Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(F)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronirile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3 X 400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(C)(=O)=O)cn2)CC1
Yield: 70.3 %

Procedure:
To a stirred solution of 2-bromo-5-methanesulfonyl-pyridine (0.24 g, 1.0 mmol, 1.0 equiv; prepared as described in EP 1298 116 A1 (Pfizer Products Inc., USA)) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.1 mmol, 1.1 equiv) in acetonitrile (6.0 mL) was added N-ethyl diisopropylamine (0.87 mL, 0.66 g, 5.0 mmol, 5.0 equiv) drop by drop at rt and the reaction mixture heated to reflux for 19 h. The reaction mixture was poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.25 g (70%) of the title compound as light brown oil. MS (ISP): 356.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([NH2:23])[CH:18]=1)[CH:13]=2.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>CN1C(=O)N(C)CC1>[CH2:24]([NH:23][C:17]1[CH:16]=[CH:15][C:14]2[C:19]([CH:18]=1)=[N:20][C:21]1[C:12](=[CH:11][CH:10]=[C:9]([NH:8][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH:22]=1)[CH:13]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc2cc3ccc(N)cc3nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CCCCCCCCCCCCCCCCCCCCNc1ccc2cc3ccc(NCCCCCCCCCCCCCCCCCCCC)cc3nc2c1
Temperature: 50 °C
Reaction time: 86 h

Procedure:
2.53 g of anhydrous potassium carbonate are added to a solution of 2.5 g of 3,6-diaminoacridine hydrochloride and 2.95 g of 1-eicosyl bromide in 20 ml of N,N'-dimethylethyleneurea, and the mixture is stirred at 50° C. for 86 hours. The cooled reaction mixture is subsequently poured into water, and the orange-brown suspension is extracted with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. After evaporation, 2N HCl is added to the brown oil. The red precipitate formed is filtered off, washed with water and then dried in a high vacuum. The resultant red-brown crystals are taken up in methylene chloride/methanol (10:1) and chromatographed on silica gel. After evaporation, the residue is taken up in diethyl ether/methanol (10:1) and re-chromatographed on silica gel, giving the title compound as red crystals, absorption spectrum (ethanol): λmax =472 nm; ε=42 200.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[C:28](N=C(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[CH2:29][CH:28]([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(C)c(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1cc(C)c(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(4,6-dimethyl-3-pyridinyl)benzenesulfonamide (100 mg, 0.258 mmol) and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (44.2 mg, 0.258 mmol) were dissolved in acetonitrile (1 mL). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.028 mL, 0.258 mmol) was added. The reaction was stirred at room temperature for 20 hours, then additional 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (44.2 mg, 0.258 mmol) and 1-bromo-2-methylpropane (0.028 mL, 0.258 mmol) were added. The reaction was heated to 60° C. and stirred for a further 2 hours. The solvent was removed in vacuo and the residue was partitioned between water (5 mL) and dichloromethane (5 mL). The organic layer was separated, concentrated and purified by mass directed autoprep (formic acid modifier). The required fractions were combined and concentrated to provide the title compound (17 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.04 mins, m/z (ES+) 444 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[N:17]([CH3:47])[C@@H:18]([C:30](=[O:46])[N:31]([CH3:45])[C@@H:32]([C:40]([NH:42][NH:43][CH3:44])=[O:41])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:49](OC(=O)C)(=[O:51])[CH3:50].N1C=CC=CC=1>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[N:17]([C@@H:18]([C:30](=[O:46])[N:31]([C@H:32]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]([NH:42][N:43]([C:49](=[O:51])[CH3:50])[CH3:44])=[O:41])[CH3:45])[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH3:47])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 110 %

