Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:36])=[O:35])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of compound 61b (200 mg, 0.371 mmol) in 5 mL of DCM at rt was added TFA (2.00 mL, 26.1 mmol). After stirring at rt for 6 h, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:9 MeOH-DCM) to afford the title compound 107 (with 1 eq of TFA) as a bright yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.97 (br. s., 1H), 8.35 (br. s., 2H), 7.88-8.05 (m, 2H), 7.65-7.79 (m, 2H), 7.51-7.65 (m, 1H), 6.16 (d, J=5.6 Hz, 1H), 4.09 (br. s., 4H), 3.90-4.03 (m, 4H), 3.19 (br. s., 2H), 2.84 (br. s., 2H), 1.93 (br. s., 2H), 1.78-1.89 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C27H26N6O3, 483.5 (M+H). found 483.4.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([C:33]4([OH:39])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CCOCC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 196. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.29 (dd, J=8.7, 4.0 Hz, 1H), 8.23-8.10 (m, 1H), 7.88 (s, 1H), 7.49-7.35 (m, 2H), 4.85-4.76 (m, 1H), 4.39-4.11 (m, 1H), 4.07-3.68 (m, 9H), 3.17-3.03 (m, 1H), 2.11-1.99 (m, 3H), 1.84-1.51 (m, 5H). LCMS (ES+) m/z 564 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][C:24]4[CH:25]=[C:26]5[C:21]([CH:20]=[CH:19][NH:18]5)=[CH:22][CH:23]=4)=[O:29])=[CH:37][CH:36]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5cc[nH]c5c4)cc3)[nH]c2c1

Procedure:
Compound 664 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O3: 427.17; found: 426.99.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:5]=1[CH2:6][C@@H:7]([CH:22]=[CH2:23])[C@@H:8]([OH:21])[C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:10].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([O:21][C@@H:8]([C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:10])[C@H:7]([CH:22]=[CH2:23])[CH2:6][C:5]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:4]=1[F:3])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=C[C@H](Cc1ccc(F)cc1F)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](Cc1ccc(F)cc1F)[C@@H](OCc1ccccc1)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
An oven-dried 100 mL Schlenk flask was cooled under nitrogen and was then charged with NaH (60% dispersion in mineral oil, 1.24 g, 31.0 mmol) and anhydrous DMF (50 mL). A solution of (2S,3R,4S)-4-(2,4-difluorobenzyl)-2-((4-methoxybenzyl)oxy)hex-5-en-3-ol (8.06 g, 22.2 mmol) in anhydrous DMF (10 mL) was added via canula over a period of 6 min followed by an anhydrous DMF rinse (5 mL) of the source flask and needle. Gas evolution was observed, and the resulting white suspension was stirred at room temperature for 90 min, at which point the reaction color had turned red. Benzyl bromide (4.23 mL, 35.6 mmol) was added and the reaction was heated to 40° C. After stirring for 3 hours, the heat source was removed and the reaction was cooled to room temperature. Saturated aqueous NH4Cl solution (20 mL) was added, and the mixture was allowed to stir for 30 min, at which point gas evolution had ceased. The crude mixture was then diluted with H2O (50 mL) and extracted with Et2O (100 mL×3). The combined organic extracts were washed with saturated aqueous NH4Cl solution (100 mL), dried over anhydrous MgSO4, filtered, concentrated, and the residue was purified by column chromatography on SiO2 (0%→10% methyl tert-butylether (MTBE)/hexane gradient) to furnish the title product as white solid (90% Pure, 8.47 g, 84%): mp 141-144° C.; 1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 4H), 7.30-7.24 (m, 3H), 7.05-6.96 (m, 1H), 6.90-6.84 (m, 2H), 6.76-6.67 (m, 2H), 5.57 (dddd, J=17.1, 10.3, 9.0, 1.3 Hz, 1H), 4.88 (dd, J=10.2, 1.9 Hz, 1H), 4.87 (d, J=11.4 Hz, 1H), 4.72 (ddd, J=17.2, 1.8, 0.5 Hz, 1H), 4.63 (d, J=11.4 Hz, 1H), 4.53 (d, J=11.3 Hz, 1H), 4.40 (d, J=11.3 Hz, 1H), 3.79 (s, 3H), 3.70 (qd, J=6.2, 3.8 Hz, 1H), 3.52 (dd, J=6.9, 3.9 Hz, 1H), 3.09 (d, J=10.4 Hz, 1H), 2.59-2.44 (m, 2H), 1.25 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 161.24 (dd, J=245.7, 11.9 Hz), 161.09 (dd, J=247.0, 11.6 Hz), 159.11, 138.90, 138.24, 132.05 (dd, J=9.4, 6.7 Hz), 130.92, 129.17, 128.33, 127.97, 127.53, 123.45 (dd, J=15.9, 3.7 Hz), 116.95, 113.78, 110.59 (dd, J=20.8, 3.7 Hz), 103.33 (dd, J=26.5, 25.0 Hz), 83.67, 76.56, 74.18, 70.41, 55.28, 47.98, 29.75, 14.24; 19F NMR (376 MHz, CDCl3) δ −113.06 (d, J=6.8 Hz), −113.95 (d, J=6.4 Hz); ESIMS: m/z 475 ([M+Na]+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:14]1[CH2:15][CH2:16][CH:12]([OH:11])[CH2:13]1
Reactant: O[C@@H]1CCNC1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC1CCN(c2nc3ccccc3o2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
To a stirring solution of 5.1 mL (44.6 mmol) of 2-chlorobenzoxazole in 35 mL of THF at 0° C. was added 4.28 g (49.0 mmol, 1.1 equiv.) of (R)-3-hydroxypyrrolidine and 4.42 mL (32 mmol, 0.72 equiv.) of triethylamine. The resulting solution was stirred 12 h at RT, the precipitate was filtered, washed with THF (3×5 mL), and the filtrate concentrated in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 to EtOAc as eluent afforded 3.74 g of the title compound: low resolution MS (ESP) m/e 205 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]#[C:11][NH2:12].[Na]>C(OCC)C>[C:1]([NH:12][C:11]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CN
Agent: [Na]
Solvent: CCOCC
Product: N#CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Benzoylcyanamide was prepared by the addition of benzoyl chloride (6.33 g, 0.045 mol) in 100 ml of diethyl ether to a suspension of monosodium cyanamide (5.76 g, 0.090 mol) in 100 ml of ether at 4° C. The reaction was stirred overnight at room temperature and the pale yellow solid which formed was collected and dissolved in water. On acidification of the solution to pH 1, a precipitate formed which was collected and recrystallized from ethyl acetate (EtOAc)/petroleum ether (30-60° C) to give 2 (5.89 g, 89.7% yield), mp 140°-142° C. [reported mp 139°-140° C⟧ Anal. Calcd for C8H6H2O: C, 65.75; H, 4.11; N, 19.18. Found: C, 65.79; H, 4.35; N, 19.04.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C=O)cc(F)c1Oc1ccc(C#N)cn1
Yield: 66.9 %

