Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([OH:16])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4].[O:18]1[CH:20]2[CH2:21][C:22]3[C:27]([CH:19]12)=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>C(O)C.O>[OH:18][C@@H:20]1[CH2:21][C:22]2[C:27](=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=2)[C@H:19]1[O:16][C:7]1[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=[C:5]([C:3]([N:2]([CH3:1])[CH3:17])=[O:4])[CH:6]=1
Reactant: COc1cccc2c1C1OC1C2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cn2c1C
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc2c1[C@@H](Oc1cc(C(=O)N(C)C)cn3c(C)c(C)nc13)[C@H](O)C2
Reaction time: 4 h
Yield: 19.3 %

Procedure:
To a solution of 0.8 g (3.4 mmol) 6-(N,N-dimethylamino-carbonyl)-8-hydroxy-2,3-dimethyl-imidazo[1,2-a]pyridine in 16 ml ethanol and 4 ml water are added 1.0 g (6.2 mmol) 1,2-epoxy-7-methoxy-indane and 0.48 ml triethylamine. After 4 h at 30° C., the mixture is cooled down and partitioned between di-chloromethane and saturated aqueous ammonium chloride. The organic layer is separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether:triethylamine (8:1:1) yields 0.26 g (19%) of the title compound as a colourless solid (m.p. 129° C.).
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[N:8]=2)=[C:4]([F:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)=[O:30])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:14]([NH:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[C:4]([F:20])=[CH:3][C:2]([NH:1][C:34]([C:31]3([C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)=[O:30])[CH2:33][CH2:32]3)=[O:35])=[C:18]([F:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)(=[O:16])[CH3:15]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CC(=O)Nc1nccc(Oc2cc(F)c(N)cc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nccc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a solution of Example A3 (300 mg, 1.07 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (240 mg, 1.07 mmol) (as prepared in Example B1) in DMF (20 mL) was added HATU (440 mg, 3.2 mmol) and DIEA (280 mg, 2.1 mmol) in portions. The reaction mixture was stirred at 60° C. under nitrogen overnight. After cooling to room temperature water (30 mL) was added and the solution was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (3×50 mL), dried over sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (42 mg, 8% yield) as a white solid. 1HNMR (300 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.40 (s, 1H), 9.75 (s, 1H), 8.49-8.51 (d, J=5.7 Hz, 1H), 7.94-8.01 (dd, J=12.3 Hz, J=8.1 Hz, 1H), 7.48-7.60 (m, 3H), 7.05-7.16 (m, 2H), 6.83-6.84 (d, J=5.4 Hz, 1H), 1.92 (s, 3H), 1.53-1.59 (d, J=19.2 Hz, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:25]CC)(=O)[CH2:18][C:19]([O:21]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:19]([OH:21])=[CH:18][C:17](=[O:25])[N:15]([CH3:16])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(=O)n(Cc2ccccc2)cn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(=O)cc(O)c2c(=O)n(Cc3ccccc3)cnc21
Yield: 56.9 %

Procedure:
3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (2 g, 9.3 mmol, 1 eq) and diethyl malonate (2 mL, 14.5 mmol, 1.55 eq) were heated in phenyl ether (3 mL, 19 mmol, 2 eq) at 240° C. in a microwave reactor for 6 hours. Upon cooling a precipitate formed which was filtered and washed with ether to give 1.5 g of the title compound as a tan solid (57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.51 (s, 3H) 5.20 (s, 2H) 5.72 (s, 1H) 7.31 (br. s., 1H) 7.38 (d, J=3.03 Hz, 4H) 8.93 (s, 1H) 11.61 (s, 1H). [M+H] calc'd for C15H13N3O3, 284. found, 284.
