Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[NH:1]([CH:8]1[CH2:9][C:10](=[O:11])[C:12]2[C:13](=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(Nc2ccccc2)N(c2ccccc2)c2nc(Cl)ccc21
Temperature: 80 °C
Yield: 66.7 %

Procedure:
A mixture of 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.08 g, 0.21 mmol) and NaH (0.009 g, 0.23 mmol) in THF (6 mL) was heated to 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc provided 2-anilino-7-chloro-1-phenyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (49 mg, 68%) as an off-white solid: LC-MS RT: 2.56 min, MH+: 348.2. This transformation can be accomplished by using the combination of other aprotic solvents such as dioxane and DMF with other bases such as t-BuOK.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7]C[C:5]2([CH3:14])[CH3:13].BrC1C=C2C(CCC2(C)C)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][C:5]2([CH3:13])[CH3:14]
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: CC1(C)CCc2ccc(Br)cc21
Product: CC1(C)CC(=O)c2ccc(Br)cc21
Yield: 75 %

Procedure:
Following a procedure similar to that for the preparation of 6-bromo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 3) while using 6-bromo-1,1-dimethyl-indan (Compound 11, 2.45 g, 10.9 mmol) as the starting material afforded the title compound (1.95 g, 75% yield) as a white solid:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.C([NH:22][C:23]1[C:32]([Cl:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([O:34][CH3:35])[CH:24]=1)(=O)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].[OH-].[K+]>O1CCCC1>[Cl:33][C:32]1[C:23]([NH:22][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:24][C:25]([O:34][CH3:35])=[C:26]([CH:31]=1)[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1cc(NS(C)(=O)=O)c(Cl)cc1C(=O)O
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 52.2 %

Procedure:
A cooled (-60° C.) solution of diisopropylamine (11.13 g, 0.110 mole) in anhydrous tetrahydrofuran (150 ml) under nitrogen was treated (via syringe) with 2.4N n-butyllithium/hexane (0.105 mole), warmed to -20° C., stirred for 5 minutes, then treated in portions with 4-(N-acetylamino)-5-chloro-2-methoxybenzoic acid, methyl ester (25.8 g, 0.100 mole). After 30 minutes at 25° C., the mixture was cooled (0° C.), treated dropwise with a solution of methanesulfonyl chloride (25.0 g, 0.218 mole) in anhydrous tetrahydrofuran (50 ml), and maintained at room temperature for 30 minutes and at 50° C. for one hour. The mixture was partially concentrated in vacuo and added to ice water (600 ml), and the aqueous mixture was extracted with methylene chloride (3×250 ml). The combined organic solution was dried (sodium sulfate), concentrated in vacuo, taken up in 60:40 water/ethanol (300 ml), treated with potassium hydroxide (33.6 g, 0.60 mole), and refluxed for three hours. Most of the ethanol was removed in vacuo and replaced with water, and the aqueous solution was extracted with ether (2×200 ml), then cooled in an ice bath and treated with concentrated hydrochloric acid solution (60 ml). The suspension was filtered and the solid was washed with water, air dried, and recrystallized from 95% ethanol to afford 14.60 g (52%) of the title compound as a colorless solid; mp 248°-250° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[CH:12]=2)[C:3]=1[C:4]#[N:5].[NH3:20]>C(O)C.C1COCC1>[NH2:20][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: COc1cc(C)cc(Sc2cccc(F)c2C#N)c1
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)cc(Sc2cccc(N)c2C#N)c1
Temperature: 145 °C

Procedure:
A solution of 0.1 g (0.00037 mol) of 2-fluoro-6-[(3-methyl-5-methoxyphenyl)thio]benzonitrile (Example 23) in 10 mL of absolute ethanol and ca. 2 mL of THF was saturated with ammonia. The resultant solution was sealed in a glass-lined Parr bomb and heated to 145° C. for 48 h. The solvent was removed in vacuo. 20 mL of 1 NaOH was added. This aqueous solution was extracted with 3×20 mL of EtOAc. The EtOAc solution was dried over MgSO4. After solvent removal, the crude product was chromatographed on silica gel (flash; CH2Cl2), resulting in 0.03 g (30%) of 2-amino-6-[(3-methyl-5-methoxyphenyl)thio]benzonitrile as a white solid: mp 108°-110° C.; NMR (Me2SO-d6, 200 MHz) δ 2.32 (s, 3H), 3.78 (s, 3H), 6.28 (br s, 1H), 6.4 (apparent d, 1H), 6.7-6.8 (m, 2H), 6.8-6.9 (narrow m, 2H), 7.28 (apparent d, H). Anal. Calc. for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; S, 11.36. Found: C, 66.46; H, 5.22; N, 10.25; S, 11.71.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=[O:23]>O1CCCC1>[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5 (94 mg, 0.58 mmol), 31 (120 mg, 0.49 mmol), and triphenylphosphine (321 mg, 1.23 mmol) in tetrahydrofuran (10 mL) at 65° C. under nitrogen was added diisopropyl azodicarboxylate (247 mg, 1.23 mmol). The mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give crude 32 (230 mg, contained Ph3PO).
