Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:20][CH:19]=1)([CH2:15][CH3:16])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:22][CH:23]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 123.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.21 g), sodium hydrogen carbonate (1.76 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-sec-butoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.34 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.47 g, 49%).
Reaction SMILES: C([Li])CCC.[CH3:6][S:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[CH2:17]([C:21]1[CH:26]=[C:25](Cl)[N:24]2[N:28]=[CH:29][CH:30]=[C:23]2[N:22]=1)[CH2:18][CH2:19][CH3:20]>C1COCC1.C(OCC)(=O)C>[CH2:17]([C:21]1[CH:26]=[C:25]([CH2:6][S:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[N:24]2[N:28]=[CH:29][CH:30]=[C:23]2[N:22]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOP(=O)(CSC)OCC
Reactant: CCCCc1cc(Cl)n2nccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1cc(CSCP(=O)(OCC)OCC)n2nccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
30.7 ml of n-butyl lithium (1.63 M, n-hexane solution) was diluted with 35 ml of THF, and the diluted solution was cooled to −78° C. in an atmosphere of argon. Thereto was added a solution of 10.4 g of diethyl methylthiomethylphosphonate in 10 ml of THF, followed by stirring at −78° C. for 1 hour. Thereto was added dropwise a solution of 5 g of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine in 5 ml of THF, followed by stirring at −78° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed sequentially with aqueous ammonium chloride solution, water and saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:3→1:1). As a result, 5.9 g of diethyl (5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate was obtained as an oily product.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[C@@H:37]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][C@H:41]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40]3)[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.6 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (21 mg, 0.051 mmol) in DMA (2 mL) was added (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (20 mg, 0.076 mmol) and Cs2CO3 (33 mg, 0.10 mmol). The reaction vial was sealed, and the reaction was heated to 90° C. and stirred for 6 hours. DMA was removed under reduce pressure. The residue was diluted with EtOAc (20 mL), washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL), and concentrated. Silica gel chromatography of the crude material (DCM/MeOH 10:0.5) provided the desired product (15 mg).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH2:23](N(CC)CC)[CH3:24].C(OCC=C)(=O)C>C1(C)C=CC=CC=1>[CH2:23]=[CH:24][CH2:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: CCN(CC)CC
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: C=CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 80 °C

Procedure:
Into a round bottom flask equipped with a stir bar was charged noroxymorphone (2.89 g, 10.1 mmol), triethylamine (4.20 mL, 30.1 mmol), toluene (50 mL), tetrakis(triphenylphosphine)palladium[0](1.15 g, 1.00 mmol), and allyl acetate (1.40 mL, 12.9 mmol). The flask was equipped with a reflux condenser and the resulting reaction mixture was stirred and heated at 80° C. for 64 hours. The mixture was cooled to a temperature of about 20° C. and filtered through a plug of CELITE. The filtrate was concentrated under reduced pressure. The concentrated material was dissolved in a mixture of ethyl acetate (150 mL) and 0.75N aqueous hydrochloric acid (100 mL) and allowed to stir at a temperature of about 20° C. for 20 minutes. The layers were separated and the aqueous layer was washed with an additional 150 mL of ethyl acetate. The aqueous layer was basified to a pH of 9.05 with 28% ammonium hydroxide and extracted twice with dichloromethane (100 mL for each extraction). The organic portions were combined and concentrated under reduced pressure. Naloxone (HPLC purity of 76%) was isolated as an oil, contaminated with triphenylphosphine and 3-allyl-naloxone (isolated 2.78 g crude of 76% purity containing about 6.37 mmol of naloxone)).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]1(=[O:19])[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:13]2[C:12](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:26][C:25]=1[NH2:27])=[O:28])[CH3:21]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1ccccc1[N+](=O)[O-]
Yield: 69 %

Procedure:
Upon heating a solution of 7.6 g of 2-nitrobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-4-(2-nitrophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 212°C (alcohol) is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH3:30])[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:28]=1[C:20]([C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]3)=[CH:21][NH:22]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cccc(OC)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c12
Temperature: 60 °C
Yield: 39.7 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.539 g, 2.87 mmol) and (4-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.656 g, 2.81 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (10 mL, 10 mmol) dropwise over 5 minutes. The mixture was heated at 60° C. for 15 h, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (30–40% hexane/EtOAc) gave the title compound (0.414 g, 40%) as a red solid, which was dried under vacuum overnight. 1H NMR (400 MHz, DMSO-d6) 11.49 (br s, 1H), 11.08 (s, 1H), 7.49 (dd, J=7, 3 Hz, 1H), 7.30 (d, J=3 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.86–7.05 (m 4H), 6.39 (d, J=7 Hz, 1H), 6.42 (d, J=3 Hz, 1H), 3.76 (s, 3H), 3.34 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370 (M−−1). HRMS 372.1347 (M++1, calcd for C22H18N3O3 372.1348).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1[N:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([NH:28]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.CCOC(C)=O>Br.C1C=CC=CC=1>[NH2:28][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][N:21]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=3[N:10]=2)[CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCN(c3nc4c(c(=O)n(C)c(=O)n4C)n3Cc3ccccc3)C2)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: Oc1ccccc1
Product: Cn1c(=O)c2c(nc(N3CCCCC(N)C3)n2Cc2ccccc2)n(C)c1=O

