Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:40])[C:11]([OH:39])([CH3:38])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[CH2:26][N:25]([CH2:27][C:28]3[CH:33]=[CH:32][C:31](OC)=[CH:30][CH:29]=3)[C:24](=[O:36])[N:23]2[CH3:37])=[CH:15][CH:14]=1)[CH3:8].CN1C(CCOS(C2C=CC(C)=CC=2)(=O)=O)CN(CC2C=CC([C:67]([F:70])([F:69])[F:68])=CC=2)C1=O>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:40])[C:11]([OH:39])([CH3:38])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH:22]2[CH2:26][N:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:67]([F:70])([F:69])[F:68])=[CH:32][CH:33]=3)[C:24](=[O:36])[N:23]2[CH3:37])=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1

Procedure:
Cesium carbonate (8.72 g, 26.76 mmol) is added to a solution of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (2.0 g, 8.92 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (4.34 g, 9.51 mmol) in DMF (50 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, dried, concentrated, and purified by flash chromatography (25% acetone in hexanes) to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.50 (d, 2H, J=8.2 Hz), 7.32 (d, 2H, J=8.2 Hz), 7.03 (d, 2H, J=8.2 Hz), 6.65 (d, 2H, J=8.2 Hz), 4.40, 4.32 (ABq, 2H, J=14.7 Hz), 4.14-4.07 (m, 2H), 3.91 (t, 2H, J=5.7 Hz), 3.61-3.55 (m, 1H), 3.33 (t, 1H, J=8.2 Hz), 2.96-2.79 (m, 6H), 2.22-2.15 (m, 1H), 1.87-1.80 (m, 1H), 1.40 (s, 3H), 1.21 (t, 3H, J=7.4 Hz). Rf=0.38 in 50% acetone in hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])=[C:2]([NH:1][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(Br)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(Br)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC

Procedure:
A solution of 12.38 g of N-[2-(2-amino-4-bromo-phenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide, 3.68 mL of ethyl bromoacetate, and 7.88 mL of N,N-diisopropylethylamine in 100 mL of N,N-dimethylformamide was stirred at 55° C. for 16 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 7.38 g of ethyl [5-bromo-2-[2-(5-cyano-2-methoxybenzenesulfonylamino) ethyl]phenylamino]acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]([O:29][C:30](=[O:40])[CH2:31][CH:32]([NH2:39])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30](=[O:40])[CH2:31][C@H:32]([NH:39][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:26])([CH3:28])[CH3:27]
Reactant: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Reactant: CON(C)C(=O)C(N)CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Reaction time: 16 h
Yield: 92 %

