Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:19]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:19])[C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)[nH]c(C)n2)cc1OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(-c2cc(=O)n(C)c(C)n2)cc1OC
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4 dimethoxyphenyl)-2-methylpyrimidin-4-one (2.0 g) in N,N-dimethylformamide (20 ml) were added potassium tert.butoxide (1.08 g) and methyl iodide (1.0 ml), and stirred at ambient temperature for an hour. Resulting mixture was poured into water, and extracted with ethyl acetate. The organic layer was chromatographed on silica gel eluting with chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2,3-dimethylpyrimidin-4-one (1.38 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[C:30]1[CH:31]=[CH:32][C:33]([CH:36]=[O:37])=[N:34][CH:35]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:33]3[CH:32]=[CH:31][C:30]([CH:26]4[O:27][CH2:28][CH2:29][O:25]4)=[CH:35][N:34]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C2OCCO2)cn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(C2OCCO2)cn1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (4.40 g) in ethanol (50 mL) were added 5-(1,3-dioxolan-2-yl)pyridine-2-carbaldehyde (2.70 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (375 mg) and triethylamine (755 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (4.40 g, yield 67%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 528 (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:42])=[C:30]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:42])=[C:30]([NH:32][S:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(=O)(=O)c5ccccc5)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-((R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-phenylsulfonamide (which was obtained in Example 32) according to the procedure of Example 73 as a white solid; mp>150° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.39(m, 4 H), 1.85(m, 4 H), 2.64 (m, 2 H), 2.89(s, 3 H), 4.48(m, 1 H), 6.77(d, J=6 Hz, 1 H), 6.86(m, 2 H), 7.02(m, 2 H), 7.48(m, 2 H), 7.72(d, J=6 Hz, 1H); MS (ES) m/z: 597.0 (MH+, 100%); HRMS Calcd. for C29H32N4O6S2(MH+): 597.1836. Found: 597.1827.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>CN(C)C=O>[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=2)=[O:10])=[CH:12]1
Reactant: O=C(c1ccc(C(F)(F)F)nc1)c1c[nH]c2ccccc2c1=O
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cn(Cc2cccc(Br)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 71 mg (0.22 mmol) of 3-(6-trifluoromethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 11 mg (0.27 mmol) of 60% sodium hydride, 67 mg (0.27 mmol) of 3-bromobenzyl bromide and 1 mL of N,N-dimethylformamide. Yield: 85 mg of a white solid: LC-MSD, m/z for C23H14BrF3N2O2 [M+H]+=487.0, 489.0; HPLC retention time: 2.7 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.[C:30](O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:17]([O:18][C:19]([C@H:20]1[C@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14]1)=[O:29])[CH3:30]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 255.7 %

Procedure:
To a solution of benzyl-methoxymethyl-trimethylsilanylmethyl-amine (2.05 mL, 8.0 mmol) and (E)-3-(4-chloro-phenyl)-acrylic acid methyl ester (1.57 g, 8.0 mmol) in dichloromethane (16 mL) was added TFA (275 mg, 2.4 mmol). The mixture was stirred at 23° C. for 30 min then treated with saturated aqueous NaHCO3 (20 mL), extracted with dichloromethane (2×50 mL), dried with MgSO4, filtered, and concentrated. Purification of the crude by flash chromatography (SiO2, hexane to 1:1 hexane:EtOAc) gave (trans)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (2.11 g, 80%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=2[CH2:11][N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=1)=O.[CH:30]([C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:34]=1[NH2:35])([CH3:32])[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:33]([CH:30]([CH3:32])[CH3:31])[C:34]=1/[N:35]=[CH:1]/[C:3]1[N:8]=[C:7]([C:9]2[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=2[CH2:11][N:12]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:6]=[CH:5][CH:4]=1)([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1-c1cccc(C=O)n1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2ccccc2CN(C(=O)OC(C)(C)C)c2ccccc2)n1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Tetrahydrofuran (50 mL) and 4 angstrom molecular sieves (ca. 15 mL) were added to tert-butyl 2-(6-formylpyridin-2-yl)benzyl(phenyl)carbamate (11) (03.63 g, 9.34 mmol). Then 2,6-diisopropylaniline (1.66 g, 9.34 mmol) was added followed by a catalytic amount of p-toluenesulfonic acid monohydrate (0.003 g, 0.015 mmol). The mixture was stirred overnight then filtered and evaporated to a thick yellow oil. After several days the oil began to crystallize. Methanol (40 mL) was added and the mixture was stirred to give a yellow crystalline solid. The mixture was cooled to 5° C. for a couple of hours then the solid was collected on a glass fit and dried under reduced pressure. Yield: 3.93 g, 76.8%. 1H NMR (CD2Cl2, 500 MHz): 8.26 (s, 1H), 8.19 (d, 1H), 7.87 (t, 1H), 7.54 (d, 1H), 7.32-7.42 (m, 4H), 7.02-7.20 (m, 8H), 5.11 (s, 2H), 2.99 (sept, 2H), 1.34 (s, 9H), 1.18 (d, 12H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(OC([N:24]1[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][C@@H:25]1[C:33](O)=[O:34])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:30]([N:27]1[CH2:28][CH2:29][NH:24][C@@H:25]([C:33]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)=[O:34])[CH2:26]1)([CH3:32])[CH3:31]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)C1
