Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=O)[C:6]([NH2:9])=[N:7][CH:8]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>[OH:12][N:10]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=2)[N:9]=[C:3]1[C:2]([F:14])([F:13])[F:1]
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: On1c(C(F)(F)F)nc2ncc(C(F)(F)F)cc21

Procedure:
5-(Trifluoromethyl)-3-nitro-2-aminopyridine (10.0 grams) in trifluoroacetic anhydride (10 ml.) and pyridine (20 ml.) were heated in a steam bath for 2 hours. Solvents were then evaporated on a rotary evaporator at 100° C. for one hour, and the residue was taken up in ethyl acetate and hydrogenated over 2.0 g. of 5 percent palladium on carbon. The reaction mixture was then filtered, evaporated, and taken up in ethanol; subsequently, the mixture was washed with 10 percent hydrochloric acid, dried over magnesium sulfate, and evaporated. The resulting 1-hydroxy-2,6-bis(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from acetone, m.p., 239°-40° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:14])[NH:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:14])[C:5]([CH:2]([NH:1][C:19]([CH:15]3[CH2:18][CH2:17][CH2:16]3)=[O:20])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CC2)[nH]c1=O
Reactant: O=C(Cl)C1CCC1
Product: CCC(NC(=O)C1CCC1)c1nnc(C2CC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 250 mg (1.29 mmol) 6-(1-aminopropyl)-3-cyclopropyl-1,2,4-triazin-5(4H)-one, 150 mg (1.29 mmol) cyclobutanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[C:6]=2[CH:32]=1.[C:33](O)(=O)[CH3:34].[C:37]([BH3-])#[N:38].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:21])[C:13]3[CH:14]=[CH:15][C:16]([CH2:19][NH:38][C:37]4[CH:6]=[CH:32][CH:2]=[CH:3][C:33]=4[CH3:34])=[CH:17][CH:18]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[C:6]=2[CH:32]=1
Reactant: CC(=O)O
Reactant: CN1CCN(C(=O)CC2CCCN(C(=O)c3ccc(C=O)cc3)c3ccc(Cl)cc32)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1NCc1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonyl-methyl]-1-(4-formylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.29 g) in methanol (30 ml) are added o-toluizine (0.2 ml) and acetic acid until the mixture becomes pH 4. The mixture is heated with stirring at 50° C. for 8 hours, and thereto is added sodium cyanoborohydride (0.085 g) with ice-cooling, and the mixture is stirred for one hour. The mixture is evaporated to remove the methanol, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol =100:1→50:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[4-(2-methylanilinomethyl)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.1 g) as colorless amorphous.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.IC1C=CC=CC=1.[CH2:16]([C:20]1([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:25][C:24](=[O:26])[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[CH2:21]1)[CH2:17][C:18]#[CH:19].C(C1(C2CCCC2)OC(=O)CC(=O)C1)CC#C>>[CH:30]1([C:20]2([CH2:16][CH2:17][C:18]#[C:19][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=3)[O:25][C:24](=[O:26])[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[CH2:21]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Oc1cccc(I)c1
Reactant: C#CCCC1(C2CCCC2)CC(OCC)=CC(=O)O1
Agent: C#CCCC1(C2CCCC2)CC(=O)CC(=O)O1
Solvent: Ic1ccccc1
Product: CCOC1=CC(=O)OC(CCC#Cc2cccc(O)c2)(C2CCCC2)C1

Procedure:
The title compound was prepared analogously to Example 6, except 3-iodophenol was used for iodobenzene, and 6-but-3-ynyl-6-cyclopentyl-4-ethoxy-5,6-dihydro-pyran-2-one, described in Step 2 of that example, was used for 6-but-3-ynyl-6-cyclopentyl-dihydro-pyran-2,4-dione. 1H NMR (CDCl3): δ 1.26 (t, 2H, J=7.16 Hz), δ 1.51-1.81 (m, 8H), δ 2.10 (t, 2H, J=7.54 Hz), δ 2.36 (t, 1H, J=8.10 Hz), δ 2.48 (d, 1H, J=17.71 H), δ 2.52 (t, 2H, J=7.35 Hz), δ 2.68 (d, 1H, J=17.52 Hz), δ 3.94 (q, 2H, J=7.35 Hz), δ 5.14 (d, 2H, J=6.22 Hz), δ 6.77 (dd, 1H, J=5.65 Hz, J=2.45 Hz), δ 6.87 (s, 1H), δ 6.95 (d, 1H, J=6.59 Hz), δ 7.14 (t, 1H, J=7.91 Hz). Anal. Calcd. For C22H26O4 0.3 EtOAc: C, 73.16, H 7.52. Found: C, 73.18, H, 7.57; ESIMS (M+Na+) 377.1.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](=[O:23])([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:23][CH2:20][CH2:4][CH2:3][CH2:2][CH2:11][CH3:10])[CH:3]=2)[CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2cc(OCCCCCC)ccc2c1
Yield: 132.3 %

