Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:12][N:13]([CH3:15])[CH:14]=3)=[C:4]2[CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[N:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[CH2:38][CH2:37]1>>[CH3:15][N:13]1[CH:14]=[C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:2]([C:45]4[CH:44]=[N:43][C:42]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[N:47][CH:46]=4)=[CH:3][C:4]=23)[C:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12]1
Reactant: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ncc(-c3cc4c(-c5cn(C)nc5-c5ccc([N+](=O)[O-])cc5)ccnc4n3S(=O)(=O)c3ccccc3)cn2)CC1

Procedure:
Following the procedure described for Intermediate 241 using 2-iodo-4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine and 2-(4-methyl-1-piperazinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine provided the title compound. ESMS [M+H]+: 636.0.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3][CH2:2]1.C1(NC(C2NC=C(C(C3C(C4C=CC=C([F:55])C=4)=NOC=3C)=O)C=2)=O)CCC1>>[CH:4]1([NH:5][C:6]([C:8]2[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:55])[CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH2:1]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1cc(C(=O)NCC2CC2)n(C)c1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCC2)c1
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)c1cc(C(=O)NC2CCC2)n(C)c1
Yield: 34.2 %

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid cyclobutylamide (example 174) in 34.2% yield as white solid. (m/e): 382.1 (M+1; 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].C[CH:18]([C:22](=O)[CH3:23])[C:19](=[O:21])C>>[CH3:23][C:22]1[CH:18]=[C:19]([OH:21])[C:12]2[C:11](=[C:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH:15]=[CH:14][CH:13]=2)[N:16]=1
Reactant: CC(=O)C(C)C(C)=O
Reactant: Cc1cc(C)c(-c2ccccc2N)c(C)c1
Product: Cc1cc(C)c(-c2cccc3c(O)cc(C)nc23)c(C)c1
Temperature: 170 °C

Procedure:
A mixture of 2′,4′,6′-trimethyl-biphenyl-2-ylamine(607 mg, 2.88 mmol) and methyl acetylacetone (607 mg, 5.75 mmol) in polyphosphoric acid (3 ml) was heated in 170° C. oil bath for 2.5 hours. The mixture was quenched with water and extracted twice with chloroform. The organic layer was washed with brine, dried and concentrated to give the title compound as an oil. The oil was pumped in vacuo, then trituated with a mixture of ether and hexane to give 642 mg (81%) of the title compound as a beige solid. The solid was recrystallized from ethyl acetate to give a beige solid, mp>250° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(C)c(N)c(Br)c1
Reactant: OB(O)c1ccccc1
Product: Cc1cc(C)c(N)c(-c2ccccc2)c1
Yield: 68 %