Reaction SMILES: CC1SC2C(SC)=NC=NC=2C=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[O:24][N:25](C)C(=O)C1C=CC=CC=1.[CH3:35][S:36][C:37]1[C:38]2[S:45][C:44]([CH2:46][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:48])=[CH:43][C:39]=2[N:40]=[CH:41][N:42]=1.N([O-])=O.[Na+]>C1COCC1.O.C(O)(=O)C>[CH3:35][S:36][C:37]1[C:38]2[S:45][C:44]([C:46](=[N:25][OH:24])[C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:48])=[CH:43][C:39]=2[N:40]=[CH:41][N:42]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CSc1ncnc2cc(CC(=O)c3ccccc3)sc12
Agent: CSc1ncnc2cc(C)sc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=N[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CSc1ncnc2cc(C(=NO)C(=O)c3ccccc3)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
6-Methyl-4-(methylthio)thieno[3,2-d]pyrimidine, (intermediate 22) (665 mg) was dissolved in THF (10 mL) and added slowly, over 15 minutes, to a stirred solution of LHMDS in THF (1M, 3.39 mL) at −78° C. After 10 minutes, N-methoxy-N-methylbenzamide (616 mg) was added and the reaction mixture warmed to 0° C. After 2 hours at 0° C. the resultant solution of 2-[4-(methylthio)thieno[3,2-d]pyrimidin-6-yl]-1-phenylethanone was acidified with acetic acid (10 mL), diluted with water (10 mL) and re-cooled to 0° C. Sodium nitrite (280 mg) was added and the mixture was stirred overnight. After evaporation of the solvents, the solid residue was collected with water by filtration, and dried to give the title compound as a brown solid (959 mg, 86%);
Reaction SMILES: C(N(CC)C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=1.[N:24]1([NH2:33])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[CH:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:24]1([NH:33][C:21]([C:18]2[CH:19]=[N:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[N:16][CH:17]=2)=[O:23])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[CH:25]1
Reactant: Nn1ccc2cccnc21
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nn1ccc2cccnc21)c1cnc(-c2ccccn2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Diethyl-iso-propylamine (1.13 mmol) is added a solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU in anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at 80° C. overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water twice, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to give a crude product. The product is crystallized from EtOAc to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridine-1-ylamide (78 mg, 25%) as a solid. MS: 317 (M+H); 1H NMR (300 MHz, CD3OD): δ 6.56 (m, H) 7.24 (m, H), 7.53 (m, H), 7.61 (m, H), 8.01-8.17 (m, 2H), 8.27 (d, H), 8.69 (m, H), 8.78(m, H), 9.51 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][N:6]([C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][N:6]([C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([OH:24])=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 88.4 %

Procedure:
0.78 g of {[2-{2-(S)-[Benzyloxy-carbonyl]-pyrrolidin-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester were dissolved in 50 mL of methanol and hydrogenated for 3 h at room temperature using 0.4 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.58 g (89%) of the title compound as a colorless oil. (−)-APCI-MS: 477 ([M−H]−).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](OCC)=[O:18])[N:15]=1)(=O)[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH2:7]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)[CH3:8]
Reactant: CCOC(=O)Cc1csc(NC(C)=O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(CCO)cs1
Yield: 51.9 %

Procedure:
