Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[S:1]1[C:5]([B:23]([OH:26])[OH:24])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: COB(OC)OC
Reactant: c1csc(-c2cccs2)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cccs2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
In a flame-dried, 3-neck, 250 mL rbf, 2,2′-bithiophene (5.0 g, 30.1 mmol) was dissolved in anhydrous THF (100 mL) and cooled to −78° C. (dry ice/acetone). A solution of n-BuLi in hexanes (2.5 M, 12.6 mL, 31.6 mmol) was added slowly over a period of ˜5 minutes. The reaction mixture was allowed to stir at −78° C. for 15 minutes, and then trimethyl borate (10.1 mL, 90 mmol) was added dropwise over a period of 5 minutes. The reaction was allowed to stir at −78° C. for 2 hours, then warm to RT and stir for a further 1 hour. The yellow reaction mixture was quenched by pouring it into a 10% HCl solution (250 mL). The mixture was extracted with ether (2×100 mL) and the combined organic portions were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting yellow solid was washed with water, filtered and air dried to afford (109) (6.15 g, 97%). The material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:3]=1>C(O)C.O.[Pd]>[CH3:12][N:8]([C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1)[CH2:9][CH2:10][OH:11]
Reactant: CN(CCO)c1cc(Cl)ncn1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN(CCO)c1ccncn1
Reaction time: 8 h

Procedure:
To 9.4 g (50 mmol) 2-[(6-chloropyrimidin-4-yl)-methylamino)ethanol in 50 ml ethanol and 10 ml water, 1 g of a 10% Pd/C paste is added and the resulting mixture is subjected to hydrogenation at a pressure of 60 atmospheres and at room temperature for 8 h.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.O>CN(C)C=O>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(Nc1ccc(OCCN2CCCC2)cc1)C1CCCCC1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C1CCCCC1)N(Cc1cccc(F)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of cyclohexanecarboxylic acid (4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amide (0.250 g, 0.79 mmol) in 5 mL N,N-dimethylformamide at 0° C. was added sodium hydride (0.041 g of a 60% dispersion in mineral oil, 1.03 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and 3-fluorobenzyl bromide (0.117 mL, 0.95 mmol) was added. The reaction mixture was stirred at room temperature for 24 hr. and water was added. The aqueous solution was washed with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (methylene chloride to 5% methanol/methylene chloride) afforded the title compound. MS 425.2 (M+1)+
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)=[O:15]
Reactant: CO
Reactant: O=C(O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 55 %

Procedure:
A mixture of nitroterephthalic acid (Aldrich, 20 g, 0.095 mol) in anhydrous methanol (100 mL) was heated to reflux in the presence of concentrated sulphuric acid (10 mL) for 1 h. The solvent was evaporated and the residue poured into saturated sodium bicarbonate (200 mL). The aqueous layer was washed with chloroform and 2N hydrochloric acid added to the aqueous layer to bring the pH close to 2. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water and brine. The organic extract was concentrated after drying over sodium sulphate and the residue was recrystallized from ethyl acetate-hexane to give 11.8 g (55%) of 4-methoxycarbonyl-2-nitrobenzoic acid as cream-colored crystals, mp 131°-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:44][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:43][CH:42]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.098 g, 0.24 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (0.049 g, 0.24 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 20 mg of 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.36 (s, 1H), 8.54 (s, 1H), 7.43 (d, 2H, J=7.9 Hz), 7.29 (m, 2H), 7.18 (dd, 2H, J=2.0 Hz, J=7.9 Hz), 7.03-7.05 (m, 1H), 4.38 (q, 2H, J=7.1 Hz), 3.44 (s, 2H), 3.08 (t, 2H, J=7.4 Hz), 3.01 (t, 2H, J=7.5 Hz), 2.52 (br s, 8H), 2.36 (s, 3H), 2.19-2.29 (m, 2H), 1.39 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([CH3:7])[CH3:6])[CH3:2].[H-].[Na+].CI.