Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:2].[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=C=O)[CH:30]=[C:31]([Cl:33])[CH:32]=1>C1COCC1.C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[NH:34][C:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC=O)CC2)c1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)Nc3cc(Cl)cc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-(3-{1-[4-(formylamino)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,5-dichlorophenyl isocyanate: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:21][CH2:20][CH2:19][O:18][CH3:17])[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: COCCO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-methoxyethanol and DBU in THF. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27](=O)[CH2:28]Br>O>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3cccc(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 30 %

Procedure:
4-[4-(3-Chloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (82 mg, 30%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-chlorophenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.12 (br s, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.42 (s, 1H), 8.28 (dd, J=8.0, 1.9 Hz, 1H), 8.12-8.16 (m, 2H), 8.03-8.07 (m, 1H), 7.76-7.81 (m, 1H), 7.62-7.68 (m, 1H), 7.41-7.55 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([F:44])[CH:43]=1)[C:39]#[N:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:14][O:15][C:43]3[C:36]([F:35])=[CH:37][C:38]([C:39]#[N:40])=[CH:41][C:42]=3[F:44])[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 3,5-difluorobenzonitrile (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:tert-butyl methyl ether (100:0 to 50:50). The product-containing fractions were pooled and chromatographed on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile and water. Colorless foam (49%). MS (Turbo Spray): m/z=528.1 [M+H].
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.C(N(C(C)C)CC)(C)C.[C:14]1([C:20]2[CH:27]=[CH:26]C(CBr)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([C:20]2[CH:27]=[CH:26][C:3]([CH2:2][SH:1])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: OCCS
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: SCc1ccc(-c2ccccc2)cc1
Reaction time: 0.04 h
Yield: 907.7 %

Procedure:
To a peptide synthesis vessel containing 2.3 grams (0.43 mmole) of NpSSMpact-PEG-PS resin 12 was added 15 mL of DMF, 0.25 mL (3.5 mmole) of β-mercaptoethanol and 0.4 mL (2.3 mmole) of diisopropylethylamine and mixture shaken for 2-3 minutes. The red colored mixture was then filtered and the process repeated two more times using the same quantities of BME and DIEA. The resin was then washed five times with DMF, three times with methanol, four times with CH2Cl2 and then three times with DMF. To the resin was then added 0.3 grams (1.21 mmole) of 4-phenyl benzyl bromide dissolved in 15 mL of DMF and 0.5 mL (2.87 mmole) of DIEA and shaken in the dark for 6.5 hours. After 6.5 hours, the mixture was then filtered and washed five times with DMF, three times with methanol and six times with CH2Cl2 in that order. The resin was then dried under pump vacuum to give 2.2 grams of 14.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+]>O>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
A batch type process wherein the catalyst compositions are stirred in from 0.1 to 5.0 molar (preferably 0.5 to 2.0 molar) solutions of ammonium fumarate in water at 5.0 to 10.0 pH (preferably 7.5 to 9.5 pH) for periods of 1.0 to 100 hours (preferably 8 to 48 hours) at temperatures below 50° C. (preferably 20° to 40° C). Broadly from 0.05 to 50 g of immobilized cells, preferably from 1.0 to 15 g, are used per 1.0 mole of starting ammonium fumarate. After the conversion, the catalyst compositions may be removed by filtration or the equivalent for reuse in converting fresh batches of fumarate solutions. The product solutions are obtained in a form suitable for conventional processing to isolate the L-aspartic acid (acidification, precipitation, filtration, washing, recrystallization, drying).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:24]1[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)([O-])=O.O>O1CCCC1>[C:15]([Si:12]([CH3:13])([CH3:14])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:24]3[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=3)=[N:3][C:4]=2[CH:10]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Aldehyde intermediate preparation: A solution of 2-mercapto-5-(tert-butyl-dimethyl-silanyloxy)-benzimidazole (2.07 g, 7.38 mmol) in tetrahydrofuran (15 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.472 g, 11.8 mmol) and tetrahydrofuran (5 ml) at 0° C. The mixture is stirred at room temperature for 3 hours. A solution of 5-nitro-2-furaldehyde (1.04 g, 7.38 mmol) in tetrahydrofuran (10 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. Water (10 ml) is then added and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in a minimal volume of ethyl acetate and is filtered through a silica gel plug (20 ml) that is eluted with 500 ml of ethyl acetate. The organic filtrates are concentrated under reduced pressure and are purified on a silicagel column (120 g) eluted with a mixture of cyclohexane and ethyl acetate (7/3, v/v) to yield 1.4 g of 5-[5-(tert-butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-carbaldehyde as a brown oil. Yield=51%. Analytical LC/MS (method B): retention time=4.62 min., m/z=375.05 (positive ion mode).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11]C)[CH:6]=[O:7].S(=O)(=O)(O)O>>[CH:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([OH:11])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S(=O)(O)O
Product: COc1cc(C=O)cc(OC)c1O

