Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1)(=O)=O.[CH3:36][NH2:37]>CO>[CH3:36][NH:37][CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: CN
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(COS(C)(=O)=O)c3ccccc32)cc1
Solvent: CO
Product: CNCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 100 °C

Procedure:
To 5-methanesulfonyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is added a 30% solution of methylamine in methanol (50 ml), and the mixture is heated at 100° C. for 3 hours in a sealed tube. After cooling, the reaction solution is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol:aqueous ammonia=100:10:1) to give 5-methylaminomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][CH:33]=[O:34])([CH3:31])[CH:27]=1.C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([OH:36])=[O:34])([CH3:31])[CH:27]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC=O)CC1)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclohexylamine according to conditions described in general procedure C. Mp: 118-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.00-1.23 (m, 6 H), 1.60-1.74 (m, 10 H), 3.10-3.29 (m, 5 H), 6.10-6.30 (m, 1 H), 6.97-7.00 (m, 2 H), 7.17 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.62 (m, 3 H), 7.83 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 8.21 (s, 1 H), 10.47 (s, 1 H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[OH-].[Li+]>C(#N)C.O>[C:15]([O:14][C:12]([N:6]1[CH2:7][C:8]([F:10])([F:11])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (Example 14a, 7.53 g, 28.403 mmol) was dissolved in acetonitrile (330 mL) and a solution of lithium hydroxide (1.36 g, 56.807 mmol) in water (110 mL) was added. After stirring for 16 h at 25° C., the acetonitrile was removed in vacuo and the aqueous phase was slowly acidified with 1.0 M aqueous hydrochloric acid solution until a precipitate formed. The product was extracted into ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford the desired product, 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.54 g, 6.13 mmol, 95.6% yield) as a brittle, tan solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 1.51 (9H, s), 2.50-2.84 (2H, m), 3.71-3.90 (2H, m), 6.73 (1H, bs).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:13]=[N:12]2)[C:8]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][C@@H:30]3[CH2:29][O:28][C:27]([CH3:39])([CH3:26])[O:31]3)[N:34]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)n1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)n1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(6-methyl-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 77) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(6-methyl-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light tan foam as a mixture of diastereomers (0.95 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[NH:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[Cl:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C(C)=CC=CC=1C>ClCCl>[Cl:25][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=1[O:13][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][S:33]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[C:8](=[O:11])[NH:7][C:6]2=[O:12]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2N)C(=O)NC3=O)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2NS(=O)(=O)c2ccc(Cl)cc2)C(=O)NC3=O)c(Cl)c1

Procedure:
Compound 30.2 (25 mg, 0.07 mmol) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol) were stirred in dichloromethane (0.5 mL) with 2,6-lutidine (0.25 mL, 0.21 mmol) at 25° C. for 14 h. The reaction mixture was loaded directly on a silica gel column and purified using 20% EtOAc/hexane as the eluent to give methyl 2-(3-chloro-4-(6-(4-chlorophenylsulfonamido)-1,3-dioxoisoindolin-5-yloxy)phenyl)acetate, and a compound with LC-MS matching a bis-sulfonamide. Both acetates were hydrolyzed in MeOH/THF/water (0.3 mL each) with LiOH.H2O (6 mg, 0.14 mmol) at 25° C. for 2 h to give the same desired product (30). The reaction mixtures were acidified to pH ˜3 and extracted with dichloromethane to give compound 30 as a pale-yellow solid. MS ESI (pos.) m/e calcd for (M+H3O)+ 539.0. found 539.0. 1H NMR (500 MHz) (DMSO-d6) δ 12.46 (br. s, 1H); 10.42 (s, 1H); 7.79 (d, J=8.3 Hz, 2H); 7.64 (d, J=8.5 Hz, 2H); 7.50 (d, J=1.9 Hz, 1H); 7.24 (dd, J=11.9, 8.3 Hz, 1H); 7.18 (s, 1H); 7.08 (s, 1H); 6.98 (s, 1H); 6.81 (d, J=8.2 Hz, 1H); 3.64 (s, 2H).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[C:30](=[O:32])[CH2:29][CH2:28]2>CO>[Cl:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[C:30](=[O:32])[CH:29]([F:21])[CH2:28]2
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: O=C1CCc2cc(F)cc(Cl)c21
Agent: F[B-](F)(F)F
Solvent: CO
Product: O=C1c2c(Cl)cc(F)cc2CC1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Selectfluor™ (2.49 g, 7.02 mmol) was added to a solution of 7-chloro-5-fluoro-1-indanone (CAS No. 1260008-48-7, 1.08 g, 5.85 mmol) in MeOH (30 mL) at room temperature. The mixture was refluxed for 2 hours. After cooling to room temperature, the resulting mixture was evaporated to remove the solvent under reduced pressure. To the residue was added DCM and the insoluble matter was filtered off. The filtrate was concentrated in vacuo. The residue was dissolved in MeCN (20 mL) and 5 N HCl (10 mL) and the solution was stirred at room temperature for 1 hour. After concentration of the solution in vacuo, the residue was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound (1.13 g, 5.58 mmol).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-fluorobenzenesulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2[S:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]=2[CH:16]=1>CCOCC>[C:17]([C:8]1[C:9]2[S:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:16]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)cc2c1SCC2(C)C
Solvent: CCOCC
Product: CNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CS2

