Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:46])[N:16]2[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH2:35][C:36]3[N:41]=[CH:40][C:39]4[O:42][CH2:43][CH2:44][O:45][C:38]=4[CH:37]=3)C(=O)OC(C)(C)C)[CH2:23][CH2:22]2)=[N:11][CH:10]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C>CO>[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:46])[N:16]2[CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([NH:27][CH2:35][C:36]3[N:41]=[CH:40][C:39]4[O:42][CH2:43][CH2:44][O:45][C:38]=4[CH:37]=3)[CH2:25][CH2:26]2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To a solution of 0.66 g of tert-butyl (1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 8 mL of methanol, 8 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, the mixture was stirred for 18 hours, and then the solid was filtered off. Subsequently, the solid was suspended in 3 mL of chloroform, thereto was added 6 mL of trifluoroacetic acid at room temperature, the mixture was stirred for 2 hours, and the solvent was then distilled off under reduced pressure. The residue was charged with chloroform and water and adjusted to pH 9 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The aqueous layer was extracted with chloroform three times and combined with the organic layer, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.31 g of 7-amino-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one as a white foam.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([CH:6]=[CH:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[CH2:15][CH2:16][C:17]4[C@:22]([C:24]=3[CH2:25][CH2:26]2)([CH3:23])[CH2:21][CH2:20][C:19](=[O:29])[CH:18]=4)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].[C-:30]#[N:31].C([Al+]CC)C>>[C:30]([C@:17]12[CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C@:22]1([CH3:23])[C:24]1[CH2:25][CH2:26][C@@:27]3([CH3:28])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@H:8]([CH3:9])[CH:7]=[CH:6][C@H:4]([CH3:5])[CH:2]([CH3:1])[CH3:3])[C:14]=1[CH2:15][CH2:16]2)#[N:31]
Reactant: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Reactant: [C-]#N
Agent: CC[Al+]CC
Product: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@]1(C#N)CC3

Procedure:
1.54 g ergosta-4,8,22-trien-3-one were treated with 11.73 ml diethylaluminum cyanide solution (1 N, toluene) as described in example 58. After aqueous work up and chromatography 0.90 g 5-cyano-5α-ergosta-8,22-dien-3-one were isolated as a white solid (beside the corresponding 5β-cyano-compound).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>C(Cl)Cl>[Cl:26][C:10]1[C:11]2[CH2:16][O:15][CH2:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)COC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid which was dissolved in dry methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid which was purified by flash column chromatography (1:9 EtOAc:Hexane) to give 4-Chloro-2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]-pyrimidine (78 mg, 73%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:22][C:21]1[CH:20]=[C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:36])=[O:2])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-({3-Chloro-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (48.7 mg, 0.089 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (37 mg, 0.89 mmol) in water (3 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 34.8 mg (73%). MS m/e 531.9 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:23])[NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][O:15][C:16](=[O:23])[NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4COC(=O)NC4CCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using cyclopentyl-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: CC1(C)C(C=C[C:13]2[CH2:39][CH2:38][CH2:37]/[C:15](=[CH:16]/[CH:17]=[C:18]3/C(C)(C)C4C(N/3CCCCS(O)(=O)=O)=CC=CC=4)/[C:14]=2[O:40][C:41]2[CH:46]=[CH:45][C:44](OCCCCNCC3OC(O)C(N)C(O)C3O)=[CH:43][CH:42]=2)=[N+](CCCCS([O-])(=O)=O)C2C1=CC=CC=2.[O-]C1C=CC=CC=1.[Na+].C(=O)(OCC=CC1C=CC=CC=1)OCC>C1COCC1.[Cl-].[Na+].O>[C:15]1([CH:14]([O:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:13]=[CH2:39])[CH:16]=[CH:17][CH:18]=[CH:38][CH:37]=1
Reactant: CC1(C)C(C=CC2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: CC1(C)C(/C=C/C2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: CCOC(=O)OCC=Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
[(COD)Ir(κ2-L1)(L1)] (Ir-2) (13.8 mg, 0.0100 mmol), [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) and sodium phenoxide (232 mg, 2.00 mmol) were dissolved in 1.0 mL of THF. Ethyl cinnamyl carbonate (192 mg, 0.930 mmol) was added to the reaction mixture by syringe. After being stirred at room temperature for 2 h, the reaction mixture was poured into brine, extracted with ether, dried, filtered, and concentrated. 1H NMR analysis of the mixture indicated that the ratio of branched to linear regioisomers was 95/5. The residue was purified by flash chromatography on silica gel (1% Et2O/Hexanes) to afford 157 mg (75%) of 1-phenyl-1-phenoxy-2-propene as a viscous oil. [Rf 0.85 (5% Et2O/Hexanes)] HPLC analysis indicated an enantiomeric excess of 94% [Chiralcel® OJ-H column, eluting with 99.75/0.25 hexane/i-PrOH, 0.6 mL/min, 220 nm; major enantiomer TR, 45.4, minor enantiomer TR 55.3 min]; [α]D20=+8.9 (c 1.4, CHCl3); 1H NMR (500.13 MHz, CDCl3) δ 7.48-7.27 (m, 8H), 7.01-6.96 (m, 2H), 6.15 (ddd, J=17.2, 10.4, 5.9 Hz, 1H), 5.70 (d, J=5.9 Hz, 1H), 5.41 (d, J=17.2 Hz, 1H), 5.31 (d, J=10.4 Hz, 1H). 13C NMR (125.7 MHz, CDCl3) δ 157.9 (C), 140.1 (C), 137.9 (CH), 129.3 (CH), 128.6 (CH), 127.8 (CH), 126.6 (CH), 121.0 (CH), 116.5 (CH2), 116.2 (CH), 80.8 (CH).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:20][CH2:21]OCC>C(O)(=O)C>[CH3:13][C:10]([CH3:11])([CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[C:20]([CH3:21])[NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCOCC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)(C)C

