Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)[O:13][CH2:12]1.[Cl-].[NH4+]>C1COCC1.C(O)C.[Pd]>[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][CH:17]([C:3]3[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=3)[CH2:16][CH2:15]2)[O:13][CH2:12]1
Reactant: O=C1CCCCC12OCCO2
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1cc(F)cc(C2CCC3(CC2)OCCO3)c1
Reaction time: 5 h
Yield: 54.5 %

Procedure:
A Grignard reagent prepared from dried magnesium and 50 g (0.26 mol) of 1-bromo-3,5-diflorobenzene in THF was added dropwide at room temperature to a solution of 34 g (0.22 mol) of cyclohexanedion monoethylene ketal in 500 ml of THF and the mixture was stirred for 5 hours. The reaction solution was added to 500 ml of a saturated ammonium chloride and the mixture was stirred. The reaction product was extracted with ether. The extract was dried over magnesium sulfate and the solvent was distilled off. The residue and 2 g of p-toluenesulfonic acid were added to 300 ml of toluene, and the mixture was refluxed for 3 hours, while removing the produced water using Dean-Stark. The reaction solution was washed successively with water, a saturated aqueous sodium carbonate and water, dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (eluting solvent: heptane/ethyl acetate=3/1), and the solvent was distilled off under reduced pressure. The residue thus obtained was hydrogenated in ethanol in the presence of 2 g of 5% palladium/carbon. The catalyst was filtered off and then the solvent was distilled off to afford 31 g (0.12 mol) of 4-(3,5-difluorophenyl)-cyclohexanone mono-ethylene ketal.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:30])[O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH:17][C:18]2[N:23]=[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:21]=[C:20](Cl)[N:19]=2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:32][CH2:33][CH3:34].O1CCCC1>O>[C:1]1([C:7]2[C:8](=[O:30])[O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH:17][C:18]2[N:23]=[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:21]=[C:20]([N:35]([CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:31][CH2:32][CH2:33][CH3:34])[N:19]=2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCNCCCCO
Reactant: CCN(CC)c1nc(Cl)nc(Nc2ccc3cc(-c4ccccc4)c(=O)oc3c2)n1
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCCO)c1nc(Nc2ccc3cc(-c4ccccc4)c(=O)oc3c2)nc(N(CC)CC)n1

Procedure:
21.1 Parts of 3-phenyl-7-[(6-chloro-4-diethylamino-s-triazine-2-yl)amino]coumarin and 14.2 parts of N-butylamino-4-butanol were added to 20 parts of tetrahydrofuran and reacted for 6 hours under reflux. The reaction product was poured into water, and the crystals thus precipitated were collected by filtration. The product was recrystallized from a mixed solvent of chloroform:ethyl acetate (1:1 by volume) to obtain 20 parts of 3-phenyl-7-[[6-(4-hydroxybutylbutylamino)-4-diethylamino-s-triazine-2-yl]amino]coumarin. The resulting compound had a melting point of from 124° to 126° C.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>ClCCCl.C(Cl)Cl>[C:42]([NH:46][C:7]1[CH:8]=[C:3]([CH:2]([F:10])[F:1])[CH:4]=[CH:5][N:6]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: [O-][n+]1ccc(C(F)F)cc1
Reactant: CC(C)(C)N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1cc(C(F)F)ccn1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 64.9 %

Procedure:
A suspension of 4-difluoromethyl-pyridine-N-oxide (4.95 g, 34.1 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (20.7 g, 44.3 mmol), triethylamine (15.6 mL, 111 mmol), and anhydrous tert-butylamine (4.6 mL, 43 mmol) in DCE (100 mL, 0.33 M) was sealed in pressure tube and stirred at 100° C. for 3.5 hr. After cooling to rt, the mixture was diluted with CH2Cl2 and washed with sat. aq. NaHCO3. The organics were dried over MgSO4 and following concentration, the reaction residue was purified by flash column chromatography (100:0-80:20 heptanes/EtOAc) to afford N-tert-butyl-4-(difluoromethyl)pyridin-2-amine as a yellow liquid (4.43 g, 65%); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=5.2 Hz, 1H), 6.65-6.28 (m, 3H), 4.62 (br s, 1H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[OH:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[ClH:39]>O.CN(C)C=O>[ClH:1].[ClH:39].[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][CH2:7][C@@H:6]([OH:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[S:11][C:10]=2[CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc2c(c1)SC(CCCCl)C(O)CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S[C@H](CCCN1CCN(c3ccccc3)CC1)[C@H](O)CO2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol (500 mg), N-phenylpiperazine (500 mg), potassium iodide (50 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C for 8 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate-methanol=10:10:1), and a colorless oil obtained was converted to hydrochloride and recrystallized from methanol-acetone to give a white powder of cis 7-methoxy-4-[3(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol dihydrochloride obtained in Reference Example 26.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][CH:7]([S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][CH:37]=1)[CH2:17][NH:18][C:19]([C:21]1[C:22](C)=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[N:25][CH:26]=1)=[O:20])(=[O:11])=[O:10])[CH3:8]>>[CH3:8][CH:7]([S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][CH:37]=1)[CH2:17][NH:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[N:25][CH:26]=1)=[O:20])(=[O:10])=[O:11])[CH3:6]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NCc1cccc(CNS(=O)(=O)C(C)C)c1
Agent: CS(=O)(=O)Cl
Product: CC(C)S(=O)(=O)NCc1cccc(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)c1