Procedure:
Methylisocyanate (0.14 mL, 2.28 mmol) is added dropwise to a solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzothiophene (550 mg, 2.33 mmol) in Et2O (5 mL). A solid gradually forms and the reaction is quenched with H2O (10 mL). The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to a tan solid. This solid is recrystallized from EtOAc to give the product as white prisms, mp>150° C.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[Cl:19])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:20](Br)[C:21]#[CH:22]>>[CH2:22]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[C:11]([Cl:19])[CH:12]=1)[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: CC(C)CCCC(C)Oc1ccc(C(=O)O)cc1Cl
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)c(Cl)c1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)oxy]-3-chlorobenzoic acid with propargyl bromide, there is obtained 4-[(1,5-dimethylhexyl)oxy]-3-chlorobenzoic acid propargyl ester; nD26 = 1.5155.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]4[C:18]([CH3:21])=[N:19][N:20]=[C:13]4[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=[C:9]2N2C=NC=N2)=CC=1>FC(F)(F)C(O)=O>[CH3:21][C:18]1[N:14]2[C:15](=[O:17])[C:16]3[NH:8][C:9]([N:14]4[CH:13]=[N:20][N:19]=[CH:18]4)=[N:10][C:11]=3[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:20][N:19]=1
Reactant: CCCCCn1c2nc(-n3cncn3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc(-n3cnnc3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 0.12 mmol) in trifluoroacetic acid (10 mL) was stirred at 60° C. overnight. The mixture was concentrated and purified by preparative LC-MS to give the desired product (20 mg, 52%). LCMS calculated for C14H18N9O (M+H): 328.2. Found: 328.2.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].F[C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:22]([O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7]3)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: CC(C)Cn1ncc2cc(O)ccc21
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 110 °C
Yield: 80.8 %

Procedure:
To a solution of 1-isobutyl-1H-indazol-5-ol (2.33 g, 12.2 mmol) and K2CO3 (2.03 g, 14.7 mmol) in DMF (75 mL) was added 2,5-difluorobenzonitrile (1.87 g. 13.5 mmol). The mixture was heated to 110° C. for 18 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was chromatographed on Biotage eluting with hexanes/ether (5:2) to afford 3.05 g of pale yellow oil (81% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[NH2:21][C:22]1[N:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=1>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:23]2[C:24](=[O:28])[NH:25][CH:26]=[N:27][C:22]=2[NH:21][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: Nc1cc(=O)[nH]cn1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2nc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
500 mg (1.85 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are mixed with 308 mg (2.77 mmol) of 6-aminopyrimidin-4(3H)-one, dissolved in 10 ml of isopropanol and heated under reflux under argon for 2 days. The mixture is then concentrated and the residue is recrystallized from methanol. 341 mg (51% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: CCOC(=O)c1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 80.7 %

Procedure:
A mixture of methyl thiosalicylate (2.0 g, 11.9 mmol), ethyl 6-cyano-2-pyridinecarboxylate (2.1 g, 11.9 mmol), triethylamine (3.0 ml, 21.5 mmol) and toluene (6 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from diisopropylether-tetrahydrofuran to give the titled compound (3.0 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)nc1C

