Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:24])[N:17]([CH3:23])[C:18](SC)=[N:19][CH:20]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:24])[N:17]([CH3:23])[C:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][CH:20]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ncc(-c2ccc(OCc3ccccc3)cn2)c(=O)n1C
Reactant: Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)cn2)c1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2.5 g, 7.5 mmol) was suspended in 1,4-dioxane (40 ml) and aniline (6.4 ml, 70 mmol) and hydrochloric acid (concentrated, 0.10 ml, 3 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (120 C) and stirred. After stirring at 120 C-130 C for almost 2 days, TLC shows mostly product formed. The reaction was cooled to room temperature, concentrated, and purified on silica gel (˜3 inches; DCM->100:1 DCM/MeOH->40:1->25:1->20:1->5:1 DCM/MeOH). Fractions with product were collected, concentrated, and put on high vac to afford the desired product 5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (1.5 g, 3.9 mmol, 53% yield). MS (ESI pos. ion) m/z: 385 (MH+). Calc'd exact mass for C23H20N4O2: 384.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2.52 g of N-[3-(3-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)phenyl]propanamide, 100 ml of dimethylformamide and 0.43 g of sodium hydride (60% in oil) was stirred at room temperature. A 1.53 g portion of methyl iodide in 10 ml of dimethylformamide was added and the procedure of Example 1 was followed, giving 1.15 g of the desired product, mp 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:28])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>ClCCCl.C(N(CC)CC)C>[Cl:28][C:3]1[C:2]2[N:1]=[C:30]([OH:32])[N:12]([CH2:13][CH2:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNc2c(N)c(Cl)nc3ccccc23)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCn2c(O)nc3c(Cl)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 0.60 g of tert-butyl 4-[2-(3-amino-2-chloro-4-quinolylamino)-ethyl]-1-piperidinecarboxylate and 0.44 g of triphosgene in 10 ml of 1,2-dichloroethane, 0.41 ml of triethylamine was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with 1,2-dichloroethane. The extract was washed with saturated brine, and dried, and the solvent was evaporated. The residue was washed with diisopropyl ether to give 0.57 g of colorless crystals. Recrystallization from 1,2-dichloroethane gave colorless crystals having the melting point of from 222 to 223° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:17]=[C:16]([F:27])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:17]=[C:16]([F:27])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(OC3CCOCC3)cc2F)OC1(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OC3CCOCC3)cc2F)n1
Yield: 77 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 equiv.) at 100° C. for 30 min in microwave to give methyl 6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinate in 77% yield. LC/MS=368.0 (MH+), Rt=0.95 min.
Reaction SMILES: [OH-].[Na+].C(#N)C.[NH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>O>[CH3:16][N:17]([CH3:22])[S:18]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[NH2:6])(=[O:20])=[O:19]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)n1c(N)nc2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of sodium hydroxide (1.8 g) in water (9 mL) add acetonitrile (44 mL). To this solution, add 2-aminobenzimidazole (3.0 g, 22.5 mmol) and dimethylsulfamoyl chloride (2.4 mL, 22.5 mmol). Stir the reaction mixture at room temperature, overnight. Then, cool the mixture at 0° C. and the product crystallized from solution. Filter the product and dry it in vacuum to provide 5.0 g (90% yield) of the title compound as a white solid. MS(ES+): m/z=241.1 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:21])=[CH:23][CH:24]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(OCCN1CCOCC1)c1ccc(-c2ccccc2)cc1
Yield: 93 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-morpholinoethanol was used instead of the triethanolamine, and 4-phenylbenzoyl chloride was used instead of the benzoyl chloride, to give 2-morpholinoethyl 4-phenylbenzoate in a yield of 93%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7].CC(C)=O>O>[N:1]([S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])=[N+:2]=[N-:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
In a three-necked flask fitted with stirrer and dropping funnel 65 g of sodium azide is dissolved in 900 ccs of water. While stirring and cooling till 0°-5° C a solution of 198 g of m-chlorosulphonyl-benzoic acid in 900 ccs of acetone is added dropwise. Then stirring is continued for 30 minutes whereupon the solution obtained is poured into 2 liters of water. The white precipitate formed is sucked off, washed with water and dried in vacuo. Melting point: 143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C(c2ccc([N+](=O)[O-])cc2)(c2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(c2ccc(N)cc2)(c2ccc(N)cc2)c2ccc(N)cc2)cc1

