Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=[O:2].N[CH:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]1=[O:26].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:24]([O:23][C:21]([CH2:20][N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][C:9](=[O:2])[C:10]1=[O:26])=[O:22])[CH3:25]
Reactant: CC(C)(C)ON=O
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
t-Butyl nitrite (31 ml) was added with stirring to a solution of 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2-one (55 g) in chloroform (1000 ml) and acetic acid (2.8 ml). The reaction mixture was refluxed under nitrogen for 3.5 hours, and then cooled to 0°. While stirring was maintained, m-chloroperbenzoic acid (43.5 g) was added in five portions during 0.5 hour. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (500 ml), concentrated aqueous ammonia (2×250 ml), and saturated brine (250 ml). The organic solution was dried over sodium sulfate, treated with charcoal, and evaporated under reduced pressure to give an oil which was triturated with ether to give 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2,3-dione, m.p. 112°-114°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:13])([CH:11]=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C(OC(=O)C(NC=O)C(O)(C)C=C)C.S(Br)(Br)=O.[P:32]([O:39]CC)([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35]>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:9])/[C:10](/[CH3:13])=[CH:11]/[CH2:12][P:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:39])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: C=CC1(C)OC=NC1C(=O)OCC
Agent: C=CC(C)(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(NC=O)/C(C)=C/CP(=O)(OCC)OCC

Procedure:
The starting material is manufactured as follows: 5-Methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester, b.p. 65°-75° (13 Pa) is obtained by reaction of isocyanoacetic acid ethyl ester with methyl vinyl ketone in a manner analogous to that described in Example 30. By hydrolysis of the 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1, 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained.Reaction of the 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester in the form of a colourless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=2[N:9]=1.[C:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)#[CH:27]>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:27]#[C:26][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Fc1cc2nc(-c3ccccc3Br)n(CC3CCCCC3)c2cc1F
Reactant: C#Cc1ccc(C#N)cc1
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). Off-white powder (30%). MS (Turbo Spray): m/z=452.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2F)=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:31][O-:32].[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[O:32][CH3:31])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(OC)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 130 °C

Procedure:
A solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (49.7 mmol, 0.112 mmol, Example 105) in methanol (4 mL) was treated with sodium methoxide (25 wt % in methanol, 0.29 mL, Aldrich) and heated at 130° C. in microwave for 3 hours. The reaction was concentrated and the crude product was purified on silica gel (95:5 methylene chloride/methanol) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro-2,6-dimethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 454.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:8]1)=[O:4].C([O-])=O.[NH4+]>[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]=2[C:9]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:8]1)=[O:4]
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2c(/C=C/C(=O)OC(C)(C)C)cccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COC(=O)CCn1cc(Cc2cccnc2)c2c(CCC(=O)OC(C)(C)C)cccc21
Yield: 90.2 %

Procedure:
Treatment of t-butyl (E)-3-[1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-4-yl]-2-propenoate (5.15 g) with 10% palladium on carbon (0.50 g) and ammonium formate (7.71 g) according to the method of Preparation 23 gave the title compound, (4.67 g) m.p. 80°-82° C. Found: C,71.43; H,7.06; N,6.35. C25H30N2O4 requires: C,71.06; H,7.16; N,6.63%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17][C:16]=1[NH:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31]([OH:33])=O)(=[O:27])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17][C:16]=1[N:22]([CH3:23])[C:31](=[O:33])[C:30]1[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:26])=[O:27])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnc(C)cc1-c1ccccc1OCc1ccccc1
Product: Cc1cc(-c2ccccc2OCc2ccccc2)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(2-(benzyloxy)phenyl)-N,6-dimethylpyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (1.49 g, 5.55 mmol, example 114, intermediate a) after a reaction time of 3.5 days at room temperature. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 10:90). Off-white solid (53%). MS (ESI): m/z=555.156 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: O=c1[nH][nH]c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1[nH]c(=O)c2ccccc21)C(F)(F)F
Reaction time: 336 h
Yield: 21.5 %