Procedure:
To a solution of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-1-(N'-methylhydrazinocarbonyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid ((9H-fluoren-9-yl)methyl) ester (0.18 g, 0.28 mmol) in methylene chloride (2 ml) was added acetic acid anhydride (0.053 ml) and pyridine (0.027 ml) and the mixture was stirred overnight. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.21 g (110%) of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid ((9H-fluoren-9-yl)methyl) ester as a colourless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[N:15]=[C:16]([Cl:20])[C:17]([CH:28]=[O:29])=[N:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)N(Cc1ccccc1)c1cncc(Cl)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Phosphoryl chloride (5.6 mL) was added dropwise to DMF (12 mL) at 0° C. The mixture was stirred for 15 min, and a solution of N-benzyl-6-chloro-N-(1-methylethyl)pyrazin-2-amine (3.40 g) in DMF (3 mL) was added dropwise thereto. The mixture was stirred at 100° C. for 13 hr, water (50 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5-420% ethyl acetate/hexane) to give the title compound (2.42 g, 70%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][CH2:19][C:20]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.2 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenyl-propionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 3-phenyl-1-(3-phenylpyrrolidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 521 mg of colorless oil.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([N+:17]([O-])=O)=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]>C(O)C.O.[Fe]>[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([NH2:17])=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]
Reactant: CCOC(=O)/C=C/c1cnc([N+](=O)[O-])c(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C/c1cnc(N)c(OC)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
Iron (1.6 g) and ammonium chloride (3 g) were added to the suspension of (E)-3-(5-methoxy-6-nitropyridin-3-yl)acrylic acid ethyl ester (787 mg) in ethanol (40 mL) and water (8 mL) obtained above, and the reaction solution was heated to reflux for 1 hour. After the reaction solution was allowed to be cooled to room temperature, deposited substance was filtered by celite. Ethyl acetate and saturated sodium bicarbonate water were added to the filtrate, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 2:1), and 506 mg (66%) (E)-3-(6-amino-5-methoxypyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)=O.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]>C(O)C>[O:24]=[C:19]1[C:18]2[NH:25][CH:26]=[CH:27][C:17]=2[C:16]2[CH:15]=[C:14]([C:12]3[N:9]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[S:8][CH:11]=3)[CH:23]=[CH:22][C:21]=2[NH:20]1.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: NC(=S)c1ccccc1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(-c4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 21.1 %

Procedure:
54 mg (1.2 mmol) of thiobenzamide is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 29 mg (21%) of 4-oxo-8-(2-phenyl-thiazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:12])([OH:3])=[O:2].[C:13](Cl)(=O)C.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:12])([O:3][CH3:13])=[O:2]
Reactant: Cc1cc(=O)c(C(=O)O)c(C)o1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(C)oc(C)cc1=O

Procedure:
42 g of 3-carboxy-2,6-dimethylpyr-4-one is dissolved in 250 ml of methylene chloride. In a second flask, 20 ml of acetyl chloride is cautiously added to 400 ml of methanol. The two solutions are mixed and refluxed for 5 hours. Solid sodium carbonate is added and the solvent removed after a water wash. The residue is distilled (115°-125° at 0.1 mm) to give 40 g of 3-carbomethoxy-2,6-dimethylpyr-4-one as a waxy solid.
Reaction SMILES: [CH:1]1([C@H:7]([O:20][CH3:21])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:23][CH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:20][CH3:21]
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CO)C1CCCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a solution of (S)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-phenyl]-methanol (340 mg, 1.2 mmol) in methylene chloride (10 mL) at 0° C. was added carbon tetrabromide (485 mg, 1.46 mmol) and stirred for 10 minutes followed by addition of triphenylphosphine (383 mg, 1.46 mmol). Reaction was stirred at 0° C. for 1 hour and allowed to warm to room temperature and stirred for 16 hours. Reaction was concentrated in vacuo and purified on 25+S Biotage column eluting with 0-20% ethyl acetate in heptane (10 CV), 20% (2CV), to yield the title compound (270 mg, 66%) as a colorless oil. This oil solidified upon standing and was recrystalized from hexane to yield crystals (mp=43-45° C.), which were submitted to X-ray crystallography to establish absolute configuration. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (m, 4H) 1.3 (m, 2H) 1.6 (m, 3H) 1.7 (m, 1H) 2.0 (d, J=12.6, 1H) 3.2 (s, 3H) 4.2 (d, J=7.9, 1H) 4.5 (d, J=10.3 Hz, 1H) 4.6 (d, J=10.3 Hz, 1H) 7.4 (d, J=8.3 Hz, 1H) 7.5 (d, J=8.3 Hz, 1H) 7.6 (s, 1H). [α]D20=−50 deg (c=11.5 mg/mL, acetone)
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C1COCC1.Cl>[Br:15][C:13]1[CH:12]=[CH:11][C:7]2[C:8](=[O:10])[O:9][C:1](=[O:2])[NH:5][C:6]=2[CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Br)ccc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reaction time: 2 h

