Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](/B(O)O)=[CH:27]\[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH3:30])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCC/C=C/B(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCC/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 60.7 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (200 mg, 0.45 mmol) and trans-1-penten-1-ylboronic acid (205 mg, 1.80 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 96 mg, 0.045 mmol) and 2M aqueous solution of K2SO4 (0.90 mL, 1.80 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (145) as white solid (107 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](Cl)(Cl)=[O:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]=[O:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(F)c(Cl)c1
Temperature: 110 °C

Procedure:
At -10° to 0° C. and while stirring, a solution of 156 parts by weight of 3-chloro-4-fluoroaniline (J. Chem. Soc., 1928, 423) is metered into a solution of 250 parts by weight of phosgene in 1,000 parts by weight of toluene. The mixture is slowly heated to 110° C. (internal temperature), at which temperature it becomes clear.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][CH2:11][CH2:12][C:13]3[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=3[O:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]([CH2:26][CH2:27][CH3:28])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCOCC1.[Cl:40]N1C(=O)CCC1=O>O>[Cl:40][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][CH2:11][CH2:12][C:13]2[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=2[O:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]([CH2:26][CH2:27][CH3:28])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[NH:1][CH:2]=1
Reactant: CCCN(CC(O)COc1ccccc1CCCc1cccc2[nH]ccc12)C(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCN(CC(O)COc1ccccc1CCCc1cccc2[nH]cc(Cl)c12)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.9 %

Procedure:
A mixture of 6.3 g of the product of Step A, 100 ml of dioxane and 2 g of N-chlorosuccinimide was stirred under an inert atmosphere for 19 hours at room temperature and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-cyclohexane-triethylamine mixture to obtain 4.73 g of N-[3-[2-[3-(3-chloro-1H-indol-4-yl)-propyl]-phenoxy]-2-hydroxypropyl]-N-propyl-trifluoroacetamide.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1>[C].[Rh].C(O)(=O)C>[CH3:6][N:7]1[C:11]2[CH2:12][CH2:13][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1ccc2c(c1)ncn2C
Agent: [Rh]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)C1CCc2c(ncn2C)C1
Reaction time: 92 h
Yield: 77.6 %

Procedure:
In an autoclave 6.6 g (22.9 mmols) of methyl 1-methylbenzimidazole-5-carboxylate sulfate, 60 ml of acetic acid and 3.0 g of 5% rhodium-carbon powders were charged and hydrogenation was carried out at 80° C. for 92 hours under 60 atms. After cooling, rhodium-carbon powders were filtered off and the filtrate was distilled off under reduced pressure. After 200 ml of water was added to the residue, 1 N sodium hydroxide solution was added to the mixture at 0° to 5° C. to adjust pH to 9 to 10 followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 3.45 g (77.7%) of methyl 1-methyl-4,5,6,7-tetrahydrobenzimid-azole-5-carboxylate (oil).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:36])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:36][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To 5-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-thiophene-2-sulfonic acid tert-butylamide (example 304) (0.170 g, 0.32 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between TBME and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.135 g, 88%). MS (ISP) 476.2 [(M+H)+]; mp>250° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8](=[O:10])[NH2:9])=[C:6]([CH3:11])[NH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C:19]([CH3:21])=O>C(O)C.CCCCCC>[C:8]([C:7]1[C:3]([N:2]=[C:19]([CH3:21])[CH3:18])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:5][C:6]=1[CH3:11])(=[O:10])[NH2:9]
Reactant: Cc1[nH]c(-c2ccccc2)c(N)c1C(N)=O
Reactant: CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)=Nc1c(-c2ccccc2)[nH]c(C)c1C(N)=O
Yield: 82 %

