Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.C(N(CC)CC)C>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:6](=[O:8])[CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)OCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
A tetrahydrofuran (6 L) solution of 140 g of 2-isopropoxyacetic acid and 540 mL of triethylamine was cooled to −20° C., to which a tetrahydrofuran (100 mL) solution of 145 g of 2,2-dimethylpropanoyl chloride was added dropwise, followed by stirring the reaction mixture at −10 to −20° C. for 3 hours. The reaction mixture was cooled to −30° C., to which 80 g of anhydrous lithium chloride and then 225 g of (4S)-4-benzyl-1,3-oxazolidin-2-one was added, followed by stirring the reaction mixture overnight at room temperature. The reaction mixture was filtered and subjected to vacuum concentration. The residue was dissolved in 3 L of ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution (1.5 L), and dried with anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was purified using silica gel column chromatography to obtain 196 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (5:1→2:1)-eluted fraction.
Reaction SMILES: COC(=O)COC1C=C(OC)C(SCCCNC2C=CC(C3C=CC=CC=3)=CN=2)=CC=1C.C=O.C[O:36][C:37](=[O:68])[CH2:38][O:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([S:48][CH2:49][CH2:50][CH2:51][N:52]([CH2:65]C)[C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:55][N:54]=2)=[CH:42][C:41]=1[CH3:67]>>[CH3:47][O:46][C:44]1[C:43]([S:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:65])[C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[CH:55][N:54]=2)=[CH:42][C:41]([CH3:67])=[C:40]([CH:45]=1)[O:39][CH2:38][C:37]([OH:68])=[O:36]
Reactant: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Agent: C=O
Agent: COC(=O)COc1cc(OC)c(SCCCNc2ccc(-c3ccccc3)cn2)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCCCN(C)c1ccc(-c2ccccc2)cn1

Procedure:
Compound 64B was reacted with paraformaldehyde in a manner analogous to Compound 64C to give the title product. MS m/z 467 (M+1). Step 2. Preparation of (5-Methoxy-2-methyl-4-{3-[methyl-(5-phenyl-pyridin-2-yl) amino]-propylsulfanyl}-phenoxy)-acetic acid (Compound 66)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: O=Cc1cccc(O)c1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C=O)c1
Yield: 87.4 %

Procedure:
(E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (3.0 g, 10.52 mmol), 3-hydroxybenzaldehyde (1.41 g, 1.1 eq) and potassium carbonate (3.0 g, 3.0 eq) were together refluxed for 15 hours in acetonitrile (CH3CN, 30 mL)/H2O (5 mL). Concentration at a reduced pressure removed the reaction solvent. The residue was stirred in water (50 mL) and the aqueous layer was extracted twice with 50 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to give (E)-methyl 2-(2((3-formylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (3.0 g, yield 87%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C1(C=CC(O)=CC=1)O>>[CH2:19]([O:21][CH:22]([N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1])[CH3:23])[CH3:20]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: C=COCC
Agent: Oc1ccc(O)cc1
Product: CCOC(C)n1c(C)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 180 °C
Yield: 68.3 %

