Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:31]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:31][CH3:32])[CH:37]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (144 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (297 mg, 97%) in an orange oily form.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)C>[Cl:8][C:7]1[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Yield: 69.8 %

Procedure:
A 500 mL round bottom flask was charged with 2,3-dichloropyrazine (10.0 g, 67.1 mmol), tert-butyl piperazine-1-carboxylate (25.0 g, 134 mmol) and ethanol (200 mL). The resulting solution was heated at reflux overnight. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 5%-10% EtOAc in petroleum ether, to afford 14.0 g (70%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.08 (d, J=2.4 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 3.55 (m, 4H), 3.38 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=O)[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.P(Cl)(Cl)(Cl)=O>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C#N)ccc(Br)c12
Temperature: 105 °C
Yield: 98.1 %

Procedure:
Step 1 A suspension of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 2.2 g, 6.09 mmol) in phosphorus oxychloride (45.4 mL, 487 mmol) was heated at 105° C. for 1 h. The suspension was cooled to rt and concentrated to give a brown solid, which was suspended in water. The precipitate was collected by filtration, washed with water and dried to provide ethyl 5-bromo-8-cyano-9H-carbazole-2-carboxylate (2.05 g, 98%) as light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H) 8.71 (d, J=8.57 Hz, 1H) 8.24 (s, 1H) 7.95 (d, J=8.57 Hz, 1H) 7.89 (d, J=8.13 Hz, 1H) 7.61 (d, J=8.13 Hz, 1H) 4.39 (q, J=7.10 Hz, 2H) 1.37 (t, 2H). Mass spectrum m/z 360, 362 (M+NH4)+.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>ClCCl>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCCC2
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCCC2
Yield: 31.3 %

Procedure:
Synthesized as described for 52 except using a solution of 77 (1.30 g; 5.64 mmol) in anhydrous dichloromethane (11 mL), methyl 3-aminothiophene-2-carboxylate (892 mg; 5.67 mmol), pyridine (1.14 mL; 14.10 mmol) and anhydrous dichloromethane (11 mL). This afforded the desired product as yellow solid (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)nc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (6-chloro-pyridin-3-yl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 2,4-pentanedione.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:40][CH3:39])[CH2:44][CH2:45]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: COCCN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OC(C)C)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methoxy-ethyl)-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H49N4O3Cl2 [(M+H)+] 679.3176, observed 679.3180.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([CH3:13])=[CH:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:14]=1.CO[C:17]1C=CC2CCCCN(CC)C=2[CH:29]=1.OC1C=CC2CCCCN(CC)C=2C=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([CH3:13])=[CH:11][CH2:10][CH2:9][N:8]([CH2:17][CH3:29])[C:7]=2[CH:14]=1
Reactant: CCN1CCCCc2ccc(OC)cc21
Reactant: COc1ccc2c(c1)NCCC=C2C
Agent: CCN1CCCCc2ccc(O)cc21
Product: CCN1CCC=C(C)c2ccc(O)cc21

