Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[C:10]([CH3:12])=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N.[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH:33]=[CH:32]1>C(C(C)=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.CO>[CH2:15]([O:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH:16]1[O:18][CH2:17]1.[CH:1]([C:32]1=[CH:33][C:34]([O:36][C:31]1=[O:37])=[O:35])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: C=C(C)C(=O)OCC1CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Solvent: CCC(C)=O
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Temperature: 70 °C
Reaction time: 10 h
Yield: 516.1 %

Procedure:
A monomer mixture comprising 600 g of styrene (hereinafter referred to as "St") and 70 g of glycidyl methacrylate (hereinafter referred to as "GMA") was dissolved in 1000 g of methyl ethyl ketone (hereinafter referred to as "MEK") in a four -necked flask fitted with a dropping funnel, a nitrogen inlet tube, a thermometer, a condenser and a stirrer and the solution was heated to 70° C. Another monomer mixture comprising 15 g of azobisisobutyronitrile (hereinafter referred to as "AIBN") as the polymerization initiator, 260 g of St, 70 g of maleic anhydride (hereinafter referred to as "MAH") and 280 g of MEK was stepwise dropped thereinto to initiate polymerization. After 10 h, the flask was cooled to room temperature arid the reaction mixture was immediately poured into a large quantity of methanol. The polymer thus precipitated was recovered by decantation, dried under reduced pressure in a vacuum drier axed Finely pulverized to give 870 g of styrene-maleic anhydride glycidyl methacrylate copolymer (3). According to GPC, the copolymer (3) had a number-average molecular weight (in terms of polystyrene ) of 15,000. The infrared absorption spectrum of the copolymer (3) is given in FIG. 1.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C@H:37](O)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:35][CH:36]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CCCC[C@@H](O)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC[C@H](Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (275 mg), (R)-1-(4-isobutylphenyl)pentan-1-ol (179 mg) and triphenylphosphine (213 mg) in a mixture of tetrahydrofuran and toluene (1:4, 10 ml) was added diethyl azodicarboxylate (0.13 ml) at -25° C. After stirring for 1 hour, the reaction mixture was concentrated in vacuo. The concentrate was chromatographed on silica gel using hexane and ethyl acetate (3:1) to give ethyl (S)-4-[3-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl]indol-1-yl]butyrate (279 mg).
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[N:28](CC4C=CC(OC)=CC=4)[N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:40][CH2:41][C:42]([F:44])([F:45])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c(Cl)cc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)c1ccc(OCCCOc2cc(NC(=O)c3nnn[nH]3)c(C)cc2Cl)c(CCC(F)(F)F)c1O

Procedure:
A solution of 3 g (4.5 mmol) of N{{3-{3[- 4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy}-propoxy}-4-chloro-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is refluxed for 60 minutes. The reaction mixture is concentrated under reduced pressure, about 150 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide thus obtained, of melting point 236°-238° (decomposition) is dissolved in 50 ml of tetrahydrofuran, and one equivalent of sodium, dissolved in 5 ml of methanol, is added. After addition of ether, crystallisation starts. The sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methylphenyl}}-1 H-tetrazole-5-carboxamide of melting point 9020 (decomposition) is thus obtained.
Reaction SMILES: [H-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[O:19][CH3:20])[NH:15][C:14](=[O:21])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[O:19][CH3:20])[N:15]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[O:21])[CH2:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a mixture of 95% dry sodium0 hydride (24 mg, 1.00 mmol) in anhydrous N,N-dimethylformamide (8 mL) at room temperature was added a solution of 6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (7) (110 mg, 0.38 mmol) in N,N-dimethylformamide. The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl bromoacetate (390 mg, 2.00 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature until majority of the starting material was converted (as shown by LCMS), then it was quenched by addition of methanol (10 mL). The mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added to the residue, and the solvent removed under reduced pressure, to afford crude (tert-butyl 2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([PH:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:31]=[CH2:32])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([P:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([CH:31]=[CH2:32])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=1
Reactant: CCO[PH](=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(P(=O)(OCC)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1OC(C)C
Temperature: 70 °C
Yield: 2.8 %

Procedure:
To a degassed solution of ethyl 3,5-bis(trifluoromethyl)-phenylphosphinate (3.33 g, 15.24 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (3.33 mg, 13.8 mmol) in DMF (25 mL) were added the triethylamine (3.85 mL, 27.6 mmol) and tris(dibenzylideneacetone)dipalladium (2.53 g, 2.76 mmol). The mixture was heated in an oil bath at 70° C. overnight. The volatiles were removed in vacuo and the mixture was purified by column chromatography with 20 to 70% ethyl acetate in petroleum ether to afford compound BA3 (185 mg) as an oil in 2.8% yield.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 11 was repeated, provided that the shown in 1st, 2nd and 3rd columns of the following table were used in place of the 1-amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone, cyanuric chloride and 3-aminobenzenesulfonic acid, respectively, thereby obtaining a corresponding anthraquinone compound. The color shade obtained by dyeing cotton with the compound is as shown in a 4th column of the table.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Mg].II.[B:13](OC)([O:16]C)[O:14]C>O1CCCC1>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([B:13]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: CSc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1cccc(B(O)O)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 3-bromothioanisole (10.3 g, 50.9 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a stirred mixture of magnesium turnings (1.86 g, 75 mmol) and a crystal of iodine under nitrogen. Once the reaction was initiated, the remainder of the solution was added at such a rate as to keep the reaction mixture under reflux. When the addition was complete, the mixture was stirred under reflux for a further 1 hour, allowed to cool to room temperature and then added to a solution of trimethyl borate (5.8 ml, 51 mmol) in anhydrous tetrahydrofuran (25 ml), whilst keeping the internal temperature at about −10° C. The reaction mixture was allowed to warm to about 0° C., stirred for 30 minutes and then quenched with 2M hydrochloric acid. The resulting mixture was extracted with ether, then the combined extracts extracted, in turn, with 2M aqueous sodium hydroxide solution. The combined aqueous extracts were acidified with concentrated hydrochloric acid and extracted with ether. The combined ether extracts were dried (MgSO4) and evaporated under reduced pressure to provide the title compound (7.8 g, 100%) as a white solid. δ(DMSOd6): 2.45 (s,3H), 7.27 (m,2H), 7.54 (m,1H), 7.67 (s,1H), 8.05 (brs,2H),
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2ccccc2o1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2o1
Temperature: 25 °C

Procedure:
To benzofuran-2-yl-methanol (4.3 g, 29.0 mmol, 1 eq., Example 140, Step 1), dichloromethane (200 mL) was added and the solution was cooled using an ice-ethanol bath. Then carbon tetrabromide (10.6 g, 31.9 mmol, 1.1 eq.) and 1,3-bis(diphenylphosphino)-propane (6.6 g, 16.0 mmol, 0.55 eq.) were added under argon, and the reaction was allowed to slowly warm to room temperature for 2.5 hours. After work-up and flash column chromatography, 2-bromomethyl-benzofuran was obtained in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.9 (s, 2 H) 7.0 (dd, J=5.3, 0.5 Hz, 1 H) 7.3 (dd, 1 H) 7.4 (m, 1 H) 7.6 (m, 2 H).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34]>>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Nc1c(Cl)cncc1Cl
Product: CCc1cc2c(C(=O)Nc3c(Cl)cncc3Cl)cnc(OC)c2o1
Yield: 74.8 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) and 4-amino-3,5-dichloropyridine (0.11 g). Purification by trituration with ether gave the title compound (0.16 g) as a white solid.
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a suspension of (3S,4S)-4-methyl-piperidin-3-ol hydrochloride (intermediate 26; 0.04 g, 0.3 mmol) in dichloromethane (1 ml) was added triethylamine (0.04 ml, 0.3 mmol) and acetic acid (0.03 ml, 0.5 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.08 g, 0.3 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.07 g, 0.4 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=468.1 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]3[C:17]([CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:24]=O.[ClH:26]>>[ClH:26].[ClH:26].[C:1]12([CH2:11][CH2:12][N:13]3[C:17]4[CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH:20][CH2:24][C:16]=4[N:15]=[CH:14]3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C=O
Reactant: N[C@@H](Cc1cncn1CCC12CC3CC(CC(C3)C1)C2)C(=O)O
Agent: Cl
Product: O=C(O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.8 g 3-(2-(1-adamantyl)ethyl)histidine.2HCl in 100 mL 1N HCl is treated with 5 mL 36% formaldehyde, stirring 30 min at 25° C. followed by 90 min at reflux. Evaporation gives 1-(2-(1-adamantyl)ethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid dihydrochloride as a white solid. NMR (D2O) 8.90 (s,1H,2-Im).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(C)c2c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(OC)cc1
Yield: 78.8 %

Procedure:
A solution of ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate (Example 12b, 0.518 g, 1.96 mmol) and (4-methoxyphenyl)methanamine (1.15 mL, 8.86 mmol) in toluene (10 mL) and DMF (5 mL) were stirred at 115° C. under nitrogen for 12 hrs. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel (0% to 50% EtOAc in hexanes) to give the title compound as an oil (563 mg, 79%). 1H NR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.6 Hz, 3H), 2.45 (s, 3H), 2.78 (s, 3H), 3.73 (s, 3H), 4.2-4.3 (m, 4H), 6.27 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.19 (m, 3H), 7.48 (m, 1H), 7.58 (d, J=8.4 Hz, 1H). MS 365 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C@H:3]([OH:14])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[C:18](=[O:19])([O:14][C@H:3]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6]1)[C:2]([CH3:16])([CH3:15])[CH3:1])[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[C@H](O)Cn1ccc(C(F)(F)F)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](Cn1ccc(C(F)(F)F)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To 875.3 mg (3.71 mmol) of (2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol in 12 mL of 1,2-dichloroethane at room temperature was added 746.8 g (3.71 mmol) of 4-nitrophenyl chloroformate. Then, 359.6 μL (4.45 mmol) of pyridine was added and the solution was heated at reflux for 22 h. Upon cooling to room temperature, saturated aqueous sodium bicarbonate was added to the solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 1.39 g (93%) of 4-nitrophenyl (1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl carbonate. Rf=0.29 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.28 (d, J=9 Hz, 2H), 8.07 (s, 1H), 7.31 (d, J=9 Hz, 2H), 6.74 (s, 1H), 4.87 (d, J=8 Hz, 1H), 4.69 (d, J=14 Hz, 1H), 4.42 (dd, J=15 Hz, J=10 Hz, 1H), 1.03 (s, 9H); ES-LCMS m/z 424 (M+H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Title compound in example 659. A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1-((1R,5S)-8-{2-[4-(1,3-benzodioxol-5-yl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (0.18 g, 82%). 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 1H), 7.29 (m, 3H), 6.83 (m, 2H), 6.75 (m, 1H), 6.21 (m, 1H), 6.00 (s, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.38 (m, 2H), 2.98 (m, 2H), 2.86 (s, 3H), 2.56 (m, 2H), 2.31 (m, 4H), 2.07-2.21 (m, 4H), 1.82 (m, 4H), 1.26 (s, 9H). HRMS C34H44N4O3 m/z 557.3492 (M+H)Cal., 557.3495 (M+H)Obs..
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([NH:11][C:12](=[O:18])[C:13]([O:15]CC)=[O:14])[C:7](=[O:19])[C:6]=2[CH:20]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([NH:11][C:12](=[O:18])[C:13]([OH:15])=[O:14])[C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CCOC(=O)C(=O)Nc1coc2ccc(Cl)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Nc1coc2ccc(Cl)cc2c1=O

Procedure:
Ethyl (6-chloro-4-oxo-4H-1-benzopyran-3-yl)aminooxoacetate (2.7g, 0.92 mole) was suspended in ethanol (100 ml) and water (100 ml). 0.1N sodium hydroxide solution was added dropwise, with occasional warming on a steam bath, until the reaction mixture remained slightly basic. The color of the mixture changed to orange on addition of the base and then back to white. The sodium hydroxide solution was added until a faint orange color persisted. The product was filtered off, triturated with 1N hydrochloric acid, washed with water and sucked dry on filter. Recrystallization from methanol gave white crystals (2,3g, 94%), m.p. 213°-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[CH:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[CH:2]
Reactant: C#Cc1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of 3-ethynylbenzaldehyde (650 mg, 5 mmol) and morpholine (0.87 mL, 10 mmol) in DCE (15 mL) was added NaBH(OAc)3 (1.325 g, 6.25 mmol), followed by AcOH (0.2 mL). The resulting mixture was stirred for 2 h at rt. Aqueous workup followed by extraction with EtOAc gave crude 4-(3-ethynylbenzyl)morpholine (0.98 g) as a light brown oil. The title compound (1.75 g, quantitative yield over 2 steps) was obtained as a light brown oil using the method (PhCH3=12 mL, 1 mol % HRuCl(CO)(PPh3)3, 50° C., 2 h) for the preparation of Example A42A. 1H NMR (400 MHz, CDCl3) δ7.47 (s, 1H), 7.46-7.37 (m, 2H), 7.35-7.27 (m, 2H), 6.19 (d, J=18.4 Hz, 1H), 3.78-3.68 (m, 4H), 3.52 (s, 2H), 2.52-2.42 (m, 4H), 1.32 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.2.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)=[CH:9][C:8]=1[CH3:23].CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)=[CH:9][C:8]=1[CH3:23]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(C)c2)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccc(O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A 1.0 M BBr3 solution in CH2Cl2 (3.4 mL, 3.40 mmol) was added to an ice-cold solution of methyl 4′-methoxy-3′-methyl-[1,1′-biphenyl]-3-carboxylate (345 mg, 1.35 mmol) in CH2Cl2 (13 mL). The reaction mixture was stirred at 25° C. for 2 h then was cooled to 0° C. MeOH (5 mL) was added and the mixture was stirred at 0° C. for 15 min then was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexane, 10 to 15%) to yield the title compound (278 mg, 85% yield) as a white solid.