[C:18](=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]([CH3:7])([C:8]1[N:9]=[CH:10][N:11]([CH3:18])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1c[nH]cn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1cn(C)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.82 g of 2-(1H-imidazol-4-yl)-2-methyl-propionic acid ethyl ester [CAS 21149-99-5] in 20 ml of dry N,N-dimethylformamide is treated with 0.480 g sodium hydride (60% dispersion). The mixture is stirred for 30 minutes at 60° C. 0.81 ml of methyl iodide are added and the mixture stirred for 4 hours at 60° C. The reaction mixture is poured onto saturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (3×). The combined extracts are washed with brine, dried over sodium sulphate and concentrated by evaporation. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[O:20][N:19]=1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.80-7.61 (m, 4H), 7.57 (d, J=8.5 Hz, 1H), 5.83 (s, 2H), 3.05-2.75 (m, 2H), 1.70-1.41 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (ES) m/z 413 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]N(C)C=O.CI>O>[CH3:20][N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)[C:15](=[O:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.25 G of N-[3-(6-chloro-3-pyridazin-yl)-phenyl]acetamide, 0.48 g of sodium hydride (50% in oil) and 100 ml of dimethylformamide was stirred under argon for 1 hour. To the mixture was added 0.6 ml of methyl iodide and after stirring 5 hours, an additional 0.6 ml of methyl iodide. After stirring overnight, 0.3 g of sodium hydride (50% in oil), then 0.6 ml of methyl iodide were added and stirring continued for 2 hours. The mixture was poured into water, filtered and the filtrate extracted with 60 ml portions of dichloromethane. The extracts were combined, evaporated in vacuo and the residue triturated with hexane. The resulting solid was chromatographed as described in Example 26 to give 1.45 g of product which was recrystallized from dichloromethaneether to give the desired compound as crystals, mp 118°-20° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:23]([O:25]CC)=[O:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])C.[OH-].[Na+]>C(O)C.O>[C:4]([C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:34])[CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]([OH:25])=[O:24])([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(CCCCSCCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCCSCCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Yield: 68.3 %

Procedure:
A solution of 6-(5-ethoxycarbonyl-5-phenylhexylsulfanyl)-2-methyl-2-phenylhexanoic acid ethyl ester (6.00 g, 12.0 mmol) and sodium hydroxide (3.1 g, 74.0 mmol) in ethanol (40 mL) and deionized water (4 mL) was heated to reflux for 2 h. The ethanol was evaporated in vacuo and the residue was dissolved in water (20 mL) and extracted with diethyl ether (20 mL). The organic phase was discarded. The aqueous layer was acidified with 2 N hydrochloric acid (15 ml) to pH 2-3 and extracted with diethyl ether (4′ 50 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo. The residue (4.53 g) was purified by column chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 6-(5-carboxy-5-phenyl-hexylsulfanyl)-2-methyl-2-phenyl-hexanoic acid (3.63 g, 68%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 7.42-7.20 (m, 10H), 2.45 (t, J=7.3 Hz, 4H), 2.15-1.80 (m, 4H), 1.65-1.45 (m, 4H), 1.56 (s, 6H), 1.40-1.15 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 182.43, 142.89, 128.41, 126.91, 126.05, 50.00, 38.53, 31.80, 30.00, 24.03, 22.40. HRMS (LSIMS, nba): Calcd. for C26H35O4S1 (MH+): 443.2256, found: 443.2231.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:25]([F:28])([F:27])[F:26])([C:5]1[N:6](C)[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)[NH2:4].ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:28][C:25]([F:26])([F:27])[C:3]1([C:2]([F:29])([F:30])[F:1])[C:5](=[N:9][C:8](=[O:39])[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2nc(C(N)(C(F)(F)F)C(F)(F)F)n(C)c2-c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)N=C2NC(c3ccc(C)cc3)=NC2(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 4.1 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-methylphenyl)-1-methyl-1H-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, m-chloroperbenzoic acid (0.40 g, 2.3 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution. 