Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][CH2:25][C:10]2([N:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH:11]2[CH3:24])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:13]1[C:10]2([CH2:25][CH2:26][CH2:27][NH:8][CH2:9]2)[CH:11]([CH3:24])[CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 189 %

Procedure:
To a solution of an optically-active compound of 3-methyl-1,6-diazaspiro[3,5]nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (78 mg) in chloroform (2 ml) cooled to 4° C. was added trifluoroacetic acid (0.4 ml), and the mixture was warmed to room temperature and stirred for additional 1 hour. The reaction mixture was basified by the addition of 1M aqueous sodium hydroxide solution, and extracted with chloroform. The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (108 mg).
Reaction SMILES: [Li]CCCC.Br[C:7](Br)=[CH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.O.Cl>C1COCC1>[C:8]([CH:9]1[CH2:10][CH2:11][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:13][CH2:14]1)#[CH:7]
Reactant: CCCc1ccc(C2CCC(C3CCC(C=C(Br)Br)CC3)CC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#CC1CCC(C2CCC(c3ccc(CCC)cc3)CC2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
23.7 ml (38.0 mmol) of n-BuLi are added to 7.70 g (16.4 mmol) of 4-(2,2-dibromovinyl)-4′-(4-propylphenyl)bicyclohexyl in 40 ml of THF at −75° C. When the addition is complete, the mixture is stirred at this temperature for 2 h and subsequently warmed to −20° C. Water and dil. hydrochloric acid are added, and the batch is extracted a number of times with MTBE. The combined organic phases are washed with water and sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=95:5). 4-Ethynyl-4′-(4-propylphenyl)bicyclohexyl is obtained as a colourless solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2n(C)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2cc(F)ccc21
Yield: 86.2 %

Procedure:
Cyclohexylamine (1.98 mL, 17.34 mmol) was added to a solution of Compound 41 (2.3 g, 8.67 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 2.38 g (97%) of white solids. M.P. 193° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 3.62 (s, 3H), 3.90 (m, 1H), 7.70 (m, 3H), 7.77 (d, J=8.0 Hz, 1H), 10.41 (s, 1H). EIMS m/z 341 (M+23).
Reaction SMILES: C([C@@H:5]1[CH2:10][N:9]([CH2:11][CH2:12][CH3:13])[C@@H:8]([CH3:14])[CH2:7][C:6]1=[O:15])(OC)=O.[OH-].[Na+]>Cl>[CH3:14][CH:8]1[CH2:7][C:6](=[O:15])[CH2:5][CH2:10][N:9]1[CH2:11][CH2:12][CH3:13]
Reactant: CCCN1C[C@@H](C(=O)OC)C(=O)C[C@@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCN1CCC(=O)CC1C