Procedure:
Using a method similar to Example 710, Step 2, using 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (Journal of Organic Chemistry (1986), 51(2H), 4072-3.) (2.84 g, 16.7 mmol), 6-chloronicotinonitrile (2.31 g, 16.7 mmol) and K2CO3 (3.46 g, 25.0 mmol) gives 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinonitrile (3.04 g) as a white solid. 1HNMR (CDCl3): 9.94 (s, 1H), 8.37 (s, 1H), 7.98 (d, 1H), 7.36 (m, 2H), 7.20 (d, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11]Cl)[CH:10]=1)=[O:5])[CH3:2].[C-:14]#[N:15].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11][C:14]#[N:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc(CCl)c(C)s1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CC#N)c(C)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
A solution of the 4-chloromethyl-5-methyl-thiophene-2-carboxylic acid ethyl ester mixture from part 2 (25.6 g) in DMF (350 mL) is treated with potassium cyanide (20 g, 0.312 mol) and heated to 70° C. with stirring for 2 h. After cooling to room temperature, the solution is diluted with water and extracted with chloroform (2×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (10% ethyl acetate in heptane) to give 4-cyanomethyl-5-methyl-thiophene-2-carboxylic acid ethyl ester (4.7 g, 18.8%; 2 steps) as a white solid. mp 55-57° C.; 1H NMR (CDCl3, 300 MHz) δ 7.63 (s, 1 H), 4.28 (q, J=6.0 Hz, 2 H), 3.60 (s, 2 H), 2.48 (s, 3 H), 1.38 (t, J=6.0 Hz, 3 H).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:17][C:18](=O)[CH2:19][C:20](=O)[CH3:21].N1CCCCC1>>[CH2:1]([N:11]1[C:18]([CH3:17])=[CH:19][C:20]([CH3:21])=[C:13]([C:14]#[N:15])[C:12]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCCCCCCCNC(=O)CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCn1c(C)cc(C)c(C#N)c1=O

