 4.85 (septuplet, 1H), 5.01 (b s, 2H), 7.48 (s, 1H), 8.31 (s, 1H); m/z 252 (35Cl), 254 (37Cl); m/z 250 (35Cl), 252 (37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CCOCC.O>[CH3:13][O:14][C:15]([C:16]1[C:4]([C:3]2[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:6][O:7][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: COC(=O)C#Cc1ccccc1
Reactant: ON=C(Cl)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1ccccc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 2-chloro-6-fluorobenzoylchloride oxime (1.04 g, 5.00 mmol) and methyl-3-phenyl-2-propynoate (1.20 g, 7.50 mmol) in Et2O (25 ml) at 0° C. under nitrogen was added a solution of triethyl amine (0.834 ml, 6.00 mmol) in Et2O (3 ml) over 1 h. The reaction was allowed to warm to room temperature overnight (17 h). The mixture was diluted with Et2O and H2O, the layers separated, and the organic fraction was dried (MgSO4). Column chromatography (silica gel, hexane/Et2O gradient) gave the title compound (1.53 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2>CN(C=O)C>[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:31]2
Reactant: Fc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc(F)c4C3)c(F)cc2c1=O
Yield: 81.9 %

Procedure:
180 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 210 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 196 mg of the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C(#N)C>[CH2:2]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: c1c[nH]cn1
Reactant: CC(=O)CCCBr
Solvent: CC#N
Product: CC(=O)CCCn1ccnc1

Procedure:
5-Bromo-2-pentanone (1.65 g.) and imidazole (3.5 g.) in 15 ml. acetonitrile were stirred at 60° C. for 48 hours and the solvent removed. The residue was chromatographed on silica gel, eluting with 10% methanol in dichloromethane to give 1-(n-pentan-4-onyl)imidazole. This material in 40 ml. methanol was reduced with sodium borohydride in a similar manner to that described in Preparation 2A to give 1-(4-hydroxy-n-pentyl)imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][NH:7][N:6]=1)=[O:4]>[Pd].C(O)C.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1n[nH]cc1N
Reaction time: 8 h

Procedure:
A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (10 g, 58 mmol) and 10% palladium on carbon (500 mg) in ethanol (150 ml) and DMF (30 ml) stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through celite reduced in vacuo and dried through azeotrope with toluene and methanol to afford 4-amino-1H-pyrazole-3-carboxylic acid methyl ester as a dark amber tar (9.35 g). (LC/MS (acidic): Rt 0.39 min, [M+H]+ 142).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: C=O
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoro-1-methyl piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (from Example 381) and formaldehyde following General Procedure R.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1>CO.N=[N+]=[N-].[Ni]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#CCc1ccc(-n2cnc3cnc4ccc(Cl)cc4c32)cc1
Agent: [Ni]
Agent: [N-]=[N+]=N
Solvent: CO
Product: NCCc1ccc(-n2cnc3cnc4ccc(Cl)cc4c32)cc1

Procedure:
In analogy to Example 42, the title compound is prepared from 400 mg (1.25 mmol) [4-(8-chloro-imidazo[4,5-c]quinolin-1-yl)phenyl]-acetonitrile (Example 39) in 65 ml methanol/HN3 aqu. 10% and 250 mg Raney-Ni. mp: 140-141° C.; MS: 323 (M++1); HPLC: tret=8.98 min (Grad 3).