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 4-biphenylsulfonyl chloride as described for EXAMPLE 30 with tile exception that it was not recrystallized. Yield 96 mg, 24%: 1H NMR (DMSO) δ 7.8-7.95 (m, 4H), 7.65-7.75 (m, 2H), 7.35-7.55 (m, 3H), 4.23 (q, 2H); 2.39 (s, 3H), 1.26 (t, 3H); MS-ES (neg) m/z 401.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 710.4 [(M+H)+]
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:17])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([Cl:17])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1ccc2c(c1)OCO2

Procedure:
3-Benzo[1,3]dioxol-5-yl-propionic acid (2.50 g, 12.9 mmol) and thionyl chloride (20 mL, 274 mmol) were heated to 79° C. for 4 h then concentrated to afford 3-(benzo[d][1,3]dioxol-5-yl)propanoyl chloride as a brown oil. 2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-2-methyl-propylamine (100 mg, 0.432 mmol) and methylene chloride (20 mL) were added and the reaction mixture stirred at rt for about 2 h. The reaction mixture was filtered, filtrate washed with K2CO3 (100 mL, sat. aq.), and the organic layer was dried over Na2SO4. Filtration, concentration and purification using column chromatography gave 40 mg of 3-benzo[1,3]dioxol-5-yl-N-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-2-methyl-propyl]-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.92 (s, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 6.70 (m, 3H), 5.90 (s, 2H), 3.59 (d, 2H), 2.94 (t, 2H), 2.57 (s, 3H), 2.40 (t, 2H), 1.28 (s, 6H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:28]([NH2:30])[CH3:29].CN(C=O)C>O>[CH2:28]([NH:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH3:29]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.55 g of potassium carbonate, 0.16 g of ethylamine hydrochloride and 3 ml of DMF was stirred while heating at 80° C. for 4.5 hours. To the mixture, 0.55 g of potassium carbonate, 0.16 g of ethylamine hydrochloride and 2 ml of DMF were added, and the reaction mixture was stirred while heating for further three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of ethyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]amine (hereinafter, referred to as “active compound 84”).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:21][CH2:20][C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:37])C=1Cl>C1COCC1.O>[CH2:25]([O:24][C:22]([C:10]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[C:20](=[O:37])[CH2:21][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=2)[CH:9]=1)=[O:23])[CH3:26]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (190 mg, 0.5 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (139 mg, 0.6 mmol) was added a mixture of THF-H2O (9:1, 8 mL) at ambient temperature. The reaction mixture was allowed to stir at ambient temperature for 2 hours. Additional DDQ (139 mg, 0.6 mmol) was added, and the mixture was stirred at ambient temperature for another 2 hours. The solvent was removed in vacuo, and the residue was taken up in EtOAc and washed thoroughly with saturated sodium bicarbonate solution and then with brine. The organic phase was dried with sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (85:15) to give the title compound as a yellow solid (180 mg, 92%); 1H-NMR (CDCl3): δ 11.4 (1H, s), 8.52-8.48 (2H, m), 7.66-7.62 (2H, m), 7.48-7.46 (1H, m), 7.37-7.31 (2H, m), 7.22-7.17 (2H, m), 4.53 (2H, s), 4.38 (2H, q), 1.35 (3H, t); MS (ES): 393 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:16]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:30]CC>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]=[O:30]
Reactant: CCOCC
Reactant: COc1ccccc1C1CCCCC1CC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCCCC1CC=O
Yield: 96 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-acetonitrile (0.346 g, 1.51 mmol), diisobutylaluminum hydride (2.7 mL, 2.72 mmol), and ether (8.0 mL) at −10° C. After 1 hour quenched reaction at 0° C. with 1N HCl and added ethyl acetate. Separate layers, wash with brine, and dry over anhydrous sodium sulfate. Concentrate to yield the titled compound (0.336 g, 96%). TLC Rf=0.08 in 5% ethyl acetate/hexanes. 1H NMR (CDCl3): 9.3 (s, 1H), 7.2 (m, 1H), 7.0 (m, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.3 (m, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.2 (m, 2H), 1.6 (m, 7H).