Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([F:23])[CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Temperature: 47.5 °C
Yield: 94.2 %

Procedure:
A solution of 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid methyl ester (400 mg, 1.2 mmol) in ethanol (8 mL) was treated with a 1N aqueous sodium hydroxide solution (2.5 mL). The solution was heated at 45-50° C. for 5 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (40 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (360 mg, 94%) as a yellow solid: EI-HRMS m/e calcd for C16H19FN4O2 (M+) 318.1487, found 318.1492.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[C:9]([CH2:22][CH3:23])[C:10]([CH2:19][NH:20][CH3:21])=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[C:28]([C:32]([NH:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([F:62])=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]4[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]4)[CH:43]=3)[CH:41]=2)=[O:33])[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:22][CH3:23])=[C:10]([CH2:19][N:20]([CH2:25][C:26]3[CH:27]=[C:28]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([F:62])=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:60])([CH3:59])[CH3:61])=[O:56])[CH2:53][CH2:54]6)[CH:43]=5)[CH:41]=4)=[O:33])[CH:29]=[CH:30][CH:31]=3)[CH3:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CCl)c4)ccc3F)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)Cc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
To a solution of 1,6-diethyl-5-[(methylamino)methyl]-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.0432 g, 0.136 mmol) in DMF (1.0 mL) was added 1,1-dimethylethyl 4-({5′-[({[3-(chloromethyl)phenyl]carbonyl}amino)methyl]-2′-fluoro-3-biphenylyl}methyl)-1-piperazinecarboxylate (0.075 g, 0.136 mmol), and K2CO3 (0.0188 g, 0.136 mmol). This mixture was stirred at room temperature for 18 h after which was added NaI (0.0204 g, 0.136 mmol) and stirring continued for another 25 h. Then the mixture was diluted with EtOAc (5 mL), washed with H2O (2×3 mL), brine (3 mL), concentrated, and purified by CombiFlash chromatograph to afford the title compound 0.055 g (49%). LC-MS m/z 833 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]3[CH2:22][CH:21]([NH:23]C(=O)OC(C)(C)C)[CH2:20][CH2:19][N:18]3[CH:31]=2)[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]3[CH2:22][CH:21]([NH2:23])[CH2:20][CH2:19][N:18]3[CH:31]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CCn2cc(-c3cccc(F)c3)nc2C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCn2cc(-c3cccc(F)c3)nc2C1
Reaction time: 1 h

Procedure:
A 4 N hydrochloric acid-1,4-dioxane solution (5 ml) was added to the tert-butyl (2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate (116 mg) obtained in (Example 2.7) <Step 5>, and the obtained mixture was then stirred for 1 hour. Thereafter, the solvent was distilled away under reduced pressure, and the title compound (133 mg) was obtained in the form of a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:17])[C:14]#[N:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CCc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C#N)c1nc(-c2ccc(F)cc2)cs1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
To a stirred solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile (500 mg, 2.29 mmol) in THF (10 mL) at −78° C. was added LiHMDS (1M in THF; 2.06 mL, 2.06 mmol) and the reaction mixture was stirred at −78° C. for 10 min. Iodomethane (0.12 mL, 2.06 mmol) in THF (2 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution, water, brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the crude product; which was purified on a Teledyne ISCO automated column chromatography system (0-30% EtOAc/Hexanes) to give 2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (180 mg, yield 34%). MS (ESI) m/z: Calculated for C12H9FN2S: 232.05. found: 233.1 (M+H)
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>N1C=CC=CC=1>[F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11]([SH:32])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Product: Cc1ccc2c(S)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 170 °C

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazolin-4-ol (413 mg, 1.35 mmol) were added Lawesson's reagent (820 mg, 2.03 mmol) and pyridine (3.5 mL), and the mixture was heated at 170° C. in a microwave reactor for 20 min. The mixture was partitioned between EtOAc (30 mL) and saturated aq NaHCO3 (50 mL), and the separated aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with 2N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure onto Celite. The mixture was purified by silica get chromatography eluting with 0-30% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazoline-4-thiol as an impure mixture (0.249 g). LCMS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 3-chloro-2-methylaniline (9.0 g, 63.56 mmol) in EtOH (75 mL) was treated with acetic anhydride (7.2 mL, 76.31 mmol) and the resulting mixture was stirred at rt for 3 h. Concentration was followed by crystallization from hexanes/EtOAc (1:3) to afford 11.2 g of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.30-7.23 (m, 2H), 7.17-7.13 (m, 1H), 2.18 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:12]1[S:14][CH2:13]1.[Cl-].[NH4+]>N>[N:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][CH2:10][OH:11])[CH2:12][CH2:13][SH:14])=[CH:4][CH:3]=1
Reactant: OCCCc1ccncc1
Reactant: C1CS1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: OCCC(CCS)c1ccncc1
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To stirred liquid ammonia (2 liters) was added ferric nitrate (0.1 gm) followed by sodium metal (6.3 gms) in small pieces. The mixture was allowed to stand for 30 minutes and 3-(4-pyridyl)-propan-1ol (19 gms) was then added. A deep yellow colour was allowed to develop over a period of 2 hours after which time ethylene sulphide (8.3 gms) was added quickly. A vigorous reaction occurred and the mixture was stirred for a further 4 hours. Ammonium chloride (10 gms) was added and the solvent was allowed to evaporate overnight. The residual tacky solid was extracted into pyridine and the mixture was filtered and the solvent evaporated. Distillation of the residual oil yielded 3-(4-pyridyl)-5-hydroxy-pentane-1-thiol (12.7 gms, 60% conversion); b.p. 177°-185° C/1 mm Hg, m.p. 50°-52° C, characterised by the following spectra:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCCN1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.8 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 3.13 grams of 4-amino-1-n-butyl piperidine and 21.2 grams of sodium carbonate in 50 milliliters of water and 50 milliliters of chloroform. After stirring overnight at room temperature, the chloroform layer was separated, washed with water, dried and evaporated to give a brown solid which was triturated with ether to give 5.0 grams of the title compound as the hemihydrate. Melting point 190°-191°C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1>>[CH2:1]([N:3]([CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2]
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1CCC(Oc2ccc(C=O)cc2)CC1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 59.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 4-(1-methylpiperidin-4-yloxy)benzaldehyde (94 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.NC(N)=[S:13].O1CCCC1>O>[SH:13][C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1
Reactant: NC(N)=S
Reactant: COC(=O)c1nsc(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nsc(S)n1
Reaction time: 6.5 h
Yield: 92.4 %