Procedure:
A solution of 6.5 g of predominantly (±)-trans-5-carbomethoxy-2-methyl-4-oxo-1-propyl piperidine and 30 mL of 20% hydrochloric acid was heated to reflux for 2 h. The solution was cooled in an ice bath, basified by addition of NaOH pellets until the pH was 9-10 and extracted with 5×100 mL of chloroform. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. After azeotropic dying with toluene there was obtained 5.6 g of predominantly (±)-2-methyl-4-oxo-1-propyl piperidine as an amber oil: TLC (EtOAc); 1H NMR (400 MHz, CDCl3) 3.1 (m, 1H), 2.9 (m, 1H), 2.8-2.6 (complex m, 3H), 2.5 (m, 4H), 1.5 (m, 2H), 1.15 (d, 3H), 0.9 (t, 3H).
Reaction SMILES: C(O[C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:32])=[N:18][C:19]=3[NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[O:7][C@@H:6]1[CH2:33][O:34]C(=O)C)(=O)C.[CH3:38]O>C[O-].[Na+]>[Cl:32][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@@H:9]3[O:10][C:11]([CH3:12])([CH3:38])[O:13][C@@H:5]3[C@@H:6]([CH2:33][OH:34])[O:7]2)=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Nc3ccc(Cl)cc3F)nc(Cl)nc21
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (400 mg) in methanol (7 ml), sodium methoxide, 25% in methanol, (3 drops) was added. On stirring for 15 min at 20° C. the reaction mixture went clear. On stirring at 20° C. for a further 90 min a precipitate formed. The precipitate was collected by filtration and dried in vacuo for 16 hours. This was dissolved in a mixture of acetone (15 ml) and 2-2-dimethoxypropane (3 ml), and para-toluene sulphonic acid (193 mg) added. The mixture was stirred at 20° C. for 3 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 ml), washed with water (50 ml) and brine (30 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with cyclohexane:ethyl acetate (1:1) gave the title compound as a white foam (240 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:34](O)[CH3:35]>O1CCCC1>[CH2:34]([CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])[CH3:35]
Reactant: CCOC(=O)COc1ccc(CC(NS(=O)(=O)c2ccccc2)c2cccnc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(CC(NS(=O)(=O)c2ccccc2)c2cccnc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-[2-benzenesulfonamido-2-(3-pyridyl)ethyl]phenoxyacetate (70 mg) was dissolved in 2 ml of ethanol and 2 ml of tetrahydrofuran, followed by addition of 0.30 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature for one hour. The solvent was concentrated under reduced pressure, and neutralized with 2N hydrogen chloride. Then, the crystalline deposited was taken out by filtration and recrystallized in aqueous ethanol, to yield 15 mg of ethyl 4-[2-benzenesulfonamido-2-(3-pyridyl)ethyl]phenoxyacetic acid. The spectrometric data thereof supports the structure of [21] as follows.
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH:7]=O.[CH3:27][NH2:28].[BH4-].[Na+].O>CO.CO.CCOC(C)=O>[CH3:27][N:28]1[CH2:7][CH2:6][CH2:5][CH:4]([C:9]2[N:13]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:3]1=[O:26]
Reactant: COC(=O)C(CCC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2C2CCCN(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a magnetically stirred solution of (+/−)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-5-oxo-pentanoic acid methyl ester 35c (0.085 g, 0.253 mmol) in methanol (1 mL) at room temperature under Ar atmosphere was added a 40% aqueous solution of methyl amine (MeNH2) (0.021 mL, 0.253 mmol). The reaction mixture was stirred for 1 h at room temperature. NaBH4 (0.019 g, 0.506 mmol) was added at room temperature. After 30 min, water (30 mL) was added, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (EtOAc, then 4:96 MeOH/EtOAc as eluent) which gave the title compound (0.03 g, 31%) as a white solid. The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude product. 1H NMR (400 MHz, CDCl3) δ 1.99 (m, 3H), 2.11 (m, 1H), 2.31 (s, 3H), 2.38 (s, 3H), 3.05 (s, 3H), 3.41 (m, 1H), 3.53 (m, 1H), 4.25 (m, 1H), 6.99 (d, J=9.1 Hz, 1H), 7.22 (m, 3H), 7.46 (s, 1H), 7.53 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 18.9, 21.5, 23.1, 26.1, 35.4, 39.7, 50.3, 117.4, 119.1, 121.5, 121.7, 127.0, 129.1, 129.3, 132.4, 137.5, 143.9, 144.4, 168.7. Mass spectrum m/e 335 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)=[O:11].Br[C:29]1[C:34]2[C:35]([NH2:38])=[N:36][NH:37][C:33]=2[CH:32]=[CH:31][N:30]=1>>[NH2:38][C:35]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][C:33]=2[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])=[CH:18][CH:17]=2)[NH:37][N:36]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: Nc1n[nH]c2ccnc(Br)c12
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccnc4[nH]nc(N)c34)cc2)c1

Procedure:
1-(2-Fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]urea is coupled, by Suzuki reaction, with 4-bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine according to a protocol similar to that for the preparation of Example 3. A yellow powder of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].I[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1)[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1ncc2ccc(C(=O)OC)cc21
Temperature: 60 °C

Procedure:
To a mixture of methyl 1H-indazole-6-carboxylate (0.95 g) in DMF (10 mL) was added 60% NaH (0.216 g). The mixture was heated to 60° C. and 1-iodobutane (0.61 mL) was added. The mixture was heated at 60° C. for 72 h and 1-iodobutane (0.61 mL) was added every 24 h. The mixture was removed from heat and cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% ethyl acetate in hexanes as eluent to give 0.356 g of the title compound: 1H NMR (CDCl3) δ 0.938, 1.34, 1.92, 3.97, 4.43, 7.73, 7.79, 8.03, 8.18.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][NH:7][C:6](=[O:13])[C:5]=2[C:4]([CH3:14])=[CH:3]1.CC(C)([O-])C.[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>C1COCC1>[Cl:25][CH2:24][CH2:23][CH2:22][N:7]1[CH2:8][CH2:9][C:10](=[O:12])[C:11]2[N:2]([CH3:1])[CH:3]=[C:4]([CH3:14])[C:5]=2[C:6]1=[O:13]
Reactant: Cc1cn(C)c2c1C(=O)NCCC2=O
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cn(C)c2c1C(=O)N(CCCCl)CCC2=O
Yield: 50.3 %