Procedure:
A mixture of N-(n-decyl)cyanoacetamide (93.4 g., 0.417 mole), 2,4-pentanedione (41.7 g., 0.417 mole), piperidine (8 ml.) and 2 B-ethanol (500 ml.) is stirred and refluxed for 17 hours. The mixture is cooled in an ice bath and the solid which crystallizes out is collected by filtration to give 1-(n-decyl)-3-cyano-4,6-dimethylpyrid-2-one, 95.2 g. mp. 82°-83° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[C:14]3[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Temperature: 70 °C
Yield: 77.6 %

Procedure:
A solution of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthalenecarboxylate (1.00 g, 3.0 mmol), tetrakistriphenylphosphine palladium (142 mg, 0.12 mmol) and 4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl-) phenol (799 mg, 3.6 mmol) in a mixture of 1,2-dimethoxyethane (16 mL) and 2M aqueous Na2CO3 (13 mL) was heated in a 70° C. oil bath for 90 minutes. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by chromatography on silica gel, hexane to 3:7 ethyl acetate:hexanes, to provide the title compound (0.648 g, 77.7%). 1H NMR (DMSO-d6): δ 9.65 (s, 1H), 8.94 (s, 1H), 8.18-8.13 (m, 2H), 8.05 (d, J=8 Hz, 1H), 7.85 (dd, J=2, 9 Hz; 1H), 7.60 (d, J=9 Hz, 2H), 7.56-7.53 (m, 1H), 6.90 (d, J=9 Hz, 2H), 3.93 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>[Pd].CO>[NH2:1][C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cccc([N+](=O)[O-])c3N2)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc(N)c3N2)cc1
Yield: 200.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 5-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-ylmethyl ester (3.64 g, 10.0 mmole), p-toluenesulfonic acid monohydrate (3.8 g, 20.0 mmole) and 0.50 g of 10% palladium on carbon in 140 mL of methanol was treated with 50 psi of hydrogen on a Parr shaker for 1 hour. The catalyst was filtered and washed with additional methanol. The solvent was evaporated in vacuum to yield 6.7 g of the p-toluenesulfonate salt of the title compound as a pink solid. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]2)[C@H:13]([F:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@@H:13]([F:24])[C@@H:14]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C[C@@H](F)[C@@H](C2(C(=O)O)CC2)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
1-Benzyloxycarbonyl-4-(S)-(1-ethoxycarbonylcyclopropyl)-3-(S)-fluoropyrrolidine (4.67 g, 13.92 mmol) was dissolved in ethanol (50 ml). Then a 1 N aqueous solution of sodium hydroxide (50 ml) was added dropwise into this solution. Then the liquid reaction mixture was stirred at 40° C. for 1.5 hours and ethanol was removed by evaporation under reduced pressure. Water (50 ml) was added to the residue followed by washing with chloroform (100 ml). The aqueous layer was separated and acidified by adding dropwise 1 N hydrochloric acid thereinto. Next, it was extracted successively with chloroform (200 ml×2) and diethyl ether (100 ml). The combined organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure to obtain 3.94 g (92.1%) of the title compound as a colorless amorphous substance.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][NH2:21]>C1COCC1>[CH3:20][NH:21][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(N)c(N)c2)n1
Solvent: C1CCOC1
Product: CNc1nccc(Oc2ccc(N)c(N)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-methanesulfonyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step B, 400 mg, 1.4 mmol, 1.0 eq) in anhydrous THF (4 mL) was added 1 mL of 2 M CH3NH2 in THF (2 mmol, 1.4 eq). The solution was heated to 80° C. for 1 h. The THF was removed under reduced pressure. The crude was purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) to yield 4-(2-methylamino-pyrimidin-4-yloxy)-benzene-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([N:6]=[C:22]=[O:24])=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOc1cc(N=C=O)c(F)cc1Cl

