Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][OH:32]>CC(C)=O>[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:31]([OH:3])=[O:32]
Reactant: CC(C)=O
Reactant: CC1=C(C)C(=O)C(C(CCCC#CCO)c2ccccc2)=C(C)C1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC1=C(C)C(=O)C(C(CCCC#CC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Jones' reagent (2.25 ml) was added dropwise to a solution of 7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenyl-2-heptyne-1-ol (1.01 g, 3.0 mmole) in acetone (15 ml) at room temperature over the 15-minutes period. The mixture was stirred at room temperature for another 30 minutes and the acetone was distilled off under reduced pressure. Isopropyl ether and water were added to the residue, and extraction was effected. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was recrystallized from isopropyl ether to give 7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenyl-2-heptynoic acid (0.71 g, 68%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:23][O:24]/[C:25](=[CH:30]\[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][CH3:44])[CH:38]=2)=[CH:33][CH:32]=1)/[C:26]([O:28][CH3:29])=[O:27]>>[CH3:23][O:24]/[C:25](=[CH:30]\[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N:43]([CH3:44])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH:38]=2)=[CH:33][CH:32]=1)/[C:26]([O:28][CH3:29])=[O:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
3.9 g (19.4 mmol) of 4-nitrophenyl chloroformate and then 3.4 mL (19.4 mmol) of diisopropylethylamine are added to a solution of 4.8 g (16.1 mmol) of methyl (Z)-2-methoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate. The reaction medium is stirred at room temperature for 2 hours. The reaction medium is hydrolyzed and then extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. 7.4 g (100%) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate are obtained in the form of a tacky foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][O:6][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
A solution of 3-bromo-5-nitrobenzyl alcohol (5 g, 21.5 mmol), in N,N-dimethylformamide (5 mL) was treated with tert-butyldimethylsilyl chloride (4.9 g, 32.3 mmol) and imidazole (2.5 g, 36.6 mmol) and stirred at room temperature for 14 h. The reaction was quenched with water and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (0-75% ethyl acetate inhexanes) afforded [(3-bromo-5-nitrobenzyl)oxy](tert-butyl)dimethylsilane (7.32 g, 20.1 mmol, 93% yield) as a yellow oil.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:23]=[CH:22][C:9]2[N:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)[CH:11]=[N:12][C:8]=2[CH:7]=1)#[N:5].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[C:4]([C:6]1[CH:23]=[CH:22][C:9]2[N:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[C:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)#[N:5]
Reactant: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3=CCCCC3)c2c1

Procedure:
A solution of sodium methoxide (0.25 g, 4.6 mmol, 3 equivalents), 5-cyano-1-(indol-5-yl)benzimidazole (0.40 g, 1.54 mmol), and cyclohexanone (0.175 mL, 1.69 mmol, 1.1 equivalents) in N,N-dimethylformamide (8 mL) was heated at 130° C. under nitrogen for 12 hours. The solvent was removed by evaporation under reduced pressure, and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was separated, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue (0.16 g) using silica gel (approximately 5 g) and elution with ethyl acetate/hexanes [1:1] afforded the title compound. (19%) as a pale yellow solid. Rf =0.3 in ethyl acetate/hexanes [1:1]; 1H NMR (CDCl3) δ10.35 (br s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.45-7.43 (m, 3H), 7.21 (s, 1H), 7.07 (dd, J=8.5 and 1.9 Hz, 1H), 6.04 (br m, 1H), 2.32 (br m, 2H), 2.08 (br m, 2H), 1.72-1.60 (m, 2H), 1.60-1.50 (m, 2H); 13C NMR (CDCl3) δ145.7, 142.4, 137.5, 136.7, 130.9, 126.8, 125.7, 124.8, 123.8, 123.6. 122.5, 119.5, 119.2, 118.2, 117.2, 112.7, 112.1, 105.6, 28.4, 25.5, 22.9, 22.2.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=O)c1ccco1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1ccco1
Reaction time: 3 h