Reaction time: 4 h
Yield: 35.3 %

Procedure:
1-[5-(Trifluoromethyl)pyridin-2-yl]piperazine (170 mg) and (2R)-1-(tert-butoxycarbonyl)-4-isopropylpiperazine-2-carboxylic acid (200 mg) were dissolved in dry THF (10 ml) followed by addition of N′N-di-isopropylethylamine (0.15 ml) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-TetramethylUronium Hexafluorophosphate (307 mg) and the reaction was stirred for 4 hours. The solvent was evaporated under reduced pressure, redissolved in DCM (50 ml) and washed with saturated aqueous NaHCO3 (20 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (3-10% MeOH:DCM) afforded the crude product (231 mg) as a foam which was then dissolved in TFA/DCM (1:1, 10 ml) and stirred for 30 minutes. The solvents were removed under reduced pressure, the residue taken up in 1M aqueous NaOH (30 ml) and extracted with DCM (2×30 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (5-25% MeOH:DCM) afforded the title compound (100 mg) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.[Na+].[SH-:12].O.[CH3:14]O>>[Cl:1][C:2]1[C:3]([S:12][CH3:14])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Reactant: CO
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: CSc1nc(Cl)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution was prepared by dissolving 25 grams (0.115 mole) of tetrachloropyrazine in 300 milliliters of methanol. To this solution was added over a 90 minute period, a solution of 115 milliliters of ~1.0 molar sodium mercaptide in methanol. The temperature was maintained below 20° C during the addition. The reaction mixture was stirred at room temperature overnight and thereafter poured into 400 milliliters of water. The precipitate which formed was removed by filtration and recrystallized from hexane. The 3,5,6-trichloro-2-methylthiopyrazine product was recovered in a yield of 7.11 grams, 27 percent of theoretical, and melted at 45°-47° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=3)[CH2:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].ClC(Cl)(Cl)C.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:7][O:6][Si:5]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:3][CH2:2][NH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: NCCN1CCNCC1
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: CC(Cl)(Cl)Cl
Product: CO[Si](CCCNCCN1CCNCC1)(OC)OC
Temperature: 80 °C
Yield: 93.7 %

Procedure:
A one-liter, four-necked flask was equipped with a thermometer, a condensor, an inlet tube for nitrogen gas and an outlet tube for vent gases. Chloropropyltrimethoxysilane (198.72 g) was introduced into the flask, together with 50 g of anhydrrous 1,1,1-trichloroethane and 86.14 g of 1-(2-aminoethyl)- piperazine. The mixture was heated to 80° C. with continuous agitation for four hours and then cooled to room temperature. The reaction mixture was rapidly filtered to collect the 1-(2-aminoethyl)piperazine hydrochloride salt which had formed. The filtrate was distilled to yield 182 g of 1-[2-[3-(trimethoxysilyl)- propyl]aminoethyl]piperazine, bp 120°-143° C. at 10 mm Hg (69 kPa) as a pale yellow oil. The yield corresponded to 64% of theoretical. This material was used as an accelerator and adhesion promoter in the sealant compositions of this invention as detailed below in Example 5.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.Cl[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>C1COCC1>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1
Reactant: Clc1nc2ccccc2o1
Reactant: OCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 500 ml THF cooled to -78° C. is added butyl lithium (2 eq.) followed by 4-bromobenzyl alcohol (27.2 g; 145 mmol) slowly over 45 minutes in a solution of THF (100 ml) keeping the temperature below -72° C. After 10 minutes following the final addition of the alcohol is added 2-chlorobenzoxazole (23.3 g; 145 mmol) in 25 ml THF slowly over 45 minutes. The temperature is maintained at -78° C. for 1 hour and then warmed to -40° C. for 15 minutes. The reaction is then quenched with 15 ml of acetic acid and allowed to warm to room temperature, diluted with 800 ml ether, washed 3x with H2O and brine, dried (MgSO4) and concentrated in vacuo to obtain a brown oily solid which is washed with 400 ml petroleum ether and filtered to obtain 4-(benzoxazol-2-yl)benzyl alcohol as a tan solid which is used directly in Step B.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](O)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:25]([C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[NH:16][CH:17]=[CH:18]4)=[O:26])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (300 mg, 1.21 mmol), 1H-indole-5-carboxylic acid (195 mg, 1.21 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.84 mmol) in N,N-dimethylformamide (10 mL) was add HBTU (688 mg, 1.81 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (50 mL). This was extracted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with n-hexane/ethyl acetate=1/1) to give 403 mg (94% yield) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[S:38][C:37]([NH2:39])=[N:36][CH:35]=2)=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]2[S:38][C:37]([NH:39][C:14](=[O:15])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:2][CH2:3]4)(=[O:5])=[O:6])=[CH:12][CH:11]=3)[O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:36][CH:35]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(Oc2cnc(N)s2)cc1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 33.3 %

Procedure:
The compound of example A76 was obtained by similar method described in example A75 using (4-Cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.5 g, 1.47 mmol), 4-(2-Amino-thiazol-5-yloxy)-benzoicacid methyl ester (0.441 g, 1.76 mmol), HOBt (0.237 g, 1.76 mmol), and EDCI (0.337 g, 1.76 mmol), N-methyl morpholine (0.178 g, 1.76 mmom) in DMF (10 mL) to provide the title compound (280 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.F[P-](F)(F)(F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:30][O:29][N:20]([CH3:24])[C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
A mixture of 1H-indole-2-carboxylic acid (from Aldrich, 2.5 g, 16 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.6 g, 20 mmol) and triethylamine (11 mL, 78 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (2.0 g, 20 mmol) was added and the resulting suspension was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated and purified on silica gel (eluting with 0-50% EtOAc in hexane) to give the desired product (2.7 g, 85%). LCMS calculated for C11H13N2O2(M+H)+: m/z=205.1. Found: 205.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[S:41])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: Cc1ccccc1
Product: S=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
Dissolve 0.50 g (0.12 m mole) of 8-chloro-11-[1-(1-(3-pyridyl)methylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine (Example 2 of Table 2) and 0.5 g (0.12 m mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) in 15 mL of toluene and stirr for 18 hours at room temperature and 18 hours at 80° C., under nitrogen. Filter the reaction mixture and concentrate under vacuo. Dissolve the residue in 50 mL of 1N HCl and extract with 200 mL of CH2Cl2. The water layer was neutralized with Na2CO3 and extracted with CH2 Cl2. The organic layer was dried over MgSO4 and concentrated under vacuo giving the product as a white solid, mp=92°-93° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH2:13](N)[CH2:14][CH2:15]C#C>ClCCl>[CH2:12]([NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2])[CH2:11][CH2:15][C:14]#[CH:13]
Reactant: C#CCCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C#CCCCNC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Add 1,1′-carbonyldiimidazole (0.539 mg 1.05 equiv; 3.26 mmoles) slowly portion wise to a −78° C. solution of 4-pentyn-1-amine (0.258 mL; 1.0 equiv; 3.10 mmoles) in dichloromethane (10 mL). Allow the reaction to warm to ambient temperature and stir for 72 hours. Use the solution directly for subsequent chemistry: MS (m/z): 178(M+1).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:27]([F:30])([F:29])[F:28])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: CCOC(=O)CCCOc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, ethyl 4-(4-chloro-9-oxo-9H-fluorene-2-yloxy)butyrate (69.4 g) was dissolved in THF (700 ml), and N-(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide (6.4 g) was added. To the reaction mixture was added dropwise a solution of trimethyl(trifluoromethyl)silane (52.0 ml) in THF (140 ml) at −16° C., and the mixture was stirred at the same temperature for 15 min. To the reaction mixture were successively added acetic acid (23.0 ml) and 1M tetrabutylammonium fluoride/THF solution (222 ml), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated, and to the obtained residue were added toluene (500 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) to allow for layer separation. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (150 ml, twice), 1N aqueous sodium hydroxide (100 ml), water (100 ml), 1N hydrochloric acid (100 ml), water (100 ml) and saturated brine (100 ml). To the obtained organic layer were added anhydrous magnesium sulfate and silica gel (150 g), and the mixture was stirred for 10 min. The insoluble material was filtered off, and the insoluble material was washed successively with toluene (300 ml) and ethyl acetate (800 ml). The obtained filtrate and the toluene washing were combined and the solvent was evaporated to give the title compound (72.1 g). Also, the solvent in the ethyl acetate washing was evaporated, to the obtained residue were added silica gel (40 g) and a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane 2:1, 300 ml), and the mixture was stirred at room temperature. The insoluble material was filtered off, and the insoluble material was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane=2:1, 300 ml). The solvent in the obtained filtrate was evaporated to further give the title compound (20.3 g).