Procedure:
Monodemethylation of 3,4,5-trimethoxy benzaldehyde using sulphuric acid at 40° C. for 8 hours as described above in Example 1 yields syringaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:13][CH2:12][CH:11]([CH3:26])[CH3:10])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, starting with 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone substituting 3-methyl-1-butanol in place of isobutanol (yield: 0.3932 g, 94%). mp 117-120° C. 1H NMR (300 MHz, DMSO d6) δ 0.79 (d, J=6 Hz, 6H), 1.41-1.59 (m, 3H), 3.30 (s, 3H), 4.42 (d, J=5 Hz, 2H), 7.36 (m, 2H), 7.65 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 431 (M+H)+, 448 (M+NH4)+. Anal. calc. for C22H23FN2O4S: C, 61.38; H, 5.39; N, 6.51. Found: C, 61.42; H, 5.30; N, 6.40.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[CH2:14]([OH:17])[CH2:15][OH:16].[H-].[Na+].O>O1CCCC1>[OH:16][CH2:15][CH2:14][O:17][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1OCCO

Procedure:
To solution of 34.4 grams of pentachlorobenzonitrile in tetrahydrofuran was added a mixture of 8.0 grams ethylene glycol, 8.0 grams of a 50% sodium hydride-mineral oil dispersion and 250 ml tetrahydrofuran. The resulting reaction mixture was heated at reflux for one hour and then poured into a large volume of water. Filtration afforded an almost colorless solid which was dissolved in tetrahydrofuran. Treatment with magnesium sulfate followed by filtration and removal of the solvent gave rise to beta-hydroxyethoxy-tetrachlorobenzonitrile. This material is identical basis both nmr and infrared spectral data to the product formed from the reaction of tetrachlorocyanophenol with ethylene oxide as set forth below.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCCCCC>ClCCl.[H-].C([Al+]CC(C)C)C(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CCCCc1ccc([N+](=O)[O-])cc1
Temperature: 21 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a stirred solution of methyl 4-(4-nitrophenyl)butanoate (63) (0.45 g, 2.02 mmol) in dichloromethane (30 mL), 1M diisobutylaluminum hydride (DIBAL) solution in hexane (2.62 mL, 2.62 mmol) was added at −78° C. After 30 min, the reaction mixture was quenched with saturated Rochelle's salt solution. The resulting mixture was stirred at 21° C. until both phases were clearly separated and the organic layer was clear. After extraction, the separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude 4-(4-Nitrophenyl)butanal (64) was purified by flash column chromatography (hexane:ethyl acetate, 8:1) to give 4-(4-Nitrophenyl)butanal (64) (0.28 g, 72%): 1H NMR δ 9.79 (s, 1H), 8.16 (d, 2H, J=8.7 Hz) 7.34 (d, 2H, J=8.7 Hz) 2.77 (t, 2H, J=7.7 Hz) 2.51 (t, 2H, J=7.1 Hz), 1.95-2.04 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[C:9]([Cl:18])[CH:8]=1)[CH3:6])[CH3:2].[Cl:20]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([Cl:20])[CH:15]=[N:14]2)=[C:9]([Cl:18])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: ClCl
Reactant: CCOC(=O)C(C)c1ccc(-n2cccn2)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 12 h

Procedure:
2.79 g (0.01 mole) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid ethyl ester are dissolved in 30 ml of methylene chloride, and 700 mg of chlorine (dissolved in 5 ml of methylene chloride) are added. Stirring is effected for 12 hours at room temperature, followed by washing of the reaction solution with sodium carbonate solution and water, drying, concentration and distillation. 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid ethyl ester is obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=O)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=O)[CH3:8].Cl.O=P(Cl)(Cl)[Cl:34]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:34][C:17]1[C:18]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[C:7]([CH3:8])[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1ccccc1NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(N2C(=O)c3ccccc3C2=O)c(Cl)nc2ccccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
1.4 g (10.4 mmol) of K2CO3 were added to a solution of 2.7 g (6.9 mmol) of N-(2-acetylphenyl)-2-(1,3-dioxoisoindolin-2-yl)-acetamide in DMF (27 ml), and the mixture was heated for 16 h at 60° C. After cooling to RT, the pH was adjusted to 2-3 with 2N hydrochloric acid. The resulting precipitate was filtered off with suction and dried in vacuo at 70° C. 9 ml (97 mmol) of POCl3 were added to the residue. This solution was heated for 2 h at 100° C. and then stirred for 16 h at RT. Toluene was then added and concentration was carried out in vacuo. This procedure was repeated, there being obtained as residue 2.13 g (5.5 mmol, 79%) of 2-(2-chloro-4-methylquinolin-3-yl)isoindoline-1,3-dione, which was reacted further without additional purification.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])([CH3:17])[CH3:16]>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:15]([CH3:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)c1ccccc1O
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC(C)c1ccccc1Oc1nnc(N)nc1-c1ccccc1
Yield: 4.1 %

