Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:12]([F:13])([F:14])[F:15])(=[O:31])=[O:30]
Reactant: OCCCCCCCCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
1.0 g of 9,9,10,10,10-pentafluorodecan-1-ol is dissolved in 8 ml of abs. pyridine, 985 mg of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 2 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 1.5 g of 9,9,10,10,10-penta-fluorodecyl tosylate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:30])=[C:9](\[CH2:28][CH3:29])/[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:30])=[C:9](\[CH2:28][CH3:29])/[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C(CC)=C(\C)c2ccc(Br)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C(CC)=C(\C)c2ccc(Br)cc2)cc1)C(=O)O
Yield: 95.8 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (Example 96) (0.78 g, 1.64 mmol) and sodium hydroxide (1M, 3.3 ml, 3.3 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (0.703 g, 96%) as a pale yellow oil, which contained a small amount of dichloromethane; 0.703 g (96%).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[Br:8][C:9]1[CH:16]=[CH:15]C(CBr)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:8][C:9]1[CH:16]=[CH:15][C:5]([CH2:4][CH2:3][C:2](=[O:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 2,4-pentanedione (200 mg, 206 μL, 2 mmol), the 4-bromobenzyl bromide (2 mmol), and anhydrous potassium carbonate (276 mg, 2 mmol) in methanol (10 mL) was heated at reflux temperature for 16 h. The mixture was then cooled to room temperature, methanol was removed under reduced pressure, and the resulting residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (3×10 mL). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, and then the solvent was removed under pressure. The resulting oil was chromatographed on a silica gel column using hexanes-ethyl acetate as mobile phase to give 4-(4-bromophenyl)-2-butanone as a clear liquid (302 mg, 67%): Rf=0.38 (hexanes-ethyl acetate 3:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.15 (s, 3H), 2.75 (t, J=7.2 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 7.07 (d, J=8 Hz, 2H), 7.40 (d, J=8.4 Hz, 21; 13C NMR (100 MHz, CDCl3): δ 29.2, 30.2, 44.9, 120.0, 130.2, 131.7, 140.2, 207.4; HRMS (ESI) Calcd. for C10H11BrONa: 248.9891 [M+Na+]. Found: 248.9880.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14](Br)[N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNc1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Agent: [Pd]
Solvent: CCO
Product: CNc1cc(S(=O)(=O)c2ccccc2)ccn1
Reaction time: 18 h
Yield: 36.6 %

Procedure:
0.09 g (0.000275 mol) of (4-benzenesulphonyl-6-bromopyridin-2-yl)-methylamine was dissolved in 7 ml of ethanol, treated with 0.009 g of Pd/C (10%) and hydrogenated under normal pressure for 18 hrs. Thereafter, the catalyst was filtered off, the solvent was removed and the residue was partitioned in ethyl acetate and saturated bicarbonate solution. The organic phase was washed with sat. sodium chloride solution and dried over MgSO4. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4 and 1:3. There was obtained 0.025 g (37%) of (4-benzenesulphonylpyridin-2-yl)-methylamine as beige crystals; m.p.: 142-143° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH3:18])[C:10]=1[C:11]#[N:12])=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH3:18])[C:10]=1[C:11]#[N:12])=[O:7]
Reactant: CNc1cccc(NC(=O)COC(C)=O)c1C#N
Agent: N
Solvent: CO
Product: CNc1cccc(NC(=O)CO)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-(acetoxyacetylamino)-6-(methylamino)benzonitrile (2 g) in methanol (250 ml) is added dropwise 28% aqueous ammonia (5.5 ml). The mixture is stirred at room temperature for 30 minutes, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanoltoluene to give the title compound (1.4 g) having the following physical properties.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[NH2:19][N:20]1[C:24]([N:25]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[N:26]2)=[N:23][N:22]=[C:21]1[SH:32].C(=O)(O)[O-].[Na+]>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[CH:9]1[S:14][CH2:15][C:6]([CH2:5][S:32][C:21]1[N:20]([NH2:19])[C:24]([N:25]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[N:26]3)=[N:23][N:22]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Cc1cc(C)n(-c2nnc(S)n2N)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)n(-c2nnc(SCC3=C(C(=O)O)N4C(=O)C(N)C4SC3)n2N)n1