Procedure:
2-Bromo-4,6-dimethylaniline was coupled with phenyl boronic acid under Suzuki conditions to give 2-amino-3,5-dimethylbiphenyl in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:5].[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[CH2:23][CH:22]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])[CH2:21][CH2:20]2>>[CH3:1][O:2][C:3](=[O:15])[C:4]([N:6]1[CH:10]=[C:9]([NH:11][C:30](=[O:31])[CH:29]([NH:28][CH:22]2[CH2:21][CH2:20][C:19]3[C:24](=[C:25]([F:27])[CH:26]=[C:17]([F:16])[CH:18]=3)[CH2:23]2)[CH2:33][CH2:34][CH3:35])[N:8]=[CH:7]1)([CH3:14])[CH3:5]
Reactant: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid to afford the title compound; MS 449.3 m/z (M+1).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:9]1([CH2:14][CH2:15][OH:16])[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:16][CH2:15][CH2:14][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCn1ccnc1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCCn1ccnc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In a nitrogen atmosphere, 148 g of caproyl chloride was added dropwise to a mixture of 112 g of 2-(1H-imidazol-1-yl)ethanol, synthesized in Synthesis Example 1, 121 g of triethylamine and 1,000 g of methylene chloride at 0° C. Then the reaction mixture was heated at 20° C. and stirred for 5 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by vacuum distillation, obtaining 189 g of 2-(1H-imidazol-1-yl)ethyl caproate (boiling point 127° C./20 Pa, yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2.Cl[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[C:34]([CH2:33][CH:14]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:31])=[CH:25]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])#[N:35]
Reactant: N#CCCl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC(CC#N)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A mixture of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (419 mg, 1 mmol), (prepared as described in Example 70), in DMF (6 ml) containing chloroacetonitrile (114 mg, 1.5 mmol), potassium carbonate (346 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol) was stirred at ambient temperature overnight. The mixture was poured into water and the precipitate was filtered, washed with water and dried under vacuum. The residue was purified by column chromatography, eluting with methylene chloride, followed by methylene chloride/methanol (98/2 and 95/5). After removal of the solvent under vacuum, the residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (304 mg, 66%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22](N(OC)C)=[O:23])[CH2:16][CH2:15]2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]#[N:43])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[CH3:44][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH2:21][CH:22]([OH:23])[CH3:44])[CH2:18][CH2:19]2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.74 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.27 g, 98%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2[S:18]([NH:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[CH3:28])(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:8]3[NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(N)cccc23)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NC(=O)C(C)C)cccc23)c1C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Isobutyryl chloride (0.144 mL, 1.38 mmol) was added dropwise to a solution of Example 3 (0.350 g, 1.10 mmol) in pyridine (1 mL) and acetone (7 mL). The mixture was stirred for 2.5 hours and the acetone was removed under vacuum to leave a thick brown residue, which was added dropwise to half-saturated sodium hydrogen carbonate (30 mL). The pH of the resulting mixture was adjusted to 8-8.5 with saturated sodium hydrogen carbonate. The crude product was precipitated by acidifying the solution to pH 1.5 with 6N hydrochloric acid, filtered and dried. Recrystallization from methanol/water afforded 51% of a solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@@H:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][C@H:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@H]1CCC[C@@H](c2cccnc2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CCC[C@@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 93 °C
Reaction time: 9 h
Yield: 13.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (457 mg, 1.65 mmol), cis-3-(3-pyridyl)cyclohexylamine (348 mg, 1.97 mmol) and diisopropylethylamine (0.63 mL, 3.63 mmol) in anhydrous DMSO (8 mL) was stirred at 93° C. for 9 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(3-pyridyl)cyclohexylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (96.0 mg, 13%) as a yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](F)=[N:15][CH:16]=1>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:15][CH:16]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(Br)cn1
Temperature: 30 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
3-(Dimethylamino)propan-1-ol (3.09 g, 29.95 mmol) was added to a mixture of sodium hydride (2.4 g, 60.00 mmol) in DMF (50 mL) over a period of 20 min at r.t. 5-Bromo-2-fluoropyridine (5.81, g, 33.01 mmol) was added and the resulting solution stirred for 4 h at 30° C. The reaction was then quenched by the addition of a sat. aqueous solution of ammonium chloride and the resulting mixture concentrated under vacuum. The residue was purified by FCC, eluting with DCM/MeOH in Et2O (10:1) to afford the desired material (5.2 g, 67%) as yellow oil. Mass Spectrum: m/z (ES+)[M+H]+=259.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][C:2]1=[O:12].[BrH:13].C(O)(=O)C>O>[Br:13][CH2:4][CH2:5][C:6]1([CH2:1][C:2]([OH:3])=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Br
Reactant: O=C1CC2(CCCCC2)CCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC1(CCBr)CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 3-oxaspiro[5.5]undecan-2-one (16.9 g)was added a 30% hydrogen bromide/acetic acid solution (75 mL). The reaction solution was stirred at room temperature for 48 hours. Water was added to the solution, and the crystals thus separated were recovered by filtration and washed with water. The resulting crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give crude crystals. The crude crystals thus obtained were recrystallized from ethyl acetatehexane to give the title compound (20.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 4-(4-chlorophenyl)cyclohexanecarboxylic acid (0.5 g, 2.095 mmol) in methanol (10 mL) was added one drop of conc. sulfuric acid. After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate and washed with water, saturated sodium bicarbonate and brine. It was then dried over anhyd. magnesium sulfate, concentrated and dried in vacuo to yield methyl 4-(4-chlorophenyl)cyclohexanecarboxylate a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.23-7.30 (2H, m), 7.10-7.17 (2H, m), 3.70 (3H, s), 2.44-2.56 (1H, m), 2.36 (1H, tt, J=12.13, 3.60 Hz), 2.07-2.16 (2H, m), 1.92-2.01 (2H, m), 1.38-1.67 (4H, m).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:8](Cl)[C:9](Cl)=[O:10]>[Zn].C(O)(=O)C>[CH:2]12[CH2:8][C:9](=[O:10])[CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3]2
Reactant: C1=CCCC=C1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC2C=CCCC12