Procedure:
To a stirred solution of 4-chloro-2 fluoro-5-[(2-propynyl)oxy]-aniline (5.0 gm) and triethylamine (5.1 gm) in CH2Cl2 (100 mL) under N2, at 10° C. (ice-bath) was added triphosgene portionwise. The solution was heated to reflux for 5 hours. The solution was evaporated under vacuum and suspended in Et2O (200 mL). The suspension was filtered and the filtrate evaporated to dryness to give the title compound as a white solid (4.68 gm), 83%; IR (nujol, cm-1): 3295 (C≡C) and 2257 (N=C=O). This crude product was used as such in the next reaction.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]CN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+].CI>CN(C=O)C>[CH3:31][N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH2:28])=[O:27])=[CH:29][CH:30]=3)[N:18]=2)[CH2:13]1
Reactant: NC(=O)c1ccc(-c2noc(C3CNCCN3C(=O)COc3ccccc3)n2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(C(=O)COc2ccccc2)C(c2nc(-c3ccc(C(N)=O)cc3)no2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.1 mmol of 4-{5-[1-(2-Phenoxy-acetyl)-piperazin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzamide are dissolved in 1 ml DMF and 1 eq. DIPEA and Na2CO3 added. To the suspension 1 eq. of MeI is added and the reaction stirred at room temperature overnight. The product is isolated via preparative HPLC.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C1CSCCN1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: c1ccncc1
Product: CC1COc2c(N3CCSCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 22.9 %

Procedure:
A mixture of 0.18 g (0.6 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 0.3 ml (3.0 mmol) of thiomorpholine and 20 ml of pyridine was heated under reflux for 21 hours. The solution was evaporated to dryness, the residue was triturated with hot methanol, and filtered to give 0.05 g of the title compound, mp>300°.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:2]=1.CS(O)(=O)=O>O.CO.[Pd]>[CH:17]1[C:16]([NH2:19])=[CH:15][CH:14]=[C:13]([S:10]([C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][CH:4]=2)(=[O:12])=[O:11])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Temperature: 50 °C
Reaction time: 0.29 h
Yield: 69.5 %

Procedure:
In autoclave at room temperature 4,4′-dinitrodiphenylsulfone (0.0649 mol, 20.0 g), 5% palladium on 50% wet carbon (1.4 g), 70% methanesulfonic acid in water (0.130 mol, 17.8 g), water (10 ml) and methanol (70 ml) are loaded. The mixture is left to react under hydrogen pressure (4-5 atm) at a temperature of 55-60° C. for about 8 hours. The mixture is filtered on a Perlite layer washing with methanol (10 ml for 2 times), subsequently with water (80 ml). The solution is concentrated under reduced volume to remove the organic phase. The aqueous phase is extracted with ethyl acetate (50 ml for 3 times) and the organic washings are discarded. Discolouring carbon (1.0 g) is added under vigorous stirring and after 15-20 minutes the mixture is filtered on a Perlite layer. To the aqueous solution heated at about 50° C. a aqueous solution of 30% sodium hydroxide is slowly added to reach a pH higher than 10. After about 30 minutes the mixture is cooled to 0-5° C. and then filtered, washing the solid with water cooled at 0-5° C. (20 ml for three times). After oven-drying at 50° C., 11.2 g of crude Dapsone are obtained that are then crystallized from a mixture of isopropanol (35 ml) and water (25 ml) to obtain 10.2 g of dry Dapsone, having a chemical purity evaluated by HPLC equal to about 98.5%.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH2:9])=[O:8])[C:3]=1[O:10][CH2:11][CH3:12].C(Cl)Cl.N[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[C:3]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1c(C(N)=O)csc1Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1c(C(=O)Nc2ccccc2)csc1Cl

Procedure:
A 4.50 g. portion of 5-chloro-4-ethoxy-3-thiophenecarbonyl chloride (prepared as in Example 4) was dissolved in 40 ml. of methylene chloride and stirred overnight with 2.8 ml. of triethylamine and 1.86 g. of aniline. The mixture was filtered and the filtrate extracted with 3 N hydrochloric acid. The methylene chloride layer was treated with activated charcoal, dried over anhydrous sodium sulfate and diluted with petroleum ether to give 3.62 g. of the product of the example as a white crystalline solid, m.p. 69° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([O:31][CH2:32][CH2:33][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)[CH3:29]
Reactant: CCOCCBr
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Compound A2 (0.13 mmol, 50 mg), and 1-bromo-2-ethoxy-ethane (0.65 mmol, 99 mg) were dissolved in DMF (1 mL) and triethylamine (0.91 mmol, 127 μL). The reaction was heated in a microwave at 80° C. for 20 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by prep-TLC provided Compound A12 as a yellow solid (20 mg, 33%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.06 (s, 1H), 8.29 (s, 1H), 7.84 (d, 2H), 7.74 (d, 2H), 5.39 (s broad, 1H), 3.53 (m, 2H), 3.39 (q, 2H), 2.86 (s, 3H), 2.77 (m, 2H), 2.65 (m, 3H), 2.04 (m, 2H), 1.92 (m, 3H), 1.09 (m, 3H). LCMS (ESI), m/z 466.3 (M+H+, 100%).