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue (75% benzamide and 25% ester analyzed by HPLC with a (DL)-phenylglycine column eluted with 10% isopropanol-hexane) was purified by HPLC on a silica sorbax column which was eluted with dichloromethane to give the title compound (40 mg, 4%) as a semisolid: MS m/e 442 (M+ +H); 1H NMR (CDCl3 /TMS) δ 3.00(s,6H,CH3), 3.13(s,3H,NCH3), 7.27-7.37(m,4H,Harom), 7.57(d,J= 7 Hz,2H,Harom), 7.90(d,J=7 Hz,2H,Harom).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:35][CH2:34][CH2:33][N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: NCCN1CCOCC1
Product: O=S1CCN(c2nc(NCCN3CCOCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine and 2-morpholinoethyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccc(F)cc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-fluoro-benzene using the conditions described in Example 237C to provide 1-Chloro-4-(4-fluoro-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide 4-[2-amino-4-(4-fluoro-benzyloxy)-phenylsulfanyl]-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1)and 3,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].Cl>C1COCC1>[CH2:15]([C:2]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC(CCCC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl malonate (25 g, 156 mmol) was dissolved in 150 mL dry THF in a 3 necked round bottom flask, and NaH (18.74 g of 60% dispersion in mineral oil, 469 mmol, 3.0 eq.) was added portionwise. The suspension was magnetically stirred for 30 minutes. Subsequently, 58.1 g 5-bromo-1-pentene (390 mmol, 2.5 eq.) was added in one portion via syringe. The yellow suspension was heated at reflux overnight and cooled to room temperature. Aqueous 1 M HCl was added until the pH of the mixture was ≦7. The THF was removed via rotary evaporation and diethyl ether (300 mL) was added. The mixture was extracted with 2×150 mL aqueous 1 M HCl and 2×150 mL brine. The organic layer was then dried over MgSO4, filtered, and concentrated to give a yellow-brown oil, diethyl di-(4-pentenyl)malonate. This oil was placed in a 500 mL round-bottomed flask and 100 mL ethanol was added, followed by a large excess (30 g, ˜5 eq.) of NaOH, some of which did not dissolve. H2O (5 mL) was added and the resulting mixture was stirred at reflux overnight. Subsequently, the entire mixture was poured into a large beaker, cooled to 0° C. using an ice water bath, and stirred (additional H2O may be added to dissolve any residual solids interfering with stirring). Concentrated aqueous HCl was added portionwise until the pH of the mixture was ≦7; solids were formed upon acidification. Diethyl ether (300 mL) was added to the mixture at room temperature, and the aqueous layer was extracted with 2×150 mL diethyl ether. The combined organic layers were extracted with 4×150 mL 1 M aqueous NaOH. The combined aqueous fractions from the extractions were then transferred to a beaker and acidified with concentrated aqueous HCl until the pH of the mixture was ≦7. Diethyl ether (200 mL) was added. The aqueous layer was extracted with 3×100 mL diethyl ether, and all of the combined organic layers were dried over MgSO4 and filtered. Volatiles were removed to give 2,2-di-(4-pentenyl)malonic acid as a yellow-brown oil. Subsequently, 2,2-di-(4-pentenyl)malonic acid (60 g, 250 mmol) was placed in a large round-bottomed flask equipped with a reflux condenser and heated with vigorous magnetic stirring to 200° C.-210° C. using an oil bath. Gas evolution was observed upon reflux. After a 1 hour period, decarboxylation (evidenced by vigorous frothing) was complete and the mixture was cooled to room temperature and purified by flash chromatography on silica using 15% ethyl acetate:hexanes as mobile phase to give 2-(4-pentenyl)-6-heptenoic acid (23 g, 79%). 1H NMR (CDCl3): δ 11.2-12.2 (br, 1H), 5.6-6.0 (m, 2H), 4.8-5.0 (m, 4H), 2.2-2.4 (m, 1H), 1.9-2.1 (m, 4H), 1.8-1.9 (m, 2H), 1.2-1.8 (m, 6H) ppm.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])(O)=O.[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+].[O:26]=[C:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=2)[NH:28]1.[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:42]=1[CH2:43]Br>O.CC(C)=O>[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:42]=1[CH2:43][S:36]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:26])[CH2:35]2)(=[O:38])=[O:37]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=P([O-])([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Temperature: 30 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
