Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Mg][CH2:3][CH:4]=[CH2:5].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:13]3[O:14][CH:12]3[C:11]=2[CH:22]=1>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C@@H:13]([CH2:5][CH:4]=[CH2:3])[C@H:12]([OH:14])[C:11]=2[CH:22]=1.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C@@H:13]([OH:14])[C@H:12]([CH2:5][CH:4]=[CH2:3])[C:11]=2[CH:22]=1
Reactant: Fc1ccc2c(c1)C1OC1c1ccccc1C2
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@@H]1c2cc(F)ccc2Cc2ccccc2[C@H]1O
Product: C=CC[C@@H]1c2ccccc2Cc2ccc(F)cc2[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %
Yield: 19 %

Procedure:
Bromo-2-propenyl-magnesium (0.0542 mol) was added dropwise to a solution of intermediate 2 (0.04956 mol) in tetrahydrofuran(120 ml) under N2 atmosphere. The reaction mixture was stirred for 30 minutes at room temperature, then stirred and refluxed for 2 hours. The reaction mixture was cooled on an ice-bath, quenched with a 20% NH4Cl solution, and extracted with ethylacetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified and separated into two regio-isomers by HPLC over silica gel (eluent: hexanes/ethylacetate 9/1). Two pure fraction groups were collected and their solvent was evaporated, yielding 4.79 g (36%) of (±)-trans-8-fluoro-10,11-dihydro-11-(2-propenyl)-5H-dibenzo [a,d]cyclohepten-10-ol (intermediate 3) and 2.52 g (19%) of (trans)-2-fluoro-10,11-dihydro-11-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate 4).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:24]([OH:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[O:17][CH2:16]2)[CH:9]=1>>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C@H:15]2[C@@H:24]([OH:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH:22]=3)[O:17][CH2:16]2)[CH:9]=1
Reactant: Oc1ccc2c(c1)C(O)C(Cc1cccnc1)CO2
Reactant: Clc1ccccn1
Product: O[C@H]1c2cc(Oc3ccccn3)ccc2OC[C@H]1Cc1cccnc1

Procedure:
By the method of Example 1, 2-chloropyridine and 3-(3-pyridylmethyl)-4,6-chromandiol were converted to present title product in like yield; mp 67-68° C.; IR(CHCl3) 1598; 1491 cm-1.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[C:13]([F:20])=[CH:12][C:5]=1[C:6]([O:8]CC#C)=[O:7].Cl>CO>[F:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[C:13]([F:20])=[CH:12][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1cc(F)c(C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a mixture of 20 ml of methanol and 20 ml of a 15% aqueous sodium hydroxide solution was added 7.3 g of 2-propynyl 2,5-difluoro-4-(2-propynyloxy)benzoate, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was added to hydrochloric acid, and a produced solid was collected by filtration. The solid was dried and then washed with hexane, and 3.8 g of 2,5-difluoro-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: C(Cl)(=O)C.C(O)C.Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.O=[C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH2:22][C:21]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Add acetyl chloride (8.5 mL, 120 mmol) to absolute ethanol (30 mL) and stir for 1 h. Add 4-methoxyphenylhydrazine hydrochloride (1.74 g, 10 mmol) and N-(4-oxo-cyclohexyl)-isobutyramide (Preparation 2) (1.83 g, 120 mmol) and reflux with stirring for 56 h. Cool to room temperature, dilute with ethyl acetate (100 mL) and wash with sodium bicarbonate solution (2×50 mL), brine, dry (MgSO4), filter and concentrate in vacuo. Dissolve the residue in dichloromethane and pass over a silica pad, eluting with 20% ethyl acetate/dichloromethane to obtain 2.32 g of a solid. Triturate the solid in diethyl ether with a small amount of dichloromethane, filter and dry under house vacuum to obtain 2.14 g (75%) of an off-white solid. MS (ES): m/z 287 (M+1), 285 (M−1); 1H NMR(DMSO-d6): δ 10.52 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.13 (d, 1H, J=8.8 Hz), 6.85 (s, 1H), 6.64 (dd, 1H, J=8.8, 2.2 Hz), 4.02 (m, 1H), 3.75 (m, 3H), 2.90 (dd, 1H, J=15.0, 5.3 Hz), 2.78 (m, 2H), 2.42 (m, 2H), 1.96 (m, 1H), 1.79 (m, 1H), 1.03 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[F:14][C:15]1[CH:32]=[CH:31][C:18]2[S:19][C:20]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)O)=[C:21]([CH3:22])[C:17]=2[CH:16]=1>>[F:14][C:15]1[CH:32]=[CH:31][C:18]2[S:19][C:20]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:4]3[C:3](=[O:7])[C:2]([CH3:1])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]=3[OH:6])=[C:21]([CH3:22])[C:17]=2[CH:16]=1
Reactant: Cc1c(C(O)c2ccccc2)sc2ccc(F)cc12
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)sc2ccc(F)cc12

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 427.5 ([M−H]−).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:13]([O:15][C:16]([C:18]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 110.1 %

