Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([NH2:28])=[N:27][C:22]2=[CH:21][CH:20]=1>ClCCl.O1CCCC1.O>[Cl:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([NH:28][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])=[N:27][C:22]2=[CH:21][CH:20]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1nc2ccc(Cl)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(Cl)nc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropanecarboxylic acid (129 mg, 1.50 mmol) in dichloromethane (5 mL) were added oxalyl chloride (190 mg, 1.50 mmol) and N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to a solution (10 mL) of 5-chloro[1,3]thiazolo[5,4-b]pyridine-2-amine (185 mg, 1.00 mmol) in tetrahydrofuran at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture was added water (10 mL), and the mixture was extracted with ethyl acetate (30 mL×3). The organic layer was concentrated under reduced pressure to give N-(5-chloro[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH:34]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH3:35])[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: CC(c1ccccc1)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccc1)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(O)c2C1=O
Temperature: 70 °C
Yield: 79.9 %

Procedure:
To a stirred solution of 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-(1-phenylethyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (37) (76 mg, 134 μmol, Eq: 1.00) in methanol (5 ml) was added HCl (conc) (195 mg, 163 μl, 5.35 mmol, Eq: 40) and the reaction mixture was heated at 70° C. for 48 hrs. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 0 to 5% methanol-dichloromethane) to obtain an off-white solid. The solid was triturated with diethyl ether, filtered, and dried to obtain 6-((1-(4-chlorophenyl)cyclopentyl)methyl)-9-hydroxy-2-(1-phenylethyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (38) (off-white powder, 51 mg, 107 μmol, 79.8% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17].[OH-].[NH4+:19].ClCCl>CN1C(=O)CCC1.[Cu-]=O>[NH2:19][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17]
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(Br)c(F)cc21
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2CC2)c2cc(N)c(F)cc21
Temperature: 110 °C

Procedure:
To a solution of 6-bromo-1-cyclopropyl-5-fluoro-3,3-dimethylindolin-2-one (example 36b, 400 mg, 1.34 mmol) in NMP (7 ml) were added ammonium hydroxide (6.3 g, 7 ml, 44.9 mmol) and copper(I) oxide (38.4 mg, 268 μmol). The reaction mixture was heated in a sealed tube to 110° C. for 24 hours and then poured into dichloromethane (20 ml). The organic phase was washed with 1 M aqueous sodium bicarbonate solution and with water, dried over sodium sulfate and concentrated in vacuo. The NMP was removed by kugelrohr distillation. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as off-white crystals (257 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Reactant: CCCCN
Solvent: CCOCC
Product: CCCCNP(=O)(CN(CC(=O)OCC)C(=O)SCc1ccccc1)NCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (11.3 g.; 0.029 mol.) dissolved in 100 ml. of diethyl ether was added to a solution containing n-butylamine (8.6 g.; 0.118 mol.) in 100 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(n-butylamino)phosphinylmethyl]-glycinate (12.5 g.) as a solid having a melting point of 45°-48° C., and the following analysis:
Reaction SMILES: S([O-])(=O)(=O)C.[CH2:6]([N:13]1[CH:22]([CH3:23])[CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:6]([N:13]1[CH:22]([CH3:23])[CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1Cc2cccc(-c3ccccc3)c2C(=O)N1Cc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Product: CC1Cc2cccc(-c3ccccc3)c2CN1Cc1ccccc1

Procedure:
Heating 3,4-dihydro-3-methyl-8-phenylisocoumarin and benzylamine hydrobromide in benzylamine at 160° C. gives N-benzyl-6-(2-hydroxy-2-methylethyl)2-biphenylcarboxamide which is converted to the corresponding mesylate and then cyclized to 2-benzyl-3,4-dihydro-3-methyl-8-phenyl-1(2H)-isoquinolone with sodium hydride. This compound is then reduced with lithium aluminum hydride to give 2-benzyl-3-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline. Hydrogenation of this product using 5% palladium-on-carbon on the catalyst affords 3-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline. Reacting 3-methyl-8-1,2,3,4-tetrahydroisoquinoline with formaldehyde and formic acid affords 2,3-dimethyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][N:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][N:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: ON=C1CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCc3ccccc32)cc1
Reaction time: 3 h