Procedure:
Using Compound 12 (0.96 g, 5 mmole), potassium t-butoxide (1.12 g, 10 mmole), 1-bromo-3-chloropropane (3.46 g, 22 mmole) and THF (50 ml), the title compound (676 mg) was obtained in a similar manner as in Preparation Example 6 (yield: 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14](F)[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1.CC1(C)O[C@@H]2CC[C@@H]([N:31]3C4C(F)=NC=C(F)C=4N=C3)[C@@H]2O1>N>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14]([NH2:31])[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)CC[C@H]2O1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)CC[C@H]2O1
Agent: N
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)CC[C@H]2O1
Temperature: 85 °C

Procedure:
Liquid ammonia (200 mL) was added to a mixture of 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-6) (2.4 g, 8.1 mmol, 1 equiv) and 3-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-3H-imidazo[4,5-c]pyridine (1-5) (2.5 g, 8.5 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 85° C. for 5 days. The mixture was then concentrated and purified via flash chromatography on a 120 g silica gel column (gradient elution 0 to 100% ethyl acetate in dichloromethane and then 100% methanol to elute 1-7) to yield 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-1H-imidazo[4,5-c]pyridin-4-amine (1-7) as a tan solid in addition to 3-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-3H-imidazo[4,5-c]pyridin-4-amine (1-8) and recovered starting material 1-5. 1H NMR (1-7) (500 MHz, CD3 OD): δ 8.13 (s, 1H); 7.62 (d, J=3.7 Hz, 1H); 4.95-4.87 (m, 3H); 2.52-2.42 (m, 1H); 2.21-1.99 (m, 3H); 1.50 (s, 3H); 1.33 (s, 3H). LRMS m/z (M+H) 293.0 found, 293.1 required. 1H NMR (1-8) (500 MHz, CDCl3): δ 7.86-7.81 (m, 1H); 7.76-7.73 (m, 1H); 5.07 (s, 1H); 5.01 (s, 2H); 4.87 (t, J=4.6 Hz, 1H); 4.62 (d, J=6.2 Hz, 1H); 2.66-2.57 (m, 1H); 2.46-2.38 (m, 1H); 2.24-2.17 (m, 2H); 1.57 (s, 3H); 1.35-1.30 (m, 3H). LRMS m/z (M+H) 293.0 found, 293.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Yield: 20 %

Procedure:
A mixture of 6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (200 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg, 0.78 mmol), 4-dimethylaminopyridine (95 mg, 0.78 mmol), methane sulfonamide (150 mg, 1.56 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (48 mg, 20%) as a light yellow solid: MS (ESI) M+1=462.2.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:17])[CH2:11][CH:12]2OCC[O:13]2)[CH2:5]1)([CH3:3])[CH3:2].ClCCl>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CC(C)=O>[CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:17])[CH2:11][CH:12]=[O:13])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCCC(C(C)CC2OCCO2)C1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C1CCCC(C(C)CC=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 585.3 %

Procedure:
2-[2-(3-isopropylcyclohexyl)propyl]-1,3-dioxolane (5 g, 20.8 mmol) and a 4:1 mixture of dichloromethane:acetone (300 mL) were charged into a 3 L three-necked round-bottom flask equipped with a reflux condenser and a mechanical stirrer. Iron (III) chloride hexahydrate (19.7 g, 72.8 mmol, 3.5 eq) was added at ambient temperature. The reaction mixture was then stirred at ambient temperature for 4 h and subsequently quenched at 5-10° C. with the addition of saturated aqueous NaHCO3 (500 mL). The organic phase was then washed with brine (500 mL), dried over magnesium sulphate and concentrated. The resulting crude product was distilled via a Vigreux column (1.3 mBar, 89° C.), to give 3-(3-isopropylcyclohexyl)butanal (23.9 g, gc purity>91%; yield 62%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.[Pd]>[NH2:17][CH2:16][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:14]=1[CH3:15]
Reactant: Cc1c(C#N)ccnc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(CN)ccnc1NC(=O)OC(C)(C)C
Yield: 84.3 %