Procedure:
To a stirring solution of diisopropyl amine (38.0 mmol, 3.84 g) in THF (50 mL) cooled to -78° C. was added n-butyl lithium dropwise (41.2 mmol, 16.5 mL of a 1.6M solution in hexanes). To this was added piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester (31.7 mmol, 8.16 g) in 20 mL THF. The reaction was allowed to stir for 5 min. and benzyl bromide (31.7 mmol, 5.42 g) was added. The reaction was then allowed to warm to room temperature. The reaction was then diluted with ethyl acetate (200 mL) and washed with 10% KHSO4. The aqueous layers were extracted with ethyl acetate (100 mL). The organics were combined, washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated under reduced pressure to give 12.13 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:22]([CH3:35])=[CH:21][N:20]=2)=[C:11]([O:36][CH3:37])[CH:10]=1>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:22]([CH3:35])=[CH:21][N:20]=2)=[C:11]([O:36][CH3:37])[CH:10]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reactant: CNCCN(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 42.1 %

Procedure:
N1,N1,N2-Trimethylethane-1,2-diamine (221 mg, 2.16 mmol) was added to a suspension of N-(4-Fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 79, 400 mg, 0.98 mmol) in DMA (4 mL). The mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). This solution was washed with water (2×100 mL) and sat. brine (100 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% methanolic ammonia in CH2Cl2 gave the title compound (202 mg, 42%) as an orange dry film; m/z: ES+ MH+ 444.55.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1
Reactant: OCC1CCNCC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (89 g) in N,N-dimethylformamide (1 L) were added 4-piperidinemethanol (50 g) and potassium carbonate (60.0 g), and the mixture was stirred at room temperature for 2 hr. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained oil and triethylamine (242 mL) in dimethyl sulfoxide (1 L) was added sulfur trioxide pyridine complex (138 g), and the mixture was stirred at room temperature for 1 hr. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (85 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1.O>CN(C)C=O.ClCCl>[OH:1][CH2:2][C:3]1[N:8]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH:7]=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([O:19][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2cn(Cc3ccc(OC)cc3)c(CO)cc2=O)cc1
Product: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a suspension of 2.613 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 100 ml of dimethyl-formamide were added sequentially 2.073 g of potassium carbonate and 2.35 g of p-methoxybenzyl chloride, and the mixture is stirred at room temperature for 40 hours. The reaction mixture is added to 200 ml of water and 400 ml of dichloromethane, and the organic layer is washed with 200 ml of water. The organic layer is dried over anhydrous magnesium sulfate, condensed under reduced pressure and subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroformmethanol (20:1) to perform separation and purification. 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-1-(p-methoxybenzyl)-4-pyridone and 6-hydroxymethyl-3,4-bis[(p-methoxybenzyl)oxy]-pyridine are obtained as colorless crystals in amounts of 1.749 g and 1.527 g, respectively. 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-1-(p-methoxybenzyl)-4-pyridone;
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:28])([F:27])[F:26])=[N:4][N:5]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[CH:6]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:26])([F:27])[F:28])=[N:4][N:5]([C:7]2[CH:12]=[C:11]([S:13]([CH2:14][C:15]([F:18])([F:17])[F:16])=[O:40])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[CH:6]=1
Reactant: Cc1cc(F)c(-n2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
0.24 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 0.11 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.21 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:15]3)C3C(=CC=CC=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:43]([NH2:46])[CH2:44][CH3:45]>>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:46][CH2:43][CH2:44][CH3:45])=[O:41])[CH2:15]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCN
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Product: CCCNC(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Yield: 93 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]pentanoic acid (0.09 g, 0.16 mmol) prepared in Example 128 and n-propylamine (52 μl), the same procedure as shown in Example 129 was repeated to give the titled compound (0.09 g, overall yield: 93%) as a white powder (cis:trans=5:2).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[OH:9])[CH2:4][CH2:3]1.BrCC1C=C[C:26]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=CC=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:34][N:32]1[N:31]=[N:30][C:29]([CH2:26][N:2]2[CH2:7][CH2:6][CH:5]([CH:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=3)[OH:9])[CH2:4][CH2:3]2)=[N:33]1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(CN2CCC(C(O)c3ccc(OC(F)(F)F)cc3)CC2)n1

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 3, using 7.0 grams (0.026 mole) of 4-piperidyl[4-(trifluoromethoxy)phenyl]methanol, hydrochloride, 6.8 grams (0.026 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetraazole (prepared in a manner analogous to that of Steps A–C of Example 4), and 9.9 grams (0.077 mole) of N,N-diisopropylethylamine in about 40 mL of DMSO. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1)(=O)[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37]>COCCO>[CH2:10]([C:9]1[CH:8]=[C:7]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[N:37]=[C:36]([NH2:38])[N:35]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CC(=O)c1cn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCc1cc(-c2c[nH]c3ncccc23)nc(N)n1