Procedure:
2,6-Dihydroxynaphthalene (30.0 g, 0.19 mol) reacted with n-hexylbromide (97.5 g, 0.59 mol) in the presence of potassium carbonate (81.6 g, 0.59 mol) in 400 mL of DMF at 90° C. overnight. The reaction was poured into 700 mL of water and the precipitate was filtered, washed with water and methanol, and dried. The crude product was recrystallized from methanol to give light gray solid 41.3 g (67% yield). 1H NMR CDCl3) δ (ppm): 0.91 (t, J=6.9 Hz, 6H), 1.32-1.40 (m, 8H), 1.44-1.54 (m, 4H), 1.77-2.86 (m, 4H), 4.02 (t, J=6.6 Hz, 4H), 7.06-7.12 (m, 4H), 7.60 (d, J=8.8 Hz, 2H); M.p. 78-79° C.
Reaction SMILES: C(O[NH:5][C:6](=[NH:20])[CH2:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)(=O)C.C(OCC)(=O)C>C(O)C.[Pd]>[C:14]1([C:13]2[C:8]([CH2:7][C:6]([NH2:20])=[NH:5])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)ONC(=N)Cc1ncccc1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(N)Cc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred degassed solution of (161) (2.7 g, 10.04 mmol) in ethanol (135 mL) was added 10% Pd—C (270 mg), the mixture was stirred 16 h under H2 (hydrogen bubbler) at room temperature. Silica thin layer chromatography was performed (ethyl acetate, Rf=0.1). The reaction mixture was filtered through celite, washed with 10% methanol in dichloromethane (5×100 mL), dried and concentrated. The yellow solid was washed with 10% ethyl acetate in hexane (3×30 mL) to get pure 2-(3-phenyl-pyridin-2-yl)-acetamidine with acetic acid (162) (1.7 g, 62.5%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C(CCCC1CCCCCCCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCC1CCCCCCCCCC1)C(=O)OCC

Procedure:
4.4 g of 5-cycloundecyl-2-methylenevaleric acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 7.6 g of (3-cycloundecylpropyl)-malonic acid ethyl ester, 0.84 g of paraformaldehyde, 7 ml of pyridine and 0.3 ml of piperidine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)N=[N:36][C:34]=2[CH:35]=1.C1(N)C=CC=CC=1N>O>[NH2:38][C:33]1[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=1[NH:36][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:24])=[CH:16][CH:15]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(C(=Cc2ccc(C(=O)O)cc2)C(=O)NC2CC2)cc1
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=Cc2ccc(C(=O)Nc3ccccc3N)cc2)C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 45 %

Procedure:
To a suspension of 4-(3-(cyclopropylamino)-2-(4-methylphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (0.2 g, 0.6 mmol, prepared according to the procedure described in Example 99, step I-III) in DMF (3 mL) EDCl (0.23 g, 1.1 mmol), HOBt (0.08 g, 5 mmol), o-phenylenediamine (0.08 g, 0.7 mmol), were added followed by TEA (0.23 mL, 15 mmol). The reaction mixture was stirred for 4 hours after which the mixture was added to cold water (100 mL) and kept 0° C. for 1 hour to obtain a pale yellow solid. The solid was filtered and washed with water (50 mL) dried under vacuum to afford the title compound (0.110 g, 45% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51 (2H, m, —CH2), 0.63-0.65 (2H, m, —CH2), 2.33 (3H, s, —CH3), 2.67-2.75 (1H, m, —CH), 4.87 (2H, s, —NH2), 6.55-6.58 (1H, m, Ar—H), 6.74-6.76 (1H, m, Ar—H), 6.93-6.97 (1H, m, Ar—H), 7.04 (2H, d, Ar—H), 7.11 (3H, m, Ar—H), 7.19 (2H, m, Ar—H), 7.25 (1H, s, ═CH), 7.76-7.78 (3H, m, Ar—H and —NH), 9.57 (1H, s, —NH), MS m/z: 412.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])(=[O:25])=[O:24])=[C:18]([CH3:36])[CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1.[C:40](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:40])[S:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])(=[O:24])=[O:25])=[C:18]([CH3:36])[CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(S(=O)(=O)Nc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(S(=O)(=O)N(C)c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1