Procedure:
A solution of p-toluenesulfonyl chloride (266 g) in pyridine (300 ml) was added dropwise to a stirred solution of 2,3-dihydro-1-hydroxyimino-1H-indene (100.8 g) in pyridine (600 ml) at 0°-5°. The mixture was stirred for 3 hours at 0°, then was poured into water and the title compound filtered. This was washed several times with water and air-dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=C)=[CH:6][C:5]=1[OH:14].[BH4-].[Na+].C[OH:19].C(Cl)Cl>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][OH:19])=[CH:6][C:5]=1[OH:14]
Reactant: CO
Reactant: C=CCOc1ccc(C(=O)OC)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCO)cc1O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 4-allyloxy-2-hydroxy-benzoic acid methyl ester(10.952 g, 52.6 mmol) in methanol/methylene chloride (1/1) (300 mL) was cooled to −40° C. then ozone was bubbled through the reaction mixture for 50 minutes. The solution was then purged with nitrogen for 20 minutes, sodium borohydride (2.643 g, 69.86 mmol) was added and warmed to room temperature over 1 hour. The reaction was quenched by the addition of water (20 mL), poured into brine and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (30/70 to 40/60) to afford 2-hydroxy-4-(2-hydroxy-ethoxy)-benzoic acid methyl ester (9.745 g, 87%) as a white solid. 1H NMR (300 MHz, CDCl3); δ 11.00 (s, 1H), 7.75 (d, 2H), 6.46 (m, 2H), 4.11 (t, 2H), 3.98 (t, 2H), 3.93 (s, 3H), 1.90 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([NH:25][C:26](=[O:28])[CH3:27])[CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:41])C(=O)C1>C(#N)C>[C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:9][O:10][C:11]1[C:12]([Cl:41])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([NH:25][C:26](=[O:28])[CH3:27])[CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1cc2c(cn1)COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: CC#N
Product: CC(=O)Nc1cc2c(cn1)COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc1-2
Temperature: 25 °C
Yield: 79.1 %

Procedure:
The stirred solution of (5)-tert-butyl(1-((2-acetamido-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.220 mmol) (prepared as described in Example 18, Part H) and NCS (29.3 mg, 0.220 mmol) in acetonitrile (15 mL) was heated to 80° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (25 mL) and DCM (25 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford (S)-tert-butyl(1-((2-acetamido-9-chloro-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (120 mg, 0.174 mmol, 79% yield) as an off-white solid. The product was used as is for the next step without purification. LCMS (ESI) m/e 490.2 [(M+H)+, calcd for C25H33ClN3O5 490.2]; LC/MS retention time (Method D): tR=1.98 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:32])[N:11]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.CNC1N=C(C2N(C3CCNCC3)C=NC=2C2C=CC=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:32])[N:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CNc1nccc(-c2c(-c3ccccc3)ncn2C2CCNCC2)n1
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCNCC1

Procedure:
The title compound was prepared from tert-butyl 4-[4-(4-fluorophenyl)-2-methyl-5-pyrimidin-4-yl-1H-imidazol-1-yl]piperidine-1-carboxylate (C30) according to the general procedure for the synthesis of N-methyl-4-(4-phenyl-1-piperidin-4-yl-1H-imidazol-5-yl)pyrimidin-2-amine (C26) in Example 12, except in this case the extraction was carried out with dichloromethane. Yield: 35.7 mg, 0.106 mmol, 50%. LCMS m/z 338.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.96-2.01 (m, 2H), 2.14-2.24 (m, 3H), 2.61-2.68 (m, 2H), 2.65 (s, 3H), 3.19-3.24 (m, 2H), 4.57 (tt, J=12.3, 3.9 Hz, 1H), 6.96 (dd, J=8.8, 8.8 Hz, 2H), 7.12 (dd, J=5.3, 1.4 Hz, 1H), 7.29 (dd, J=8.9, 5.5 Hz, 2H), 8.55 (d, J=5.3 Hz, 1H), 9.30 (d, J=1.3 Hz, 1H).
Reaction SMILES: O1CC[CH:4]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=4)[N:20]=3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[N:34]=C(O)C=C[CH:30]=1>>[Cl:28][C:29]1[N:34]=[C:4]([O:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:27])([F:25])[F:26])=[N:22][N:23]=4)[N:20]=3)[CH2:13][CH2:14]2)[CH:3]=[CH:2][CH:30]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(COC4CCOCC4)CC3)nn12
Reactant: Oc1cccc(Cl)n1
Product: FC(F)(F)c1nnc2ccc(N3CCC(COc4cccc(Cl)n4)CC3)nn12
Yield: 75 %