Procedure:
A 1.36 g. portion of 7-aminocephalosporanic acid, 1.05 g. of 4-amino-5-(3,5-dimethyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol and 0.84 g. of sodium bicarbonate are reacted by the procedure of Example 1, giving the desired product, I.R. 5.60μ (β-lactam carbonyl).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([Cl:26])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:27].Cl>O1CCOCC1.O>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:28])=[O:4])=[C:8]2[CH3:27])(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[CH3:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(C)c(Cl)c2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)cc1Cl
Reaction time: 2.5 h

Procedure:
1M Aqueous NaOH (0.25 mL) is added to a stirring solution of [1-(3-chloro-4-methyl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (80 mg, 0.20 mmol) in 1:1 dioxane/water (2 mL). After 2.5 hours, the reaction mixture is acidified to pH 1 with 1M HCl which leads to the formation of a precipitate. The solid is isolated by filtration, washed with water and dried to afford [1-(3-chloro-4-methyl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=379.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH3:12])[CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH3:12])[CH2:6][CH2:5]2)=[O:19]
Reactant: CN1CCc2cc(N)ccc2C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)Nc2ccc3c(c2)CCN(C)C3)cc(OC)c1OC

Procedure:
6-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 3,4,5-trimethoxybenzoyl chloride as in Example 16 to yield 6-(3,4,5-trimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline. It was recovered as the HCl salt; m.p. 233.5°-235° C. after purification in methanol.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(N1CCCO[CH:19]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)C1C=CC=CC=1.C(Cl)(=[O:35])CC.[OH-].[Na+]>C(Cl)Cl>[C:26]1([NH:25][C:24](=[O:35])[CH2:19][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
iPr2EtN (4.72 mL, 27.1 mmol) was added to a solution of (4-benzyl-1,4-oxazepan-2-ylmethyl) phenyl amine (80) (27.1 mmol) in CH2Cl2. The solution was cooled to 0° C. in an ice bath, then propionyl chloride (5.17 mL, 59.6 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature, with stirring, overnight. CH2Cl2 and 10% aqueous NaOH was added. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2×). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by silica gel chromatography (97:1:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain 4-benzyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (81) as a pale yellow oil. 1H NMR (CDCl3, ppm) 7.36-7.19 (8H, m), 6.94 (2H, broad d, J=6.5 Hz), 3.89-3.38 (5H, m), 3.65 (1H, d, J=13.3 Hz), 3.54 (1H, d, J=13.3 Hz), 2.88-2.75 (2H, m), 2.55 (1H, ddd, J=12.5, 8.9, 4.2 Hz), 2.34 (1H, dd, J=13.5, 8.9 Hz), 1.98-1.68 (4H, m), 0.98 (3H, t, J=7.5 Hz). 13C NMR (CDCl3) 174.05, 143.19, 139.64, 129.60, 129.15, 128.46, 128.35, 127.79, 127.10, 76.80, 67.25, 62.61, 59.05, 54.43, 51.64, 30.42, 27.91, 9.70 ppm. LRMS: 352.72.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3]1.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccsc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccsc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
2-(Thiophen-3-yl)ethanamine hydrochloride (3 g, 18 mmol) was taken in THF (40 mL) and treated with triethylamine (9.92 mL, 71.2 mmol). The reaction was cooled down to 0° C. and benzoyl chloride (2.55 mL, 21.9 mmol), diluted with THF was added dropwise to the reaction. The reaction was stirred for 3 h and the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and washed with an aqueous saturated solution of sodium bicarbonate, water and brine. The organic solution was dried with sodium sulfate and purified by flash chromatography using a gradient of 25 to 70% ethyl acetate in hexanes to afford an off-white solid (4 g). MS (M+H)+ 232.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.I[C:13]1[CH:14]=[CH:15][C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH2:19][CH2:18][C:17]=3[CH:21]=2)[CH:3]=1
Reactant: Ic1ccc2c(c1)CCO2
Reactant: Clc1ccnc2ccccc12
Product: Clc1cc(-c2ccc3c(c2)CCO3)nc2ccccc12