Procedure:
Phosgene (1.9 M in toluene, 18.4 mL, 35 mmol) was added dropwise over 1 h to a solution of 2-amino-4-bromobenzoic acid from Step A (2.5 g, 11.7 mmol) in THF (30 mL) and 1 N HCl (20 mL). After 2 h, the precipitate was collected by filtration, washed with H2O, then ethyl acetate, and dried in vacuo to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[C:12]1[C:7](=[C:8]([Cl:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+].[Br:27]Br>ClCCl>[Br:27][C:14]1[C:15](=[O:18])[CH2:16][CH2:17][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=1[C:12]1[C:7](=[C:8]([Cl:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2
Reactant: BrBr
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)c(Cl)c1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (555 mg, 1.82 mmol) in anhydrous dichloromethane (18.2 mL) was treated with sodium bicarbonate (765 mg, 9.1 mmol) and bromine (0.093 mL, 1.82 mmol). The mixture was stirred at room temperature for 30 minutes and then diluted with CH2Cl2 (50 mL) and washed with water (50 mL). The organic phase was dried over MgSO4, filtered through a pad of silica gel (10 mL) with a 10 mL CH2Cl2 rinse, and the solvent evaporated under vacuum. The residue (0.55 g) was lyophilized from benzene to afford 4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:13])[CH:11]=[CH2:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:20]1)C[C:15]2=O>ClCCl.COC(OC)(C)C>[CH:11]([CH:10]1[O:13][C:14]([CH3:20])([CH3:15])[O:1][CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9]1)=[CH2:12]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: C=CC(O)CC(O)CC(=O)OCC
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: C=CC1CC(CC(=O)OCC)OC(C)(C)O1
Reaction time: 8 h

Procedure:
The crude β,δ-dihydroxy-6-heptenoic acid, ethyl ester from the previous step was dissolved in a mixture of 30 ml of dichloromethane and 10 ml of 2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and the mixture was stirred overnight. Concentration of the reaction mixture and flash chromatography of the residue yielded 1.1 g of 6-ethenyl-2,2-dimethyl-1,3-dioxane-4-acetic acid, ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>[N+](C)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:16]=3[F:15])=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C(c1cccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (4, 0.525 g, 2.66 mmol) is combined with aluminum trichloride (2.05 g, 15.4 mmol) and 10 mL of nitromethane. 2-Fluoro-3-nitro-benzoyl chloride (17, 0.521 g, 2.56 mmol) in 5 mL of nitromethane is added and the reaction is heated at 45° C. for 6 hours. The reaction is quenched by slowly adding 5 mL of methanol. The resulting precipitate is collected by filtration and combined with ethyl acetate, water and celite, then stirred for 30 minutes and filtered. The organic layer is isolated and washed with water, then brine, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum to provide the desired compound (18, 151 mg). MS (ESI) [M−H+]−=362.4 and 364.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][OH:11]>>[CH3:10][O:11][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=[N+]([O-])c1ccccc1
Product: COc1ccc(N)cc1

Procedure:
The method of claim 1 wherein nitrobenzene is reacted with methanol to form p-methoxyaniline.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[Cl:13][CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16]>>[Cl:13][C:14]1[C:15]([CH3:16])=[N:3][N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[C:18]=1[CH3:19]
Reactant: NNc1ccc(CCO)cc1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1Cl

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 3-chloropentane-2,4-dione: MS (ESI) m/z 251 [M+H]+, 1H-NMR (CDCl3) δ 7.32-7.25 (4H, m), 3.76 (2H, t, J=6.7 Hz), 2.85 (2H, t, J=6.7 Hz), 2.32 (1H, br.s), 2.28 (3H, s), 2.27 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:19][C:18]1[CH:22]=[CH:23][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[C:7]([CH:24]=[CH:3][CH:4]=3)[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:1])[NH:13][C:12](=[O:14])[N:11]=2)=[CH:16][C:17]=1[CH3:21]
Reactant: NCCCN1CCOCC1
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3cccc(C(=O)NCCCN4CCOCC4)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.9 %

Procedure:
3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]benzoic acid (Compound 289, 15.5 mg, 48 umol) and commercially available 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added commercially available 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by commercially available 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 5 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 8.65 (t, 1H), 8.51 (s, 1H), 8.28-8.23 (m, 2H), 8.02-7.96 (m, 2H), 7.87 (dd, 1H), 7.63 (t, 1H), 7.46 (s, 1H), 6.92 (d, 1H), 3.56 (t, 4H), 3.36-3.32 (m, 2H), 2.40-2.33 (m, 6H), 2.20 (s, 3H), 1.78-1.68 (m, 2H). MS (EI): 450 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:35](=[O:36])[O:37][CH3:38])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (207 mg, 0.608 mmol) in dichloromethane (10 mL) was added three equivalent of triethyl amine (0.252 mL, 1.8 mmol), followed by methyl chloroformate (0.071 mL, 0.91 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-ylcarbamate (272), (181 mg 75%). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2 H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H).