Procedure:
From the compound of Example 33 and acetone, yield 82%, m.p. 221°-23° C. (from ethanol/hexane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[O:11])=[C:4]([I:12])[CH:3]=1.C([SiH](CC)CC)C.[CH2:20](O)[CH:21]=[CH:22][CH3:23].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][CH2:20][CH:21]=[CH:22][CH3:23])=[C:4]([I:12])[CH:3]=1
Reactant: COc1nc(Cl)cc(I)c1C=O
Reactant: CC=CCO
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC=CCOCc1c(I)cc(Cl)nc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A three-necked 500-mL round-bottom flask is equipped with a mechanical stirrer. Under nitrogen, the flask is charged with 6-chloro-4-iodo-2-methoxypyridine-3-carbaldehyde (53.0 g, 178 mmol) obtained as prepared in U.S. Pat. No. 5,254,690 to Comins et al. issued Oct. 19, 1993, triethylsilane (42.7 mL, 267 mmol) and crotyl alcohol (60.8 mL, 713 mmol). The slurry is cooled to 0° C. and trifluoroacetic acid (90.0 mL, 1.17 mmol) is added over 1 h. The reaction is allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture is slowly poured into a rapidly stirred solution of saturated sodium bicarbonate in water (1.5 L). The mixture is extracted with methyl t-butyl ether (4×300 mL). The combined organic layers are washed with brine (700 mL) and dried over anhydrous sodium sulfate (150 g). The drying agent is removed by filtration and the solvents are removed in vacuo to afford 6-chloro-4-iodo-2-methoxy-3-(2-butenyloxymethyl)pyridine as crude product. The product can be purified by vacuum distillation to provide 6-chloro-4-iodo-2-methoxy-3-(2-butenyloxymethyl)pyridine as a light yellow oil. 1H NMR (200 MHz, CDCL3) δ1.75 (d, J=6.1 Hz, 3H), 3.92 (s, 3H), 4.00 (m, 2H), 4.59 (s, 2H), 5.74 (m, 1H) 5.75 (m, 1H), 7.39 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:27][C:28]1[CH:29]=[C:30]([OH:37])[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35]>C(C(C)=O)C(C)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[O:37][C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(Oc2ccc([N+](=O)[O-])c(C)c2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 95.2 %

Procedure:
This product was prepared as described in Example 31: 7.0 g (0.022 mol) of product of Example 19, 3.31 g (0.024 mol) of K2CO3, 3.33 g (0.022 mol) of 3-methyl-4-nitrophenol in 75 ml of methyl isobutyl ketone were reacted affording 9.18 g of an oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent gave 5.31 g (55.1%) of product as a yellow solid; mp 55°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([CH3:18])[N:11]=1.[Se](=O)=[O:20]>COCCOCCOC.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([CH:18]=[O:20])[N:11]=1
Reactant: O=[Se]=O
Reactant: Cc1nc(Nc2ccc(F)cc2F)ccc1C#N
Solvent: CC(=O)O
Solvent: COCCOCCOC
Product: N#Cc1ccc(Nc2ccc(F)cc2F)nc1C=O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,4-difluorophenylamino)-2-methylnicotinonitrile (350 mg, 1.4 mmol) and selenium dioxide (238 mg, 2.14 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (7.00 mL) and 0.2 mL of glacial acetic acid was heated in an oil bath at 120° C. for 10 min. The temperature of the oil bath was slowly warmed to 155° C. in 30 min and stirred at this temperature for 3 h. The reaction mixture was cooled to RT, filtered through a pad of Celite washing with EtOAc, and concentrated. The remaining brown solution was purified on an ISCO 12 g column and the product eluted with 50-80% EtOAc in hexanes to afford 6-(2,4-difluorophenylamino)-2-formylnicotinonitrile in residual amount of 1-methoxy-2-(2-methoxyethoxy)ethane. MS (ESI, pos.ion) m/z: M+1=260.0
Reaction SMILES: BrC1C=CC(Cl)=CC=1C#CC(OCC)(OCC)OCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[C:24]([C:46]#[C:47][C:48](OCC)([O:52]CC)[O:49][CH2:50][CH3:51])[CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.O.CCOC(C)=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[C:24]([C:46]#[C:47][C:48]([O:49][CH2:50][CH3:51])=[O:52])[CH:23]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2C#CC(OCC)(OCC)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(C#Cc1cc(Cl)ccc1Br)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In a separate round-bottomed flask, 1-bromo-4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)benzene (487 mg, 1.3 μmol) and [Pd(PtBu3)Br]2 (105 mg, 135 μmol) were mixed. The reaction vessel was evacuated under vacuum and backfilled with argon. Toluene (5 mL) was added, and the mixture was heated to 50° C. for 5 minutes and then transferred by syringe to the enolate solution. The aryl bromide-Pd flask was rinsed with toluene (1 mL) and added to the reaction mixture. The resulting mixture was heated at 50° C. under nitrogen. After 90 minutes, the reaction was cooled to 23° C., diluted with EtOAc (100 mL), and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 4-6% EtOAc/hexane+1% TEA) affording the desired coupled product 1-tert-butyl ethyl 4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate. A solution of the 1-tert-butyl ethyl 4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate in EtOH (10 mL) and water (2 mL) was treated with p-toluenesulfonic acid monohydrate (69.3 mg, 364 μmol). The reaction was stirred at 23° C. for 30 minutes, and then diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (2×50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 12-16% EtOAc/hexane), affording 155 mg of 1-tert-butyl ethyl 4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate. MS m/e=486.1 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH:24](=[C:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl.CO>[CH:24](=[C:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C1COc2ccccc2N1CCCCl
Reactant: CCCC=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CCCC=C1CCN(CCCN2C(=O)COc3ccccc32)CC1
Yield: 76.1 %