Procedure:
A mixture of 2-methyl-4,5-diphenylimidazole (3.00 g, l3 mmol), ethyl vinyl ether (9.23 g, l2.30 mL, l30 mmol) and hydroquinone (0.l4 g, l.2 mmol) was heated at 180° C. in a sealed vessel for 17 hours. The excess ethyl vinyl ether was evaporated and the residue chromatographed on a column of silica gel using a mixture of diethyl ether and hexanes (3:2) as eluent. Elution gave 1-(1-ethoxyethyl)-2-methyl-4,5-diphenyl-1H-imidazole (2.68 g, 68%), mp 87°-89° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:34][CH3:35])=[C:31]([F:33])[CH:32]=4)=[N:18][CH:19]=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:26][C:27]3[CH:28]=[N:29][C:30]([O:34][CH3:35])=[C:31]([F:33])[CH:32]=3)=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[N:10]=1
Reactant: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of methyl 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.965 g, 1.542 mmol) and triflic acid (0.685 mL, 7.71 mmol), in 6 mL TFA was heated in a flask fitted with a reflux condenser and drying tube at 80° C. for 30 min. The dark red reaction was cooled and triflic acid (0.685 mL, 7.71 mmol) was added, and the reaction was reheated to 80° C. After 30 min, the reaction was judged complete. The reaction was cooled to 0° C., and ice was added, along with solid sodium bicarbonate, in portions, with rapid stirring. DCM was added. Upon complete quenching of acid, the thick mixture was extracted with 3×10% iPrOH/DCM, 2×10% iPrOH/EtOAc (EtOAc layers were washed 1× brine). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in diethyl ether, sonicated, and filtered, rinsing with 3× diethyl ether to give methyl 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.400 g, 1.038 mmol, 67.3% yield) as an orange solid. m/z (ESI, +ve ion) 386 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.37 (s, 1H), 9.26 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.31 (dd, J=12.4, 2.2 Hz, 1H), 8.01 (br. s., 1H), 7.84 (br. s., 1H), 3.95 (s, 3H), 3.88 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:32]=[C:31]([O:33][CH3:34])[C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)=O)(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].ClCCl.C(N(CC)CC)C.P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+]>ClC1CC(C(C)C)CCC1(Cl)C>[CH3:1][O:2][C:3]([C:4]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[S:13](=[O:14])(=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]=1[C:24]1[CH:32]=[C:31]([O:33][CH3:34])[C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)=[O:35]
Reactant: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(=O)c1cc(OC)c2c(c1)OCO2
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(c2cc(OC)c3c(c2)OCO3)c2ccccc2S(=O)(=O)N1c1ccccc1C
Temperature: -60 °C
Reaction time: 18 h

