Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[Cl:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1O.Cl.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:33][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([O:32][CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]5[Cl:34])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reactant: OC1CCCCC1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(OC1CCCCC1Cl)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reaction time: 8 h

Procedure:
To a solution of 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (E, 160 mg) in dichloromethane (5 ml) are added, at room temperature, 2-chlorocyclohexanol (57 mg), 4-dimethylaminopyridine (4 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (94 mg). The mixture is stirred overnight, and water is then added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solids are filtered off and the solvent is distilled off. The residue is purified by chromatography. This gives 2-chlorocyclohexyl 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (100 mg, 50%).
Reaction SMILES: [Sn](Cl)[Cl:2].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=1[C:16]#[N:17])([O-])=O>Cl.C(O)C>[ClH:2].[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:14]2[NH:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:4]=[C:16]([NH2:17])[C:15]=2[CH:18]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1ccccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Yield: 89.9 %

Procedure:
Add a solution of tin(II) chloride (567 mg, 3 mmol) in 12 N hydrochloric acid (1.8 mL) to a solution of 2-(2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (307 mg, 1 mmol) in ethanol (10 mL). Reflux for 24 hours, then concentrate under vacuum, add water and filter. Wash the resulting solid with water and dichloromethane then dry under vaccum to yield the titled compound as a yellow solid (282 mg, 90%): mp 334–336° C.; 1H NMR (DMSO-d6) δ 7.05–7.19 (m, 4H), 7.34 (d, 1H), 7.86 (dd, 1H), 7.87 (s, 1H), 8.79 (s, 1H), 9.26 (s, 1H), 9.75 (s, 1H), 12.40 (s, 1H). MS (ESI/neg) m/z (rel intensity) 276.1 (100).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (1.06 g, 3.26 mmol) (obtained as described in Reference Example 65(2)) in methylene chloride (50 ml) were added methanesulfonyl chloride (0.38 ml, 4.89 mmol) and triethylamine (0.68 ml, 4.89 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (1.16 mg, yield 91%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[CH3:8][C:9]1[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:11][NH:12][C:13]=1[NH2:14]>N1C=CC=CC=1.O>[CH3:8][C:9]1[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:11][N:12]2[CH2:3][CH2:2][C:1](=[O:5])[NH:14][C:13]=12
Reactant: C=CC(=O)OCC
Reactant: Cc1c(-c2cccnc2)n[nH]c1N
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Temperature: 25 °C

Procedure:
Ethyl acrylate (0.5 mL) was added to a solution of 4-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (300 mg, 1.72 mmol) in pyridine (4 mL) and water (1 mL) and the resulting mixture heated to reflux overnight. After cooling to rt, the solvent was removed in vacuo and the residue re-crystallized from MeOH to give the desired product: MS (m/z): 229.1 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.80 (d, 1 H, J=1.2 Hz), 8.53 (dd, 1 H, J=1.2 Hz, J=4.8 Hz), 8.07-8.09 (m, 1 H), 7.52 (dd, 1 H, J=4.8 Hz, J=8.0 Hz), 4.36 (t, 2 H, J=7.2 Hz), 2.94 (t, 2 H, J=7.2 Hz), 2.13 (s, 3 H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.50 g (55%) of the product 4-(4-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[N:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH:17][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][N:2]=[CH:3]2)[CH3:13]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2cn[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc2cn[nH]c12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-Indazole-7-carbaldehyde (175 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([CH3:69])([CH3:68])[C:21]([NH:23][C@H:24]([C:28]([N:30]([CH3:67])[C@@H:31]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:32]([O:61][CH3:62])[CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C@H:41]([O:59][CH3:60])[C@@H:42]([CH3:58])[C:43]([NH:45][C@H:46]([C:54]([O:56][CH3:57])=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:44])=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.C1COCC1.C(NCC)C>>[NH2:18][CH2:19][C:20]([CH3:69])([CH3:68])[C:21]([NH:23][C@H:24]([C:28]([N:30]([CH3:67])[C@@H:31]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:32]([O:61][CH3:62])[CH2:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C@H:41]([O:59][CH3:60])[C@@H:42]([CH3:58])[C:43]([NH:45][C@H:46]([C:54]([O:56][CH3:57])=[O:55])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:44])=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CN)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a stirring solution of #125 (235 mg, 0.246 mmol, 1.00 eq.) in 2 mL of THF, (1 mL, 10 mM, 40.6 eq.) of diethylamine was added. The reaction was allowed to stir at room temperature for 3 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #126 (101 mg, 56%) as a white solid. LC-MS (Protocol Q): m/z 732.2 [M+H+] retention time=1.32 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.51 (dd), 8.28 (d), 7.15-7.29 (m), 5.77 (s), 4.55-4.77 (m), 4.44-4.54 (m), 3.94-4.10 (m), 3.73-3.79 (m), 3.66 (d), 3.49-3.60 (m), 3.40-3.48 (m), 3.10-3.36 (m), 3.00-3.09 (m), 2.83-2.98 (m), 2.57-2.77 (m), 2.19-2.46 (m), 1.87-2.14 (m), 1.61-1.86 (m), 1.36-1.55 (m), 1.23-1.36 (m), 1.12-1.22 (m), 0.97-1.11 (m), 0.82-0.96 (m), 0.73-0.81 (m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH:31]=O)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:31][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:23][C:24]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:28])[O:26]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CN1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A solution of ethyl 2-(benzyloxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.503 g, 1.13 mmol), piperidine (0.39 mL, 4 mmol) and acetic acid (0.23 mL, 4 mmol) in 1,2-dichloroethane (20 mL) was stirred for 15 minutes then treated with sodium triacetoxyborohydride (0.85 g, 4 mmol). After stirring for 2 h at 65° C. the solution was cooled to room temperature and concentrated. The resulting residue was purified using a combiflash system (12 g silica gel column, 10-100% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-(piperidin-1-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (300 mg, 52%). 1H NMR (CDCl3) δ: 7.36 (m, 5H), 6.05 (bs, 1H), 5.14 (d, 1H), 5.03 (d, J=11.2 Hz, 1H), 4.19 (m, 2H), 3.06 (d, J=13.8 Hz, 1H,), 2.59 (d, J=13.8 Hz, 1H), 2.34 (m, 4H), 2.15 (m, 1H), 1.78-1.70 (m, 1H), 1.45-1.25 (m, 12H), 1.22 (s, 12H), 1.02 (m, 1H), 0.73 (t, J=7.8 Hz, 2H). MS found for C28H45BN2O7 m/z[517(M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19].[OH-:20].[Na+].[OH-].[K+]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][C:11]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cc(O)cc1Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cc(O)cc1Cl
Temperature: 0 °C