Procedure:
To a solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (0.29 g) and 1,2-dihydroindazol-3-one (0.17 g) in anhydrous dimethylsulfoxide (1 mL) was added sodium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 1.0 mL). After 14 days, the reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (eluted with 1% ethanol-methylene chloride) to give 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1,2-dihydroindazol-3-one as a white solid (91 mg), m.p. 141° C.-144° C.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][CH:13]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14]1>CC(=O)CC>[CH:1]1([NH:11][CH2:15][CH2:14][CH:13]([S:17]([OH:19])(=[O:18])=[O:16])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCc2ccccc21
Reactant: CC1CCOS1(=O)=O
Solvent: CCC(C)=O
Product: CC(CCNC1CCCc2ccccc21)S(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthylamine (2.01 g, 13.6 mmol) in 2-butanone (15 mL) was added 2,4-butane sultone (1.95 g, 14.3 mmol). The solution was stirred at for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.56 (s (broad), 1H), 7.49 (dd, 1H, J=8.0 Hz, 11.9 Hz), 7.29 (m, 1H), 7.26 (m, 1H), 7.19 (d, 1H, J=8.0 Hz), 4.40 (d, 1H, J=13.7 Hz), 3.14 (m, 2H), 2.75 (m, 3H), 1.96 (m, 5H), 1.40 (m, 1H), 1.23 (m, 3H). 13C (DMSO, 125 MHz) δ ppm 138.81, 131.81, 130.40, 130.28, 130.16, 129.41, 126.76, 126.73, 54.97, 54.58, 54.08, 44.18, 43.23, 29.50, 28.84, 24.84, 24.76, 18.23, 18.20, 17.79, 17.01. ES-MS 284 (M+1).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][S:10][C:11]1[S:12][C:13]2[CH:19]=[C:18]([CH2:20][CH2:21][CH:22]=[O:23])[CH:17]=[CH:16][C:14]=2[N:15]=1.[Cl:24]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:24][CH:21]([CH2:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([S:10][CH3:9])[S:12][C:13]=2[CH:19]=1)[CH:22]=[O:23]
Reactant: CSc1nc2ccc(CCC=O)cc2s1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Product: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
L-proline (0.22 g, 1.9 mmol) was added to a solution of 3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (2.3 g, 9.7 mmol) in DCM (40 mL) at 0° C. followed by addition of N-chlorosuccinimide (1.4 g, 10 mmol). The reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with 10:1 to 2:1 petroleum ether/EtOAc to afford 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal as a yellow oil (2.1 g, 79%). 1H NMR (300 MHz, CDCl3) δ 9.56 (dd, J=1.2, 2.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.63 (d, J=0.6 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 4.44-4.39 (m, 1H), 3.51-3.44 (m, 1H), 3.20-3.13 (m, 1H), 2.78 (s, 3H). LCMS (ESI) m/z 290 (M+18+H)+.
Reaction SMILES: [C@@H:1]12[NH:8][CH2:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:23][C:19]1[N:18]=[C:17]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]3)[CH2:7]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Reactant: Cc1cccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]32)n1
Yield: 14.9 %

Procedure:
To a microwave safe vial was added Intermediate 39 (375 mg, 1.77 mmol), 2-chloro-6-methylpyridine (0.39 mL, 3.53 mmol), CH3CN (10 mL) and DIPEA (0.61 mL, 3.53 mmol). The resulting mixture was heated to 180 C in a microwave reactor. After 3 h the crude mixture was concentrated and purified directly by FCC (SiO2, ethyl acetate/hexanes, 0-40%) to yield (1R,6S)-tert-butyl 8-(6-methylpyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (80 mg, 15%). MS (ESI) mass calcd. for C17H25N3O2, 303.2; m/z found, 304.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.31 (t, J=7.7 Hz, 1H), 6.50-6.40 (m, 1H), 6.09 (dd, J=45.4, 8.1 Hz, 1H), 4.44-4.27 (m, Hz, 2H), 4.04-3.89 (m, 1H), 3.84-3.66 (m, 2H), 3.60-3.22 (m, 2H), 2.86-2.72 (m, 1H), 2.37 (s, 3H), 2.07-1.96 (m, 1H), 1.92-1.80 (m, 1H), 1.44-1.28 (m, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:12]1([C:15](=[O:22])[CH2:16][C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])[CH2:14][CH2:13]1.O>FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:22])[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1
Temperature: 20 °C