To a stirred solution of 1.0 M LiAlH4 in THF (179 mL, 179 mmole) was added dropwise a solution of ethyl 2-acetylamino-4-thiazoleacetate (4.4 g, 17.9 mmole) in THF (50 mL). After complete addition, the reaction mixture was heated at reflux for 3 hr, then was worked up by sequential addition of H2O (0.7 mL), 10% NaOH (0.7 mL), and H2O (2.1 mL). The resulting mixture was filtered through celite® and the filtrate was concentrated. Purification by flash chromatography on silica gel (5% MeOH/CH2H2) gave the title compound (1.6 g, 53%) as an amber oil: MS (ES) m/e 173 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:47](=[O:48])[N:46]([CH3:50])[CH3:45])=[CH:31][CH:30]=1)#[N:2]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OC(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of COMPOUND 117 (42 mg, 0.082 mmol) in DMF (1 mL) were added K2CO3 (36 mg, 0.26 mmol) followed by dimethylcarbamoyl chloride (15 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 145 as a white solid (41 mg, 84%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.13 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.81 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=12.0 Hz), 2.73-3.05 (m, 9H), 3.23-3.28 (m, 1H), 3.51-5.56 (m, 1H), 3.75 (s, 2H), 3.87-3.93 (m, 1H), 6.50 (d, 2H, J=7.8 Hz), 6.86 (d, 2H, J=8.1 Hz), 6.93-7.00 (m, 3H), 7.42-7.50 (m, 4H), 8.42-8.44 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.53, 29.34, 30.75, 31.32, 36.75, 36.87, 37.04, 38.99, 40.24, 43.97, 48.81, 52.57, 57.43, 60.97, 112.84, 114.79, 119.36, 122.74, 127.68, 128.77, 129.57, 130.45, 130.83, 131.40, 134.47, 139.04, 142.64, 143.47, 146.18, 155.88, 162.90, 170.23. ES-MS m/z 582 (M+H). Anal. Calcd. for C35H43N5O3.1.0H2O: C, 70.09; H, 7.56; N, 11.68. Found. C, 70.35; H, 7.56; N, 11.95.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:39]=[C:40]([C:45](=O)[CH3:46])[CH:41]=[CH:42][C:43]=1[Cl:44].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:45]([C:40]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=2)[CH:46]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Cl)c(Cl)c4)ccc3c1)n2C1CCCCC1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,4-dichloro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (12 mg, 10% yield).
Reaction SMILES: [H-].[Na+].C1COCC1.[OH:8][CH:9]([CH2:36][CH2:37][CH3:38])[CH2:10][CH2:11][C:12]1[C:13](F)=[C:14]([F:34])[C:15]([F:33])=[C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[CH:17]=1.C1(C)C=CC=CC=1>CN(C=O)C>[F:33][C:15]1[C:14]([F:34])=[C:13]2[C:12]([CH2:11][CH2:10][CH:9]([CH2:36][CH2:37][CH3:38])[O:8]2)=[CH:17][C:16]=1[C@H:18]1[CH2:19][CH2:20][C@H:21]([C@H:24]2[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][CH3:32])[CH2:28][CH2:29]2)[CH2:22][CH2:23]1
Reactant: CCCC(O)CCc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC1CCc2cc([C@H]3CC[C@H]([C@H]4CC[C@H](CCC)CC4)CC3)c(F)c(F)c2O1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Under nitrogen replacement, 1.23 g of sodium hydride (60% in oil) was suspended in 18 ml of DMF. Into this, the THF (36 mL) solution containing 9 g of 5-(3-hydroxy-1-hexyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene was added dropwise for 30 minutes, and stirred for 3 hours at 40° C. and then for 3 hours at 50° C. After toluene was added and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by carrying out column chromatography (silica gel, hexane), recrystallization (hexane), recrystallization (hexane/ethanol) to obtain 2.5 g of 7,8-difluoro-6-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-2-propylchroman as colorless needlelike crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:16]=[C:15]([N:17]3[C:21]4=[N:22][CH:23]=[CH:24][C:25]([C:26]5[CH:27]=[N:28][C:29]6[C:34]([CH:35]=5)=[CH:33][CH:32]=[CH:31][CH:30]=6)=[C:20]4[C:19]([C:36]([F:39])([F:38])[F:37])=[N:18]3)[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH2:4][CH2:3]1.C([OH:42])C.[OH-].[Na+].OO>CS(C)=O.O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:16]=[C:15]([N:17]3[C:21]4=[N:22][CH:23]=[CH:24][C:25]([C:26]5[CH:27]=[N:28][C:29]6[C:34]([CH:35]=5)=[CH:33][CH:32]=[CH:31][CH:30]=6)=[C:20]4[C:19]([C:36]([F:39])([F:38])[F:37])=[N:18]3)[CH:14]=[CH:13][C:10]=2[C:11]([NH2:12])=[O:42])[CH2:6][CH2:7]1