Procedure:
To 2-benzyloxy-benzenesulfonyl chloride (3.11 g, 11 mmol) in dichloromethane (50 mL) and pyridine (2.6 mL, 3 equiv) was added 3-amino-N-methoxy-N-methyl-succinamic acid tert-butyl ester (1 equiv). The reaction stirred for 16 h and was washed with 10% sulfuric acid, water, and then brine. To give (S)-3-(2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a yellow oil (4.82 g, 92%) that was sufficiently pure for further use. 1H NMR (CDCl3) 7.88(d,1H), 7.57(d,2H), 7.40(m,3H), 7.17(d,1H), 7.03(m,2H), 5.92(d,1H), 5.25(s,2H), 4.73(bs,1H), 3.57(s,3H), 2.86(s,3H), 2.63-2.39(AB quartet, 2H), 1.40(s,9H).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:18][C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][N:15]3[N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[C:23]([OH:26])(=[O:25])C.Cl>C1COCC1.[Zn]>[CH:23]([OH:26])=[O:25].[NH2:1][C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:18][C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][N:15]3[N:14]=2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(=O)O
Reactant: CC(C)(N=[N+]=[N-])c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(N)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Product: O=CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]-triazin-4-one (115 mg, 0.39 mmol) in 2 ml THF are added zinc dust (128 mg, 1.96 mmol) and acetic acid (225 μl, 3.93 mmol) and the mixture is stirred for 18 hours at room temperature. The suspension is diluted with THF and acidified with a small amount of 25% hydrochloric acid. The mixture is filtered with suction. The filtrate is washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by preparative HPLC to afford 2-[4-(1-amino-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one formate salt as white solid; HPLC/MS 1.25 min (C), [M-NH2]+ 252;
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:18]([OH:20])=O)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].C([N:35]([CH2:38]C)CC)C>C1COCC1>[CH3:21][O:22][N:35]([CH3:38])[C:18]([C:9]1[O:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1oc(-c2ccccc2)nc1-c1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of the above-prepared 2,4-diphenyl-oxazole-5-carboxylic acid (427 mg, 1.61 mmole, 1.0 eq) in dry THF was treated with carbonyldiimidazole (340 mg, 2.09 mmole, 1.3 eq) and the mixture heated at 50° C. for 3 hours. Triethylamine (360 uL, 2.58 mmole, 1.6 eq) and N, O-dimethylhydroxylamine-HCl (236 mg, 2.42 mmole, 1.5 eq) were added and the mixture heated at 50° C. for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil. The crude oil was chromatographed on silica gel eluting with (7:3) hexanes-ether to give 371 mg (75%) of the title compound as a brown crystalline solid. 1H NMR (CDCl3) δ 3.35 (s, 3H), 3.8 (s, 3H), 7.3-7.6 (m, 6H), 7.95 (dd, 2H), 8.15 (dd, 2H).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[C:18](=[O:28])[C:19]3[N:20]([CH3:27])[C:21]([CH3:26])=[CH:22][C:23]=3[CH2:24][O:25][C:16]=2[CH:15]=1.C[O:32][C:33](=O)[O:34]C>O1CCCC1>[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[C:18](=[O:28])[C:19]3[N:20]([CH3:27])[C:21]([CH2:26][C:33]([OH:34])=[O:32])=[CH:22][C:23]=3[CH2:24][O:25][C:16]=2[CH:15]=1
Reactant: Cc1cc2c(n1C)C(=O)c1ccc(Cl)cc1OC2
Reactant: COC(=O)OC
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(CC(=O)O)cc2c1C(=O)c1ccc(Cl)cc1OC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of diisopropylamine (12.5 g, 0.124 m) in dry tetrahydrofuran (40 ml) under a nitrogen atmosphere is added N-butyllithium (0.124 m) and the solution stirred for 10 minutes followed by cooling to -78° C. A mixture of 7-chloro-1,2-dimethyl-4,10-dihydro-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole (31.3 g, 0.12 m), dimethylcarbonate (11.7 g, 0.13 m) and tetrahydrofuran (50 ml) is then added dropwise over 10 min. The bath is then removed and the mixture allowed to warm to room temperature and is stirred for four hours. Water (50 ml) is added and the reaction mixture is further stirred overnight. Aqueous sodium hydroxide is then added and the mixture is filtered. The filtrate is acidified to yield 7-chloro-4,10-dihydro-1-methyl-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole-2-acetic acid.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=1>ClCCl>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]3[O:7][N:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:9]=3)[CH2:11][CH2:12]2)[C:31]=1[CH3:32]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Temperature: 27 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride (2.0 gm, 0.008369 moles) and diisopropylethylamine (2.78 gm, 0.0215 moles) in dichloromethane (30 ml) was added to an ice-cooled solution of 4,6-dichloro-5-methylpyrimidine (2.1 gm, 0.001295 moles) in dichloromethane (10 ml) and the reaction was stirred at 27° C. for 2 h. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by flash column chromatography (silica gel, 15% ethyl acetate in hexane) to afford the title compound as a white solid (43% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:2]=1.S(Cl)([Cl:18])=O>CN(C)C=O>[ClH:18].[Cl:18][C:13]([C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][CH2:10][CH2:9][S:8]1)=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2cccnc2)CCCCS1
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)C1(c2cccnc2)CCCCS1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The 2-(pyrid-3-yl)-tetrahydrothiopyran-2-carboxylic acid thus obtained (16.4 g) is added in small portions, in the course of 30 minutes, to thionyl chloride (25 cc) to which dimethylformamide (0.05 cc) has been added. The reaction mixture is then stirred at the boil for 2 hours 30 minutes, cooled to a temperature of about 20° C. and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 70° C. This gives crude 2-chloroformyl-2-(pyrid-3-yl)-tetrahydrothiopyran hydrochloride (26 g) in the form of an orange oil, which is used immediately without further purification.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15](CC3C=CC(OC)=CC=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[C:3]([O:5][CH3:6])=[O:4].OS(O)(=O)=O.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (266 mg, 0.596 mmol) in Trifluoroacetic acid (TFA) (2.5 mL) was treated with conc. H2SO4 (185 μl, 3.47 mmol), and anisole (370 μl, 3.39 mmol). After stirring for 1 hour, the reaction was warmed to rt for 2 hours, and then quenched with sat. NaHCO3 until neutral. The mixture was extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) afforded methyl 2-hydroxy-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (130.1 mg, 0.399 mmol, 66.9% yield) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 10.94 (br. s., 1H), 7.36 (dd, J=7.3, 12.5 Hz, 2H), 7.30-7.20 (m, 3H), 6.12-6.03 (m, 1H), 5.42 (s, 1H), 3.82-3.73 (m, 4H), 3.67 (s, 3H), 2.42 (s, 3H); LCMS (m/z) ES+=327 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:15]([OH:17])=O)[CH2:9][C:10]1[N:14]=[CH:13][NH:12][CH:11]=1.CN(C([O:25]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:47][CH:48]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[C:70](O)[CH:69]=1)[C:49]([N:51]1[CH2:54][C:53]([O:62][CH2:63][CH2:64][CH2:65][CH3:66])([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[CH3:61])[CH2:52]1)=[O:50].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:63]([O:62][C:53]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[CH3:61])[CH2:52][N:51]([C:49](=[O:50])[CH:48]([NH:47][C:15](=[O:17])[CH2:8][CH2:9][C:10]2[NH:14][CH:13]=[N:12][CH:11]=2)[CH2:67][C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][C:69]=2[OH:25])[CH2:54]1)[CH2:64][CH2:65][CH3:66]
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)Cc2ccc(OC)c(O)c2)C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(OC)cc2O)NC(=O)CCc2cnc[nH]2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.6 %