Procedure:
4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.068 g, 0.30 mmol), K2CO3 (0.12 g, 0.90 mmol), NaI (0.090 g, 0.60 mmol) and 4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according to GP12. Prep TLC (SiO2; CH2Cl2/MeOH 10:1) gave the title compound (81MF25) (0.070 g, 71%). 1H NMR (CDCl3) δ 7.12 (d, J=6.8 Hz, 1H), 7.03-6.95 (m, 3H), 5.12 (J=7.4 Hz, 1H), 4.56 (s, 1H), 3.99 (t, J=7.6 Hz, 2H), 2.41-2.36 (m, 6H), 2.26-2.17 (m, 2H), 1.98-1.81 (m, 4H), 1.38-1.28 (m, 2H), 0.87 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 164.3, 145.5, 136.0, 128.7, 123.8, 122.8, 122.8, 117.1, 115.2, 67.7, 55.7, 55.6, 54.9, 39.7, 36.1, 29.2, 28.4, 24.8, 23.2, 13.8.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:30])[C:9](=O)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:21]1[C:22]([CH2:27][CH3:28])=[N:23][O:24][C:25]=1[CH3:26])=[O:11]>O1CCCC1>[CH3:30][N:8]([CH2:9][CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:21]1[C:22]([CH2:27][CH3:28])=[N:23][O:24][C:25]=1[CH3:26])[OH:11])[CH3:7]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(O)CN(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 9.9 g (0.26 mole) of lithium aluminum hydride and 950 ml. tetrahydrofuran under nitrogen there is added 21.0 g. (0.065 mole) of N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide in 735 ml. of tetrahydrofuran, while maintaining the temperature between 20° to 25° C. After addition is complete, the mixture is stirred at room temperature for 5 hours then cooled to 0° and quenched by the addition dropwise of 20 ml. of water in 180 ml. of tetrahydrofuran. The resulting solids are filtered and the tetrahydrofuran dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethanol to give α-(dimethylaminomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-methanol; m.p. 178° to 180° C.
Reaction SMILES: C(O[CH:4]1[O:19][C:7]2=[C:8]([O:17][CH3:18])[C:9]3[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=3[CH:16]=[C:6]2[CH2:5]1)C>C(O)=O>[CH3:18][O:17][C:8]1[C:9]2[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=2[CH:16]=[C:6]2[CH:5]=[CH:4][O:19][C:7]=12
Reactant: CCOC1Cc2cc3ccc(=O)oc3c(OC)c2O1
Solvent: O=CO
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 100 mg. (0.38 mmole) of 2-ethoxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one in 2 ml. of formic acid was heated at 100° for 30 min. The reaction was cooled and evaporated to leave a residue which was filtered through alumina using benzene/ethyl acetate, 4:1 to yield, upon evaporation of the filtrate, pure 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one, mp 145°-146°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=O)[CH2:6][C:5]2([CH3:14])[CH3:13].[C:15]1(C)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[CH2:15])[CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Reactant: Cc1ccccc1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: C1CCOC1
Product: C=C1CC(C)(C)c2cc(Br)ccc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-4,4-dimethyl-chroman-2-one available in accordance with U.S. Pat. No. 5,399,561 incorporated herein by reference (1 g, 3.92 mmol) in 8 mL of anhydrous tetrahydrofuran was treated with a 0.5 M solution of μ-chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminum (Tebbe reagent) in toluene (8.23 mL, 4.12 mmol). After 10 minutes, the reaction mixture was poured into ice-water mixture containing 50 mL of 1M sodium hydroxide and extracted with hexane. The hexane extract was washed with brine (×1), filtered over a bed of celite and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent to afford the title compound (0.74 g, 74%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][BH:17][O:16]1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([B:17]2[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:22])([CH3:14])[O:16]2)[CH:3]=1)[OH:13]
Reactant: CC1(C)OBOC1(C)C
Reactant: O=C(c1cccc(Br)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cccc(C(O)C(F)(F)F)c2)OC1(C)C
Temperature: 95 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To an oven-dried round bottom flask fitted with a stir bar and a rubber septum was added 1-(3-bromo-phenyl)-2,2,2-trifluoro-ethanone (560 mg, 2.2 mmol, as prepared in Example 28, step a), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.96 mL, 6.6 mmol, Aldrich Chemical Company), (PPh3)2PdCl2 (93 mg, 0.132 mmol, Strem Chemicals, Inc., Newburyport, Mass.), and Et3N (1.8 mL, 13.2 mmol). The reaction mixture was evacuated, purged with argon, and then suspended in dioxane (16 mL). After stirring for 18 hr at 95° C., the reaction was allowed to cool and then filtered through Celite.® The filtrate was concentrated in vacuo and the residue was purified by chromatography (SiO2, flash elution: 5% EtOAc in hexanes) to give 350 mg (53%) of an oil that was used without further purification.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=[O:7])C.[CH3:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:26])[NH:18]1.P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>>[Cl:26][C:23]1[C:24]2[CH2:25][CH:17]([CH3:16])[N:18]3[C:19]=2[C:20]([C:11](=[O:13])[C:5]([C:6]([OH:8])=[O:7])=[CH:4]3)=[CH:21][CH:22]=1
Reactant: CC1Cc2c(Cl)cccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CC1Cc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 60 °C
Yield: 71.1 %