Procedure:
Obtained in 75% yield by an analogous method to Example 447, starting from [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methanol (obtained as described in Example 294, preparation of starting materials) and 6-chloropyridin-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.[C:22](=O)=[O:23]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:5]2[C:4]=1[C:22](=[O:23])[O:13][CH:6]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=O
Reactant: COc1cccc(C(O)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc2c1C(=O)OC2c1ccccc1

Procedure:
To 3-methoxybenzhydrol (42.8 g.) in dry ether (800 ml.) is added 2.3 M. n-butyl lithium in hexane (250 ml.), dropwise with stirring under nitrogen. The deep red solution is stirred and heated under reflux for 2 hours and then poured into a stirred slurry of a large excess of solid carbon dioxide in ether and stirred until no carbon dioxide remains. The resulting suspension is extracted with water, the extract is acidified with concentrated hydrochloric acid, the precipitate is filtered off, washed with water, dried, and recrystallised from isopropanol to give 7-methoxy-3-phenylphthalide, m.p. 135°-138°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:6][CH2:7][CH3:8])[CH3:2].Cl[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:37][CH:38]=1)([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: ClCc1ccc(OCCN2CCCCCC2)cc1
Reactant: CCCC(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Product: CCCC(Cc1ccc(OCCN2CCCCCC2)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (3.5 g, 11.7 mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (3.9 g, 12.8 mmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M+H)+.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH:9]1[C:18]2[N:19]3[C:23]([C:24](=O)[C:16]4[C:17]=2[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][CH:10]=1)=[CH:22][CH:21]=[CH:20]3>O.C(O)C.N1C=CC=CC=1>[C:6]([CH2:5][CH2:4][O:3][N:2]=[C:24]1[C:16]2[C:17]3[C:12]([CH:13]=[CH:14][N:15]=2)=[CH:11][CH:10]=[CH:9][C:18]=3[N:19]2[C:23]1=[CH:22][CH:21]=[CH:20]2)([OH:8])=[O:7]
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Reactant: NOCCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=C(O)CCON=c1c2nccc3cccc(c32)n2cccc12
Yield: 75.2 %

Procedure:
A solution of 3-aminooxypropionic acid hydrochloride (12 g.) in water (36 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (12 g.) in ethanol (360 cc.) and pyridine (6.64 g.). Boiling is maintained for 3 hours 10 minutes. After cooling, the yellow crystals obtained are filtered off and then washed with 90% ethanol, with absolute ethanol and finally with diethyl ether. After drying, 7-(2-carboxyethoxyimino)-7H-indolizino[5,6,7-ij]isoquinoline (12.59 g.), melting at 250° C. with decomposition, is obtained.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:19]=[C:20]([CH3:25])[C:21]([OH:24])=[CH:22][CH:23]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(N)ccc1O
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: Cc1cc(NC(=O)c2cc(NC3CCCCC3)ncn2)ccc1O

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-o-cresol (Aldrich), the title compound was obtained as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH3:23])([CH3:22])[CH2:7][C:8]3([CH2:14][C:13]([CH3:16])([CH3:15])[C:12]4[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:11]=4O3)O[C:4]=2[CH:3]=1.OC1C=CC(C2(C3C=CC(O)=CC=3)C3C=CC=CC=3C3C2=CC=CC=3)=CC=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C(=O)C)=CC=1.OC1C=CC(C(=O)CCCCC(C2C=CC(O)=CC=2)=O)=CC=1.CC(C)(C1C=CC(O)=CC=1)C1C=CC(C(C)(C)C2C=CC(O)=CC=2)=CC=1.CC(C)(C1C=CC(O)=CC=1)C1C=CC=C(C(C)(C)C2C=CC(O)=CC=2)C=1.OC1C=CC(C2C=CC(O)=CC=2)=CC=1.C1(C=CC(O)=CC=1)O.C1(C=CC=C(O)C=1)O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH3:23])([CH3:22])[CH2:7][C:8]32[C:17]2[C:12](=[CH:11][CH:20]=[C:19]([OH:21])[CH:18]=2)[C:13]([CH3:15])([CH3:16])[CH2:14]3)=[CH:24][CH:25]=1
Reactant: CC1(C)CC2(CC(C)(C)c3ccc(O)cc3O2)Oc2cc(O)ccc21
Agent: CC(=O)C(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(C(C)(C)c2ccc(O)cc2)cc1
Agent: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Product: CC1(C)CC2(CC(C)(C)c3ccc(O)cc32)c2cc(O)ccc21