Reactant: CCO
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1N[C@H]1CC[C@H](O)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1N[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
Compound (1f) (0.450 g) was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO, 2 mL) and ethanol (4 mL). An aqueous sodium hydroxide solution (4 M, 0.851 mL) and a 30% hydrogen peroxide solution (0.193 mL) were added to the resulting solution in this order at room temperature, followed by stirring for 30 min. Water was added to the reaction solution, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1) (0.300 g, 65%) as a white solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].O.ON1C2C=CC=CC=2N=N1.[CH3:44][N:45]([CH3:58])[C:46](=[O:57])[C@@H:47]([NH2:56])[CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[NH:56][C@H:47]([C:46](=[O:57])[N:45]([CH3:58])[CH3:44])[CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:21])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(=O)NCCCC[C@H](N)C(=O)N(C)C
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (824 mg, 4.30 mmol) was added at 0° C. to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (1.20 g, 4.30 mmol) and 1-hydroxybenzotriazole hydrate (659 mg, 4.30 mmol) in dichloromethane (15 ml) and N,N-dimethylformamide (15 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of the hydrochloride salt of (2S)-6-acetylamino-2-aminohexanoic acid dimethylamide (1.86 g, 6.44 mmol) in N,N-dimethylformamide (10 ml) was added. Ethyidiisopropylamine (2.98 ml, 17.2 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (200 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed. The crude product was purified by flash chromatography on silica (60 g), using dichloromethane/methanol (10:1) as eluent to give 1.81 g of N-[(1R)-1-((1S)-5-(acetylamino)-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:8]([Cl:16])[C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].Br[CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:17]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:26][CH2:25][CH2:24]2)[CH:7]=[C:8]([Cl:16])[C:9]=1[O:10][CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(Br)c2)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a suspension of NaH (0.65 g, 60% in paraffin oil) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and 1,3-dibromo propane (1.61 g, 8.0 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash column chromatography to give ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.12 g) as a thick syrup.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:14]=3)[C:9]2=[O:23])=CC=1>FC(F)(F)C(O)=O>[CH3:22][C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:23])[NH:8][CH2:17][CH2:16]2)([CH3:21])[CH:19]=[O:20]
Reactant: COc1ccc(CN2CCc3cc(C(C)(C)C=O)ccc3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C=O)c1ccc2c(c1)CCNC2=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
2-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionaldehyde (420 mg, 1.25 mmol) was taken up in trifluoroacetic acid (5 mL) and the resulting mixture was stirred at 80° C. for 2.5 hours and then cooled to room temperature. The trifluoroacetic acid was removed under reduced pressure at 60° C., and then co-evaporated with ethyl acetate (5×). The residue was taken up in ethyl acetate (175 mL) and then washed with water (3×50 mL) and finally with brine (1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica gel eluting with a gradient of 50% ethyl acetate in hexanes to neat ethyl acetate gave the title compound as a white powder (228 mg). MS (ESI) 218.0 (M+H)+.