Procedure:
0.25 ml (0.6 mmol) of triethylamine is added to a solution of 90 mg (0.6 mmol) of desamino-histidine and 207 mg (0.6 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 250 mg (0.4 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)propan-1-one trifluoroacetate are added and the mixture is stirred for 72 h at ambient temperature. 10 ml of a saturated aqueous solution of sodium hydrogen carbonate are then poured into the reaction medium, which is extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography (eluent: 90/10 dichloro-methane/methanol). 30 mg of N-[2-(3-butoxy-3-o-tolyl-azetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoro-acetate are obtained in the form of a beige powder with a yield of 11%.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.CO.[OH-].[Na+].C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc3[nH]ccc23)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2cccc3[nH]ccc23)cc1Nc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To the obtained tert-butyl 2-(4-fluoroanilino)-4-(1H-indol-4-yl)benzoate were added methanol 1.0 mL,dioxane 1.0 mL and 2.0 mol/L sodium hydroxide aqueous solution 0.23 mL, it was stirred at 50° C. for 2 hours and 30 minutes, subsequently 2.0 mol/L sodium hydroxide aqueous solution 0.23 mL was added, it was stirred at 50° C. for 4 hours, furthermore 2.0 mol/L sodium hydroxide aqueous solution 0.23 mL was added, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, toluene and water were added to it. The water layer was separated and collected, it was adjusted to pH3.0 with 1.0 mol/L hydrochloric acid after washing with toluene, and ethyl acetate was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(1H-indol-4-yl)benzoic acid 23 mg of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[F:12][C:13](F)(F)[C:14]([OH:16])=[O:15]>>[F:12][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1.[N:6]1[CH:3]=[CH:9][CH:8]=[CH:7][C:5]=1[O:16][C:14](=[O:15])[C:13]1[CH:5]=[CH:4][CH:3]=[CH:9][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(F)cc1OC
Product: O=C(Oc1ccccn1)c1ccccc1