Procedure:
The 2-[(2,6-dichloro-4-methoxyphenyl)amino]phenylacetic acid (0.1 mol) from example 22 was added in portions to a melt of 200 g of pyridine hydrochloride (1.75 mol) at 170° C. The mixture was heated at 180° C. for 3 h and poured onto 2000 ml of ice water while hot. The precipitated product was filtered off, washed with water, and dissolved in 1000 ml of ethyl acetate. The organic phase was washed with 200 ml of 1N HCl in water (2×100 ml) and evaporated to give N-(2,6-dichloro-4-hydroxyphenyl) oxindole. To a solution of 8 g of N-(2,6-dichloro-4-hydroxyphenyl)-oxindole in 200 ml of n-butanol were added 7 g of NaOH and 1 g of KOH, and the reaction mixture was refluxed for 24 h and evaporated in vacuo. The residue was dissolved in 700 ml of water and the aqueous solution was extracted with ether (2×200 ml), cooled to 0° C., and acidified with concentrated HCl. The precipitate was taken up in 300 ml of ether. The organic phase was washed with 30 ml of water, 0.5N NaHCO3 (5×80 ml), and 80 ml of 2N KHCO3 solution. The combined NaHCO3 extracts were cooled to 0° C. and acidified with 2N HCl, and the precipitate was dissolved in 200 ml of ether. The organic layer was washed with 30 ml of water and evaporated to yield 2-[(2,6-dichloro-4-hydroxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.068 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH:13](N)[N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:5][CH:4]=1.C(N(CC)C1C=CC=CC=1)C.Cl>CN1CCCC1=O>[C:18]1(=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][C:10]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:27]=[CH:26][C:6]=3[O:7][CH2:8][CH:9]=2)[C:15](=[O:24])[C:16]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]12
Reactant: COc1ccc(OCC#CCCC(N)N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCO2

Procedure:
A mixture of 40 g of 6-(4-methoxyphenoxy)-1-phthalimido-4-hexynylamine and 8.5 g of N,N-diethylaniline in 400 ml of N-methylpyrrolidinone is heated at 210° for 30 hours. After pouring onto water containing 57 ml of 1N hydrochloric acid the product is extracted with ether, dried, and the solvent is removed in vacuo. The residue is crystallized from isopropanol to afford 4-(3-phthalimidopropyl)-6-methoxy-2H-[1]-benzopyran, m.p. 78°-80°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.COCCOCCOC>[Cu]I.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Ic1ccncc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Oc3ccncc3)cc2)cc1
Yield: 86.5 %