Procedure:
To a dry 100-mL flask was added {[2-(7-methoxy-benzo[1,3]dioxole-5-carbonyl)-benzenesulfonyl]-o-tolyl-amino}-acetic acid methyl ester (2.0 g, 4.2 mmol), dry 4 angstrom molecular sieves (8 g), and Ti(TfO)2Cl2 (0.56 g, 0.48 mmol). The flask was cooled to -60° C. and dichloromethane (45 mL) was added. A solution of triethylamine (1.35 g, 9.73 mmol) in dichloromenthan (18 mL) was added. The mixture was warmed to 5° C. over 2 hours, followed by refrigeration at 0° C. for 18 hours. The mixture was poured in to 50-mL ammonium phosphate buffer solution (pH 7), stirred 20 minutes, and filtered. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to an oil. The oil was chromatographed on 150 g silica gel eluted with a mixture of ethyl acetate and hexane (40:60). The appropriate fractions were evaporated in vacuo, and the residue was evaporated to a foam, 1.02 g, 53%. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH2:2][CH3:3])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow oil. IR (liq.) 2973, 2936, 2874, 1606, 1566, 1481, 1441, 1396, 1287, 1230, 1203, 1181, 1124, 1078, 1046 cm−1; OAMS supporting ions at: ESI+ 406.2; MS (EI) m/z 405 (M+); HRMS (FAB) calcd for C21H28CLN3O3+H1 406.1897, found 406.1889.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35].O>O1CCCC1>[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:35][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Solid carbonyldiimidazole (79.10 g, 0.488 mol) was added to a room temperature solution of N-benzyloxycarbonyl-glycine (117.11 g, 0.560 mol) in anhydrous tetrahydrofuran (THF, 600 mL). The resulting solution was stirred for 45 minutes until CO2 evolution had ceased. A solution of L-phenylalanine methyl ester (79.65 g, 0.444 mol) in anhydrous THF (~200 mL) was then added. The reaction temperature was maintained below 40° C. by application of a water bath to the exterior of the reaction vessel. After two hours, a small portion of water (1.5 mL, ~0.08 mol) was added to the reaction mixture to hydrolyze any remaining acylimidazolides and the resulting solution was left to stir overnight. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (~1 L). This ethyl acetate solution was extracted with 1 N HCI (2×300 mL--the first aqueous extract was acidified a pH of 1 by addition of 6 N HCl), water (300 mL), saturated aqueous sodium carbonate (300 mL), half-saturated aqueous sodium carbonate (250 mL), and brine (250 mL). The organic phase was dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to constant weight. Field desorption mass spectrometry (FDMS) of the resulting oil (160.88 g, ~0.434 mol, 98%) indicated the presence of a single component (M+=370). This material was not further purified, but was instead converted directly into cyclo-glycyl-L-phenylalanine (8) by catalytic hydrogenation (vide infra).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)[CH:3]=1.[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[F:32])[CH3:19].CS(Cl)(=O)=O>N1C=CC=CC=1.CCOC(C)=O>[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([S:28](=[O:29])(=[O:30])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)=[CH:24][C:23]=1[F:32])[CH3:19]
Reactant: Nc1ccc(Cl)cc1-n1nnc2ncccc21
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine (153.5 mg, 0.626 mmol) in pyridine (2 mL) was added 4-chlorosulfonyl-2-fluoro-benzoic acid ethyl ester (200 mg, 0.752 mmol) followed by methanesulfonyl chloride (32 μL, 0.47 mmol) at 0° C. under a nitrogen atmosphere. The resultant reaction mixture was allowed to warm to room temperature and stirred for overnight. The following day, reaction mixture was diluted with EtOAc (25 mL), washed with 2N HCl (2×15 mL), dried (Na2SO4) and evaporated. The resulting bis-sulfonamides crude mixture was treated with 1 N TBAF (in THF, 2 mL) at room temperature for 1 hour. The reaction mixture was then diluted with EtOAc (25 mL), washed with 2 N HCl (2×15 mL), water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated. The resulting crude product was purified by SiO2 chromatography using 50→100% EtOAc in hexanes solvent system to obtain 4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-2-fluoro-benzoic acid ethyl ester. Step 2: The title compound was prepared via conversion from its ethyl ester according to general procedure Y: MS (ES) M+Na expected 484.0, found 484.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12](=S)OCC)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=1)COS(C1C=CC(C)=CC=1)(=O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.CC(C)([O-])C.[K+]>O1CCCC1>[O:17]([C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=1)[CH2:12][S:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2cccc(Oc3ccccc3)c2)cc1
Reactant: CCOC(=S)Sc1ccc2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(Oc2cccc(CSc3ccc4ncccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of dithiocarbonic acid O-ethyl ester S-quinolin-6-yl ester described in Preparation Example W-1 (50 mg, 0.201 mmol), toluene-4-sulfonic acid 3-phenoxybenzyl ester (110 mg, 0.313 mmol) and methanol (1 ml) in tetrahydrofuran (5 ml) was added potassium tert-butoxide (135 mg, 1.20 mmol) under nitrogen atmosphere, which was then stirred at room temperature for 24 hours. This reaction solution was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1), and the title compound (39 mg, 0.114 mmol, 57%) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:16][CH3:17])[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:16][CH3:17])([CH2:14][CH2:13][OH:12])[C:11]([NH:1][NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: COC1(c2ccc(F)cc2)CCOC1=O
Reactant: NN
Solvent: CCO
Product: COC(CCO)(C(=O)NN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
A solution of hydrazine (29 mg) in ethanol (0.5 mL) was added to a solution of 3-(4-fluorophenyl)-3-methoxydihydrofuran-2-one (37 mg) in ethanol (1.2 mL), and the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain 41 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].[OH-].[Na+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(F)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1-c1c(F)cnn1C
Temperature: 50 °C
Yield: 47 %

Procedure:
4-Fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (205 mg, 0.817 mmol) in EtOH (25 mL) was treated with Sn(II) chloride dihydrate (626.3 mg, 2.45 mmol) and heated to 50° C. for 12 hours. The reaction was allowed to cool to room temperature and 10% NaOH (100 ml) was added. EtOAc (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50mL) and the organics combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was dissolved in DMSO (5 ml), and purified by preparative HPLC to afford 85 mg (47%) of 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine as a light brown oil. LCMS m/z (%)=222 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, JH,F=4.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.64 (d, J=2.8 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.21 (s, 2H). 19F NMR (376 MHz, CDCl3) δ: −175.50 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:11])[NH:24][N:23]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: NN
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2cccc(C(F)(F)F)c2)c2ncccc12