Procedure:
The procedure described in Example 19 was repeated by using 3.0 g 4-carboxybenzaldehyde and 3.06 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.7 g, mp 175°-178° C. in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. Yield 5,3 g (41%).
Reaction SMILES: NCC(C1C=CC=CC=1)=O.N1C=CC(C=O)=CC=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:36])[CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)O>CO>[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:36])[CH:27]=[CH:28][C:30]1[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=1
Reactant: Nc1ccccc1C(=O)CC(O)c1ccncc1
Agent: NCC(=O)c1ccccc1
Agent: O=Cc1ccncc1
Solvent: CO
Product: Nc1ccccc1C(=O)C=Cc1ccncc1

Procedure:
The procedure is as in Example 13 starting from 4 g of 2-aminoacetophenone and 6.42 g of pyridine-4-carbaldehyde in 14 ml of methanol. 5.2 g of a 50/50 mixture of 1-(2-aminophenyl) 3-(4-pyridyl) 3-hydroxy 1-propanone and of 1-(2-aminophenyl) 3-(4-pyridyl) 2-propene-1-one are obtained. The constituents of this mixture are separated by chromatography on a silica column (eluant: mixture of 80 parts by volume of ethyl acetate and 20 parts by volume of cyclohexane). 2.3 g of 1-(2-aminophenyl) 3-(4-pyridyl) 2-propene-1-one, melting at 168° C. are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:14][C:15]1([CH2:28][N+:29]([O-])=O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(OCC)C.O1CCCC1.C(OCC)(=O)C>[NH2:29][CH2:28][C:15]1([S:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(C[N+](=O)[O-])(SCc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)(SCc2ccccc2)CC1
Yield: 28.1 %

Procedure:
To a mixture of lithium aluminum hydride (0.4 g) and diethyl ether (20 ml) was added a solution of tert-butyl 4-(benzylthio)-4-(nitromethyl)piperidine-1-carboxylate (1.28 g) in diethyl ether (5 ml) at 0° C. The reaction mixture was heated under reflux for 1 hr. The excess lithium aluminum hydride was decomposed with ethyl acetate, and water was added. The reaction mixture was diluted with a mixed solvent of tetrahydrofuran and ethyl acetate, and the inorganic salt was removed by filtration. The filtrate was washed with saturated brine, dried (MgSO4), and concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (0.33 g, yield 28%) as a colorless oil from a fraction eluted with ethyl acetate-methanol (2:1, volume ratio).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:23])[N:11]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][CH:6]=2)(=[O:23])=[O:24])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.6 %

