Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCC1CC(=O)C1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1CC(O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
3-(2-{[Tert-butyl(diphenyl)silyl]oxy}ethyl)cyclobutanone (5.11 g, 14.5 mmol) (WO 2006063281) was dissolved in tetrahydrofuran (120 mL). Sodium borohydride (548 mg, 14.5 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with water and saturated aqueous sodium bicarbonate and stirred for 20 min until the bubbling ceased. The reaction mixture was diluted with ether and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)cyclobutanol (3.58 g, 69.6%) as a clear oil. Partial 1H NMR indicated a ˜3.5:1 mix of cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.08 (quintet, J=7.42, 0.78H) and 4.34 (quintet, J=6.83, 0.22H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH2:10])[CH:4]=[CH2:5].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([O:1][CH2:2][CH:3]([O:6][CH2:7][C@@H:8]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH:9]=[CH2:10])[CH:4]=[CH2:5])(=[O:28])[CH3:27]
Reactant: C=CC(CO)OC[C@H](C=C)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(COC(C)=O)OC[C@H](C=C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a mixture of tert-butyl [(1S)-1-({[1-(hydroxymethyl)prop-2-en-1-yl]oxy}methyl)prop-2-en-1-yl]carbamate (268 mg, 1.04 mmol) in methylene chloride (10 mL) was added with triethylamine (435 μL, 3.12 mmol). The mixture was cooled to 0° C., and acetyl chloride (150 μL, 2.1 mmol) was added drop wise. The reaction was stirred at room temperature for 2 h, then quenched with water. The organic layer was concentrated and the resultant residue purified on silica gel (eluting with 20% ethyl acetate/hexanes) to give the desired product (0.26 g, 85%). LCMS calculated for C10H18NO3 (M−100+H)+: m/z=200.1. Found: 200.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:5][CH:4]=1)#[N:2].[OH-:28].[K+].Cl>C(O)(C)(C)C.O>[C:15]([C:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:28])=[CH:8][CH:7]=2)=[C:10]2[CH:27]=[N:26][NH:25][C:11]2=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[F:24])#[N:16]
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2c(C#N)c(-c3ccc(O)cc3F)nc3[nH]ncc23)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1c(-c2ccc(O)cc2F)nc2[nH]ncc2c1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 0.06 g (0.17 mmol) of 4-(4-cyanophenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 0.08 g (1.40 mmol) of potassium hydroxide in 6 ml of tert-butanol is refluxed for 4 h. The mixture is then cooled to room temperature, diluted with water, acidified with 1N HCl, and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 0 to 10%) to yield 0.019 g (30%) of 4-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)benzamide in the form of yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]2[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:20][C:21]1[C:26]([CH2:27]O)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:20][C:21]1[C:26]([CH2:27][O:14][C:12]2[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:19])=[CH:6][S:7][C:8]=3[CH:13]=2)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(C(F)(F)F)c12
Reactant: Cc1ccc(CO)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(C(F)(F)F)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a mixture of methyl(6-hydroxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate (60 mg) and THF (dry) (2 mL) were added (2,6-dimethylpyridin-3-yl)methanol (31.2 mg), ADDP (62.6 mg), and tri-n-butylphosphine (0.153 mL) at room temperature. After stirring at room temperature for 16 h, the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). To the mixture of crude material and THF (1 mL) was added 1N NaOH (1 mL) at room temperature, and the mixture was stirred at room temperature for 13 h. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residual solid was crystallized from EtOAc-hexane to give the title compound (71.0 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15]>C(OCC)(=O)C>[Br:8][C:7]1[C:2]2[NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[N:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: CC(C)N=C=S
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Br)cc(Br)c2N1

Procedure:
The title compound was prepared from 2-amino-3,5-dibromobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 306-311° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.19 (d, 6H, CH(CH3)2), 3.90 (m, 1H, CH(CH3)2), 7.82 (d, 1H, ArH), 7.92 (br.d, 1H, NH), 8.16 (d, 1H, ArH), 9.65 (br.s, 1H, NH); MS: m/e 395/397/399 (M+); (C10H11N3Br2O2S1) calc. C, 30.25; H, 2.79; N, 10.58; found C, 30.34; H, 2.77; N, 10.48.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 5.02 mmol) and cyclohexanone (2.45 g, 25 mmol) in methanol (10 mL), acetic acid (0.3 g, 5.02 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.63 g, 10.05 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.2 g, 89.92%).