Procedure:
5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 2-isopropyl phenol (0.43 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[CH3:34])[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[CH3:34])[CH2:10]1
Reactant: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a suspension of 60% sodium hydride (560 mg, 14 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.33 g, 14 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A22. A solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 2 mmol) and 1,1′-carbonyldiimidazole (690 mg, 4 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B22. Solution B22 was added to Solution A22 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified 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% ammonium hydroxide in water) afforded N-[4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (239 mg, 26%) as a white solid: MS (ESI) M+1=458.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22](OC)=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1.O>[OH:23][CH2:22][CH:13]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alaninate (80 g, 230 mmol) in THF (800 mL) was added lithium borohydride (20 g, 920 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with water and filtered. The filtrate was concentrated under reduced pressure to give benzyl tert-butyl (3-hydroxypropane-1,2-diyl)biscarbamate. MS ESI calc'd. for C16H25N2O5 [M+H]+ 325. found 325. 1H NMR (400 MHz, CDCl3) δ 7.38-7.35 (m, 5H), 5.11 (s, 2H), 4.70 (s, 1H), 4.13-4.11 (m, 1H), 3.66-3.28 (m, 4H), 2.04 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[N:3]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: On1ccc(-c2ccccc2F)n1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1ccc(-c2ccccc2F)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-fluorophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (97%, oil).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17](O)=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:38]>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([Cl:38])=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2c(cc1F)c(C(=O)O)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Reactant: O=S(Cl)Cl
Product: Cc1cc2c(cc1F)c(C(=O)Cl)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 66 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid (300 mg, 0.58 mmol) in SOCl2 (4 mL) was stirred at 66° C. for 2 h. Volatiles were removed by a stream of nitrogen followed by vacuum to give (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride as a solid. The above prepared (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride (100 mg, 0.188 mmol) was treated with a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) and stirred at room temperature for 5 min. The mixture was then treated with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated to give (S)-1-cyclopentyl-5-fluoro-N,6-dimethyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxamide (66 mg, 67%). MS m/z 527.3 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.18 (1H, br s), 8.30 (1H, dd, J=8.0 Hz, J=2.0 Hz), 7.73 (1H, d, J=8.5 Hz), 7.66 (1H, d, J=10.5 Hz), 7.28 (1H, br s), 6.26 (1H, br s), 5.91 (1H, d, J=9.5 Hz), 4.51-4.40 (1H, m), 4.15-4.10 (1H, m), 2.84 (3H, s), 2.43 (3H, d, J=1.5 Hz), 2.30-2.23 (2H, m), 2.10-1.90 (4H, m), 1.68-1.62 (2H, m), 1.42 (3H, d, J=8.5 Hz).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1.Cl.[CH3:12][NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>C(O)C>[CH3:12][NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1
Reactant: CNc1ccccc1CCl
Reactant: Sc1nc2c([nH]1)CCCC2
Agent: Cl
Solvent: CCO
Product: CNc1ccccc1CSc1nc2c([nH]1)CCCC2
Yield: 53.3 %

Procedure:
To a suspension of 1.3 g (9 mmol) of 2-mercapto-4,5,6,7-tetrahydro-1H-benzimidazole in 20 ml of ethanol was added 1.35 g (7 mmol) of 2-methylaminobenzyl chloride hydrochloride for a period of 15 min. The solvent was distilled off, and the residue was shaken sufficiently with a combination of 1N aqueous sodium hydroxide and chloroform for performing extraction. The organic portion was taken out and then dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was crystallized from ether/hexane to give 1.02 g of the desired compound as a pale brown crystalline product, yield 53%.
Reaction SMILES: F[C:2](F)(F)S(OC1C=CC(C2NC(=O)CC2)=CC=1)(=O)=O.C(OC([N:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:31][C@H:30]([CH2:41][CH:42]=[CH2:43])[C:29]1=[O:44])=O)(C)(C)C>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C@@H:32]2[NH:28][C:29](=[O:44])[C@@H:30]([CH2:41][CH:42]=[CH2:43])[CH2:31]2)=[CH:38][C:37]=1[CH3:2])#[N:40]
Reactant: O=C1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1
Reactant: C=CC[C@H]1C[C@H](c2ccc(C#N)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C=CC[C@H]1C[C@H](c2ccc(C#N)c(C)c2)NC1=O

Procedure:
The title compound was prepared using a procedure analogous to that described in AMIDOXIME 1, Step B substituting trans-5-(4-trifluoromethanesulfonyloxy-3-methyl-phenyl)-3-(2-propenyl)-2-pyrrolidinone for 5-(4-trifluoromethanesulfonyloxyphenyl)-2-pyrrolidinone: 1H NMR δ 2.06-2.11 (m, 1H), 2.23-2.29 (m, 1H), 2.36-2.42 (m, 1H), 2.55-2.64 (m, 5H), 4.71-4.73 (m, 1H), 5.08-5.14 (m, 2H), 5.74-5.80 (m, 1H), 6.41 (br. s, 1H), 7.18 (d, J=8.0, 11H), 7.23 (br. s, 1H), 7.59 (d, J=7.8, 11H).