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2].[OH-].[K+].CO.CS(O[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:24]1)(=O)=O>O.CN(C)C=O>[C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[O:5][CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:24]1)#[N:2]
Reactant: CCCCCC1CCC(COS(C)(=O)=O)CC1
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCC1CCC(COc2ccc(O)c(C#N)c2C#N)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
5.6 g of 2,3-dicyanohydroquinone and 4.6 g of 85%-potassium hydroxide were added to a mixture solvent of 15 ml of methanol and 60 ml of N,N-dimethylformamide, followed by heating to 50° C. to provide a solution. To the solution, 11.0 g of 4-n-pentylcyclohexylmethyl methanesulfonate was added, followed by stirring for 3 hours at 100° C. After the reaction, the reaction mixture was poured into cold water and washed with ether. The water layer was acidified with 6N-hydrochloric acid aqueous solution until a pH value of 1 was shown, and was subjected to extraction with ether. The organic layer was washed successively with 5%-sodium hydrogenecarbonate aqueous solution and water, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate) and treated with activated carbon, followed by recrystallization from methanol to obtain 3.6 g of 4-n-pentylcyclohexylmethyl 2,3-dicyano- 4-hydroxyphenyl ether.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([C:25]4[CH:34]=[CH:33][C:32]5[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=5[CH:26]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH2:9]1)(C)(C)C.Cl>>[CH3:35][C:31]1([CH3:36])[CH2:30][CH2:29][C:28]([CH3:37])([CH3:38])[C:27]2[CH:26]=[C:25]([C:23]3[N:22]=[CH:21][N:20]=[C:19]([N:16]4[CH2:15][CH2:14][CH:13]([N:10]5[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]5)[CH2:18][CH2:17]4)[N:24]=3)[CH:34]=[CH:33][C:32]1=2
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCN(c3ncnc(-c4ccc5c(c4)C(C)(C)CCC5(C)C)n3)CC2)C1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3ncnc(N4CCC(N5CCC(N)C5)CC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting from (1-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:24])[C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:9][CH:8]=1.[Cl-].[NH4+]>C1COCC1>[CH3:5][N:6]([CH3:24])[C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:1][CH3:2])=[CH:9][CH:8]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
Into a reactor was introduced 102 mL (82.0 mmol; 0.80 M THF solution) of ethylmagnesium bromide under a nitrogen atmosphere. The contents were cooled to 0° C. Thereto was gradually added dropwise a solution prepared by mixing 20.0 g (74.5 mmol) of 4,4′-bis(dimethylamino)benzophenone and 40 mL of THF. This mixture was stirred at room temperature for 5 hours. Saturated aqueous ammonium chloride solution was added to the resultant reaction mixture, and the metal salt yielded was removed by Celite filtration. The organic layer was separated from the filtrate and then extracted with toluene. Thereafter, the solvent was removed under reduced pressure. The concentrate was dissolved in 150 mL of toluene, and 0.1 g of p-toluenesulfonic acid monohydrate was added thereto. Azeotropic dehydration was conducted with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. This concentrate was purified by column chromatography to obtain 13.6 g (65%) of light-yellow crystals. 1H-NMR (CDCl3) δ 1.77 (d, J=7.0 Hz, 3H), 2.92 (s, 6H), 2.98 (s, 6H), 5.94 (q, J=7.0 Hz, 1H), 6.58-6.79 (m, 4H), 7.02-7.18 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:19](=[O:20])[NH:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCCCCCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1

Procedure:
Mixture of quinolin-6-ol (1.16 g., 8 mmol), hexyl isocyanate (1.37 ml, 9.6 mmol) and of dry triethylamine (0.1 ml) in dry dimethylformamide (1 ml) was heated at 50° C. for 5 hours. Reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml), dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum and crystallized with ether to give 1a, yield: 1.2 g. (55.14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:24]([F:27])([F:26])[F:25])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([N:22]=O)[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH4+].[Cl-]>CO.O.C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:24]([F:25])([F:26])[F:27])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH2:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (0.1 g, 0.2 mmol) in MeOH (10.0 mL) was added zinc powder (77.5 mg) and NH4Cl (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H]+).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[CH:4][N:5]=[C:6]=[S:7].S(Cl)([Cl:11])(=O)=O>ClCCCl>[ClH:1].[Cl:11][C:6]1[S:7][C:3]([CH2:2][Cl:1])=[CH:4][N:5]=1