Procedure:
4.4 g of diethyl ethoxymethylenemalonate was added to 3.4 g of 2-methyl-4-chloroindoline and the mixture was heated on an oil bath at 110° to 120° C. for 40 minutes. 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide was added thereto and the mixture was heated on an oil bath at 130° to 140° C. for 1 hour. After completion of the reaction, the mixture was allowed to cool to 60° C., poured into ice water and rendered neutral with a 10% aqueous sodium hydroxide solution. The crystals precipitated were collected by filtration and washed with water. The crystals thus treated were mixed with 50 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed on an oil bath for 1 hour. As the reaction proceeded the mixture changed to a uniform solution. The solution was treated with activated carbon while hot followed by filtration. The filtrate was rendered acidic with concentrated hydrochloric acid to precipitate crystals. Recrystallization of the product from dimethylformamide gave 3.8 g of 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as white needles having a melting point of 288° to 290° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C=O.[BH3-][C:13]#N.[Na+]>CO.CC(O)=O.C(Cl)Cl>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2ccccc21
Reaction time: 1 h
Yield: 214.5 %

Procedure:
The indoline product from Example 47, Step B (16 mg, 0.049 mmol) was dissolved in MeOH (2 mL) in a 25-mL flask under N2. A catalytic amount of HOAc (1 drop) and aqueous formaldehyde (15 μL, 0.15 mmol) were added, and the mixture stirred for 1 h. NaBH3CN (16 mg, 0.25 mmol) was added, and the mixture stirred for an additional 1 h. The mixture was diluted with CH2Cl2 (50 mL), then washed sequentially with 0.5 N NaOH (25 mL) and sat. aq. NaCl (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide the N-methyl indoline product (14 mg, 87%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 6.93-7.09 (m, 3H), 6.59 (d, J=8.1 Hz, 1H), 6.29 (d, J=8.1 Hz, 1H), 4.12 (t, J=5.8 Hz, 1H), 3.52 (s, 2H), 3.30-3.37 (m, 2H), 2.91 (dd, J=11.3, 5.1 Hz, 1H), 2.82 (t, J =8.0 Hz, 2H), 2.73 (s, 3H), 2.56 (dd, J=11.3, 7.3 Hz, 1H), 2.42 (s, 3H); CI MS m/z=315 [C19H20F2N2+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.Cl[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: ClCCc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCc2ccccn2)CCN1
Yield: 33.2 %

Procedure:
Piperazinone (2.2 g, 22 mmol), 2-(2-chloroethyl)pyridine hydrochloride (3.9 g, 22 mmol) and i-Pr2NEt (5.67 g, 7.6 mL, 44 mmol) were heated at reflux for 16 h. The mixture was concentrated, and the residue was purified by column chromatography (80 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (1.5 g, 33%) as a yellow solid: ESI MS m/z 206 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>CO>[ClH:23].[ClH:23].[CH3:22][O:21][C:20]1[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccnc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccnc1N1CCCNCC1
Reaction time: 15 h

Procedure:
To 4-(3-methoxypyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (335 mg, 1.1 mmol) was added MeOH (3 mL) followed by 4M HCl in dioxane (5 mL, 20 mmol). This was stirred for 15 hours, then concentrated to give the title compound. MS (ES) m/z 208 (M+H+).