Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6]>O.[Pt]=O>[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][CH:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Agent: O=[Pt]
Solvent: O
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Yield: 74.9 %

Procedure:
Then, a suspension of 0.0687 g of platinum oxide (containing the noble metal in an amount of 1.5% by weight based on the folic acid) in 50 ml of distilled water was added to the flask, and hydrogenation was carried out in the same manner as described in Example 1 to obtain 2.973 g (74.9% yield) of tetrahydrofolic acid.
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C@@H:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:10]
Reactant: C1CCNC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCN(Cc1ccc(CCN2CCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and pyrrolidine (12 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.0 mg) was obtained.
Reaction SMILES: F[C:2](F)(F)S(OC)(=O)=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH2:17][CH2:18][NH:19][C:20](=[S:22])[CH3:21]>C(Cl)Cl>[CH3:2][S:22][C:20](=[N:19][CH2:18][CH2:17][S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH3:21]
Reactant: CC(=S)NCCSc1ccccn1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CSC(C)=NCCSc1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Add methyl trifluoromethanesulfonate (65.5 mg, 0.4 mmol) to a solution of N-(2-(pyridin-2-ylsulfanyl)ethyl)thioacetamide (85.0 mg, 0.4 mmol) in methylene chloride (10 mL) under nitrogen. Stir the reaction mixture at room temperature for 5 minutes and remove the solvent under reduced pressure to give N-[2-(pyridin-2-ylsulfanyl)ethyl)thioacetimidic acid methyl ester (0.4 mmol) as a colorless oil. MS (ES): m/z 227 (M+H).
Reaction SMILES: CN(C)C=O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][C:29]([CH3:38])([CH3:37])[CH2:28][N:27]=1>C(OCC)(=O)C.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>[CH3:37][C:29]1([CH3:38])[CH2:28][N:27]=[C:26]([C:8]2[CH:7]=[N:6][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30]1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC1(C)CN=C(Cl)c2ccccc2O1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CN=C(c2cnc3ccccc3c2)c2ccccc2O1
Temperature: 90 °C
Reaction time: 14 h
Yield: 52.8 %

Procedure:
After carrying out nitrogen replacement on a dimethylformamide solution (15 mL) of 3-quinoline boronic acid (0.70 g, 4.07 mmol) and 2 M aqueous cesium carbonate solution (4.70 mL, 9.40 mol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.63 mmol) and 5-chloro-2,2-dimethyl-2,3-dihydro-benzo[f][1,4]oxazepine (3.13 mmol) were added to this solution. This solution was then stirred for 14 hours while heating at 90° C. Subsequently, the reaction solution was cooled to room temperature followed by pouring in ethyl acetate (50 mL) and water (50 ml) and filtering with celite. The filtrate was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine (50 mL) followed by drying with magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure to obtain 0.50 g (53%) of the target compound by purifying the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1).
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:6][CH:7]([CH2:42][CH3:43])[CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[C:28]2[CH:37]=[CH:36][C:35]3[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=3[CH:29]=2)[CH2:5][CH2:4]1>O1CCCC1>[CH:3]1([NH:6][CH:7]([CH2:42][CH3:43])[CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[C:28]2[CH:37]=[CH:36][C:35]3[C:34]([CH3:38])([CH3:39])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=3[CH:29]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCC(CC)NC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C)NC1CC1
Yield: 74.5 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 300 mg (7.5 mmol) of sodium hydroxide with 410 mg (0.74 mmol) of ethyl 4′-(3-cyclopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 21b) in 30 ml of tetrahydrofuran. 290 mg of 4′-(3-cyclopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=161° C., yield=75%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([O-])=O.[N+](C1C=CC=CC=1C=CC1C=CC=CN=1)([O-])=O>>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=Cc2ccccn2)c1
Agent: O=[N+]([O-])c1ccccc1C=Cc1ccccn1
Product: COc1ccc(N)c(CCc2ccccn2)c1

Procedure:
Reduction of 2-(2-nitro-5-methoxystyryl)pyridine as described in Example 2 (a) for 2-(o-nitrostyryl)pyridine provides 2-(2-amino-5-methoxyphenethyl)pyridine having a melting point of 77.5-78.5° C. (corr.) as the monohydrate obtained by crystallization from isopropyl acetate-ethanol-water.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.6 mg, 0.078 mmol) (from Example 3 supra) in THF (2 mL) were added diisopropylethyl-amine (22 mg, 0.170 mmol) (Aldrich) and then benzoyl chloride (12.5 mg, 0.085 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 60/40) to give 3-(3-benzoylamino-phenoxy-methyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 26.0 mg, 77%).
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([SH:40])[CH:36]=[CH:37][C:38]=1[Cl:39]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:40][C:35]2[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN=C(O)c1cc([N+](=O)[O-])cc(Sc2ccc(Cl)c(Cl)c2)c1C(=O)O
Reaction time: 8 h