Reactant: S=C=NC=CCCl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: Cl
Product: ClCc1cnc(Cl)s1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
To a solution of 45 g of 3-chloroprop-1-enyl isothiocyanate in 90 ml of 1,2-dichloroethane, 50.5 g of sulphuryl chloride was added over 10 hours at -10° C. The reaction mixture was allowed to warm to 25° C. overnight, to complete the reaction. The solution was cooled to -15° C. and the product, a pale yellow solid, was isolated by filtration and washed with hexane. 38.2 g of 2-chloro-5-(chloromethyl) thiazole hydrochloride was thus obtained, having a melting point of 59°-61° C. and being a yield of 61.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:9])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(Cl)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of this Example, using 13.9 grams (0.09 mole) of methyl 3-chlorophenyl ketone and 33.3 mL of methylmagnesium bromide (3.0M in diethyl ether) in 50 mL of dry tetrahydrofuran, yielding 2-(3-chlorophenyl)propan-2-ol.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7]/[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1>O.CO>[NH2:7]/[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.246 gm (0.0105 mol) of sodium metaperiodate in 10 ml of water was added to a solution of 2.53 gm (0.01 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]-thiophen-3(2H)-one in 150 ml of methanol, and the mixture was stirred at room temperature for 15 hours. The sodium iodate precipitated thereby was removed by filtration, and the filtrate was diluted with 300 ml of water and extracted exhaustively with dichloromethane. The combined extracts were washed once with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was recrystallized from ethanol/ethyl acetate using activated charcoal, and yielded 2.28 gm (85% of theory) of pale yellow crystals, m.p. 246°-247° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]I.[CH:12]#[CH:13]>>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:12]#[CH:13]
Reactant: COC(CCCCCI)OC
Reactant: C#C
Product: C#CCCCCCC(OC)OC
Yield: 96 %

Procedure:
Acetylene was bubbled through ca. 300 ml of liquid ammonia while 8.1 g (0.35 atom) of sodium was added in small pieces. After the disappearance of the blue color, dimethylsulfoxide (150 ml) was added cautiously. 1,1-Dimethoxy-6-iodohexane (81.6 g; 0.3 Mole) was then added over a period of 10 min. while acetylene was bubbled through the stirred mixture. The ammonia was allowed to evaporate and was replaced with ether. When the mixture had reached 0°, dilute NH4Cl solution was added. The organic layer was separated, washed with water, dried (Na2SO4), and evaporated. Distillation of the residue gave 48.9 g (96%) of 1,1-dimethoxy-oct-7-yne, b.p. 91°/8 Torr.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.CCN(CC)CC>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH2:17][CH2:16]3)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2ccc3c(c2)CCC3)c2nc[nH]c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
2,6-Dichloro-9H-purine (1.89 g, 10 mmol), 5-aminoindan (1.33 g, 10 mmol) and Et3N (2.79 mL, 20 mmol) were dissolved in BunOH (15 mL). The solution was stirred for 2 h at 90° C. After cooling, PriOH (90 mL) was added slowly with stirring. After 1 h the precipitate was filtered, washed successively with small quantities of PriOH and Pri2O, and dried in vacuo to afford the title compound as a lemon-coloured powder (1.54 g, 54.1%). TLC (80:15:5 CHCl3/MeOH/AcOH): RF=0.61.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[CH:10]=[C:9]4[C:14]5[C:19]([CH2:20][C:8]4=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:18][CH:17]=[CH:16][CH:15]=5.C[C:22]([CH3:25])([O-])[CH3:23].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CS(C)=O.CCCCCCC.CO>[CH2:27]([C:20]1([CH2:5][CH2:13][CH2:1][CH2:2][CH2:3][CH2:23][CH2:22][CH3:25])[C:8]2[C:9](=[CH:10][C:11]3[C:12]([CH2:15][CH2:14][CH2:9][CH2:10][CH2:11][CH2:6][CH2:7][CH3:8])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]=3[CH:7]=2)[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCBr
Reactant: c1ccc2c(c1)Cc1cc3c(cc1-2)Cc1ccccc1-3
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2cc3c(cc21)-c1ccccc1C3(CCCCCCCC)CCCCCCCC
Temperature: 80 °C

Procedure:
6,12-Dihydroindeno[1,2-b]fluorene (24.03 g) was dissolved in DMSO (372.4 mL, Sigma-Aldrich) and sodium tert-butoxide (56.18 g) was added before heating to 80° C. Octyl bromide (110.6 g, Fluorochem) was added dropwise keeping the temperature below 90° C. The reaction was cooled, dissolved in heptane (2400 mL), washed with water (3×746 mL), dried (Na2SO4) and concentrated to give a dark solid. The solid was refluxed in methanol (480 mL) for 10 minutes, cooled to room temperature and collected by vacuum filtration. The solids were washed with methanol (2×480 mL) and dried to give the product as a dark solid. Yield; 82.56 g. 1H NMR (400 MHz, CDCl3); 7.74 (2H, m), 7.60 (2H, m), 7.32 (6H, m), 2.00 (8H, m), 1.05 (40H, m), 0.80 (12H, m), 0.60 (8H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[N:9][C:10]3[CH:11]=[C:12]([CH3:19])[CH:13]=[C:14]([OH:18])[C:15]=3[C:16]=2[CH3:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>CN(C)C=O>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:18][C:14]1[CH:13]=[C:12]([CH3:19])[CH:11]=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=1)[C:8]([CH3:20])=[N:9]2
Reactant: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 3-(4-chlorobenzyl)-2,4,7-trimethylquinolin-5-ol (0.24 g), N,N-dimethylformamide (2.0 mL), potassium carbonate (0.12 g) and bromoacetic acid methyl ester (0.12 mL) was stirred at room temperature for 17 hours. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was triturated with diethyl ether and further purification by column chromatography on silica gel, eluting with a mixture of methyl tert-butyl ether and dichloromethane (1:4 to 3:7 by volume) gave title compound, 0.078 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.CN1CCCN(C)C1=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].I[CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[CH2:30]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCI
Reactant: Cc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCNc1nc(C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To 2-amino-4-chloro-6-methylpyrimidine (10.0 g, 69.7 mmol) dissolved in 70 mL of anhydrous tetrahydrofuran was added 21 mL (2.5 equilvalents) of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at ambient temperature. The solution was cooled to ~10° C. and 69.6 mL (1.0 equivalent) of 1M lithium hexamethyldisilazide in tetrahydrofuran was added. The solution was stirred at 0° C. for 30 minutes and then 7.92 mL (1.0 equivalent) of 1-iodobutane was added at 0° C., and the reaction was allowed to warm to ambient temperature. The reaction mixture was poured into ethyl acetate and washed with water (2×); the aqueous washes were back-extracted with ethyl acetate (2×). The combined organic extracts were dried over potassium carbonate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 13% ethyl acetate in hexane to afford 4.6 g (33%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ 0.93 (t, 3H), 1.40 (m, 2H), 1.57 (m, 2H), 2.30 (s, 3H), 3.41 (m, 2H), 5.12 (bs, 1H), 6.43 (s, 1H). MS (DCl/NH3) m/e 200 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([S:29]([CH3:32])(=[O:31])=[O:30])[N:17]=2)[CH2:9]1.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1>>[CH3:32][S:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:45]3[CH2:46][CH2:47][CH:42]([C:39]4[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[CH2:43][CH2:44]3)[CH2:9]2)=[O:33])=[N:17]1)(=[O:31])=[O:30]
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Reactant: CS(=O)(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNc4nn(S(C)(=O)=O)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methanesulfonyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt and 4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:5][CH:4]=1.[C:14]([NH:21][CH2:22][CH2:23][NH2:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C[CH2:26][OH:27]>>[C:17]([O:16][C:14]([NH:21][CH2:22][CH2:23][NH:24][CH2:12][CH:11]([OH:13])[CH2:10][O:9][C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][C:7]=1[O:27][CH3:26])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NCCN
Product: COc1ccccc1OCC(O)CNCCNC(=O)OC(C)(C)C

Procedure:
Epoxide 6 (1.0 g, 5.5 mmol) and Boc-ethylenediamine (0.88 g, 5.5 mmol) were dissolved in 20 mL EtOH and the mixture was heated at reflux for 24 h. The solvent was evaporated and the residue was purified using column chromatography (1:1, Hex:EtOAc) to afford compound 11.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18]1([CH2:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.O>C1(C)C(C)=CC=CC=1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(C)cc1
Reaction time: 9 h
Yield: 12 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (13.7 g) and 1-naphthalenemethylamine (11.0 g) were dissolved in xylene (137 ml), andrefluxed underheating for 9 hr whiledehydrating with Dean-stark trap. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was concentrated under reduced pressure and isopropyl alcohol was added to the obtained residue to allow crystallization. The crystals were collected by filtration to give ethyl 5-(4-methylphenyl)-2-(1-naphthyl)-imidazole-4-carboxylate (2.5 g), melting point 190-192° C.