Procedure:
In a Parr reactor, tetrakis(4-nitrophenyl)methane (17.0 grams, 34.0 mmol; prepared as described in Example B) and palladium, weight percent on activated carbon (2.15 grams, 2.00 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) were added to tetrahydrofuran (450 milliliters). The reactor was closed, and the mixture was stirred under 200 pounds per square inch (13.6 atmospheres) of hydrogen pressure for 72 hours at room temperature. The mixture was then filtered through CELITE, solvent was removed from the filtrate by evaporation under reduced pressure, and the resulting white solid was triturated in chloroform. The solid was then recovered by filtration, washed with chloroform again, and dried under reduced pressure at room temperature to give the targeted tetrakis(4-aminophenyl)methane as a white powder in a quantitative yield (12.9 grams).
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:46]=[CH:45][C:28]([C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:27][CH:26]=4)[C:7]=3[CH:8]=2)[N:3]=1.[CH2:47](Br)[C:48]#[CH:49].C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([N:24]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:45][CH:46]=4)[CH2:49][C:48]#[CH:47])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1)C(=O)OCC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: C#CCN(c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: 110 °C

Procedure:
A mixture of diethyl N-{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl}-L-glutamate (13.5 g), propargyl bromide (32 g), calcium carbonate (10.7 g) and DMA (250 ml) was stirred and heated to 110° C. for 5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluant. There was thus obtained diethyl -{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)--amino]benzoyl }-L-glutamate as a foam (9 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:24])=[O:23])[CH:17]=[C:18]([OH:20])[CH:19]=1.[CH2:35](O)[CH2:36][CH2:37][OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[CH3:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH:19]=1)[O:20][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Diethyl azodicarboxylate (0.46 mL, 2.9 mmol) was added slowly to a solution of 1.0 g (2.9 mmol) of 5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol, as prepared in the preceding step, 0.21 mL (2.9 mmol) of 1,3-propanediol, and 760 mg (2.9 mmol) of triphenylphosphine in anhydrous tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness. The residue was triturated with hexane under sonification, and the solvent was decanted (4 times). The residue was dissolved in dichloromethane and diluted with hexane to produce a crystalline material which was discarded. The filtrate was diluted with hexane to give an oil, and the solvent was decanted. The oil was dissolved in a minimum of methanol and diluted with water to initiate crystallization. The solid was collected by filtration to afford the title compound (1.16 g, quantitative yield). 1H-NMR (300 MHz, CDCl3) δ 8.45 (dd, 1H, J=1.3, 7.8 Hz), 8.12 (dd, 1H, J=1.2, 7.8 Hz), 7.88 (td, 1H, J=1.3, 7.7 Hz), 7.74 (td, 1H, J=1.3, 7.7 Hz), 6.61-6.56 (m, 3H), 4.00 (t, 2H, J=6 Hz), 3.81 (t, 3H, J=5.9 Hz), 3.45 (s, 3H), 2.24 (s, 3H), and 1.97 (pentet, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20O7S2 : 423.1 (M+Na). Found: 423.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([NH2:26])[CH2:17][CH2:16][CH2:15][C:14]3[N:13]=[C:12]([O:18]CC4C=CC=CC=4)[CH:11]=[CH:10][C:9]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)C.[ClH:31].[H][H]>C(O)C.[Pd]>[ClH:31].[NH2:26][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:18])[CH:11]=[CH:10][C:9]1=2
Reactant: NC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: NC1(Cc2ccccc2)CCCc2[nH]c(=O)ccc21
Yield: 28 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-(phenylmethyl)-2-(phenylmethoxy)-5-quinolinamine (19.1 g) and 10% palladium-on-carbon (1.5 g) in ethanol (1 l) was acidified to about pH 2-3 with 2propanol/hydrochloric acid solution. The mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was removed by filtration, the filtrate was neutralized with 4-polyvinylpyridine and concentrated. The residue was triturated with a mixture of methanol and ethyl acetate. The precipitate was collected and recrystallized form water/methanol/ethyl acetate to afford 4.6 g (28%) of product, mp 235°-238° C. (dec), in two crops.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Oc1ccc2ocnc2c1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc2ocnc2c1
Temperature: 50 °C
Yield: 56.3 %

Procedure:
To a solution of benzo[d]oxazol-5-ol (1.50 g, 11.10 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.89 g, 12.21 mmol) in DMF was added cesium carbonate (1.81 g, 5.55 mmol) and potassium carbonate (2.30 g, 16.65 mmol). After heating to 50° C. for 16 hours, the mixture was poured into ice water and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried, and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (1.69 g, 56%) as white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile (5.7g, 22 mmol) and 1,4-dibrombutane (2.6 ml) in DMSO-ether (10 ml: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:19])[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH3:20][C@H:21]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:31]3[CH2:33][O:32]3)[CH:28]=2)[C:23](=[O:34])[O:22]1>CCO>[OH:32][CH:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:34])[O:22][C@@H:21]([CH3:20])[CH2:30]2)[CH2:33][N:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][C:3]1([CH2:2][OH:1])[CH3:19]
Reactant: CC1(CO)CN(C(=O)OCc2ccccc2)CCN1
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Solvent: CCO
Product: C[C@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)CC3(C)CO)ccc2C(=O)O1
Temperature: 80 °C