Procedure:
A solution of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)amino]sulfonyl}benzoate (32 mg, 56 μmol) in dimethylformamide (560 μL) was stirred with cesium carbonate (91 mg, 280 μmol) and methyl iodide (17.3 μL, 280 μmol) at 80° C. in a sealed vial. Water (2 mL) was added and the product was extracted with 50% ethyl acetate/hexanes. Yield=31 mg 94%) of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)(methyl)amino]sulfonyl}benzoate.
Reaction SMILES: C(=O)([O-])O.[Cs+:5].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.C(#N)C>[Cs+:5].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:20]=1)[C:15]([O-:17])=[O:16])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cesium hydrogencarbonate (194 mg, 1 mmol) was added to a solution of (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionic acid (297 mg, 1 mmol) in 5 mL water and 5 mL acetonitrile. The resulting mixture was stirred at room temperature for 10 minutes, then frozen and lyophilized to yield (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionic acid cesium salt as a white solid, which was used in the next reaction without further purification.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:21])[C@@H:9]([CH:10]=[C:11]([Br:13])Br)[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24].P(O)(O)([O-])=O.[Na+]>CCCCCC.O1CCCC1.CCOCC>[CH3:21][C:7]1([CH3:6])[C@@H:9](/[CH:10]=[C:11](\[Br:13])/[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Reactant: CCCOC(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -115 °C
Reaction time: 0.25 h

Procedure:
50 ml of a solution of 16N butyllithium in hexane were added over 25 minutes at -115° C. to a solution of 28.3 g of tert-butyl (1R,cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-1-carboxylate in 120 ml of tetrahydrofuran and 120 ml of ether and after stirring the mixture at -115° C. for 15 minutes, 10 ml of n-propyl chloroformate were progressively added thereto. The mixture was stirred at -115° C. for 20 minutes, at -65° C. for one hour and was poured into an aqueous monosodium phosphate solution. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture to obtain 3.52 g of tert.-butyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-2-propyloxycarbonyl-ethenyl]-cyclopropane-1-carboxylate and 3.16 g of the corresponding 3(E)-isomer.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([F:11])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:63][C:56]2[CH:55]=[C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[C:53]4[C:48]=3[CH:47]=[CH:46][NH:45]4)[CH:62]=[C:61]3[C:57]=2[CH:58]=[N:59][NH:60]3)=[O:10])[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(Cl)ccc1F
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
6-Chloro-3-fluoro-2-pyridinecarboxylic acid (available from Asymchem, 848 mg, 4.83 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1838 mg, 4.83 mmol) were dissolved in DMF (15 ml) and DIPEA (2.53 ml) was added. The mixture was stirred at room temperature for 30 mins. 6-(1H-indol-4-yl)-1H-indazol-4-amine (600 mg, 2.42 mmol) was added and the mixture was stirred at room temperature for 36 h. Some solvent was removed in vacuo to give ˜5 ml which was added to 2×50 g aminopropyl cartridges which had been preconditioned with methanol. The reaction mixture remained on the cartridges for 2 h before being eluted with methanol. Some solvent was removed in vacuo and a yellow precipitate crashed out which was filtered off to give the title compound (531 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:24][C:25]([CH:27]=[CH2:28])=[O:26].Cl>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:28][CH2:27][C:25](=[O:26])[CH3:24])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 20 h

Procedure:
The title compound of Example 2 (2.0 g) was dissolved in methanol (20 ml) and triethylamine (0.5 ml) added followed by methylvinylketone (0.0084 mole). The reaction was stirred under nitrogen for about 20 hours. 0.1N Hydrochloric acid (80 ml) was added and the aqueous phase extracted with ethyl ether. The organic extracts were dried over sodium sulfate, filtered, the solvent removed in vacuo and the residue chromatographed on silica to give the title compound, m.p. ca. 79°-81° C. Analysis calc. for C18 308 H28O2S(48): Calc.: C, 70.09; H, 9.15; S, 10.39. Found: C, 70.15; H, 9.00; S, 10.53.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1.[I-].[K+].O>CS(C)=O.C(OCC)(=O)C>[C:13]1([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][C:1]#[N:2])[CH2:8][CH2:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: [C-]#N
Reactant: ClCCC1CCN(c2nccc3ccccc23)CC1
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCCC1CCN(c2nccc3ccccc23)CC1
Temperature: 120 °C