Procedure:
The title compound, m. p. 130-132° C., MS: m/e=281 (M+), was prepared from 4-chloro-quinoline and 5-iodo-2,3-dihydrobenzofuran.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([CH2:14][O:15][N:16]=[C:17]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][CH2:29][S:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH3:18])=[CH:11][CH:10]=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:32][C:20]1[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][CH2:29][S:28][CH2:27]2)[CH2:23][C:24](=[O:25])[C:19]=1[C:17](=[N:16][O:15][CH2:14][C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C2CCCSC2)CC1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
In this example, 0.52 g (5.1 mmol) of triethylamine was admixed to a solution containing 1.46 g (3.7 mmol) of 2-[1-[(5-chlorothien-2-yl)methoxyimino]ethyl]-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one in 30 ml of methylene chloride at room temperature (about 20°-25° C.) followed by the dropwise addition of 0.35 g (4.4 mmol) of acetyl chloride. The mixture was stirred at room temperature overnight (about 14 hr) and then washed with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica gel to afford 1.0 g of the title compound as a pale yellow oil; IR (neat) 1775 cm-1 ; 1H NMR spectrum (90 MHz CDCl3) ε 1.00-2.60 (m, 14H), 1.93 (s, 3H), 2.00 (s, 3H), 5.07 (s, 2H) 6.73 (s, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]3[CH:20]([OH:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH2:22][CH2:23][O:24][C:9]=2[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].I[C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1>>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]([CH:20]([OH:21])[C:30]3[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:43][CH:44]=3)=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[OH:19])[CH2:22][CH2:23][O:24][C:9]=2[CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC1=C2C(O)Oc2ccccc21
Reactant: Ic1ccc(OCCN2CCCCC2)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC(c1ccccc1O)=C2C(O)c1ccc(OCCN2CCCCC2)cc1

Procedure:
Following the procedure described in Examples 76, 2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol, the compound prepared as in Example 105 above, was reacted with 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine to yield 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-(4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol as a crude oil. The crude 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin4-yl)-phenol was then further treated with HCl (12N, 4 eq., 0.67 mL) in toluene (100 mL) to generate yield 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine as a crude oil. The crude 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine was then further treated with HF•Pyridine (70% HF, 30% Pyridine, 0.5 mL) in CH3CN (20 mL) at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate:THF (1:1) and then washed with 5% NaHCO3 and brine. The reaction mixture was dried, concentrated and purified by flash chromatograph eluted with 5% MeOH in DCM to yield the title compound as a slightly yellow solid.
Reaction SMILES: [F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C([O:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][N:27]=1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([CH2:28][C:23]2[C:22](=[O:21])[NH:27][CH:26]=[CH:25][N:24]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: Fc1ccccc1C(F)CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]ccnc1CN1CCC(CC(F)c2ccccc2F)CC1
Reaction time: 8 h
Yield: 5.3 %