Procedure:
7,7'-dihydroxy-3,3',4,4'-tetrahydro-4,4,4',4'-tetramethyl-2,2'-spirobi(2H-1-benzopyrane); trans-2,3-bis(4'-hydroxyphenyl)-2-butene; 9,9-bis(4'-hydroxyphenyl)fluorene; 3,3-bis(4'-hydroxyphenyl)-2-butanone; 1,6-bis(4'-hydroxyphenyl)-1,6-hexanedione; α,α,α',α'-tetramethyl-α,α'-bis(4-hydroxyphenyl)-p-xylene; α,α,α',α'-tetramethyl-α,α'-bis (4-hydroxyphenyl)-m-xylene; 4,4'-dihydroxybiphenyl; hydroquinone; and resorcinol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:24])[CH:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[CH:10]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.O1CCOCC1>O=[Mn]=O.C1COCC1>[C:20]([O:19][C:17]([N:15]1[CH2:14][CH:13]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[C:2]3[Cl:1])=[O:24])[CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 85 °C

Procedure:
To a flask containing tert-butyl 3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)azetidine-1-carboxylate (4.75 g, 8.85 mmol, Intermediate 13: step a) was added 1,4-dioxane (200 mL) and THF (100 mL) to give a homogeneous solution. Activated MnO2 (5.0 g, 57.5 mmol) was then introduced and the mixture was heated to 85° C. After 3 hours the reaction mixture was filtered through Celite® while still warm and rinsed with additional THF and concentrated. Chromatography on silica gel (10% acetone-hexane increasing to 25% acetone) provided the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[Cl:52][CH2:53][C:54](Cl)=[O:55]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH:29][C:54](=[O:55])[CH2:53][Cl:52])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:54](=[O:55])[CH2:53][Cl:52])[CH:9]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC)c(C=CC(c2ccc(OC)c(NC(=O)CCl)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CCl)c2)c(OC)c1
Yield: 88 %

Procedure:
To a solution of 2,4,6trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in toluene, chloroacetyl chloride (10 mmol) in dioxane (10 mL) was added and the solution was refluxed for 2 h. The solution was cooled and the solvent was removed in a rotary evaporator to give 2,4,6-trimethoxystyryl-3-chloroacetamido-4-methoxybenzylsulfone in 88% yield. M.p. 163-165° C. NMR (DMSO-d6) δ 3.83(s, 3H), 3.84(s, 6H), 3.85(s, 3H), 4.14(s, 2H), 4.22(s, 2H) 6.08 (s, 2H), 7.11-7.20(d, 1H vinylic), 6.90-8.33(m, aromatic), 8.89(s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.Cl>CO>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:5]([OH:7])=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Reaction time: 22 h
Yield: 52.7 %

Procedure:
A mixture of 5 g (27.2 mmol) of ethyl trifluoroacetoacetate, 4.76 g (27.2 mmol) of 4-methoxyphenylhydrazine hydrochloride, and 0.5 ml of conc. HCl in 60 ml of methanol was refluxed with stirring for 22 hours. After removing methanol in vacuo, toluene was added and the resulting mixture was refluxed for 20 hours and cooled. The mixture was diluted with aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from methylene chloride/hexane and ethyl acetate/hexane to afford 3.7 g (53%) of 1-(4-methoxyphenyl)-3-trifluoromethyl-5-hydroxypyrazole as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.C(O)(CC)(C)C.C(OCC)(=O)C>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2F)sc1N
Reactant: OCc1cccc(Br)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(-c2ccc(F)cc2F)sc1Nc1cccc(CO)n1

Procedure:
A suspension containing 2-amino-5-(2,4-difluorophenyl)thiophene-3-carboxamide (60 mg, 0.24 mmol), (6-bromo-pyridin-2-yl)methanol (44.4 mg, 0.24 mmol), 2-dicylohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (5.62 mg, 0.012 mmol), dibenyzlideneacetone bis(triphenylphosphine) (2.161 mg, 2.36 μmol) and potassium carbonate (35.9 mg, 0.26 mmol) in tert-butanol or tert-amyl alcohol (0.5 mL) was sealed in 5 mL microwave reaction vessel and was purged of oxygen by doing 5 vacuum/argon flush cycles. After heating the reaction at 100° C. for 2 hours, the mixture was cooled, diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (2×5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase HPLC (35-95% acetonitrile/water with 0.05% trifluoroacetic acid), and then the appropriate fractions were diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (15 mL) and water (2×15 mL), dried over sodium sulfate, filtered and concentrated to yield the title compound as a light yellow solid.