Procedure:
Hydroxylamine hydrochloride (0.951 g) was added to a stirred solution of methyl 2-oxo-2-(2-furanyl)acetate (2.107 g) in methanol (30 ml). The mixture was stirred for 3 h, then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The title oxime was isolated by column chromatography of the residue using gradient elution (Kieselgel:3:1 to 1:1 hexane:ethyl acetate). (Found: M+, 169.0378. C7H7NO4 requires M, 169.0375). νmax (CHCl3 /cm-1 3555, 3278 and 1739. δH (250 MHz, CDCl3), 3.95 (3H, s), 6.57 (1H, dd, J 1.58 and 3.48), 7.45 (1H, d, J 3.22), 7.58 (1H, d, J 2.11), 9.75 (1H, br.s), m/z (EI) 169 (M+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=1>>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:3]2[CH2:4][N:1]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=3)[CH2:2]2)=[N:7][CH:8]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(OC2CNC2)nc1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(C(F)(F)F)cn3)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Example 8.8 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-5-trifluoromethyl-pyridine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 12 h at 50° C.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C)C.C(OC(C)C)(C)C>C1(C)C(C)=CC=CC=1>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([C@@H:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@H:11]3[OH:1])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)CC1OC1C2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1C
Solvent: CC(C)OC(C)C
Product: O[C@@H]1Cc2ccccc2C[C@H]1N1CCN(c2ccccc2)CC1
Yield: 64.3 %

Procedure:
A solution of 7.30 g of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene, 8.91 g of N-phenylpiperazine, and 19 ml of isopropanol in 50 ml of xylene is refluxed for five days. The xylene is removed in vacuo leaving a solid residue, which yields 9.9 g of crude material on trituration with isopropyl ether. Two recrystallizations from ethyl acetate yield 6.5 g of the title compound, melting point 152°-154° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(#N)C.[CH:15](O)=[O:16]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][CH:15]=[O:16])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CO
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=CNNc1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
459 g of 4-nitrophenylhydrazine was gradually added to 1.6 liters of acetonitrile, and then 322 g of formic acid was added to form a homogeneous solution, and, after 20 minutes, crystals formed. After allowing the reaction to proceed for 2 hours at a temperature of 80° C., the reaction system was cooled and the crystals formed were recovered by filtration, washed with acetonitrile, and dried, to provide 493 g of 2-(4-nitrophenyl)-1-formylhydrazine. Melting point: 184° to 186° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1cccc(I)c1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CS(=O)(=O)OCCCCc1cccc(I)c1

Procedure:
4-(3-Iodophenyl)butan-1-ol (1.7 g) was stirred with diisopropylamine (1.74 ml) and methanesulfonyl chloride (0.66 ml) in dichloromethane (50 ml) at 21° for 2 h. The solution was washed successively with sodium bicarbonate solution, water, water acidified with a few drops of 2M HCl and water, each time back extracting with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to give the title compound (2,23 g), tlc Rf=0.28 (1:3 ethyl acetate in cyclohexane)
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[O:10]1>>[CH:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[P:9]([N:7]([P:9]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=4[O:10]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[O:10][C:11]=2[CH:22]=[CH:21][CH:20]=1
Reactant: NC1CCCCC1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Product: c1ccc2c(c1)OP(N(C1CCCCC1)P1Oc3ccccc3-c3ccccc31)c1ccccc1-2