Procedure:
Following procedures similar to those of Example 72 (step 2) but substituting isopropanesulfonyl chloride (1.3 mmol) for methanesulfonyl chloride there is prepared 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-[(propane-2-sulfonylamino)-methyl]-benzylamide (7 mg) as a solid. MS: 443 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.20 (d, J=6.8 Hz, 6H), 3.05 (m, 1H), 4.17 (d, J=6.4 Hz, 2H), 4.55 (d, J=5.9 Hz, 2H), 7.27-7.62 (m, 5H), 8.17 (m, 1H), 8.32 (m, 1H), 9.32 (s, 2H), 9.45 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[C:11]2[C:3]1=[C:4]1[C:9]([CH2:10]2)=[CH:8][C:7]([CH3:20])([CH3:19])[CH2:6][CH2:5]1.C([Li])CCC.[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[Si:42](Cl)([CH2:45][CH3:46])[CH2:43][CH3:44])[CH:28]=[CH2:29].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[Si:42]([CH:10]1[C:9]2[C:4]([CH2:5][CH2:6][C:7]([CH3:20])([CH3:19])[CH:8]=2)=[C:3]2[C:11]1=[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]1=[CH:14][C:2]2([CH3:21])[CH3:1])([CH2:43][CH3:44])[CH2:45][CH3:46])[CH:28]=[CH2:29]
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Reactant: CC1(C)C=C2CC3=c4ccccc4=CC(C)(C)C3=C2CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1C2=CC(C)(C)CCC2=C2C1=c1ccccc1=CC2(C)C
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
There was dissolved 2.50 g (8.98 mmol) of 6,6,9,9-tetramethyl-6,7,8,9-tetrahydrobenzofluorene in 56 mL of THF, and the obtained solution was cooled down to −78° C. To the solution, 5.68 mL of a 1.58 M-concentration hexane solution of n-butyllithium was added slowly, 5.68 mL of said hexane solution containing 8.98 mmol of n-butyllithium. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3.5 hours at a room temperature. The mixture was cooled down to −78° C., and a solution of 2.92 g (8.98 mmol) of (2-allyloxy-3-tert-butyl-5-methylphenyl) chlorodiethylsilane in 12 mL of toluene was added to the mixture. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3 hours, thereby obtaining a reaction solution. A mixture of 25 mL of a 10% aqueous solution of sodium hydrogen carbonate and 25 mL of a 10% aqueous solution of sodium carbonate was added to the reaction solution at 0° C. To the obtained mixture, 29 mL of toluene was added, and the mixture was separated to the toluene solution and the aqueous solution. The toluene solution was dried over sodium sulfate, and the mixture was filtered. The obtained filtrate was concentrated under a reduced pressure, thereby obtaining quantitatively (2-allyloxy-3-tert-butyl-5-methylphenyl)(6,6,9,9-tetramethyl-6,7,8,9-tetrahydrobenzofluoren-11-yl)diethylsilane.
Reaction SMILES: CO[C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: CN
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 62, Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is added a 2.0 M solution of methylamine in MeOH (2.0 mL). This mixture is stirred for 30 min at which time the reaction is concentrated under reduced pressure, washed with ethyl ether (6 mL) and filtered to give the title compound as a white solid (190 mg, 95%), 1H NMR (300 MHz, DMSO) δ 8.38 (d, 1H), 7.63 (d, 1H), 7.46 (dd, 1H), 7.27 (d, 1H), 5.05 (dd, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H), 2.65 (d, 3H); MS for C14H15N3O4SMS m/z 322.5 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([CH2:8][C:9]#[N:10])=O.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[C:9]([NH2:10])[O:23][N:22]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: N#CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(-c2cccc(C(F)(F)F)c2)no1
Temperature: 25 °C