Procedure:
10.4 g of 5,6-diamino-1-(2,2-dimethylpropyl)-2,4-(1H,3H)-pyrimidine dione (XXVIII) was refluxed in 75 ml of acetic acid for 1 hour. 50 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 11.4 g. The amide was refluxed in 50 ml of 1N NaOH for 1 hour and then neutralized with 5N HCl. Yield 7.2 g (XXXIV). NMR (see Table I).
Reaction SMILES: F[B-](F)(F)F.C[O+](C)C.[F:10][C:11]([F:48])([F:47])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:46])[C:25]([N:27]2[CH2:37][CH2:36][C@:30]3([NH:34][C:33](=O)[CH2:32][CH2:31]3)[CH2:29][C@@H:28]2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[CH3:45])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C([BH3-])#N.[Na+].Cl.C([O-])(O)=O.[Na+]>ClCCl.CO>[F:48][C:11]([F:10])([F:47])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:46])[C:25]([N:27]2[CH2:37][CH2:36][C@:30]3([NH:34][CH2:33][CH2:32][CH2:31]3)[CH2:29][C@@H:28]2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[CH3:45])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[O+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CCCN2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of trimethyloxonium tetrafluoroborate (5.39 mg, 0.036 mmol) and (5S,7R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-N-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide (Intermediate 42, 17 mg, 0.030 mmol) in Dichloromethane (DCM) (2 ml) was stirred at rt for 3 hrs. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated. The residue was dissolved in Methanol (2 ml) and to this solution, cooled to 0° C., was added Sodium cyanoborohydride (5.73 mg, 0.091 mmol). A solution of 1.25M HCl in MeOH was added maintaining the pH around 3-4 and the reaction was left stirring at rt overnight. To the solution NaHCO3 saturated solution and DCM were added and the aqueous layer was extracted with DCM. Organic layers were combined, filtered through a phase separator tube and concentrated. The crude was purified by SP4 (12M cartridge; eluting from 90%:10% to 50%:50% Cy:EtOAc). Relevant fractions were collected obtaining the title compound, (13 mg, 0.024 mmol, 78% yield); 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (s, 1H) 7.69 (s, 2H) 7.15-7.21 (m, 1H) 6.94 (dd, 1H) 6.83 (t, 1H) 5.20-5.41 (m, 1H) 4.02-4.27 (m, 1H) 3.35-3.44 (m, 1H) 3.02-3.20 (m, 2H) 2.86 (t, 1H) 2.76 (s, 3H) 2.34 (s, 3H) 1.59-2.19 (m, 8H) 1.47 (d, 3H); UPLC: Rt=0.68 mins, m/z=546 [M+H]+; HPLC: Rt=5.67 mins.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)O1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:27]2[CH:28]=[CH:29][C:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3ccccc3C#N)c2)cc1

Procedure:
N-{4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide was prepared following procedure 3 from 2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile and N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Br:22]Br>CN(C=O)C>[Br:22][C:5]1[S:1][C:2]([C:6]2([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(C2(c3nccs3)CCOCC2)cc1
Reactant: BrBr
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(c3ncc(Br)s3)CCOCC2)cc1
Reaction time: 2 h