Procedure:
By using the molar equivalent of cyclohexylamine and two molar equivalents of 6-chloro-dibenz[c,e][1,2]oxaphosphorine, under otherwise the same conditions as those described in Example 1, there is obtained N,N-bis-(dibenz[c,e][1,2]oxaphosphorin-6-yl)-N-cyclohexylamine having a melting point of 191° C. (Compound III).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2)=[O:8].C1(C)C=CC(S(O[CH2:34][C@@H:35]2[O:37][CH2:36]2)(=O)=O)=CC=1.O>CN(C)C=O>[O:37]1[CH2:36][C@@H:35]1[CH2:34][O:18][C:17]1[C:9]([CH:7]=[O:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11]2
Reactant: CCOC(=O)c1cc2c(C=O)c(O)ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C=O)c(OC[C@H]3CO3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
Potassium carbonate (0.89 g) was added under nitrogen to a stirred solution of ethyl 4-formyl-5-hydroxyindole-2-carboxylate (1.50 g) in dry dimethylformamide (40 ml). A solution of (R)-glycidyl 4-toluenesulphonate (1.47 g) in dry dimethylformamide (30 ml) was then added and the mixture stirred at ambient temperature for 10 minutes, then at 60° C. for 3 hours. The mixture was poured into water (400 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with brine (6×200 ml), dried over magnesium sulphate and the solvent evaporated under reduced pressure. The brown solid residue was purified by flash column chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate to give ethyl (R)-5-(2,3-epoxypropoxy)-4-formylindole-2-carboxylate (1.07 g) as an off-white solid; m.p. 152-154 ° C.
Reaction SMILES: B(F)(F)F.CCOCC.C([SiH](CC)CC)C.[CH2:17]([O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35](O)[C:36]#[C:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CCOCC>[CH2:17]([O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH2:35][C:36]#[C:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCC#CC(O)c1ccc2ccccc2c1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCC#CCc1ccc2ccccc2c1OCc1ccccc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of boron trifluoride etherate (5.0 mL, 0.041 mole) in methylene chloride (150 mL) at 0°, triethylsilane (20 mL, 0.126 mole) was added, followed by a solution of methyl 7-(1-benzyloxy-2-naphthyl)-7-hydroxy-5-heptynoate (5.00 g, 0.013 mole) in methylene chloride (20 mL). The mixture was stirred for 30 minutes, then poured into saturated aqueous potassium carbonate. The crude product was isolated by extraction with ether, and chromatographed with 1:1 ether/hexane. This provided the title compound (2.42 g, 50%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>>[C:10]([N:9]=[C:12]([NH2:13])[NH:1][C:2]1[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=1)#[N:11]
Reactant: N#C[N-]C#N
Reactant: Nc1ccc(F)nc1
Agent: [Na+]
Product: N#CN=C(N)Nc1ccc(F)nc1

Procedure:
A solution of 5-amino-2-fluoropyridine and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH2:30][CH:29]2[NH:31][CH:26]([CH2:27][CH2:28]2)[CH:25]=1.CS(C)=O>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH2:25][CH:26]2[N:31]([CH2:2][CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[CH:8][NH:9]4)[CH:29]([CH2:28][CH2:27]2)[CH:30]=1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Solvent: CS(C)=O
Solvent: O
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2CCOc1cccc2[nH]ccc12
Temperature: 23 °C
Yield: 63 %

Procedure:
4-(2-Chloro-ethoxy)-1H-indole (170 mg, 0.87 mmol), 469 mg (1.74 mmol) of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene and 10 mL of DMSO are heated at 100° C. for 24 h. After cooling to 23° C., the orange reaction mixture is poured into 100 mL H2O. Extraction with CH2Cl2 (2×50 mL), combining the organic layers and washing with H2O (4×50 mL), brine (1×50 mL), drying over MgSO4, and evaporation gives an orange oil. Flash chromatography on SiO2 gel, eluting with CHCl3/MeOH (40/1 to 10/1), gives 216 mg (0.59 mmol, a 63% yield) of the title compound as an off-white solid. The corresponding oxalate salt is prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH. A white solid precipitates. Recrystallization from EtOH/Et2O gives the oxalate salt of the title compound as an off-white solid. mp: 212-215° C.; MS (ES) m/z 395 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.C([O:25][C:26]1[C:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=2[CH:29]=[C:28]([CH2:37][NH2:38])[CH:27]=1)C1C=CC=CC=1.C(N(CC)CC)C.[O-][Si]([O-])=O.[Mg+2]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:38][CH2:37][C:28]1[CH:27]=[C:26]([OH:25])[C:31]2[O:32][C:33]([CH3:35])([CH3:36])[O:34][C:30]=2[CH:29]=1
Reactant: CC1(C)Oc2cc(CN)cc(OCc3ccccc3)c2O1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(O)c2O1