Procedure:
A mixture of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (7.80 g), thiourea (3.32 g), tetrahydrofuran (24 ml) and water (8 ml) was gently boiled for 6.5 hours. The reaction mixture was post-treated according to conventional manner to give yellow powder of methyl 5-mercapto-1,2,4-thiadiazole-3-carboxylate (7.1 g), mp. 126° to 127° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:13][Si:12]([C:11]#[C:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1)([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under argon condition, 4-((trimethylsilyl)ethynyl)benzoic acid methyl ester (316 mg, 1.36 mmol) was dissolved in 5 mL of dry THF, and then cooled to 0° C., and LiAlH4 (2.04 mL, 1.0 M solution in THF, 2.04 mmol) was slowly added thereto. Upon completion of the reaction after stirring for 30 minutes at 0° C., the reaction was terminated by adding 77 μL of water, 154 μL of 10% aqueous sodium hydroxide solution and then 231 μL of water. When the white viscous precipitate was produced, the mixture was filtered through a silica pad to remove the precipitate. The resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 258 mg (1.26 mmol, 93%) of the desired compound.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.[CH:42]1([C:45]2[CH:50]=[CH:49][C:48](B3OC(C)(C)C(C)(C)O3)=[C:47]([F:60])[CH:46]=2)[CH2:44][CH2:43]1>>[NH2:31][C:30]1[S:29][C:28]([C:48]2[CH:49]=[CH:50][C:45]([CH:42]3[CH2:44][CH2:43]3)=[CH:46][C:47]=2[F:60])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:40])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Reactant: CC1(C)OB(c2ccc(C3CC3)cc2F)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(C4CC4)cc3F)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 37.8 %

Procedure:
Following the procedures from Example 210 and shown in FIG. 3, using ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester and 2-(4-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials, 222 was obtained in 37.8% yield over two steps: 1H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.10 (t, J=8.2 Hz, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 7.06 (dd, J=19.7, 10.7 Hz, 2H), 3.65 (s, 3H), 3.21-2.99 (m, 5H), 2.05-1.95 (m, 1H), 1.90-1.73 (m, 4H), 1.65-1.47 (m, 3H), 1.06-0.99 (m, 2H), 0.81-0.75 (m, 2H); MS (ESI) m/z: 470.2 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccccc1Oc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 86.8 %

Procedure:
The methyl 2-(1H-indazol-5-yloxy)benzoate (960 mg, 3.58 mmol) synthesized in Example 478 was dissolved in a mixture of tetrahydrofuran (10 ml) and methanol (5 ml), and a 1N-aqueous sodium hydroxide solution (7 ml) was added thereto at room temperature and then stirred at 60° C. for 40 minutes. After the reaction, the reaction solution was cooled to 0° C., adjusted to pH 4 with a 2N-aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 2-(1H-indazol-5-yloxy)benzoic acid (790 mg, 86%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:38])[CH2:36][OH:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:37])[CH2:35][OH:38])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CO)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (153 μl, 1.1 mmol) was added followed by glycolic acid (31 mg, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(2-hydroxy-acetylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (127 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.[CH2:9]([NH2:12])[CH2:10][NH2:11]>O1CCCC1.O>[N:4]1([CH2:3][CH2:2][N:11]=[CH:10][CH2:9][NH2:12])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: BrCCn1cccn1
Reactant: NCCN
Solvent: C1CCOC1
Solvent: O
Product: NCC=NCCn1cccn1
Yield: 50 %

