Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:50][CH2:49][CH:46]1[O:45][C:44]2[CH:51]=[C:40]([O:39][CH3:38])[CH:41]=[CH:42][C:43]=2[O:48][CH2:47]1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(F)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
5-Fluoroindole-3-butyric acid (1.2 g, 5.4 mmole), 1-hydroxybenzotriazole hydrate (0.88 g, 6.5 mmole) and 1,3-diisopropylcarbodiimide (2.0 ml, 13.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 5.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (56%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3-yl)-butanamide, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](O)=[O:12])=[C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:22]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH2:25])=[O:12])=[C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:22]=1
Reactant: COc1ccc2oc(C(=O)O)c(OCc3ccccc3)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2oc(C(N)=O)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A suspension of 5-methoxy-3-(phenylmethoxy)-2-benzofurancarboxylic acid (157 mg, 0.50 mmol) and 1,1'-carbonyldiimidazole (96 mg, 0.59 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1.5 hours. The reaction solution is cooled to room temperature, aqueous ammonium hydroxide (1 mL) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 5-methoxy-3-(phenylmethoxy)-2-benzofurancarboxamide in 47% yield; mp=70°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[C:19](=[O:23])[N:18]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)cc[nH]1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cn3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[(5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinyl)methyl]oxy}-2(1H)-pyrimidinone and 4-(Chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 492 [M+H]+; 3.79 min (ret time).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:36])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[C:37]1(C)[CH:42]=CC(S(O)(=O)=O)=C[CH:38]=1.O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:36])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@:21]6([CH3:22])[CH2:23][O:24][C:37]([CH3:42])([CH3:38])[O:25][C@H:20]6[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@@H]5OC(C)(C)OC[C@@]5(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Yield: 60.3 %

Procedure:
Methyl asiatate 2 (27.7 mg, 0.055 mmole) was dissolved in anhydrous acetone (3 ml), added with p-toluenesulfonic acid (27.7 mg) and then refluxed. Water was added to the reaction mixture, and the solution was neutralized with 5% potassium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The was chromatographed with benzene and ethyl acetate (3:2) to give pure desired compound (18 mg, 60%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:18][CH:19]=4)[C:14]3=[O:34])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CO>Cl.O1CCOCC1>[NH2:26][CH2:25][CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:11]3[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=3[CH3:35])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:6])[C:14]2=[O:34])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCNC(=O)OC(C)(C)C)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCN)cc2c1=O
Yield: 89 %

Procedure:
tert-Butyl {2-[(2-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy]ethyl}carbamate (145 mg) was dissolved in 4N HCl in dioxane (1.2 ml) and methanol (0.9 ml) stirred at room temperature for 18 hours. The orange solution was concentrated and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[7-(2-aminoethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide as a white solid (102 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.22 (s, 2H), 2.86 (m, 1H), 2.94 (t, 2H), 4.05 (m, 2H), 6.73 (d, 1H), 7.22 (d, 1H), 7.43 (m, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.76 (d, 1H), 7.87 (m, 1H), 8.46 (d, 1H); Mass Spectrum: M+H+ 378.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:22])=[CH:7][C:8]([C:18](OC)=[O:19])=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][O:15][C:13]2=[O:14])[CH:10]=1)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(N(CC)CC)C>[C:23]([N:4]([C:1](=[O:3])[CH3:2])[C:5]1[C:6]([Cl:22])=[CH:7][C:8]2[C:18](=[O:19])[C:12]3([CH2:17][CH2:16][O:15][C:13]3=[O:14])[O:11][C:9]=2[CH:10]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1CCOC1=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)=O)c1cc2c(cc1Cl)C(=O)C1(CCOC1=O)O2

Procedure:
A mixture of 23 g. of α-[(5-acetylamino-4-chloro-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone, 46 ml. of triethylamine and 230 ml. of acetic anhydride was heated at 120° C. for 5 hours. The solvents were evaporated off under reduced pressure, then the residue was poured into ice-water. The precipitating crystals were collected by filtration, washed with water and dried, followed by recrystallization from ethyl acetate to give 6-diacetylamino-5-chloro-4',5'-dihydrospiro[benzo[b]furan-2(3H), 3'(2'H)-furan]-2',3-dione melting at 181°-185° C. Yield 6.8 g.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OC(C)C)(C)C>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:13](=[O:15])[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:10]=2)=[O:16])[CH2:24][CH2:23]1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Reactant: Cc1cccc(CC2CCNCC2)c1
Solvent: CC(C)OC(C)C
Product: Cc1cccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)c1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) and 4-(3-methyl-benzyl)-piperidine according to the method described in Example 2. Melting Point: 204-208° C. (diisopropylether)
Reaction SMILES: [C:1]([C:3]([CH2:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Br)=[O:5])#[N:2].[CH2:15]([NH2:18])[CH2:16][CH3:17].N1C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([NH:18][C:4](=[O:5])[C:3]([C:1]#[N:2])([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:16][CH3:17]
Reactant: CCCN
Reactant: CCC(C#N)(C(=O)Br)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCNC(=O)C(C#N)(CC)c1ccccc1
Yield: 78.6 %