Procedure:
1.2 278 mg (2.0 mmol) of sodium carbonate are added to a solution of 314 mg (0.96 mmol) of tert-butyl 3-hept-2-inoylpyrrolo[2,3-b]pyridine-1-carboxylate and 130 mg (0.72 mmol) of guanidine carbonate in 2 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 24 hours. After cooling, the mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed using preparative HPLC, giving 4-butyl-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamine (“A1”) as colourless solid; ESI 269;
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Cl[C:15]([C:25]1[CH:26]=[N:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:29][CH:30]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[CH3:34][C:31]([C:28]1[N:27]=[CH:26][C:25]([CH:15]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:30][N:29]=1)([CH3:32])[CH3:33]
Reactant: CCOC(=O)C(Cl)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Temperature: 25 °C
Yield: 88.3 %

Procedure:
Tri-n-Butyl tin hydride (1.3 cm3) was added to a solution of ethyl (RS)-2-chloro-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (1.4 g) and a catalytic amount of 2,2'-azobisisobutyronitrile in dry toluene (10 cm3). The mixture was heated to the reflux temperature for a period of 11/2 hours, after which it was cooled to the ambient temperature, poured into water, and extracted into ethyl acetate. After concentration by evaporation of the solvent under reduced pressure, the residue was subjected to column chromatography on silica gel using hexane followed by ethyl acetate as eluent to give ethyl (RS)-2-[2-(1,1-dimethyl-ethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (1.1 g) as a pale yellow liquid, the spectral data of which were identical to those obtained for the sample generated in Example 9.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69]([N:70]3[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]3)[C:64]=2[S:63][CH:62]=1.CC1(C)C(C)(C)OB([C:85]2[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=2)O1>>[CH3:76][N:73]1[CH2:74][CH2:75][N:70]([C:69]2[C:64]3[S:63][CH:62]=[C:61]([C:85]4[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=4)[C:65]=3[N:66]=[CH:67][N:68]=2)[CH2:71][CH2:72]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CN1CCN(c2ncnc3c(Br)csc23)CC1
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CN1CCN(c2ncnc3c(-c4ccc(O)cc4)csc23)CC1

Procedure:
The compound 79B was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 79A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.85-7.89 (m, 2H), 6.48-6.88 (m, 2H), 4.06 (br, 4H), 2.91 (br, 4H), 2.53 (s, 3H). ESI (+)/MS: 327 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:11]=[CH:12][CH:13]=1>CO>[Br:7][C:8]1[CH:9]=[C:10]([C:14]#[CH:15])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(Br)c1

Procedure:
To each of 2 one-liter flasks were charged K2CO3 (68 g, 493 mmol), a large magnetic stirbar and MeOH (250 mL). Stirring was begun on both reaction mixtures and once it was satisfied that they were stirring without any problems, 3-bromophenyltrimethylsilylacetylene (12.5 g, 49.3 mmol, 10.5 mL) was added to each reaction vessel and the mixtures were refluxed overnight. The reaction mixtures were filtered and the filter cakes were washed with MeOH. The combined filtrate was concentrated in vacuo, diluted with hexanes, and washed with water twice. The organic layer was concentrated to give a yellow oil. Flash chromatography (SiO2, Hexanes), provided 9.1 g, 50%, of the title compound as a colorless to light yellow oil. 1H NMR 500 MHz (CDCl3) δ 3.08 (s, 1H); 7.16 (t, 1H, J=7.89 Hz); 7.38 (dt, 1H, J=7.77 Hz, 2.44 Hz); 7.44-7.47 (m, 1H); 7.61 (t, 1H, J=1.68 Hz).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:12][C:13](=[O:27])[CH:14](OC(=O)C)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:10][CH3:11].CCOCC>O>[CH2:8]([O:12][C:13](=[O:27])[CH:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:10][CH3:11]
Reactant: [Li]c1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
A solution containing 2.4 mmol. of phenyl lithium in benzene-ether was added dropwise at -78° under argon to a solution of 700 mg. (2.4 mmol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 15 ml. of dry ether. The mixture was stirred for 2 hours at -78°, then for 1 hour at 25°. The mixture was diluted with water, the layers were separated and the ether layer was washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel with methylene chloride to give a crude product which was rechromatographed on basic alumina to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:21])=[O:20])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(OCC)(=O)C>[ClH:21].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:1][CH2:2][CH2:3][NH:4][CH3:5])=[O:20])=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)c1ccc(OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.1 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1 and ethyl acetate (10 mL) were added 4-methoxybenzoyl chloride (1.88 g) and pyridine (0.97 mL). After stirring at room temperature for 14 hrs, 4-methoxybenzoyl chloride (0.70 g) and pyridine (0.97 mL) was further added, and stirred at room temperature for 1 hr. To the reaction solution was added ethyl acetate (80 mL), and washed sequentially with water (20 mL), saturated aqueous solution of sodium bicarbonate (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (10 mL), followed by adding 4N hydrogen chloride-ethyl acetate solution (10 mL). After stirring at room temperature for 1 hr, diethyl ether (20 mL) was added, and the depositting solid was collected by filtration. The solid was washed twice with ethyl acetate (15 mL), and dried at 60° C. under reduced pressure to give title compound as white solid (1.99 g).