Procedure:
A solution of 1-(2-bromoethyl)pyrazole [6d] (12 mmol) in tetrahydrofuran was added dropwise to a solution of ethylenediamine (0.24 mol) in water. The mixture was refluxed for 4 hours. The THF was removed under vacuum and the water phase was washed with dichloromethane. After drying under vacuum resulted a yellow oil which was formulated as pz(CH2)2NH(CH2)2NH2 (1). Yield: 50%
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH:11][CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>ClC1C=CC=CC=1>[CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH:11][CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[S:37]
Reactant: CC12CCC(C1)C(C)(C)C2NCC(=O)N(c1ccccc1)C1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Clc1ccccc1
Product: CC12CCC(C1)C(C)(C)C2NCC(=S)N(c1ccccc1)C1CCCCC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]-N-cyclohexyl-N-phenylacetamide (110 mg, 0.272 mmol) in chlorobenzene (3 mL) was added Lawesson's reagent (70 mg, 0.17 mmol). The solution was stirred at 120° C. for 2 hours. The solvent was removed under reduced pressure, and the residue purified on preparatory plate using 15% ethyl acetate/hexanes to furnish 2-[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]-N-cyclohexyl-N-phenylthioacetamide as a yellow solid. (M+1)=385.0].
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:4]2([C@@H:10]([CH3:11])[CH2:9][C:8](=[O:12])[C@:5]32[O:7][CH2:6]3)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:6][C@@:5]1([OH:7])[C:4]2([CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15][C:2]([CH3:18])([CH3:1])[CH2:3]2)[C@H:10]([CH3:11])[CH2:9][C@@H:8]1[OH:12]
Reactant: C[C@H]1CC(=O)[C@]2(CO2)C12CC(C)(C)CC(C)(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@@H]1C[C@H](O)[C@](C)(O)C12CC(C)(C)CC(C)(C)C2
Yield: 83.8 %

Procedure:
Under N2 atmosphere, a solution of (3R*,10S*)-6,6,8,8,10-pentamethyl-1-oxadispiro-[2.0.5.3]dodecan-12-one (5.65 g, 22.6 mmol) in Et2O (10 mL) was added dropwise within 20 min. to a stirred suspension of lithium aluminum hydride (1.29 g, 33.8 mmol) in Et2O (25 mL). The reaction mixture was refluxed for 3 h, and then stirred at room temp. over night, prior to quenching at 0° C. by addition of water (20 mL), followed by aq. HCl (5 N, 20 mL). The organic layer was separated, the aqueous one extracted with Et2O (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (25 mL), dried (Na2SO4) and concentrated on the rotary evaporator. The resulting residue was purified by silica-gel FC (pentane/Et2O, 4:1, Rf=0.10) to provide (1R*,2S*,4R*)-1,4,7,7,9,9-hexamethylspiro[4.5]decane-1,2-diol (4.82 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O>[C:16]1([CH:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH3:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1C
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C(C)c2ccccc2)c1C
Reaction time: 0.5 h

Procedure:
O-xylene, 5096g, was charged to a 12 liter bottom outlet Pyrex reactor equipped with a mechanical agitator, heating mantle, addition funnel, cooling coil, thermometer, and a reflux condenser. Sulfuric acid, 981g of 96%, was charged in one portion with agitation. Styrene, 3749g, was added dropwise at 80°-85° C. over 90 min. The mixture was agitated for an additional 30 min. at 80°-85° C. after the styrene addition was complete. The mixture was allowed to settle for 45 min. and the lower sulfuric acid layer was drained off (1294.3g). A solution of sodium hydroxide (80g in 552g of water) was charged and the mixture was adjusted to 80° C. while agitating for 30 min. The mixture was allowed to settle for 30 min. and the lower sodium hydroxide layer was drained off (940.8g) at 80° C. Hot water (1440g) was charged and the mixture was agitated for 15 min. then allowed to settle for 30 min. The water wash was separated leaving 7982g of crude phenylxylylethane alkylate. The phenylxylylethane alkylate was vacuum fractionated to remove excess o-xylene then pure phenylxylylethane, BP 224° C. at 100 mmHg.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].[Cl-].[Li+].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19](I)[C:20]([NH2:23])=[N:21][CH:22]=1>CN(C)C=O.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:17]1[CH:18]=[C:19]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: Nc1ncc(F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(F)cnc1N
Temperature: 55 °C

Procedure:
12.47 cm3 of ethynyltrimethylsilane, 2.24 g of copper iodide, 2.74 g of lithium chloride, 41.33 cm3 of triethylamine and 2.15 g of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride are added to a solution of 14 g of 5-fluoro-3-iodo-pyrid-2-ylamine in 440 cm3 of dimethylformamide, degassed with argon. The solution obtained is maintained at a temperature in the region of 55° C. for about 5 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated under reduced pressure (13 kPa); the residue is taken up in 300 cm3 of water and extracted with three times 100 cm3 of ethyl acetate. The combined organic phases are washed with three times 100 cm3 of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (13 kPa). 7.91 g of 5-fluoro-3-trimethylsilanylethynylpyrid-2-ylamine are thus obtained, after flash chromatography on a column of silica (eluent; dichloromethane), in the form of a solid, the characteristics of which are as follows: