Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=[O:11])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]1([C:25]#[C:26][C:2]2[CH:3]=[C:4]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:10]#[C:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:13]=3)=[O:11])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(C(=O)c1cccc(Br)c1)c1cccc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1cccc(C#Cc2ccccc2)c1)c1cccc(C#Cc2ccccc2)c1
Yield: 131.5 %

Procedure:
A solution of 3,3'-dibromobenzil (5.0 g, 0.0136 mol) and phenylacetylene (3.47 g, 0.0340 mol) in triethylamine (30 mL) is deaerated by bubbling nitrogen through the solution for ten minutes. (PPh3)2PdCl2 (0.067 g, 0.0001 mol) is then added, and the reaction mixture heated at reflux overnight. The mixture is concentrated to dryness, then taken up in CH2Cl2 (100 mL), washed sequentially with 1 M HCl, saturated aqueous NaHCO3 and dried (Na2SO4), then concentrated, giving 3.67 g (66 percent) product as a white solid: m.p. 144° C. to 145° C.; 1H NMR (CDCl3) δ 8.12 (s, 2H), 7.96 (d, J=7.9 Hz, 2H), 7.81 (d, J=7.7 Hz, 2H), 7.52 (m, 6H), 7.36 (m, 6H); 13C NMR (CDCl3) δ 192.83, 137.40, 132.82, 131.52, 129.04, 128.58, 128.25, 124.50, 122.37, 91.11, 87.62.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.[C:32]([Mg]Cl)#[CH:33]>O1CCCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:32]#[CH:33])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1
Reactant: C#C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1

Procedure:
To a solution of 3-[5-bromo-2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step C (60 mg, 0.12 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.5 mL, 0.25 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without any additional purification.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48]1[N:49]=[CH:50][S:51][CH:52]=1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:47][C:48]1[N:49]=[CH:50][S:51][CH:52]=1)[CH2:23][CH2:22]2
Reactant: ClCc1cscn1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCc3cscn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(chloromethyl)thiazole as the alkylating agent in Step 1. MS: m/e 627.5 (M+H)+, 1.56 min (method 12). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (s., 3H) 0.96 (s, 3H) 1.01 (s, 3H) 1.10 (s, 3H) 1.21 (s, 3H) 1.72 (s, 3H) 0.89-1.83 (m, 16H) 1.84-2.05 (m, 3H) 2.07-2.22 (m, 1H) 2.13 (dd, J=17.07, 6.53 Hz, 1H) 2.22-2.32 (m, 1H) 2.33-2.49 (m, 1H) 4.24 (d, J=14.05 Hz, 1H) 4.70 (s, 1H) 4.72 (d, J=13.55 Hz, 1H) 4.81 (s, 1H) 5.31 (dd, J=6.02, 1.51 Hz, 1H) 7.24 (d, J=8.28 Hz, 2H) 7.59 (s, 1H) 8.00 (d, J=8.28 Hz, 2H) 8.83 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][C:8]=2[CH:11]([CH3:13])[CH3:12])[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=2[CH3:14]
Reactant: Cc1ccc(C(C)C)c2c1C(O)C(C)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1=Cc2c(C(C)C)ccc(C)c2C1
Yield: 78 %

Procedure:
In a 1-liter egg-plant flask were charged about 40 g (0.20 mol) of 2,7-dimethyl-4-isopropyl-indanol, 500 ml of benzene, and p-toluenesulfonic acid monohydrate and the mixture was stirred under reflux for 1 hour. The reaction mixture was poured in an aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The organic layer was washed with water and with saline and dried over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure (69 to 74° C./0.5 mmHg) to obtain 29.06 g (0.156 mol) of 2,7-dimethyl-4-isopropylindene as a colorless liquid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[S:15][C:7]=1[N:8]2[CH3:14]>>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[S:15][C:7]=1[N:8]2[CH3:14]
Reactant: COC(=O)c1cc2c3c(Cl)cc(Cl)cc3n(C)c2s1
Agent: [K+]
Agent: [OH-]
Product: Cn1c2cc(Cl)cc(Cl)c2c2cc(C(=O)O)sc21
Yield: 79.5 %

Procedure:
Prepared from KOH (2.23 g), (53) (2.20 g) after reflux for 41/3 h yielding (56) 1.67 g (79.5%). M.p. 278°-281° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)=[CH:27][C:26]=3[CH3:41])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]([S:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH3:33])=[CH:27][C:26]=4[CH3:41])=[N:22][N:21]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)=[CH:13][CH:12]=1)(=[O:15])=[O:16])([CH3:19])[CH3:18]
Reactant: Cc1cc(CN(C)C(=O)OC(C)(C)C)ccc1-c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-3-methyl-phenyl]methyl]-N-methyl-carbamate (120 mg, 0.2074 mmol) in CH2Cl2 (10 mL) was added TFA (709.5 mg, 479.4 μL, 6.222 mmol) and the resulting solution stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and redissolved in CH2Cl2 (20 ml) and concentrated. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (48.0 mg, 39%); 1H NMR (400 MHz, DMSO) d 1.2 (d, 6H), 2.6 (s, 3H), 2.75 (s, 3H), 3.4-3.5 (m, 1H), 4.25 (s, 2H), 7.7 (d, 1H), 7.72 (s, 1H), 8.0-8.1 (m, 3H), 8.2 (d, 1H), 8.4 (d, 2H), 8.8 (br s, 2H) and 9.2 (s, 1H) ppm; MS (ES+) 479.4
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([C@H:29]2[CH2:33][O:32]C(C)(C)[O:30]2)([CH3:28])[CH3:27])[N:12]=1>C(Cl)Cl.C(=O)([O-])O.[Na+].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([CH3:28])([CH3:27])[C@H:29]([OH:30])[CH2:33][OH:32])[N:12]=1
Reactant: CC1(C)OC[C@H](C(C)(C)Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product from step iii) 0.34 g) in DCM (9 mL) was added iron (III) chloride hexahydrate (0.61 g) and the mixture was stirred at ambient temperature for 35 min. The reaction mixture was diluted with sat. sodium hydrogencarbonate solution and extracted with DCM (×3). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white foam. Yield: 0.20 g
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24]C2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:51][OH:52])C1C=CC=CC=1.F[C:56](F)(F)[C:57](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:57]2[CH:56]=[CH:51][CH:10]=[CH:9][CH:14]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:11][C@@:10]1([CH2:51][OH:52])[CH2:32][O:31]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 1.5 h
Yield: 149.6 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 2n (500 mg, 0.66 mmol) was dissolved in 10 mL dichloromethane, followed by dropwise addition of trifluoroacetic acid (0.2 mL, 2.62 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was washed with 10 mL saturated sodium bicarbonate solution and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 2p (360 mg, white solid), with yield: 75.3%. MS m/z (ESI): 746.2 [M+18].
Reaction SMILES: N[C:2]1[C:3]([Cl:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[CH3:12])[C:5]([O:7]C)=[O:6].N([O-])=O.[Na+].[ClH:19]>Cl.Cl[Cu]>[Cl:14][C:3]1[C:2]([Cl:19])=[C:11]([CH3:12])[C:10]([F:13])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(F)c(C)c(N)c1Cl
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1c(F)cc(C(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of methyl 3-amino-2-chloro-5-fluoro-4-methylbenzoate are diazotized with NaNO2 /HCl in aqueous solution. This diazonium salt solution is added dropwise to a solution of 4.1 g of CuCl in 16 ml of concentrated HCl. The mixture is then warmed until no further gas is formed. After cooling, the solid which has precipitated is separated off and taken up in 30 ml of 50% strength EtOH. After addition of 2.3 g of NaOH, the mixture is boiled for 1 hour. After cooling to room temperature, the mixture is acidified with HCl and the solid which has precipitated is isolated. Melting point: 179°-80°. Yield: 5.2 g.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:18][C:15]1[CH:16]=[CH:17][C:9]2[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: Cc1ccc(COc2ccccc2)c(C(=O)O)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Reaction time: 0.17 h

Procedure:
Mix 0.2 gm of the phenoxymethylbenzoic acid of Step A, 1 ml of thionyl chloride and 10 ml of dry benzene. Reflux for 1 hour and concentrate to dryness in vacuo. Dissolve the residue in 10 ml of dry 1,2-dichloroethane and add 0.3 gm of anhydrous aluminum chloride while stirring in an ice bath. After 10 minutes, pour the reaction mixture into ice water, extract with chloroform, wash with water and dry over magnesium sulfate. Concentrate to dryness and chromatograph the residue over silica gel eluting with chloroform. Concentrate the eluate to dryness and crystallize from hexane to obtain the title product.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[F:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]\[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(\c2cccc(F)c2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1/C(=C/OCCN1CCC[C@@H](C(=O)O)C1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
Z or E-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g, 0.22123 mol) (prepared as described in Method A) (opposite geometric isomer of example 9) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.3 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the resultant precipitate was dissolved by addition of ice with vigorous stirring. The organic phase was separated, dried (Na2SO4) and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.10 g, 20%) as a white solid, m.p. 193°-195°
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]2[C:22]3[N:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[C:16]3[CH2:15][N:14]([CH3:24])[CH2:13][CH2:12][C:11]2=3)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:19]1[CH:20]=[N:21][C:22]2[N:10]([CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[N:7][CH:6]=3)[OH:25])[C:11]3[CH2:12][CH2:13][N:14]([CH3:24])[CH2:15][C:16]=3[C:17]=2[CH:18]=1
Reactant: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(Br)nc2)CCN(C)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Temperature: 150 °C

Procedure:
1-(6-Bromo-pyridin-3-yl)-2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-ethanol (2 g, 4.9 mmol) was dissolved in DMF (20 mL), and the mixture was purged with nitrogen. Zinc cyanide (1.16 g, 9.9 mmol) and Pd(PPh3)4 (339 mg, 0.294 mmol) were added, and the mixture heated at 150° C. for 2 h. The reaction was monitored by LCMS. The reaction mixture was allowed to cool at RT, diluted with EtOAc (250 mL) and filtered. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude that was purified by reverse phase chromatography to obtain 100 mg of 5-[2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile. This was followed by chiral separation. 1H NMR (CDCl3, Free base) δ (ppm): 8.62 (s, 1H), 8.03 (s, 1H), 7.73 (d, 1H), 7.6 (d, 1H), 7.5 (s, 1H), 5.25 (d, 1H), 4.45 (d, 1H), 4.3 (dd, 1H), 3.55 (dd, 2H), 2.8 (m, 1H), 2.7 (m, 2H), 2.5 (s, 3H), 2.45 (s, 3H), 2.4 (m, 1H). Separation by chiral HPLC provided enantiomers II-114a-b.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[K+].CCO>[CH:20](=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 87.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.505 g, 1.97 mmol) was reacted with benzaldehyde (0.312 g, 2.94 mmol) in 3.0 mL of 4% KOH in EtOH overnight at room temperature to afford 0.596 g (88%) of the title compound as a cream-colored solid: CI-MS m/e 344 (M+), 345 (M+ +1);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH2:28][CH2:27][CH:26]([N:29]2[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]2)[CH2:25]1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH:26]3[CH2:27][CH2:28][N:24]([CH3:23])[CH2:25]3)[CH:33]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CN1CCC(n2cc(N)cn2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CN1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1
Reaction time: 2 h
Yield: 7 %

Procedure:
A stirred solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.085 g, 0.25 mmol), 1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-amine A24 (0.046 g, 0.278 mmol) and TsOH (0.003 g, 0.02 mmol) in 1,4-dioxane (4 mL) was stirred at 120° C. in the microwave for 60 minutes followed by 150° C. for 2 hours and then 160° C. for 2 hours. After cooling, the solvent was removed to afford a crude red oil that was purified by flash chromatography (0-30% MeOH in DCM) followed by HPLC (Gradient: 20-100%, Acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) to give the title compound 21 as a clear gum (0.008 g, 7% yield). LCMS-C: rt 4.34 min; m/z 466 [M+H]+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([F:4])[F:3].[N+:12]([O-])([OH:14])=[O:13]>C([O-])(=O)C.[Na+]>[N+:12]([C:8]1[CH:9]=[CH:10][C:5]([C:2]([F:3])([F:4])[F:1])=[CH:6][C:7]=1[OH:11])([O-:14])=[O:13]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Reaction time: 1 h

Procedure:
The subtitle compound was prepared by using 3-(1,1,1-trifluoromethyl)phenol (5.0 g) which was cooled to 0 C and 65% nitric acid (6 ml) was added dropwise. After the addition, the mixture was kept at 0 C for 1 hour. This was diluted with saturated sodium acetate solution, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 3.67 g
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:52]([Mg]Br)[CH3:53]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]([OH:51])[CH2:52][CH3:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)CC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 1k (0.3 g, 0.43 mmol, obtained from the synthetic method described in step 10 of example 1) in anhydrous tetrahydrofuran (10 mL) was added dropwise ethylmagnesium bromide (1.7 mL, 1.7 mmol, 1M) at 0° C. The mixture was stirred at room temperature for 16 hours, quenched with 2 mL of saturated aqueous ammonium chloride, and extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (5 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 3a as colorless oil (48 mg, 16.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.40 (m, 1H), 7.31 (m, 10H), 7.18 (m, 5H), 7.07 (m, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 4.93 (m, 2H), 4.77 (m, 2H), 4.29 (d, 1H), 4.21 (d, 1H), 4.03 (m, 3H), 3.96 (m, 4H), 3.81 (m, 1H), 3.65 (m, 2H), 2.23 (d, 1H), 1.51 (m, 2H), 1.38 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])[CH:16]=3)=[N:12][C:11]=2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:5]1([CH2:4][O:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[O:19][N:18]=[C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH3:23])[CH:16]=4)=[N:12][C:11]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
(Bromomethyl)cyclopropane (0.388 mL) was added to a mixture of tert-butyl [(1S)-2-{[5-(5-hydroxy-1,3-benzoxazol-2-yl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate (500 mg), potassium carbonate (552 mg) and DMF (13 mL), and the mixture was stirred at 60° C. for 5 hr. The solvent was evaporated under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane-ethyl acetate to give the title compound (510 mg).