Procedure:
A mixture of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and hydrazine hydrate (0.4 g) in ethanol was heated at the reflux temperature for 5 hours. On cooling and reduction of the volume of solvent by evaporation, a precipitate formed which was collected by filtration, to give the title compound as a white solid, 1.08 g, m.p. 210°-215° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].CN(C)C=O.[NH2:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>O>[NH2:10][C:11]1[CH:16]=[C:15]([S:4][CH3:3])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: CS
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2 g. sodium hydroxide, 2.4 g. methylmercaptan and 20 ml. dimethylformamide is stirred at room temperature for two hours. 3.0 g. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for 1 1/2 hours. Water is added and the crude product filtered off. Recrystallization from methanol yields pure 2-amino-4-methylthio-1-nitrobenzene.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:30]([N:32]1[CH2:36][CH2:35][S:34][CH2:33]1)=[O:31])=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:28][S:25]([NH:24][C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:30]([N:32]2[CH2:36][CH2:35][S:34][CH2:33]2)=[O:31])[NH:8][CH2:12]1)=[O:29])=[O:23])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C(=O)NS(C)(=O)=O)c2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Example 32C (372.1 mg, 0.69 mmol) in methanol (5 mL) was slowly added a solution of 4 M HCl in dioxane (1.6 mL, 6.4 mmol) at 0° C. over 10 minutes via addition funnel. The mixture was allowed to stir for 5 hours at room temperature and then was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/e 441 (M+H)+, 439 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.80 (m, 1H), 2.74 (m, 1H), 2.84 (m, 1H), 3.09 (m, 1H), 3.16 (t, 1H), 3.24 (m, 1H), 3.52 (dd, 2H), 3.55 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 4.51 (m, 1H), 4.65 (d, 1H), 4.70 (d, 1H), 7.63 (m, 1H) 8.06 (d, 1H) 8.10 (d, 1H) 8.39 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])=O.[C:15]([CH2:17][C:18](OCC)=[O:19])#[N:16]>[O-]CC.[Na+]>[CH3:1][C:2]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[O:14][C:18](=[O:19])[C:17]=1[C:15]#[N:16]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Product: Cc1c(C#N)c(=O)oc2ccc3ccccc3c12
Yield: 37.8 %

Procedure:
To a mixture of sodium ethoxide (100 ml; prepared from 1.38 g sodium and 100 ml ethanol) and 2-hydroxy-1-acetonaphthone (11.29 g, 0.06 mol) was added ethyl cyanoacetate (11.1 ml, 0.1 mol). The resulting mixture was stirred at reflux temperature for 2 h. The reaction mixture was cooled in a ice bath and the precipitate was filtered off and washed with water (20 ml) and cold ethanol (3×20 ml), dried in vacuo at 50° C. for 18 h which afforded (9 g) of crude product. The crude product (9 g) was recrystallised from a mixture of acetone (1 l) and water (25 ml) affording 5.33 g (38%) of 1-methyl-3-oxo-3H-benzo[f]chromene-2-carbonitrile as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([CH2:9][C:10]=1[CH3:11])[CH:7]=[CH:6]2)(=[O:3])[CH3:2].[H][H]>C(O)C>[C:1]([C:4]1[CH:5]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([CH2:9][C:10]=1[CH3:11])[CH2:7][CH2:6]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)C1=C(C)CC2C=CC1N2C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(=O)C1=C(C)CC2CCC1N2C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
A solution of 2-acetyl-3-methyl-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octa-2,6-diene (0.74 g, 2.81 mmol) and RhCl(PPh3)3 (0.026 g, 0.028 mmol) in 50 ml ethanol was pressurized with 45 psi hydrogen gas and shaken for about 12 hours. The solvent was then evaporated and the residue was purified by silica gel column chromatography (using 3 parts diethyl ether and 7 parts petroleum ether) to give 2-acetyl-3-methyl-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-2-en.
Reaction SMILES: C(NCC)C.Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>CN(C=O)C>[NH2:20][C:16]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:17]=1[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1cc(-c2ccccc2)oc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 68.6 ml (663 mmol) diethylamine dropwise to a mixture of 60.0 g (301 mmol) bromoacetophenone and 25.89 g (391.86 mmol) malononitrile in 130 ml DMF at RT (cooling is required to maintain the temperature). Towards the end of addition, remove the cooling, stir the mixture for 1 h at RT and then add water to 385 ml. Dilute with a further 125 ml water and stir for 20 min at RT. Filter off the precipitated solids with suction, wash twice with 125 ml water each time, dry under suction and wash with petroleum ether. Dry the residue at high vacuum. 33.3 g (50.1% of theor.) of the target compound is obtained as yellowish-brown crystals.