Procedure:
A solution of 175 mg (0.75 mmol) of 2-t-butyloxycarbonylamino-4-cyano-3-methylpyridine and 88 μL (1.5 mmol) of acetic acid in 10 mL of MeOH was hydrogenated over 75 mg of 10% Pd-C at 55 psi overnight on a Parr apparatus. The catalyst was removed by filtration, concentrated at reduced pressure, and the residue partitioned between CHCl3 and 10% Na2CO3. The aqueous layer was extracted with CHCl3 and the combined organic layers were dried over Na2SO4 and concentrated to give 150 mg of the title compound as a colorless oil:
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[CH:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(C3CCCCC3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(C3CCCCC3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 32 %

Procedure:
This compound was synthesized from (4-(4-cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 32%). 1H NMR (400 MHz, MeOD) δ 8.50 (t, J=1.5 Hz, 1H), 8.29 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.98 (m, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.05 (s, 1H), 3.90-3.86 (dt, J=11.8 Hz, 3.9 Hz, 2H), 3.65 (s, 2H), 3.55-3.49 (m, 2H), 2.69 (m, 1H), 2.35 (d, J=13.8 Hz, 2H), 2.04-1.96 (m, 4H), 1.76-1.73 (m, 2H), 1.39 (m, 6H). MS (ESI) m/z: Calculated for C25H27F3N4O3S: 520.18. found: 521.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].N1C=CC=CC=1.[CH3:23][CH2:24][O:25]CC.C(Cl)(=O)C>O>[C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])(=[O:25])[CH3:23]
Reactant: CCOCC
Reactant: Cc1csc(N)c1C(=O)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl

Procedure:
To a mixture of 62 g of 2-amino-(o-chlorobenzoyl)-4-methylthiophene, 62 g of pyridine and 2170 ml of anhydrous ether is added dropwise 62 g of acetyl chloride. The the reaction mixture is stirred under reflux for 4 hours and 30 minutes. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give an oily residure, which is crystallized from ethanol to give 2-acetylamino-3-(o-chlorobenzoyl)-4-methylthiophene having a melting point of 148° - 149°C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.[ClH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:20])[CH:14]=1>C(O)C>[ClH:20].[ClH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][S:1][C:2]2[NH:6][C:5]3=[CH:7][S:8][CH:9]=[C:4]3[N:3]=2)[CH:14]=1
Reactant: Sc1nc2cscc2[nH]1
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Solvent: CCO
Product: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
1.6 g of 2-mercaptothieno[3,4-d]imidazole and 2 g of 4-methoxypicolyl chloride hydrochloride in 50 ml of ethanol were heated at 60° C. for about one hour and stirred at room temperature for a further 40 hours. After the crystalline substance had been filtered off, it was suspended in acetone, the mixture was stirred at room temperature for one hour, and the crystals were filtered off with suction and dried in air. Colorless crystals, melting point 330° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:14]1[CH:13]=[CH:12][C:11]2[C:10]3[C:18](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:17](=[O:19])[C:16]=2[CH:15]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2-c2ccc(I)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 266.6 %

Procedure:
Add acetic acid (45 mL), concentrated sulfuric acid (5.4 grams, 0.055 moles), water (10 mL), 9-fluoreneone (9.01 grams, 0.05 moles), iodine (6.0 grams, 0.0237 moles), and periodic acid (2.85 grams, 0.0125 moles) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the reaction mixture to 45° C. and stir 1 hour, then warm to 50° C. and stir an additional 2.5 hrs. Warm the mixture to 60° C. and add additional acetic acid (45 mL). Stir the reaction mixture for an additional 10 hours, cool to room temperature and stir the reaction mixture at room temperature for about 8 hours. Collect the precipitate by filtration. Transfer the filter cake and acetic acid (40 mL) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the mixture to 70° C. and add additional acetic acid with continued warming until a clear solution is observed. Reduce the reaction mixture to 50° C. and stir at 50° C. for 2 hours. Slowly cool the reaction mixture to 25° C. and stir 1 hour. Recover the precipitate by vacuum filtration. Air-dried the resulting filter cake to provide the title compound (10.2 g, 66.6% yield). 1H NMR (CDCl3, 500.0 MHz): δ 7.95 (d, 1H, J=1.5); 7.81 (dd, 1H, J=2, 8); 7.64 (d, 1H, J=7.5); 7.50 (m, 2H); 7.33-7.24 (m, 2H).