Procedure:
To a solution of racemic benzyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (1.0 g, 3.8 mmol) (prepared as described in US Patent Application Publication No. US2007/0088039A1, Example 10) in EtOH (13 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)isochroman-1-one (773 mg, 3.80 mmol), the resulting mixture was heated at 80° C. for 16 h, the reaction mixture was concentrated to dryness and purified on silica gel to afford the title compound: LC/MS: m/e 469.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=O)[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1.[CH2:25]([Mg]Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:25]([C:10]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]2[S:13][CH2:14][CH2:15][C:8]=2[C:7]2[C:2]([OH:1])=[CH:3][C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:5][C:6]=2[O:11]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reactant: CCCCCC[Mg]Br
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)C(C)CCCCC)cc(O)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexylmagnesium bromide, using the manipulative procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: C(OC(=O)[N:7]([C:37]1[CH:38]=[N:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)=[O:15])=[C:10]([F:36])[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH2:44]([O:43][C:40]1[N:39]=[CH:38][C:37]([NH:7][C:8]2[N:9]=[C:10]([F:36])[C:11]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([CH3:25])[CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:42][CH:41]=1)[CH3:45]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(=O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOc1ccc(Nc2ccc(C(=O)c3c[nH]c4ncc(C)cc34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To (6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (71, 0.200 g, 0.309 mmol) in 10 mL of 1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.0 mmol) is added. The reaction is stirred at 80° C. for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 2-15% methanol in dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3045, 60.7 mg). MS (ESI) [M+H+]+=391.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][CH3:15])=[N:4][N:3]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:19][CH2:18]1>>[CH2:14]([C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[CH2:21][CH2:22]2)=[N:3][N:4]=1)[CH3:15]
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: CCc1nnc(Cl)c2cc(OC)ccc12
Product: CCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-ethyl-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:25][CH2:26]O>>[CH2:25]([O:14][C:13](=[O:15])[CH:12]([C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:26]
Reactant: CC(C)CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC(C)C)c1cc(F)c([N+](=O)[O-])cc1F

Procedure:
2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.11 mol) was dissolved in EtOH (200 mL) and H2SO4 (96%) 10 mL added. The reaction mixture was refluxed for 3 h and the solvent evaporated to an oil which was dissolved in EtOAc. Water (150 mL) added and the reaction mixture was extracted with EtOAc (3×100 mL). Organic phases washed with saturated NaHCO3 (50 mL), water (100 mL) and brine (100 mL) then dried under MgSO4. The evaporation of solvent under reduced pressure gave 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester as yellow oil 32.0 g, (97%), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 7.81 (dd, J=8.8, 6.2 Hz, 1H), 7.41 (dd, J=11.1, 5.6 Hz, 1H), 4.23-4.05 (m, 3H), 2.04-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 171.6, 155.0 (d, 1JCF=246.0 Hz), 151.5 (d, 1JCF=261.3 Hz), 145.5, 135.7, 118.8 (dd, 2JCF=24.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=20.0 Hz), 61.6, 41.8, 26.1, 22.5, 22.0, 14.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:31])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)[C:19]1=[O:30])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH:38]([Si:41](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])([CH3:40])[CH3:39]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:31])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:41]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:38]([CH3:40])[CH3:39])[CH2:25][CH2:24]2)[C:19]1=[O:30])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C#N)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 95.7 %

Procedure:
Stir a mixture of (R)-4-{3,5-dichloro-4-[1-(4-hydroxy-piperidin-1-yl)-2-oxo-pyrrolidin-3-ylmethyl]-phenoxy}-benzonitrile (0.238 g, 0.5 mmol) and 15 mL dichloromethane in an ice bath. Add pyridine (0.205 g, 2.59 mmol) followed by triisopropylsilyltrifluoromethane sulfonate (0.19 g, 0.62 mmol). Remove the cold bath and stir the reaction 1 hour at room temperature. Dilute the reaction with dichloromethane and wash with water. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 0% to 50% ethyl acetate in hexanes gradient to afford 0.295 g of the title compound. MS (m/z): 615 (M+).