Procedure:
0.63 g (9.57 mmol) of potassium cyanide is added portionwise to a suspension of 2.63 g (9.57 mmol) of 1-[4-(2-chloroethyl)-1-piperidyl]isoquinoline, prepared in step 2.2, and 0.048 g (0.29 mmol) of potassium iodide in 30 ml of dimethyl sulfoxide. The reaction mixture is maintained at about 120° C. for 16 hours. The mixture is allowed to cool to room temperature and 90 ml of water and ethyl acetate are then added. The aqueous phase is separated out and extracted three times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](C(CC)C)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[B:19](OC)([O:22]C)[O:20]C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:15]([C:5]1[CH:6]=[CH:7][CH2:2][C:3]([O:12][CH3:13])([B:19]([OH:22])[OH:20])[CH:4]=1)([CH2:16][CH3:17])[CH3:14]
Reactant: COB(OC)OC
Reactant: CCC(C)c1ccc(OC)c(Br)c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(C)C1=CC(OC)(B(O)O)CC=C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-Bromo-4-sec-butyl-1-methoxy-benzene (1.15 g) is dissolved in tetrahydrofuran (17 ml) and the mixture is cooled to −78° C., and thereto is added dropwise 1.6M n-butyllithium in hexanes, and the mixture is stirred at −78° C. for 15 minutes. To the reaction solution is added trimethyl borate (1.47 g), and the reaction mixture is stirred at −78° C. for 30 minutes, and thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate. The mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 5-sec-butyl-1-methoxy-benzene boronic acid (950 mg). NMR (CDCl3): 0.81 (3H, t), 1.22 (3H, d), 1.58 (2H, m), 2.58 (1H, m), 3.90 (3H, s), 6.25 (2H, s), 6.85 (2H, d), 7.25 (1H, d), 7.65 (1H, s).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:16](=O)/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH:16](=[N:13][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([N:6]=[CH:10][CH:9]=[CH:1][C:2]3[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Solvent: CCO
Product: C(=Cc1ccccc1)C=Nc1ccc(Cc2ccc(N=CC=Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 188.7 %

Procedure:
To a solution of 198.2 g (1 mole) of 4,4'-methylene dianiline in 2000 ml of ethanol was added a solution of 277.6 g (2.1 moles) of transcinnamaldehyde in 500 ml of ethanol over a 2 minute period. Immediately an exothermic reaction ensued and within 2 minutes the reaction mixture set up to a yellow solid. An additional 1000 ml of ethanol was added, the reaction mixture was heated at reflux for 1 hour with stirring, and then cooled to room temperature. The product was filtered and dried in vacuum at room temperature, yielding 402.5 g (94% of theory) of N,N'-biscinnamal-4,4'-methylene dianiline, m.p. 162.5°-163.5°C.
Reaction SMILES: ClCCl.[NH2:4][C:5]1[C:10]([C:11](OCC)=[O:12])=[N:9][C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[N+:6]=1[O-:28].[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC.O>[NH2:4][C:5]1[C:10]([CH2:11][OH:12])=[N:9][C:8]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]([CH2:24][CH:25]([CH3:26])[CH3:27])[N+:6]=1[O-:28]
Reactant: CCOC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1N
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
14 Milliliters of dry dichloromethane was added to 670 mg of 2-amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide. The mixture was cooled to -35° C. Thereto was dropwise added in about 5 minutes 4.7 ml of a solution of 1 mol of diisobutylaluminum hydride dissolved in n-hexane. After completion of the dropwise addition, a reaction was effected for 40 minutes at -30° C., then the temperature of the reaction mixture was returned to room temperature by adding 1 ml of water to the reaction mixture. Further, 30 ml of 2% hydrochloric acid was added thereto and the reaction mixture was extracted with dichloromethane, and the extract was dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 70% by volume of methanol-dichloromethane), followed by recrystallization from benzene to obtain 385 mg of 2-amino-5-benzyloxy-3-hydroxymethyl-6-isobutylpyrazine 1-oxide (Compound B-11) as pale yellow fine needle-like crystals having a melting point of 129.0°-131.3° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18](S(C1C=CC=CC=1)(=O)=O)[CH2:17][CH2:16]2.O>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:18][CH:17]=[CH:16]2
Reactant: CCOC(=O)C1c2ccc(Br)cc2CCN1S(=O)(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nccc2cc(Br)ccc12
Reaction time: 18 h
Yield: 58.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (762.3 μL, 5.10 mmol) was added to ethyl 6-bromo-2-(phenylsulfonyl)-1,2,3,4-tetrahydro-1-isoquinolinecarboxylate (1.03 g, 2.43 mmol) in toluene (12 mL) under argon and the reaction was stirred for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:3 ethyl acetate:hexanes to give 400.6 mg (59%) of ethyl 6-bromo-1-isoquinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, J=6 Hz, 1H), 8.43 (d, J=2 Hz, 1H), 8.41 (d, J=10 Hz, 1H), 8.05 (d, J=6 Hz, 1H), 7.91 (dd, J=9, 2 Hz, 1H), 4.46 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 280 (M+H)+.