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([NH2:34])[S:32][CH:33]=2)=[CH:25][CH:24]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:35])=[CH:24][CH:25]=4)[N:30]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:2]2[C:9](=[CH:10][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: Cc1ccc(-c2csc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)n2)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 4-p-tolylthiazol-2-amine (50 mg, 0.26 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-p-tolylthiazol-2-yl)benzamide as a yellow solid. Yield: 18 mg (14%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.65 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.27-7.19 (m, 3H), 7.14-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.59 (m, 2H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C@@:12]12[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C@H:24]1[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:30])=[CH:20][C:21]=3[CH2:22][CH2:23]1)[CH2:14][CH2:13]2>N1C=CC=CC=1>[C:2]([O:30][C:19]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@H:24]([C@H:25]4[C@@:12]([CH2:13][CH2:14]3)([CH3:11])[C:28](=[O:29])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
To nicotinoyl chloride hydrochloride (2.65 g, 0.015 mol) in pyridine (20 ml) at 0° C. was added estrone (2 g, 0.0074 mol). The mixture was refluxed for one hour and then poured over 100 ml of ice cold water, filtered, and dried over P2O5 under vacuum. Yield 72% (2.0076 g), m.p. 207°-210° C. NMR (CDCl3) δ9.3-9.1 (br s, 1H, C2 pyridinium proton), 8.8-8.6 (br d, 1H, C6 pyridinium proton, 8.4-8.2 (br d, 1H, C4 pyridinium proton), 7.5-7.1 (m, 2-H, C5 pyridinium proton+C1 estrone proton), 7.0-6.7 (m, 2H, C2,4 estrone protons), 3.2-1.3 (estrone skeletal protons, 15), 1.0-0.9 (s, 3H, C18 estrone protons). IR (KBr) 1750-1730 cm-1 (broad C=O stretching). Anal. calculated for C24H25NO3 ; C, 76.76; H, 6.72; N, 3.73. Found: C, 76.37; H, 6.96; N, 3.67. The product is further characterized by the structural formula: ##STR1549##
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N([O-])=O.[Na+].O.[ClH:23]>>[Cl:23][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)S(=O)(=O)N=CN2C1CCC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)N=CN(C2CCC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-4-cyclobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxide prepared in the Step above (3.48 g) in 6N HCl (40 mL) is cooled on an ice bath and then an aqueous solution of NaNO2 (2 g in 15 mL) is added dropwise. The solution obtained is added gradually to a solution of the Cu2Cl2 in concentrated HCl (30 mL). After stirring for 30 minutes at ambient temperature, water (150 mL) is added to the reaction mixture and the precipitate obtained is collected by filtration, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:29]=[O:30])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:29]=[O:30])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2)nc1C=O

Procedure:
Reaction of 4-(4-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (688 mg, 2.35 mmol), 1.5 M n-BuLi (2.0 mL, 3.0 mmol), and DMF (0.55 mL, 7.1 mmol) gave the title compound as a brown oil that was used without further purification in the next step. 1H NMR (CDCl3) 0.00 (s, 9H), 0.95 (m, 2H), 3.61 (m, 2H), 5.82 (s, 2H), 7.12 (m, 2H), 7.28 (s, 1H), 7.59 (s, 1H), 7.80 (m, 2H), 9.88 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:21][C:22]([F:44])([F:43])[C:23]1[CH:24]=[C:25]([S:29]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]2[CH2:38][S:39](Cl)(=[O:41])=[O:40])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH2:13][CH2:12][N:11]([S:39]([CH2:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][N:32]3[S:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:44])([F:21])[F:43])[CH:24]=3)(=[O:31])=[O:30])(=[O:40])=[O:41])[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=S(=O)(Cl)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCN(S(=O)(=O)CC3CCCCN3S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
1-(1-Methyl-4-piperidinyl)piperazine (1.126 mmol) was dissolved in methylene chloride (7 ml), the solution was cooled in an ice bath and triethylamine (2.8 mmol) and (1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methanesulfonic acid chloride (dissolved in methylene chloride (3 ml)) were added. The mixture was stirred for 16 h, during which it was allowed to warm slowly to room temperature. The reaction mixture was diluted with methylene chloride and washed with water and the organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with methylene chloride/methanol (19:1). Yield: 30%. MS, Rt=2.4 min, m/z=553.0 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:12]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCc1ccc(Cl)c(Br)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(CBr)cc1Br
Temperature: -5 °C
Reaction time: 1 h

Procedure:
260 g (about 1.05 mol) of crude (3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 liters of dichloromethane, the solution was cooled to −5° C. and 127.1 g (44.6 ml, 460 mmol) of phosphorus tribromide were added slowly. After the end of the addition, the mixture was stirred at −5° C. for another 1 h and then diluted with diluted with dichloromethane and water. The organic phase was removed, dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 280.5 g (about 84% of theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Yield: 79 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (85 mg, 0.19 mmol) and N-bromosuccinimide (37 mg, 0.21 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 80 mg of the title compound as a yellow solid. MS: (−) m/z 531.17, 533.12 (M-1, 79/81Br).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:13]2[C:14]([Cl:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (15.5 mg) with purity >90%. MS (pos) m/z 399.1, 401.1, 403.1.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:22])[CH2:18][C:19]([NH2:21])=[O:20])=O)C1C=CC=CC=1.[ClH:23]>CO.[C].[Pd]>[ClH:23].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:22])[CH2:18][C:19]([NH2:21])=[O:20]
Reactant: NC(=O)CC(O)CCCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCCCCC(O)CC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.04 g (3.2 mmoles) of 8-benzyloxycarbonylamino- 3-hydroxyoctanamide in 20 ml of methanol were added 3.2 ml of 1N hydrochloric acid and 200 mg of 10% palladium-carbon. The mixture was stirred under a hydrogen stream at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness to yield 670 mg of 8-amino-3-hydroxyoctanamide hydrochloride.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11](/[CH:28]=[CH:29]\[CH3:30])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([O:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[C:11](/[CH:28]=[CH:29]\[CH3:30])[CH:10]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:31])[F:32])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
tert-Butyl (Z)-4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-1-yl)phenyl]piperazine-1-carboxylate (85 mg, 0.181 mmol) was dissolved in N,N′-dimethylformamide (1.8 mL), added sodium hydride (9.5 mg, 217 mmol) and benzyl bromide (23 μL, 0.190 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (67 mg) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].O.[CH3:14][N:15]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2]>[O:12]=[C:7]1[CH2:6][CH2:5][CH2:4][C:3]2[C:2]([C:14]#[N:15])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cccc2c1CCCC2=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a stirred solution of 5-bromo-3,4-dihydronaphthalen-1(2H)-one (9.95 g, 44.2 mmol) in NMP (50 mL) was added Zn(CN)2 (10.38 g, 88.4 mmol). The mixture was degassed twice by bubbling N2 through the solution for 30 min then evacuated. Pd(Ph3)4 (0.5 g, 0.44 mmol) was added and the mixture was heated to 110° C. under N2. After 5 h, the mixture was cooled to room temperature and poured onto ice (600 mL), using water (300 mL) to complete the transfer. After the ice had melted, the solution was filtered and the resulting solid was collected, suspended in DCM, and filtered again. The solid was collected, washed with water, and purified by column chromatography (EA/hex) to provide 6.9 g (91%) of 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-1 as a white solid. LCMS-ESI (m/z) calculated for C11H9NO: 171.2; found 172.1 [M+H]+, tR=2.95 min. 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J=7.9, 1.4 Hz, 1H), 7.82 (dd, J=7.6, 1.4 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 3.20 (t, J=6.1 Hz, 2H), 2.72 (dd, J=7.2, 6.1 Hz, 2H), 2.30-2.17 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 196.22, 147.39, 137.18, 133.39, 131.59, 127.19, 116.93, 112.94, 38.48, 28.05, 22.28.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[CH:1]1([O:5][C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=Cc1ccc(OC2CCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (0.12 g) and cesium carbonate (0.49 g) in N,N-dimethylformamide (2 mL) was added cyclobutyl bromide (0.15 g), and the mixture was stirred at 65° C. overnight. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.5 mol/L aqueous sodium hydroxide solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-cyclobutyloxybenzaldehyde (0.13 g). To a solution of the obtained 4-cyclobutyloxybenzaldehyde (0.13 g) in methanol (10 mL) was added sodium borohydride (0.056 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-cyclobutyloxybenzyl alcohol (0.12 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:28][C:29]1[N:30]=[C:31]([CH3:34])[NH:32][CH:33]=1>C(Cl)Cl>[I:28][C:29]1[N:30]=[C:31]([CH3:34])[N:32]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(I)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (13.4 mL, 96.2 mmol) followed by trityl chloride (20.1 g, 72.1 mmol) were added to an ambient temperature solution of 4-iodo-2-methyl-1H-imidazole (ca. 10 g, 48.1 mmol) in methylene chloride (90 mL). After stirring at ambient temperature for 2 days, the reaction mixture was diluted with methylene chloride and washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-15% acetone/methylene chloride afforded the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:14][CH2:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzaldehyde (1.27 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.75 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.