Procedure:
After dissolving 64 mg of 4-[2-fluoro-2-(2-fluorophenyl)ethyl]piperidine in 3 ml of tetrahydrofuran, 61 mg of 3-tert-butoxy-2-pyrazinecarboxaldehyde and 90 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate). Two milliliters of a 4N hydrogen chloride/ethyl acetate solution was added to the obtained product while stirring, and the stirring was continued for 2.5 hours at room temperature. A 1N sodium hydroxide solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether/n-hexane was added to the residue and the insoluble portion was filtered out to obtain the title compound (5 mg, 5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:19][CH2:18][C@H:17]3[C:20]([O:22]C)=[O:21])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.[OH-].[Na+]>C(O)CCC>[Cl:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:19][CH2:18][C@H:17]5[C:20]([OH:22])=[O:21])=[O:15])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:26][C:27]=2[CH:33]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl) carbonyl]cyclobutane-carboxylate (100 mg, 0.32 mmol) in n-butanol (15 mL) was added 2,6-dichloro-1,3-benzothiazole (396 mg, 1.94 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was brought up in MeOH. Then 1 N aqueous NaOH (1.0 mL, 1.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated, and the residue was suspended in water. Concentrated HCl was added to adjust the acidity to pH 1, and the precipitate that formed was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutanecarboxylic acid (16 mg, 10%). LC-MS ret. time 3.69; m/z 463.1 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 2.01-2.23 (m, 3H), 2.32 (m, 1H), 3.43 (m, 1H), 4.32 (m, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.62 (d, 1H), 7.81 (m, 4H), 7.90 (d, 2H), 7.98 (m, 3H), 10.77 (s, 1H), 12.29 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[BH4-].[Na+].CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A solution of dimethyl 2,6-dichlorobenzene-1,4-dicarboxylate (2.3 g, 8.7 mmol) in tetrahydrofuran (10 mL) was treated with sodium borohydride (0.496 g, 13 mmol) and heated to refluxing temperature. The reaction mixture was then treated drop wise with methanol (1 mL) and continued refluxing for about 2 hours. The reaction mixture was warmed to room temperature and quenched with saturated aqueous ammonium chloride solution followed by partitioning with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate in hexane (10%) as an eluant to yield methyl 2,6-dichloro-4-(hydroxymethyl)benzoate as a colorless liquid (1.6 g, 80%).
Reaction SMILES: [ClH:1].CCOC(C)=O.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)#[N:9]>CCOC(C)=O.C(OCC)C>[ClH:1].[CH:20]1([CH:16]2[C:17]3[C:12](=[CH:11][C:10]([C:8]#[N:9])=[CH:19][CH:18]=3)[CH2:13][CH2:14][NH:15]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C#N)ccc2C1C1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)CCNC2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 M HCl/EtOAc (2 mL) was added to a solution of tert-butyl 6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg) in EtOAc (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture together with the precipitated crystal was diluted with diethyl ether (5 mL). The crystal was collected by filtration, washed with diethyl ether, and dried in air to obtain 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile hydrochloride (259 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(#N)C>[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:18]([O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(Cl)cc1O
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 107.7 %

Procedure:
To a solution of 4-chloro-2-hydroxybenzamide (0.608 g, 3.54 mmol) in acetonitrile (50 ml) was added dried K2CO3 (1.71 g, 12.40 mmol) followed by benzyl bromide (0.63 ml, 5.32 mmol) and the resulting reaction mixture was refluxed at 80° C. for 16 h. After the completion of the reaction (TLC monitoring), water was added followed by extraction with EtOAc (3×100 ml). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated. The residue was washed repeatedly with hexane to get rid of the excess of benzyl bromide resulting the desired product (0.75 g, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][C:12](=O)[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[N:8][C:7]=1[C:24]([F:27])([F:26])[F:25])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:30])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Cl:30])[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[N:8][C:7]=1[C:24]([F:27])([F:26])[F:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2n1CC(=O)N2c1c(C)cc(C)cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12

Procedure:
A solution of 6-oxo-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (3.04 g, 6.137 mol) in phosphorus oxychloride (70 mL) was heated at 150° C. for 72 h. The excess of phosphorus oxychloride was removed under reduced pressure, the residue was dissolved in saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried with MgSO4. The solvent was removed under reduced pressure and the crude product was dried under pump vacuum overnight. Yield—1.192 g (38%). LC/MS: tR=2.17 min., MS: [M+H]=400.