Procedure:
N-(1-(7-Benzyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)azepan-3-yl)-4-methylbenzenesulfonamide (6C) (100 mg, 0.19 mmol) was dissolved in hydrobromic acid (48%, 5 ml) and benzene (0.07 ml), and phenol (61.4 mg, 0.65 mmol) was added. The mixture was heated to reflux for three hours, and after cooling 20 ml of EtOAc was added. The layers were separated, and the aqueous layer washed with 20 ml of EtOAc. pH was adjusted to 11 with 10M sodium hydroxide. The aqueous layer was extracted with diethyl ether (3×20 ml), and the combined organic layers were dried over sodium sulphate and the solvent was evaporated. The crude product was dissolved in 5 ml of DCM and 0.5 ml of trifluoroacetic acid was added. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=7.63 min). Evaporation of the solvent gave the title compound as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.Cl[CH2:17][S:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH2:17][S:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCCl)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 5 h
Yield: 80.4 %

Procedure:
A mixture of 1-(4-chloro-butoxy)-4-nitrobenzene (1.28 g, 5.6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.6 g, 6.72 mmoles) was stirred in THF (50 ml) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (16.8 ml, 16.8 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.94 g, 4.5 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][S:8][C:9]=1SC)=[O:4].OO.N[C:20](N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[S:36]([O-:39])(O)=[O:37].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][S:8][C:9]=1[S:36]([CH3:20])(=[O:39])=[O:37])=[O:4]
Reactant: COC(=O)Oc1nsc(SC)c1C(=O)OC
Reactant: O=S([O-])O
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COC(=O)Oc1nsc(S(C)(=O)=O)c1C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The 3-Methoxycarbonyloxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl ester slurry was cooled to 0° C., and urea hydrogen peroxide addition compound (2.8 equiv, 12.8 g) was added. Trifluoroacetic acid anhydride (2.8 equiv, 19.2 mL, 28.4 g) was added dropwise over 20 minutes. The mixture stirred at 0° C. for 45 minutes, and quenched with sodium hydrogen sulfite (2.0 equiv, 10.0 g) in water (90 mL, 9 volumes) and stirred at 25° C. Most of the acetonitrile was removed under vacuum, then the aqueous residue was extracted once with 100 mL and once again with 50 mL dichloromethane to provide 5-Methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1([C:26](Cl)=[O:27])[C:21]([CH3:23])([CH3:22])[C:20]1([Cl:25])[Cl:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][C:26]([C:19]2([Cl:18])[C:21]([CH3:23])([CH3:22])[C:20]2([Cl:25])[Cl:24])=[O:27])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)Cl
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1(Cl)C(C)(C)C1(Cl)Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 90.1 %

Procedure:
4-Chloro-α-methylbenzylamine (15.6 g) and triethylamine (10.1 g) were dissolved in toluene (150 ml). With stirring, a solution of 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylic acid chloride (23.6 g) in toluene (30 ml) was added dropwise to the solution at 0° to 10° C. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the aqueous layer was extracted with toluene. The toluene layers were combined, washed with a 1% aqueous solution of hydrochloric acid, a 1% aqueous solution of sodium hydroxide and water in this order, and then dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give the desired N-(4-chloro-α-methylbenzyl)-1,2,2-trichloro-3,3-dimethylcyclopropanecarboxamide (32 g) represented by the following formula as colorless crystals. mp. 138°-139° C. ##STR35##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncn2)C1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 7.4 %