Procedure:
The title compound was synthesized from 8-methoxy-5-methyl-2,3-dihydro-1H-benzo[b]azepine following the alkylation procedure for 8-methoxy-2,3,4,5-tetrahydro-1-ethylbenzo[b]azepine followed by the demethylation procedure used to synthesize 8-hydroxy-2,3,4,5-tetrahydro-1-ethylbenzo[b]azepine: 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 7.05 (d, 1H), 6.31-6.25 (m, 2H), 5.80 (t, 1H), 5.30 (s, 1H), 3.12-3.03 (m, 4H), 2.17 (q, 2H), 1.97 (s, 3H), 1.09 (t, 3H); MS expected 203 (C13H18NO, M+1), found 203.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.[NH4+].[Cl-]>O1CCCC1>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][CH:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@@H:5]2[CH2:4]1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)CCC2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)C(Cc3cccc(F)c3)C[C@H]2C1
Temperature: -40 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a solution of the product from Example 207A (0.10 g, 0.416 mmol) in anhydrous tetrahydrofuran (4 mL) at −78° C. under N2 was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.458 mL, 0.458 mmol) dropwise over 2 minutes. To the resulting solution was added 1-(bromomethyl)-3-fluorobenzene (0.056 mL, 0.458 mmol), and the resulting mixture was stirred at −40° C. for 3 hours. A solution of NH4Cl (10% in water, 1 mL) was added, and the mixture was allowed to warm to room temperature and partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% CH3OH in CH2Cl2 to give the title compound (75 mg, 52%).
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:22])([CH3:21])[CH2:5]1)(=[O:3])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[C:12]([N+:23]([O-:25])=[O:24])=[CH:13][C:8]=2[O:7][C:6]([CH3:22])([CH3:21])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CC(C)(C)Oc2ccc(NC(=O)C(F)(F)F)cc21
Solvent: CC(=O)O
Product: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 22.0 g 4-acetyl-3,4-dihydro-2,2-dimethyl-6-trifluoroacetylamino-2H-1,4-benzoxazine in 100 ml acetic acid, was added dropwise a solution of 3.7 ml fuming nitric acid in 50 ml acetic acid, and the resulting solution was stirred at room temperature for two hours. The reaction mixture was poured into 600 ml ice water, the crystals which separated out were collected by filtration, and recrystallized from 100 ml ethanol, giving 21.6 g of 4-acetyl-3,4-dihydro-2,2-dimethyl-7-nitro-6-trifluoroacetylamino-2H-1,4-benzoxazine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][F:14])[C:8]2=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].C=C[C@@H]1[C@@H]2[CH2:25][C@H:26]([C@@H:27]([OH:38])[C:28]3C4C(=CC=CC=4)N=CC=3)[N+](CC3C=CC(C(F)(F)F)=CC=3)(CC2)C1.[Br-].C(C(C)=O)=C.[OH-].[K+]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH2:12][CH2:13][F:14])([CH2:25][CH2:26][C:27](=[O:38])[CH3:28])[C:8]2=[O:11])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: C=C[C@H]1C[N+]2(Cc3ccc(C(F)(F)F)cc3)CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Reactant: COc1cc2c(cc1Cl)C(=O)C(CCF)C2
Agent: C=CC(C)=O
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(=O)C(CCF)(CCC(C)=O)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one (34 g, 140 mmol) in toluene (1500 mL) was added N-[4-(trifluoromethyl)benzyl]cinchoninium bromide (13 g, 24 mmol) and the mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., methyl vinyl ketone (20 mL, 240 mmol) was added followed by potassium hydroxide pellets (85%, 34 g, ˜52 mmol) and the mixture was vigorously stirred for 90 minutes. The reaction mixture was diluted with dichloromethane (1000 mL), dried with MgSO4 and filtered. The filtrate was filtered through a pad of silica gel, washing with Et2O and EtOAc. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (elution with 30% to 50% EtOAc/hexanes) to give 6-chloro-2-(2-fluoroethyl)-5-methoxy-2-(3-oxobutyl)indan-1-one as a yellow oil. Analysis by chiral HPLC indicated an enantiomeric ratio of approximately 2:1 favoring the desired (2S)-enantiomer. This enantiomerically enriched material was utilized for the remainder of the synthesis.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:14]([N:16]([CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1)[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:15]
Reactant: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2nc3ccccc3cc2CO)CC1
Temperature: 25 °C

Procedure:
A suspension of 2-chloroquinoline-3-carbaldehyde (93 mg, 0.49 mmol), ethyl trans-{4-[(N-ethylamino)methyl]cyclohexyl}acetate (165 mg, 0.73 mmol) and potassium carbonate (134 mg, 0.97 mmol) in toluene (2 mL) is stirred and refluxed for 3 days. The reaction mixture is cooled to room temperature, diluted with water and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue is dissolved with ethanol (1.5 mL) and treated with sodium borohydride (18 mg, 0.48 mmol). The mixture is stirred at room temperature for 2 hours. After addition of sat. ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give ethyl trans-[4-({N-ethyl-N-[3-(hydroxymethyl)quinolin-2-yl]amino}methyl)cyclohexyl]acetate.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[C:4]1[CH3:20])[CH3:2].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:3]([CH2:1][CH3:2])[C:4]([CH3:20])=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCn1c(C)c(-c2ccccc2Br)c2cc(O)ccc21
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1Br)c(C)n2CC

Procedure:
The above compound was prepared from 1-ethyl-3-(2-bromo-phenyl)-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester analogously to Example 10.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.C([O:14][C:15]([C:17]1[S:21][C:20](Cl)=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])C>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([C:20]3[S:21][C:17]([C:15]([OH:16])=[O:14])=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Reactant: Cc1cc2nc[nH]c2cc1C
Product: Cc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)O)s3)c2cc1C