Procedure:
The starting material is prepared by the treatment of 1,3-cyclohexadiene with dichloroacetyl chloride, followed by dechlorination with zinc and acetic acid of the resulting adduct to give bicyclo [4,2,0]-oct-2-en-7-one. This compound is subjected to Baeyer-Villiger oxidation to give 7-oxabicyclo [4,3,0] non-2-en-8-one which is treated with thallium (III) nitrate under carefully controlled conditions to give 6-formyl-2-oxabicyclo [3,3,0] octane-3-one having properties identical with those reported by Corey and Ravindranathan, Tetrahedron Letters, 1971, 4753.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([CH3:9])[C:6]([OH:8])=[O:7].[H][H]>[Pt]=O.CO>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CC(=Cc1ccc(F)cc1F)C(=O)O
Agent: O=[Pt]
Solvent: CO
Product: CC(Cc1ccc(F)cc1F)C(=O)O
Reaction time: 0.5 h

Procedure:
In 800 ml. of methanol, 60 g. (0.3 mole) of 2,4-difluoro-α-methylcinnamic acid with 1.5 g. of platinum oxide catalyst is shaken under an initial pressure of 42 lbs. of hydrogen until one equivalent of hydrogen is absorbed. The reaction time is 30 minutes. The catalyst is removed by filtration and washed with methanol. The methanol, when evaporated off, leaves near colorless 2,4-difluoro-α-methyldihydrocinnamic acid as an oil which is used in the next step without further purification.
Reaction SMILES: [F:1][C@@H:2]1[C@H:9]([OH:10])[C@H:8]([OH:11])[C@H:7]([CH3:12])[O:6][C@H:3]1[O:4]C>Cl>[F:1][C@@H:2]1[C@H:9]([OH:10])[C@H:8]([OH:11])[C@H:7]([CH3:12])[O:6][CH:3]1[OH:4]
Reactant: CO[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@H]1F
Agent: Cl
Product: C[C@@H]1OC(O)[C@H](F)[C@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 93 %

Procedure:
Methy 2,6-dideoxy-2-fluoro-α-L-talopyranoside (21 mg) as prepared in Example 2 (4) given hereinbefore was dissolved in 1 ml of a mixture of 3N HCl-75% trifluoroacetic acid-water (the concentration of HCl in the whole mixture was 3N), and the resulting solution was heated at 60° C. for 1.5 hours to effect the hydrolysis. The reaction solution was then concentrated under reduced pressure to a smaller volume and the concentrated solution was admixed with a volume of water and azeotropically distilled. The residual solution was then concentrated to dryness to give 18 mg (93%) of the titled compound as a colorless solid. Specific rotation [α]D25 -21° (c 1, dioxane-water, 4:1).
Reaction SMILES: [C:1]1(=[O:13])[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[C:1]1(=[O:13])[CH:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:4]2[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCC2=C1Cc1ccccc12
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC2c3ccccc3CC12

Procedure:
3,8-Dihydrocyclopent[a]inden-1[2H]-one (7.6 g.) in ethanol (400 ml) was hydrogenated at atmospheric pressure and room temperature in the presence of 10% palladium on charcoal (0.9 g) until one molar equivalent of hydrogen had been absorbed. The catalyst was filtered off and the filtrate evaporated to dryness to give a brown gum which was distilled at 90° /0.1 torr to produce a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a 250 mL round-bottomed flask was added chloroform (60 mL) along with 2,4-dimethoxybenzoic acid (2.0 g, 10.98 mmol). The solution was cooled to 0° C. and bromine (0.566 mL, 10.98 mmol) was added dropwise over 5 minutes. The solution was allowed to warm to room temperature and stirred overnight. The resulting solid was filtered, washed with cold chloroform and dried under vacuum to give 2.49 g (8.6 mmol, 78% yield) of 5-bromo-2,4-dimethoxybenzoic acid as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1.0 mL/minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 3.95 (s, 3H), 6.78 (s, 1H), 7.86 (s, 1H). LCMS Rt=1.453 min., m/z 262.99 (M+H), 93% purity.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4c(F)cccc4F)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.053 mMol) 2,6-difluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:24]=[C:25]=[O:26]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:25]([NH:24][CH:4]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:5]2)=[O:26])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Agent: Cl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) and the corresponding isocyanate using the procedure described for compound (10).