Procedure:
11 g of 2-cyano-2-ethyl-2-phenylacetyl bromide are added dropwise under cooling, at 20° to 30° C., to a solution of 3 g of n-propylamine and 4 g of pyridine in 20 ml of dry benzene. The reaction mixture is refluxed for 30 minutes and then processed as described in Example 3. 7.9 g (68.3%) of N-(n-propyl)-2-cyano-2-ethyl-2-phenylacetic acid amide are obtained; m.p.: 55°-56° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:15][CH:14]2[CH2:16]Cl)[CH:10]=[CH:11][CH:12]=1>C(O)C>[CH3:1][N:2]([CH2:16][CH:14]1[CH2:15][C:13]1([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH2:3][CH2:4][OH:5]
Reactant: ClCC1CC1(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CNCCO
Solvent: CCO
Product: CN(CCO)CC1CC1(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
To a solution of 2-methylaminoethanol (0.29 g) in ethanol (5 ml) was added a solution of 2,2-di(m-chlorophenyl)cyclopropylmethyl chloride (0.40 g) in ethanol (10 ml) at room temperature, and stirring was carried out under reflux for 10 hours. The reaction mixture was evaporated and poured into a 10 % aqueous solution of sodium hydroxide. The chloroform extract was dried and chromatographed to afford N-methyl-N-(2-hydroxyethyl)-2,2-di(m-chlorophenyl)-cyclopropylmethylamine as an oily substance. M.P. 152° - 154° C. (hydrochoride).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:1][CH2:2][CH2:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c2[nH]ccc2c1CCN
Product: COc1cc(OC)c2[nH]ccc2c1CCNC(C)=O
Reaction time: 15 h
Yield: 54 %

Procedure:
To a cold solution of 4-(2′-aminoethyl)-5,7-dimethoxyindole (0.29 g, 1.3 mmol) in the (10 cm3) were added TEA (0.9 cm3) and acetic anhydride (0.5 cm3). The ice bath was removed and the solution stirred for 15 hours using the method of Spadoni et al. The solvent was evaporated under vacuum, and the residue was taken up into ethyl acetate and washed with a saturated aqueous solution of NaHC03, followed by saturated NaCl solution. The organic layer was dried with MgS04 and concentrated to give a crude solid, which was chromatographed on silica, using ethyl acetate:methanol (95:5), to give 4-[2′-(N-acetyl)aminoethyl]-5,7-dimethoxyindole (0.19 g, 54%) as a brown viscous oil.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH:35]([C:38](=[O:51])[NH:39][CH2:40][C:41]([O:43]CC1C=CC=CC=1)=[O:42])[CH2:36][CH3:37])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH:35]([C:38](=[O:51])[NH:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:36][CH3:37])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: CCC(OP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCC(OP(=O)(CCC(N)C(=O)O)Oc1ccccc1)C(=O)NCC(=O)O
Yield: 177.5 %

Procedure:
Next, 0.25 g (0.35 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[1-[N-(benzyloxycarbonylmethyl)carbamoyl]propyl(phenyl)phosphono]butanoate was dissolved in 30 mL of a solvent mixture of methanol and water at 20:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced for 45 minutes. The palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[1-[N-(carboxymethyl)carbamoyl]propyl(phenyl)phosphono]butanoic acid (250 mg, yield 18%) as a colorless solid.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(N(C)C)=O>[O:30]=[C:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(CBr)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CCc1ccccc1)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.863 g, 1 eq.) was suspended in dimethylacetamide (DMA) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (360 mg, 2.2 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 1-bromo-4-phenylbutan-2-one (1.1 g, 1.2 eq.) was added. The reaction was stirred at room temperature for 2 hours. The reaction was poured onto 100 mL water and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g) was used without purification. LCMS: 358 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[OH-].[Na+].ClCCl>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:24])[F:26])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: Nc1ccc(Cl)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 150 °C
Yield: 52 %