Procedure:
20.09 g (80 mmols) of 3,5-dinitrophthalic acid N-methylimide [prepared according to Example 2] are initially introduced into 300 ml of ethyl acetate and treated with 33.6 g (243 mmols) of ground, anhydrous potassium carbonate, and 15.04 g (84 mmols) of 3,4-dichlorothiophenol are then added dropwise at 25° C. After the addition of 100 ml of tetrahydrofuran, the mixture is stirred overnight and evaporated to dryness and the residue is taken up in a mixture of methylene chloride and dilute hydrochloric acid. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from methylene chloride/n-pentane, 25.74 g (84% of theory) of the title imide, with a melting point of 167°-8° C., are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:22])[N:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:29]OS(O)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].O>C(O)(=O)C>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:29])[C:9](=[O:22])[N:8]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)OO
Reactant: O=C1C(CCSc2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(CCS(=O)c2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1

Procedure:
Oxidation of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with the above solution of Caro's acid gives 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione. With respect to 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, about 1.0 to 2.0 molar equivalents, preferably 1.3 to 1.5 molar equivalents, of Caro's acid is required. These amounts of Caro's acid are based upon the potassium persulfate used to make up the Caro's acid. When performing the oxidation, a solvent is used to dissolve the starting material, 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione. Suitable solvents are inert water miscible solvents; for example, lower alkanols containing up to four carbon atoms and lower alkanoic acids containing two to four carbon atoms, or mixtures thereof. A useful solvent is acetic acid which can be used in amounts ranging from about 100 to 200 molar equivalents of acetic acid with respect to the starting material. The starting material is first dissolved in the glacial acetic acid and then the Caro's acid is added. The solution of 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione, aqueous Caro's acid and acetic acid is allowed to react until the oxidation is complete and 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione is formed. Usually, the solution is maintained at about 0° to 30° C., preferably 5° to 25° C., for about 10 to 30 hours. From the solution, 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl] -3,5-pyrazolidinedione is isolated in a conventional manner, for example, decomposition of excess Caro's acid, extraction and crystallization.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:10]([CH:12]([CH3:15])[CH:13]=[CH2:14])[CH3:11].[Li]CCCC.C1COCC1.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>C1COCC1>[CH3:37][C:32]1([CH3:38])[C:33]([CH3:36])([CH3:35])[O:34][B:30]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH:10]([CH:12]([CH3:15])[CH:13]=[CH2:14])[CH3:11])[O:31]1
Reactant: C=CC(C)C(C)Oc1ccc(C)cc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)C(C)Oc1ccc(C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-methyl-1-((3-methylpent-4-en-2-yl)oxy)benzene (820 mg, 3.05 mmol) in THF (15.200 mL) at −78° C. was added 1.6M n-BuLi/THF (2.285 mL, 3.66 mmol) and the mixture was stirred for 30 min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.746 mL, 3.66 mmol) was then added and after 30 min, bath removed and reaction allowed to warm to rt. After 3 h, partitioned between EtOAc and water. EtOAc layer was dried (Na2SO4), filtered and concentrated. Crude was used as-is in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:24]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=3[CH3:33])=[C:23]([F:34])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([OH:22])CO)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C1COCC1.P([O-])([O-])([O-])=O.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:24]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=3[CH3:33])=[C:23]([F:34])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH:19]=[O:22])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC(O)CO)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC=O)c1F
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a mixture of 6-(4-bromo-2-methyl-phenylamino)-3-(4,5-dihydroxy-pentyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11m (0.244 g, 0.456 mmol), THF (5 mL) and pH 7 phosphate buffer (3 mL) is added sodium periodate (0.195 g, 0.911 mmol). After 16 hours, the reaction mixture is diluted with ethyl acetate and washed with NaHCO3, and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to give an orange solid. Purification by FCC eluted with 4:1 methylene chloride/MeOH yields 0.189 g (82%) pure desired product as a yellow solid: MS APCI (+) m/z 505, 503 (M+1 Br pattern) detected; MS APCI (−) m/z 503, 501 (M−1 Br pattern) detected.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH2:31][OH:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].N1C=CN=C1.[CH3:38][C:39]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])[CH3:40].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:39]([Si:42]([CH3:44])([CH3:43])[O:32][CH2:31][CH2:30][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:11][CH2:10]1)([CH3:41])([CH3:40])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCN(CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
400 mg (8.4 mmol) trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide were suspended in toluene and evaporated (3×), redissolved in lml DMF and treated with 102.4 mg (1.5 mmol, 1.8 eq) imidazole. At 0° C., 176 mg (11.7 mmol, 1.4 eq) TBDMSCl in 2 ml DMF were added, and the reaction mixture was stirred at 50° C. for 1 h. The solution was added to an aqueous solution of NaHCO3 and extracted with ether. The organic layer was washed with water and brine, and dried over Na2SO4. 509 mg crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide were isolated as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.[O-]S([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:23]2[CH2:24][CH2:25][C:20]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:21][CH2:22]2)=[CH:6][CH:7]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Solvent: CO
Product: Clc1ccc(-c2ccccc2CN2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
4′-Chloro-biphenyl-2-carbaldehyde (5.00 g, 23.08 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (4.30 g, 30.0 mmol) were combined in DCE (90 mL) and methanol (68 mL). MgSO4 (˜5 g) was added, and the resulting mixture was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (14.67 g, 69.2 mmol) was then added, and the reaction was stirred for 16 hours at room temperature. The solvent was removed in vacuo, and the residue was resuspended in CH2Cl2/H2O. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The organic layers were combined, dried over MgSO4, and concentrated. Flash chromatography on silica gel (0-10% NH3 in methanol (˜2M)/CH2Cl2) afforded 8-((4′-chlorobiphenyl-2-yl)methyl)-1,4-dioxa-8-azaspiro[4.5]decane as a brown oil (4.73 g, 60% yield). MS (ESI) m/e (M+H)+: 344.5
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][CH:38]([S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH:38]([CH3:39])[CH3:37])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 86.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(propane-2-sulfonyl)phenyl boronic acid (0.12 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(propane-2-sulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (130 mg, 84%) as a white solid: LC/MS m/e calcd for C29H30N2O4S2 [M+H]+ 535.70, observed 535.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20]C)=O)=[C:4](C(OC)=O)[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.CO.C[O-].[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH2:16][CH2:17][C:18](=[O:20])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: COC(=O)CCc1c(Cl)cc2nn(C)cc2c1C(=O)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc2c3c(c(Cl)cc2n1)CCC3=O
Temperature: 100 °C
Yield: 83.2 %