Sodium monohydrogen phosphate dodecahydrate (142 g, 1.0 mol) and sodium sulfite (252 g, 2.0 mol) were dissolved in 2 L of water at room temperature, heated to 30° C., and added with 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 64b (232 g, 1.0 mol). Upon completion of the addition, the reaction mixture was stirred at 60° C. for 16 hours. A solution of 2,6-dichlorobenzyl bromide (240 g, 1.0 mol) in acetone (1.8 L) was added to the above solution, stirred at 60° C. for 1 hour, added with another acetone (200 ml) and stirred for another 2 hours. The reaction mixture was quenched with water (5 L), stirred at room temperature for 1 hour and filtered. The filter cake was washed with water (1 L) and acetone (1 L), and dried in vacuo to obtain the title compound 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (314 g, yield 88%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].[CH2:27](Br)[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][CH3:42]>CN(C)C=O>[CH2:42]([O:10][CH2:9][CH:6]([CH2:5][C:4](=[CH2:3])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][OH:8])[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][CH3:27]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C=C(CCCCCCCCCCCCCCCC)CC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(CCCCCCCCCCCCCCCC)CC(CO)COCCCCCCCCCCCCCCCC

Procedure:
A solution of 80 mg of 60% sodium hydride in 20 ml of N,N-dimethylformamide is stirred at room temperature. A 680 mg portion of 2-(2-methylene-octadecyl)-1,3-propanediol and 0.61 ml of hexadecylbromide are added and the mixture warmed very slowly to 60°-70° C. The mixture is evaporated, dissolved in ether, and is washed with water and brine then flash chromatographed (5% ethyl acetate:petroleum ether), to give 550 mg of the desired compound as colorless crystals, mp. 37°-38° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[CH2:9]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.CN(C)C=O.[CH:23](OC)(OC)[O:24][CH3:25]>C(OC(=O)C)(=O)C>[CH3:23][O:24]/[CH:25]=[C:9]1/[C:10](=[O:17])[NH:11][C:12](=[O:16])[C:13]2[C:8]/1=[CH:7][C:6]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[CH:15][CH:14]=2
Reactant: O=C1Cc2cc(-n3cccc3)ccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Temperature: 120 °C
Yield: 39.6 %

Procedure:
6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (0.1 g, 0.442 mmol) is dissolved in acetic anhydride (0.6 mL), N,N-dimethylformamide (0.15 mL) and trimethyl orthoformate (0.1 mL, 0.919 mmol). After heating at 120° C. for 0.5 h, it is cooled and the solid is filtered and washed successively with acetic anhydride, ether and hexane to yield 47 mg (40%) solid of the title compound; mp 272-273° C.; HRMS (ESI) m/z calcd for C15H12N2O3 269.09207. found 269.09210 (M+H)+1.
Reaction SMILES: CS([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[CH:8]=[C:7]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[N:6]=1)(=O)=O.[C:28]([O:32][C:33](=[O:52])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:51])[NH:43][C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:52])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:51])[NH:43][C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:5]3[N:10]4[N:11]=[CH:12][CH:13]=[C:9]4[CH:8]=[C:7]([C:14]4[CH:15]=[C:16]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[CH:17]=[CH:18][CH:19]=4)[N:6]=3)=[CH:48][CH:49]=2)=[CH:38][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Reactant: COc1ccc(-c2cccc(-c3cc4ccnn4c(S(C)(=O)=O)n3)c2)cc1
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CNC(=O)OC(C)(C)C)cc5)cc4)n3)c2)cc1
Temperature: 130 °C

Procedure:
Under an inert gas atmosphere at 130° C. bath temperature is heated neat a mixture of 7-methanesulfonyl-5-(4′-methoxy-biphenyl-3-yl)-pyrazolo[1,5-c]pyrimidine and [4-(4-amino-phenylcarbamoyl)-benzyl]-carbamic acid tertbutyl ester (compound B3) overnight. The crude product is purified by silica gel flash chromatography.