Procedure:
3-(Trifluoromethyl)benzoylacetonitrile (3.8 grams) and 125 ml. ethanol were placed in a 500 ml. flask. The solution was treated with sodium acetate (12 grams) and hydroxylamine.hydrochloride (9 grams in 125 ml. water) and then heated to reflux for two hours. After cooling to room temperature, the ethanol was removed and the residue extracted with ether. The ether extracts were then washed with water, brine, and dried with MgSO4. The solid residue obtained was recrystallized from an ethanol/water solution, m.p. 89°-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18](=O)[CH3:19])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:17]=[C:18]([CH3:19])[N:1]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:29])[CH3:13]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(=O)OC)c2)c1-c1ccccc1

Procedure:
Methyl 3-aminobenzoate (10 mmol, 1.4 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was purified over silica gel and crystallized upon standing, 1H-NMR (CDCl3, ppm): 1.15 t (3H), 2.08 s (3H), 3.88 s (3H), 4.05 q (2H), 6.56 s (1H), 7.15-7.33 bm (7H), 7.79-7.97 bm (2H).
Reaction SMILES: [F:1][C:2]1(F)[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].ClC1C=CC=CC=1C>[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(F)(F)CCC12
Agent: [Pd]
Solvent: Cc1ccccc1Cl
Product: O=C1OC(=O)c2cc(F)ccc21
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of 500 parts of 4,4-difluorohexahydrophthalic anhydride and 100 parts of 5 percent Pd/C catalyst in 3787 parts of o-chlorotoluene was charged to an autoclave reactor. The autoclave atmosphere was purged with nitrogen. The autoclave when then sealed, heated to 300°-350° and maintained thereat for about 3 hours, then cooled to about room temperature. Analysis of the reaction product, by gas chromatographic techniques indicated a 37 percent yield of 4-fluorophthalic anhydride, based on the difluorohexahydrophthalic anhydride reactant.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].C[Sn+](C)C>ClCCCl>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:20]=[N:21][CH:22]=[C:8]2[CH:7]=[N:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 85 °C
Yield: 97.6 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (140 mg, 0.34 mmol) in anhydrous 1,2-dichloroethane (2.5 mL) was added trimethyltin hydroxide (215 mg, 1.19 mmol, 3.5 eq.). The reaction mixture was heated at 85° C. for 1 hour and then cooled to RT. The reaction mixture was concentrated in vacuo, and the crude residue was diluted with ethyl acetate. The organic layer was washed with 1N HCl (3×), water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization from dichloromethane ether hexane afforded the title compound as a yellow solid (132.1 mg, 97.7%). 1H NMR (MeOD, 400 MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=10.13, 1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H); LCMS (method D1): RT=0.77 min, [M+H]+=399.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc(I)cc1OC(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OC(C)C
Yield: 99.4 %

Procedure:
A mixture of methyl 4-iodo-2-isopropoxybenzoate (4.10 g), (2,4-difluorophenyl)boronic acid (4.04 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.789 g), a 2 M aqueous sodium carbonate solution (19.2 mL), tris(dibenzylideneacetone)dipalladium(0) (0.821 g), and toluene (50 mL) was stirred at 100 C for 2 hours. The reaction mixture was poured to water at room temperature, and the mixture was passed through celite, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.90 g)
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([N:6]3C(OC(C)(C)C)=O)[CH2:4]1)[CH2:10]2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:7]12[CH2:12][C:3]3([CH2:2][OH:1])[CH2:10][CH:9]([CH2:11][CH:5]([CH2:4]3)[NH:6]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(CO)(C3)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCC12CC3CC(C1)NC(C3)C2
Reaction time: 4 h
Yield: 97 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer tert-butyl 5-(hydroxymethyl)-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-15 (0.12 g, 0.45 mmol) in DCM (5 mL) was added. The reaction mixture was cooled to 00° C. followed by addition of trifluoroacetic acid (0.26 g, 2.2 mmol). This mixture was stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-16 (0.12 g, yield=97%) as an oily mass.
Reaction SMILES: [OH:1][C:2]1([C:14]([F:17])([F:16])[F:15])[C:11]2[C:6](=[C:7]([O:12]C)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.B(Br)(Br)Br>>[OH:1][C:2]1([C:14]([F:16])([F:15])[F:17])[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1
Reactant: COc1cccc2c1C(=O)OC2(O)C(F)(F)F
Agent: BrB(Br)Br
Product: O=C1OC(O)(C(F)(F)F)c2cccc(O)c21