Procedure:
To the mixture of methyl 4-(4-(thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (570 mg, 1.88 mmol) in DMF (5 mL) was added a 1M solution of bromine in DMF (1.9 mL, 1.88 mmol). After 2 hours, additional 1M solution of bromine in DMF (1.9 mL, 1.88 mmol) was added. The reaction mixture was then concentrated to half its volume and poured into water (25 mL). The resulting solid was filtered and washed with water and dried to give methyl 4-(4-(5-bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate. 1H NMR (400 MHz, dmso-d6): δ 7.99 (d, J=8.0 Hz, 2H); 7.58 (s, 1H); 7.41 (d, J=8.0 Hz, 2H); 3.87 (s, 3H); 3.91-3.84 (m, 2H); 3.73-3.68 (m, 2H); 2.63-2.59 (m, 2H); 2.41-2.37 (m, 2H); MS found for C16H16BrNO3S (m/z): 3840.3 [M++1].
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12](=[O:14])[CH3:13])[C:5]([O:7]C(C)(C)C)=[O:6].Cl>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:12](=[O:14])[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(C)=O)C(=O)O
Reaction time: 15 h
Yield: 95.8 %

Procedure:
Tertiary-butyl 2-methoxyimino-3-oxobutyrate (805 g) was dissolved in 2.8 liters of methylene chloride. Hydrogen chloride (210 g) was blown into the solution at 3° to 6° C. over 8 hours. Then, the resultant mixture was allowed to stand at 5° C. for 15 hours. The supernatant was concentrated to dryness to give 556 g of 2-methoxyimino-3-oxobutyric acid as a crystalline solid.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH:35]1([C:41]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)C3CCCCC3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (101 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. Cyclohexanecarbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (17 mg, yield 16%).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:25][C:26](=[O:37])[N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO>[CH2:30]([N:27]([CH2:28][CH3:29])[C:26]([O:25][CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:7]=1)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COC(=O)N(CC)Cc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC

Procedure:
{2′-[(Benzyl-ethyl-carbamoyloxy)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.85 mmol) was dissolved in MeOH (5 mL) and hydrolyzed with 1N aqueous NaOH (0.85 mL, 0.85 mmol) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.OO.[BrH:12]>>[Br:12][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([CH3:9])[C:6]=1[NH2:8]
Reactant: Cc1cc(N)c(C)cn1
Reactant: Br
Agent: OO
Product: Cc1cnc(C)c(Br)c1N
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 2,5-dimethylpyridin-4-amine (3.57 g, 29.3 mmol) in 48% hydrogen bromide aqueous solution (40 mL) was heated to 75° C. Then 15% hydrogen peroxide (7 mL) was added dropwise over 30 min. The reaction mixture was stirred at 75° C. for 1 h, and concentrated under reduced pressure. The pH of the solution was adjusted to 9 with 1 N sodium hydroxide solution. The aqueous mixture was extracted with DCM (250 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (250 mL×1), dried with sodium sulfate, and concentrated to give 5.0 g of the product as a yellow solid. MS (ESI): m/z 203.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:19])[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(O)CCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1C(Cl)CCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutan-1-ol (545 g) in toluene (5.4 L) was added thionyl chloride (393 g) at room temperature. The reaction mixture was stirred at 50° C. overnight and concentrated under reduced pressure to give the title compound. This reaction was performed for 3 batches, and the obtained compounds were used in step D without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:37]=[C:36]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6C(OC(C)(C)C)=O)[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:39][O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:37]=[C:36]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:45](=[O:46])[C@@H:44]([NH:43][C:41](=[O:42])[O:40][CH3:39])[CH:48]([CH3:50])[CH3:49])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.46 g, 0.9 mmol) in a mixture of CH2Cl2 (9.0 mL) and MeOH (1.5 mL) was added HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solution was stirred at room temperature for 2 h. The solution was concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (10.0 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with aqueous HCl (1N) and brine. The aqueous layers were backextracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl {(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.46 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH3:31])=[CH:20]\[CH:21]=[CH:22]\[C:23](\[CH3:30])=[CH:24]\[C:25]([O:27]CC)=[O:26])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:17])[CH3:18])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH3:31])=[CH:20]\[CH:21]=[CH:22]\[C:23](\[CH3:30])=[CH:24]\[C:25]([OH:27])=[O:26])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc2c(cc1/C(C)=C\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, ethyl 7-(7-ethoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2E,4E,6Z-trienoate (Compound 37, 55 mg, 0.13 mmol) was hydrolyzed with 1M NaOH to yield the title compound as a yellow solid after purification by column chromatography (silica gel, 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile to yield the title compound as a light yellow solid.