Procedure:
2-(5,6-Dimethylbenzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid was prepared in a similar manner as that for Example 1 starting with the reaction of 5,6-dimethylbenzoimidazole and 2-Chloro-4-phenylthiazole-5-carboxylic acid ethyl ester. 1H-NMR(DMSO-D6) 8.82 (s, 1H); 7.98 (s, 1H); 7.82-7.92 (m, 2H); 7.58 (s, 1H); 7.42-7.52 (m, 3H); 2.39 (s, 3H); 2.38 (s, 3H). MS M/z 350 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.48 mmol) was added to a suspension of sodium hydride (60%, 149 mg, 3.73 mmol) in THF (8.28 mL) and the mixture was stirred for 30 minutes at room temperature. 2,4-Dichloropyrimidine (333 mg, 2.24 mmol) was added to the reaction mixture at 0° C. and warmed to room temperature over 3 days. The mixture was diluted with ethyl acetate (20.0 mL), and then washed with water:brine 1:1 (3×40 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (10-60% ethyl acetate in hexanes) to yield tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate. MS APCI calc'd for C14H21ClN3O3 [M+H]+ 314. found 314.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH:16][C:17]([C:19]2[NH:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[O:18])=[CH:4][CH:3]=1.[C:26]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:6]2[C:5]([NH:16][C:17]([C:19]3[NH:23][CH:22]=[C:21]([C:24]#[N:25])[N:20]=3)=[O:18])=[CH:4][CH:3]=[C:2]([C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:7]=2)=[CH:9][CH2:10]1
Reactant: O=C1CCCC1
Reactant: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Product: CC1(C)CC=C(c2nc(C3(O)CCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step) and cyclopentanone according to the procedure in Example 1, step (h).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.[OH-].[Na+].O.O.O.O.O.O.[Cl-].[Al+3:31].[Cl-].[Cl-]>O>[O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1.[Al+3:31].[O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1.[O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)c1ccc(N2CC3=C(CC=CC3)C2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)[O-])c1ccc(N2CC3=C(CC=CC3)C2=O)cc1
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A mixture of 0.5 g (0.0018 mole) of α-[4-(1-oxo-4,7-dihydro-2-isoindolinyl)phenyl]propionic acid, 0.072 g (0.0018 mole) of sodium hydroxide and 5 ml of water was stirred for about 1 hour. At the end of this time, a solution of 0.434 g (0.0018 mole) of aluminium chloride hexahydrate in 10 ml of water was added dropwise at room temperature to the mixture. The white precipitate produced was collected by filtration, washed with 75 ml of water and dried at 105° C. for 4 hours. There was obtained 0.45 g of a white solid, which was sparingly soluble in most organic solvents and slightly soluble in dimethyl sulphoxide, and which had a melting point over 300° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[F:11][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,2-difluoro-4-nitro-benzene Compound 132a (1.3 g, 8.2 mmol), K2CO3 (1.2 g, 9.0 mmol) and phenol Compound 132b (0.84 g, 9.0 mmol.) were combined with 10 mL of NMP in a sealed pressure tube. The reaction was heated in a microwave at 140° C. for 50 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO4, then filtered and concentrated down to an oil. The crude oil in ethyl acetate (25 mL) was added to 10% Pd/C (1.3 g) and placed under 40 psi of hydrogen in a Parr apparatus for 1 hr. The solution was then filtered through Celite and concentrated to give 3-fluoro-4-phenoxy-phenylamine Compound 132c (1.9 g). MS 204 (MH+). An alternative procedure for making Compound 132c is described in U.S. Pat. No. 3,652,665. Using the procedure of Example 1, 3-fluoro-4-phenoxy-phenylamine Compound 132c was used in place of Compound 1e to prepare 4-chloro-6-(3-fluoro-4-phenoxy-phenylamino)-pyrimidine-5-carbonitrile Compound 132d. Using the procedure of Example 1, Compound 132d was carried forward in place of 4-chloro-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile Compound 1f to prepare 5-(3-fluoro-4-phenoxy-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 112. MS 423 (MH+). Compound 112 was carried forward in place of Compound 1 and 4-morpholin-4-ylmethyl-phenylamine Compound 3e was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 113. MS 597 (MH+).