Procedure:
1-(8-Chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyrimidin-4-yl-propan-2-ol (200 mg, 0.56 mmol) was dissolved in DCM (5 mL), and a drop of DMF was added. The solution was cooled to 0° C. and a solution of thionyl chloride (0.2 mL) in 1 mL DCM was added dropwise. The solution was stirred at RT for 30 min. and at RT for 2.5 h. Volatiles were evaporated under reduced pressure, the residue was basified with ice cold aqueous 1N NaOH (10 mL) and the product was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to obtain 14 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.18 (s, 1H), 8.80 (d, 1H), 8.0 (s, 1H), 7.80 (d, 1H), 7.58 (s, 1H), 7.25 (m, 2H), 4.75 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([CH3:16])[N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:17]([O:15][C:14]1[C:9]([C:3]2[C:2]([O:1][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=2)=[N:10][C:11]([CH3:16])=[CH:12][CH:13]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(O)c(-c2nc(C)ccc2O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OC(=O)c2ccccc2)c(-c2nc(C)ccc2OC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3,3'-Dihydroxy-6,6'-dimethyl-2,2'-bipyridine (5) (0.22 g, 1.02 mmoles) was dissolved in 12 ml pyridine and benzoylchloride (0.30 g, 2.13 mmoles) was added. After stirring for 1.5 hours at room temperature, 100 ml chloroform was added and the solution was extracted with 100 ml saturated sodium hydrogen carbonate solution. The chloroform phase was dried and evaporated to dryness. The product was crystallized as a grey powder from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Li]CCCC>C1COCC1>[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
2-(4-Chloro-3-fluorophenyl)acetic acid (1.00 g, 5.30 mmol) was dissolved in THF (14 mL) at 0° C. and treated with triethylamine (0.81 mL, 5.8 mmol). Pivaloyl chloride (0.69 mL, 5.6 mmol) was then added to the solution, and the mixture was allowed to stir for one hour at 0° C. In a separate flask, (R)-4-benzyloxazolidin-2-one (0.987 g, 5.57 mmol) was dissolved in THF (14 mL) at −78° C. and treated with n-BuLi (2.54 mL, 5.83 mmol). The above anion solution was stirred for 20 minutes and then cannulated into the anhydride at −78° C. The reaction was then allowed to stir for one hour at −78° C., and then warmed to 0° C. for two hours. The mixture was quenched with the addition of saturated NH4Cl solution (20 mL) and concentrated in vacuo. The resulting residue was then partitioned between ethyl acetate and water. The aqueous layer was extracted once with ethyl acetate, and the organic fractions were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (3:1 hexanes:ethyl acetate) to give (R)-4-benzyl-3-(2-(4-chloro-3-fluorophenyl)acetyl)oxazolidin-2-one (0.95 g, 51%) as an oil, which solidified upon standing.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([C:27]1[C:31]([CH:32]2[CH2:35][C:34](=O)[CH2:33]2)=[CH:30][N:29]([C:37]2[C:42]([Cl:43])=[CH:41][C:40]([C:44]([F:47])([F:46])[F:45])=[CH:39][C:38]=2[Cl:48])[N:28]=1)#[N:26].O>C(Cl)Cl>[C:25]([C:27]1[C:31]([CH:32]2[CH2:35][C:34](=[C:20]([Br:24])[Br:21])[CH2:33]2)=[CH:30][N:29]([C:37]2[C:38]([Cl:48])=[CH:39][C:40]([C:44]([F:45])([F:46])[F:47])=[CH:41][C:42]=2[Cl:43])[N:28]=1)#[N:26]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=C(Br)Br)C1
Temperature: -10 °C
Yield: 81.9 %

Procedure:
Triphenylphosphine (560 mg, 2.14 mmol) was dissolved in 2 ml anhydrous DCM and cooled to -10° C. Carbon tetrabromide (355 mg, 1.07 mmol in 2 ml DCM) was added dropwise to the cooled solution, producing an amber colour. 3-Cyano-4-(3-oxocyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (200 mg, 0.53 mmol, Example 3) in DCM (2 ml) was added dropwise whereupon the reaction mixture assumed a brown colour. The reaction mixture was warmed to room temperature. After 0.5 hr the mixture was poured into water (20 ml) and extracted with DCM (3×20 ml). The combined organics were washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo to leave a brown solid. This was purified by silica chromatography (eluting with 50% DCM/hexane) to yield 230 mg of the title compound as a white solid.
Reaction SMILES: O[C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH2:13][CH2:14][OH:15])[C:10](=O)[O:11][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.[C:18](=[O:21])([O-])[O-:19].[K+].[K+].[CH3:24]I>C(O)C>[OH:15][CH2:14][CH2:13][C:9]1[C:18](=[O:21])[O:19][C:2]2[CH:3]=[C:4]([O:17][CH3:24])[CH:5]=[C:6]([O:11][CH3:10])[C:7]=2[C:8]=1[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CCO)c(=O)oc2cc(O)cc(O)c12
Reactant: CI
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)c2c(C)c(CCO)c(=O)oc2c1

Procedure:
Alternative method: 100.0 g (423 mmol) of 5,7-dihydroxy-3-(2-hydroxyethyl)-4-methyl-2H-1-benzopyran-2-one (Example 49), 175.5 g (1270 mmol) of potassium carbonate and 150.2 g (1058 mmol) of methyl iodide are stirred under reflux for 4 hours in 1800 ml of ethanol. The solution is filtered, evaporated, extracted with chloroform, and the organic phase is washed with water, dried with Na2SO4 and re-evaporated. Yield 49.3 g (44%); m.p. 148°-150° C. (from isopropanol/TBME).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=O
Yield: 95 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep36, 2.5 g, 7.3 mmol), K2CO3 (1 g, 7.3 mmol) and 1-bromo-4-chloro-butane (2.10 mL, 18 mmol) were suspended in dry DMF (10 mL). After stirring the reaction at room temperature overnight, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was purified by flash chromatography with petroleum ether-ethyl acetate (7-3) to give the title compound as a white solid (3 g, 98% yield).