Procedure:
The same procedure from Example 143, step 1 was followed using p-benzyloxyphenol (500 mg, 2.5 mmol), Cs2CO3 (1.58 g, 4.85 mmol), 4-iodo pyridine (780 mg, 3.805 mmol), anhydrous dioxane (15 ml), diglyme (34 mg, 0.24 mmol), CuI (17 mg, 0.089 mmol) to give the title compound (600 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]Br)[CH:13]=2)[N:8](C(=O)C)[C:7]=1[C:20]([F:23])([F:22])[F:21])[CH3:2].[CH3:25][NH:26][CH3:27]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:26]([CH3:27])[CH3:25])[CH:13]=2)[NH:8][C:7]=1[C:20]([F:23])([F:22])[F:21])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(CBr)cc12
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of (1-acetyl-5-bromomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (378 mg, 0.93 mmol) in THF (16.0 mL) is added a 33% solution of dimethylamine in ethanol (8.0 mL). The resulting reaction mixture is stirred for 15 h at room temperature, followed by removal of the volatiles in vacuo. The residue is purified by flash column chromatography (silica gel, CH2Cl2/MeOH 9:1) to afford the title compound as a yellow solid (303 mg, 0.92 mmol, 99%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.31 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 4.11 (s, 2H), 3.90 (s, 2H), 2.64 (s, 6H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 329 (M(C16H19F3N2O2)+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[O:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=3)=[C:7]2[N:6]=[N:5]1.S([O-])(O[O-])(=O)=[O:26].[K+].[K+].OOS([O-])=O.[K+]>CN(C=O)C.O>[CH3:1][S:2]([CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[O:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=3)=[C:7]2[N:6]=[N:5]1)=[O:26]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSCn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)Cn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Temperature: 0 °C
Yield: 90 %

Procedure:
To a 0° C. solution of 3-(methylthiomethyl)-8-(5-phenyl-1,3,4-oxadiazol-2-yl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.337 mmol, 115 mg, 1 eq.) in DMF (6 mL) was added potassium peroxymonosulfate (Oxone™) (0.37 mmol, 114 mg, 1.1 eq.) dissolved in water (1.2 mL) drop wise. The formed suspension was stirred at 0° C. and stepwise additions of Oxone™ in water were made until reaction completion. The reaction mixture was filtered and the obtained solid was washed with water, acetonitrile and ether, and dried under vacuum to give the title compound. Yield 90%. δH (DMSO-d6) 9.15 (1H, s), 8.13 (2H, dd, J: 7.96, 2.25), 7.70 (3H, m), 5.67 (1H, d, J: 13.06), 5.52 (1H, d, J: 13.06), 2.81 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccccc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccccc3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with aniline gave the title compound as a tan solid, mp 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(#N)C.[CH2:13]([NH2:16])[CH2:14][CH3:15].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCNCc1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
A solution of 48.3 g 4-chlorobenzyl chloride in 40 ml. acetonitrile was added to a mixture of 18 g. propylamine, 12.6 g. sodium hydroxide, 50 ml. acetonitrile and 30 ml. water. The mixture was shaken intermittently for 45 minutes. An exothermic reaction occurred and a white solid separated in the lower phase. After a period of four days the reaction mixture was poured into a liter of water and the organic phase isolated with ether. Distillation of the ethereal extract gave an oily product N-4-chlorobenzyl-N-propylamine, m.p. 101°-106° C./1.7-2.5 mm. Hg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]([C:28](=[O:31])[NH:29][OH:30])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:30][NH:29][C:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2C(=O)NO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.147 g (0.325 mmol) of the product of Example 58, 4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester, in 3.0 mL of dichloromethane was added 0.3 mL of trifluoroacetic acid and the reaction was stirred at room temperature for 1 h. The reaction was then concentrated in vacuo and the residue was diluted with dichloromethane. The organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.053 g of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide as a tan solid. Electrospray Mass Spec 354.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:33]=[C:32]([F:34])[C:31](F)=[C:30]([F:36])[CH:29]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH3:37][O-:38].[Na+]>CS(C)=O>[F:34][C:32]1[CH:33]=[C:28]([S:25]([N:17]2[CH2:16][CH2:15][C:14]3[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=3)[CH2:18]2)(=[O:27])=[O:26])[CH:29]=[C:30]([F:36])[C:31]=1[O:38][CH3:37]
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cc(F)c(F)c(F)c1)C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cc(F)c(OC)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (R)-methyl 1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (150 mg, 0.288 mmol) in dimethyl sulphoxide (4 mL) was added sodium methoxide (25% in methanol) (65.8 μl, 0.288 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour, then allowed to stand at room temperature overnight. The crude product was purified by column chromatography on silica gel (gradient: 0-50% ethyl acetate in isohexane) to afford (R)-methyl 6-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (150 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.51 min, m+H=534.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([F:15])[CH:7]=1.S(Cl)([Cl:18])=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[C:8]([F:15])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCCCl)cc1F
Product: O=C(Cl)c1ccc(OCCCCl)cc1F

Procedure:
4-(3-chloropropoxy)-2-fluorobenzoic acid i78 (0.68 g, 2.92 mmol, 1 eq) is refluxed in thionyl chloride (4.27 ml, 57.46 mmol, 20 eq) for 3 hours. The mixture is then concentrated under reduced pressure to give 0.73 g of crude 4-(3-chloropropoxy)-2-fluorobenzoyl chloride i80, which is used in the next step without purification.