Procedure:
The mixture of 3-amino-6-chloropyridazine (0.6487 g, 5 mmol) and piperazin-1-yl-(2-trifluoromethylphenyl)methanone (1.936 g, 7.5 mmol) in NMP (30 mL) was heated at 150° C. for 24 hours. To the reaction mixture was added 10 mL of 1 N NaOH and 100 mL of dichloromethane, and the aqueous layer was separated and extracted twice by 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, evaporated to dryness. The crude compound was purified by flash chromatography to give yellow solid. Yield 52%, 1.37 g.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C(OCC)C.N([O-])=O.[Na+].[I-:20].[K+]>O>[Cl:10][C:4]1[CH:3]=[C:2]([I:20])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: [I-]
Reactant: N#Cc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (30.5 g, 0.2 mol) in 1:1 diethyl ether/3M HCl (600 mL) at 0° C. was treated dropwise over 15 minutes with a solution of sodium nitrite (18 g, 0.26 mol) in water (100 mL), stirred 15 minutes, then treated with a solution of potassium iodide (50 g, 0.3 mol) in water (50 mL) dropwise over 45 minutes, warmed to room temperature, and stirred for 1.5 hours. The organic phase was washed with water (3×100 mL) and the combined aqueous layers were extracted with diethyl ether. The combined organic layers were combined, washed sequentially with saturated NaHCO3, 25% Na2S2O3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 19:1/hexanes:ethyl acetate, triturated in hexanes, filtered, and dried to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](Br)(Br)([Br:12])[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:10]([Br:12])[Br:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(C=C(Br)Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
4-Chlorobenzaldehyde (2.81 g) was dissolved in methylene chloride (300 mL), and carbon tetrabromide (13.3 g) and triphenylphosphine (21.0 g) were added to the solution, followed by stirring at room temperature for 90 minutes. After insoluble matter precipitated was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), to thereby give the title compound (5.54 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[O:12]1[CH2:17][CH2:16][CH2:15][CH:14](O)[CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[N:6]=[C:5]2[I:11]
Reactant: OC1CCCOC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2C1CCCOC1
Yield: 23 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and tetrahydro-3-pyranol in 23% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.86-1.93 (2H, m), 2.20-2.23 (1H, m), 2.34-2.41 (1H, m), 3.48-3.55 (1H, m), 3.80 (1H, t, J=10.4 Hz), 4.00-4.07 (2H, m), 4.50-4.58 (1H, m), 7.12 (1H, dd, J=2.4, 8.0 Hz), 7.21 (1H, td, J=2.4, 8.8 Hz), 7.39 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](CCl)=[N:8][C:9]2[C:14]([C:15]=1C1C=CC(OC)=C(OC)C=1)=[CH:13][C:12](OC)=[C:11](OC)[CH:10]=2)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N+:8]([O-:40])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: CCOC(=O)c1cc2ccccc2[n+]([O-])c1
Reaction time: 2 h
Yield: 136.8 %

Procedure:
A mixture of 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (3.0 g), m-chloroperbenzoic acid (85%, 2.3 g) and methanol (40 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was poured over chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (6:4, v/v) to yield 2-chloromethyl-6,7-dimethoxy-4-3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (2.0 g, 65%), which was then recrystallized from acetone-isopropyl ether to yield a colorless prismatic crystal having a melting point of 193 to 194° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](O)=[O:14])=[CH:7][C:6]=1[NH:16][C:17](=[O:37])[CH2:18][CH:19]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[O:35][CH3:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([NH:39][CH3:38])=[O:14])=[CH:7][C:6]=1[NH:16][C:17](=[O:37])[CH2:18][CH:19]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[O:35][CH3:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(CCC(=O)O)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC
Reactant: CN
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)NC)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-[2-t-butyl-5-(2-carboxyethyl)phenyl]-3-(2,4,5-trimethoxyphenyl)octanamide prepared as described in Preparation 84) and methylamine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]([O:26][CH3:37])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylthio]acetic acid (88.8 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[CH3:20]O>>[CH3:20][O:4][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CO
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Product: CCCCCCCCCCCCCCC(O)C(=O)OC
Yield: 85 %

Procedure:
2-hydroxyhexadecanoic acid (10.0 g, 0.0367 moles) and 8.40 g acidic resin were refluxed in 250 mls methanol for 20 hours. The solution was decolorized, filtered and concentrated giving a white solid (yield=85%)