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.42 g, 1.5 mmol) and C-(7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-methylamine hydrochloride (1.5 mmol) were coupled in N,N-dimethylformamide (10 mL) with triethylamine (0.6 mL). The crude material is dissolved in a minimum of 7.5% methanol in chloroform and then passed through a Florisil plug, eluting with 5% methanol in chloroform. The filtrate is concentrated under reduced pressure to give (4Z)-6-bromo-4-({[(7-hydroxy-2,2-dimethyl-1,3-benzodioxol-5-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as a light pink powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][C:35]([F:38])([F:37])[F:36])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(O)(C)C>[F:33][CH:31]([F:32])[O:30][C:26]1[CH:25]=[C:24]([S:21]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([O:34][C:35]([F:38])([F:36])[F:37])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3cccc(OC(F)F)c3)ccc2OC(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=S(=O)(Nc1ccc(OC(F)(F)F)c(N2CCNCC2)c1)c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.2 %

Procedure:
0.22 g 4-[5-(3-Difluoromethoxy-benzenesulfonylamino)-2-trifluoromethoxy-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.388 mmol) were dissolved in 5 ml dichloromethane. 1.5 mL 6 N hydrochlorid acid in isopropanol were added and the reaction mixture was stirred at room temperature for 2.5 h. The solvents were evaporated, the residue was dissolved in water and the pH was adjusted to 8-9 with 1 N aqueous solution of sodium hydroxide. Thereby a white suspension formed, which was extracted once with a mixture of ethyl acetate and dichloromethane. The still existent suspensions were filtered, and the combined organic filtrates were dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 0.140 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[N:7]#[C:8][NH2:9].[ClH:10].O1CCOCC1>CCOCC>[ClH:10].[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:8](=[NH:7])[NH2:9])[CH:6]=1
Reactant: Cc1cn[nH]c1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cnn(C(=N)N)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 4-Methyl-1H-pyrazole (4.9 g, 60 mmol) was added cyanamide (2.5 g, 60 mmol), HCl (5.6 mL, 62 mmol, 4 M in dioxane) and dioxane (60 mL). The reaction was heated to 110° C. and aged for 9 h. It was then aged at rt overnight. The mixture was diluted with Et2O and stirred for 10 min. The product was isolated by filtration and washed with Et2O to afford the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[C:8]#[N:9])=[CH:2]1>CCO.[Ni]>[NH2:9][CH2:8][C:7]1[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1
Reactant: N#Cc1cc(O)ccc1-c1ccoc1
Agent: [Ni]
Solvent: CCO
Product: NCc1cc(O)ccc1-c1ccoc1
Reaction time: 24 h
Yield: 72 %

Procedure:
The 2-Furan-3-yl-5-hydroxy-benzonitrile obtained above is dissolved in EtOH and to which Raney Ni (1 g of suspension in water) is added. The mixture is then subjected to hydrogenation under H2 (50 psi) for 24 hours. After which Raney Ni is filtered off from celite and EtOH is removed to provide the title compound (40 mg, 72% for two steps). MS (ESI): 190 (M+1)+1, 173 (M+1-NH3)+1.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:29])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14]1>ClCCl>[O:12]=[C:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:29])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14]1
Reactant: O=C(C=Cc1ccccc1)OC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCC(OC(=O)C=Cc2ccccc2)CC1
Reaction time: 12 h
Yield: 60 %

Procedure:
Pyridinium chlorochromate (PCC) (19.7 g, 91.5 mmol) was added to a solution of product from step 1 (15.0 g, 61 mmol) in dichloromethane (150 mL). The mixture was stirred for 12 h. The reaction mixture was then added to silica gel (30.0 g) and the solvent was evaporated. The product was purified using column chromatography (by silica gel using hexane/EtOAc gradient as eluent). The product was a white crystalline powder. Yield: 60%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:13][CH2:12]1.I[CH3:36]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([O:26][CH3:36])[C:22]([F:24])([F:23])[F:25])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C(F)(F)F)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 88.3 mg, 2.21 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (0.68 g, 1.47 mmol) and iodomethane (92.0 μL, 1.47 mmol) in tetrahydrofuran (20 mL) at 0° C. After 2 h, the mixture was allowed to warm to ambient temperature. After 2 h, additional iodomethane (92.0 μL, 1.47 mmol) and sodium hydride (60% dispersion in mineral oil; 10.0 mg, 0.27 mmol) were added. After 1 h, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→30% ethyl acetate/dichloromethane) gave the title compound (195 mg). MS 476.2 (M+1).