Procedure:
Six bomb tubes, each containing 4.8 g (30.0 mmol) of 4-fluoro-1,2-dimethoxybenzene (obtained from 3,4-dimethoxyaniline by a Balz-Schiemann reaction), 7.5 g (37.5 mmol) of (2-pyridinyl)-benzoate and 300 ml of trifluoroacetic acid, are heated at 100° for 41/2 hours while stirring magnetically. The contents of all six bomb tubes is poured into 600 ml of water while stirring vigorously and the solid substance that separates out is filtered with suction. The filtrate is extracted several times with toluene. The solid substance is dissolved in the combined toluene extracts. The toluene solution is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation. The resulting semi-solid oil is dissolved in 500 ml of warm isopropanol and treated with carbon. The filtered solution is concentrated in vacuo until crystallisation begins. After complete crystallisation, the (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone is filtered with suction and washed with cold isopropanol, yielding white crystals having a melting point of 102°-104°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10](NO)[CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:25][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:12][N:11]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: ONc1cc(-c2ccc(Cl)cc2)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Yield: 74 %

Procedure:
5-(4-Chlorophenyl)-3-hydroxyaminoisoxazole (0.58 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.48 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.69 g, 68%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(N)nc(-c2ccccc2)c1C#N
Solvent: CCO
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-Amino-4-(methylthio)-6-phenyl-pyrimidine-5-carbonitrile and benzylamine in ethanol. ES-MS m/e (%): 302 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].OO.[Cl:12]C1C=CC=C(C(O[O-])=O)C=1.P(Cl)(Cl)([Cl:25])=O>>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([Cl:12])[C:2]=1[Cl:1])#[N:9].[C:8]([C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]([Cl:25])[CH:6]=1)#[N:9]
Reactant: O=C(O[O-])c1cccc(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccncc1Cl
Agent: OO
Product: N#Cc1cc(Cl)ncc1Cl
Product: N#Cc1ccnc(Cl)c1Cl

Procedure:
3-chloro-4-cyanopyridine is converted to N-oxide by means of an oxidizing agent such as hydrogen peroxide or m-chloroperbenzoate, and phosphorus oxychloride is reacted thereto to obtain 4-cyano-2,3-dichloropyridine and 4-cyano-2,5-dichloropyridine. These compounds can be separated by column chromatography. The separated compounds are respectively hydrolyzed under an alkaline condition or an acidic condition to obtain the respective carboxylic acids, which are then subjected to Curtius rearrangement and then treated with trifluoroacetic acid to obtain 4-amino-2,3-dichloro-pyridine and 4-amino-2,5-dichloropyridine,
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:11]1[C:7]2([CH2:12][CH2:13][CH2:14][C:5]([CH2:3][OH:2])=[CH:6]2)[CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C1=CC2(CCCC2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCC1=CC2(CCCC2)CCC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (3.50 g) obtained in Step 5 in tetrahydrofuran (70 mL) was added dropwise a 1M toluene solution of diisobutylaluminum hydride (54.6 mL) under argon atmosphere at −70° C. over 15 minutes, followed by stirring the reaction mixture at −70° C. for 2 hours. After raising the temperature up to −15° C., to the reaction mixture were added successively 2N aqueous hydrochloric acid solution (60 mL) and ethyl acetate (100 mL), followed by separation of the organic layer. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=3:97 to 15:85) to give spiro[4.5]dec-6-ene-7-methanol (2.375 g).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>O1CCOCC1>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][S:28]([NH2:31])(=[O:30])=[O:29])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Reaction time: 14 h
Yield: 25.8 %

Procedure:
Prepared using General Procedure 22: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (50 mg, 0.14 mmol) in dioxane (1.5 mL) was added sulfamide (66 mg, 0.69 mmol) and the mixture was heated to 110° C. After 14 h of stirring, the solvent was evaporated and the residue was purified by column chromatography. Additional purification by recrystallization from MeOH provided 15.9 mg (26%) of (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 248. LCMS-ESI (m/z) calculated for C21H21N5O4S: 439.5; found 440.1 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.08 (dd, J=16.1, 7.9 Hz, 1H), 4.80 (dt, J=12.1, 6.1 Hz, 1H), 4.65 (s, 1H), 4.59 (d, J=8.4 Hz, 1H), 3.50 (ddd, J=17.5, 8.8, 3.7 Hz, 1H), 3.30-3.09 (m, 1H), 2.87-2.67 (m, 1H), 2.07 (dt, J=21.3, 8.2 Hz, 1H), 1.47 (t, J=6.3 Hz, 6H).