Procedure:
To a solution of methyl 6-chloro-5-(3-methoxy-3-oxopropyl)-2-methyl-2H-indazole-4-carboxylate (295 mg, 0.948 mmol) in tetrahydrofuran (10 mL) was added 28% sodium methoxide methanol solution (390 μL), and the mixture was heated under reflux for 2 hr. The reaction solution was concentrated to dryness to give crystals. The obtained crystals were added to 10% sulfuric acid (10 mL) heated to 100° C., and the mixture was heated under reflux for 4 hr. The reaction solution was neutralized with 8M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (174 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:41])([CH3:40])[CH2:29][O:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([CH2:31][O:30][CH2:29][C:28]([CH3:41])([CH3:40])[CH3:27])=[CH:33][CH:34]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)COCc1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)COCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 78.7 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (426 mg, 1 mmol) with 4-(2,2-dimethyl-propoxymethyl)-benzylamine (230 mg, 1.1 mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient) to obtain 7-chloro-6-[4-(2,2-dimethyl-propoxymethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 79%). MS (ES+) m/z: 483 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH3:9][C:10]([CH:12]=O)=O.C(OCC)(=O)C>CO>[CH3:12][C:10]1[N:8]=[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]2=[N:7][CH:9]=1
Reactant: CC(=O)C=O
Reactant: Nc1ccncc1N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cnc2ccncc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Pyridine-3,4-diamine (2.00 g, 18.3 mmol) was dissolved in methanol (100 mL) and cooled in an ice bath. Pyruvic aldehyde (40% wt., 3.36 mL, 22.0 mmol) was added, dropwise, and the solution was allowed to warm to ambient temperature where it was stirred, under nitrogen, for 18 h. The reaction was monitored by LC-MS and pyruvic aldehyde (2.5 mL, 16.4 mmol) was added and the solution stirred at room temperature, under nitrogen for an additional 5 h. The solvent was removed, in vacuo, to give a black liquid which solidified to a black solid (3.58 g) upon standing. This material was adsorbed onto silica gel and purified by column chromatography, eluting with a solution of 1:1 hexane:ethyl acetate to give a brown solid (2.18 g, 82% Yield). 1H NMR 400 MHz (DMSO): δ=9.43 (s, 1H), 9.00 (s, 1H), 8.81 (d, 1H, J=5.9 Hz), 7.91 (dd, 1H, J=5.7 Hz, J=0.8 Hz), 2.79 (s, 3H). HPLC (Column; Xterra RP18, 3.5 μm, 4.6×150 mm, Column temp.=40° C.), Flow=1.2 mL/min., 85/15-5/95, 10 min., 5/95, 5.0 min., (25 mM HCO2NH4 buffer, pH=3.5/AcN/MeOH), No impurities @ 210-370 nM, and no impurities @ 306 nM, retention time =3.5 min. Calculated mass=145.06, [M+H]+=146.