Procedure:
The title compound can be prepared analogously to the above Example (133) from 3-hydroxy-7-methoxy-3-trifluoromethyl-phthalide (see Example 133) and boron tribromide; m.p. 128°-1290° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1I)[CH3:2].[CH3:14][N:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][C:16]1=[O:30].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:19]1[CH:18]=[CH:17][C:16](=[O:30])[N:15]([CH3:14])[CH:20]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CCc1ccc(S(C)(=O)=O)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(S(C)(=O)=O)cc1-c1ccc(=O)n(C)c1
Yield: 97.1 %

Procedure:
The title compound of step 3 (62 mg, 0.2 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (57 mg, 0.24 mmol), K2CO3 (82 mg, 0.6 mmol), Pd(dppf)Cl2 (6.2 mg) in 1,4-dioxane/water (4:1) (5 mL) were heated at 85° C. under N2 overnight. Silica gel chromatography (PE:EA=1:1) gave the title compound (56.6 mg, 97%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.66 (3H, t, J=6.0 Hz), 2.63-2.71 (2H, m), 3.05 (3H, s), 3.60 (3H, s), 6.64 (1H, d, J=9.0 Hz), 7.28-7.33 (2H, m), 7.48 (1H, d, J=9.0 Hz), 7.70 (1H, s), 7.82-7.85 (1H, m). LCMS: 292 (M+1)+
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([OH:28])=O)[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][C@@H:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([NH:30][C@@H:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: COC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (S)-methyl 2-aminopropanoate hydrochloride (6.10 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=449.3 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:16]2[C:17]3[C:23](=O)[NH:22][CH2:21][CH2:20][CH2:19][C:18]=3[N:14]3[C:15]=2[C:10]([CH2:11][CH2:12][CH2:13]3)=[CH:9][CH:8]=1.O.[OH-].[Na+]>O1CCOCC1>[CH:7]1[C:16]2[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][CH2:19][C:18]=3[N:14]3[C:15]=2[C:10]([CH2:11][CH2:12][CH2:13]3)=[CH:9][CH:8]=1
Reactant: O=C1NCCCc2c1c1cccc3c1n2CCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CCC2)CCCNC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a suspension of LiAlH4 in 1,4-dioxane (26 mL) was added 5,6,8,9,10,11-hexahydro-4H, 12H-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinolin-12-one (300 mg, 1.25 mmol) under N2 at 20° C. The reaction mixture was refluxed for 15 h. The reaction mixture was cooled in an ice bath and added successively with H2O (0.3 mL), 15% NaOH (0.3 mL) and H2O (0.8 mL). The mixture was stirred for 1 h at 20° C. then filtered. The filtrate was concentrated in vacuo. The residue was dissolved in dilute AcOH and washed with Et2O. The aqueous solution was basified with 1N NaOH. A white solid was precipitated and filtered to yield 5,6,9,10,11,12-hexahydro-4H,8H-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (270 mg, 95%).
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C([C@@H]1CCCNC1)N1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@@H](C(=O)N3CCOCC3)C2)CC1
Yield: 69 %

Procedure:
(3R)-Morpholin-4-yl-piperidin-3-yl-methanone (2.25 g, 11.4 mmol) was reacted with tert-butyl 4-oxo-1-piperidinecarboxylate (1 eq., 2.27 g) under conditions analogous to those described above for the preparation of Intermediate 1 to give (3R)-3-(morpholine-4-carbonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (3.00 g, 69%).
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1
Reactant: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(CBr)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a stirred (0° C.) solution of 0.750 g (2.31 mmol) of the product of Step G, and 0.949 g (2.86 mmol) of carbon tetrabromide dissolved in 7 mL of methylene chloride was added 0.751 g of triphenylphosphine (2.86 mmol) in portions. After the addition was complete, the reaction mixture was stirred and allowed to warm to room temperature over 1 hour. The reaction mixture was then evaporated in vacuo, and the residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.703 g (78%) of the title compound.