Procedure:
A solution of 4-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-benzoic acid methyl ester (1.05 g, 2.87 mmol) in MeOH (40 mL) was treated with 1 M aqueous NaOH (8.6 mL, 8.60 mmol) and stirred at room temperature for 2.5 hours. The MeOH was removed under vacuum, the aqueous a phase diluted with water, washed with EtOAc and acidified to pH 1-2 using 1 N aqueous HCl. The acidic aqueous was extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated under vacuum to give 4-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-benzoic acid (914 mg, 91%). 1H NMR (300 MHz, DMSO) δ 13.48 (br s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.25-7.05 (m, 4H), 3.35 (d, J=7.3 Hz, 2H), 1.51-1.33 (m, 1H), 0.85 (d, J=6.6 Hz, 6H). LCMS (m/z, Method A) ES+ 352.0 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl>CN(C)C(=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Cc1ccccc1S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred, cooled (-15° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methyl propanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13 g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -10° C. for 1 hour. 4-(2-Methylphenylsulfonyl)benzenamine (1.48 g, 6.0 mmol) was then added in one portion, washed in with 2 mL of N,N-dimethylacetamide and the mixture allowed to stir at room temperature overnight. The solution was poured into water, the cloudy solution decanted from the resulting gum and filtered through a thin pad of Celite. The Celite pad was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The combined methylene chloride solution was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting gum was dissolved in a few mL of methanol and added dropwise to 100 mL of rapidly stirred 3N HCl. The aqueous phase was decanted from the gum, the gum dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was dissolved in 125 mL of methylene chloride and heated on a steam bath as 100 mL of hexane was slowly added to replace the methylene chloride. When a volume of 125 mL was reached more hexane (ca. 50 mL) was added to the cloud point. After cooling overnight the resulting solid was filtered to yield impure product. This material was further stirred with 300 mL of 0.5N HCl for 45 min., the aqueous phase decanted off and the residual gum dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed in vacuo. The material was dissolved in 100 mL of methylene chloride, 50 mL of hexane added and the solution heated on a steam bath to a final volume of 100 mL. After cooling the resulting solid was filtered and dried at 100°-120° C./0.1 torr. for 2.5 hours to yield the title propanamide (1.78 g, 77%) as a light tan solid; mp 126°-128° C. 1H-NMR (300 MHz, d6 -DMSO): 1.58 (s, 3H, CH3), 2.39 (s, 3H, aryl CH3), 7.37-8.10 (m, 8H, aromatic), 7.6 (broad s, 1H, OH), 10.4 (broad s, 1H, NH). MS (CI, CH4): 388(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:22]=[N:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CO>>[F:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([F:1])[CH:20]=1)[CH2:5][NH:6][C:7]([C:8]1[CH2:22][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2cc(F)cc(F)c2)O1
Reactant: C=NCCN1CCOCC1
Solvent: CO
Product: O=C(NCc1cc(F)cc(F)c1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of N-(3,5-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (60 mg, 0.2 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.25 mL, 0.25 mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a white powder (22 mg, 22% yield). 1H NMR (500 MHz, DMSO) δ: 11.95 (1H, br s), 9.54 (1H, br s), 8.08 (1H, t, J=6.1 Hz), 7.12–7.08 (1H, m), 7.00–6.94 (2H, m), 4.45 (2H, d, J=6.1 Hz), 4.05 (2H, s), 4.02–3.94 (2H, m), 3.83–3.77 (2H, m), 3.69–3.38 (6H, m), 3.16–3.05 (2H, m). HRMS calcd for C18H20F2N3O4 (M−H): 380.1422. found: 380.1422.
Reaction SMILES: [OH:1][C:2]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6](C(OC(C)(C)C)=O)[NH2:7])=[O:5].C(OCC)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C1(OC)C=CC=CC=1>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[OH:1][C:2]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][NH2:7])=[O:5]
Reactant: CC(C)(C)OC(=O)N(N)C(=O)c1cccc(O)c1O
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1cccc(O)c1O
Reaction time: 0.5 h

Procedure:
(2,3-Dihydroxybenzoyl)hydrazine carboxylic acid, t-butyl ester (17 g) was dissolved in 50 ml of trifluoroacetic acid/anisole (4:1) at 0° C. and stirred for 30 minutes. Diethyl ether (200 ml) was added, and (2,3-dihydroxybenzoyl)hydrazine, trifluoroacetate salt crystallized from the solution. After washing with ether and drying over silica gel, 17.2 g of (2,3-dihydroxybenzoyl)hydrazine, trifluoroacetate salt were obtained as beige, fine crystals; melting point 212° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([C:20]2[O:21][C:22]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][C:24](=[O:26])[CH:25]=2)=[CH:8][CH:7]=1.[OH-].[Na+:35]>CO>[Na+:35].[N:27]1([C:22]2[O:21][C:20]([C:9]3[C:10]4[S:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[S:18][C:19]=4[C:6]([O:5][CH2:4][C:3]([O-:33])=[O:2])=[CH:7][CH:8]=3)=[CH:25][C:24](=[O:26])[CH:23]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COC(=O)COc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])COc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [4-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-thianthren-1-yloxy]-acetic acid methyl ester (1.41 g, 2.91 mmol) in anhydrous methanol (10 ml) was added sodium hydroxide (120 mg, 2.91 mmol) in a single portion. The solution was then stirred at room temperature for 24 hours whereupon the solvent was removed in vacuo to give the title compound as an off white paste (1.43 g, 98%) that required no further purification. m/z (LC-MS, ESP): RT=3.79 min, (M−−23)=468
Reaction SMILES: [CH3:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10]C1C=CC(C)=CC=1O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:10])[CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: Cc1cccc(O)c1C
Reactant: Cc1ccc(C)c(O)c1
Product: Cc1ccc(O)c(C)c1

Procedure:
2,3-dimethylphenol; 2,5-dimethylphenol;