Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:28][C:27]([F:30])([F:29])[CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:28][C:27]([F:30])([F:29])[CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CC(F)(F)C2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CC(F)(F)C2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
184 mg (0.37 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 200 mg (purity 88%, quant.)
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: OCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.067 g) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 222 mg) and the mixture was stirred at 200 for 15 min. A solution of 2-[(6-bromohexyl)oxy]ethanol (1.157 g) in DMF (1 ml) was added and the mixture was stirred at 20° for 3.5 h. Phosphate buffer solution (pH 6.5, 20 ml) and water (30 ml) were added. The mixture was extracted with EtOAc (2×20 ml) and the combined extracts were washed with water (30 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (1.42 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:27]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(NCc4ccccc4)n3)c2)c1
Temperature: 110 °C
Yield: 19.8 %

Procedure:
A mixture of (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-3-methylbenzamide (55 mg, 0.15 mmol), benzylamine (0.033 mL, 0.3 mmol), bis(tri-t-butylphosphine)palladium(0) (8 mg, 0.015 mmol) and sodium tert-butoxide (22 mg, 0.225 mmol) in dry toluene (1 mL) was heated in a microwave reactor at 110° C. for 1 hour. After this time the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (5 mL)/methanol (5 mL), filtered through Celite and concentrated under reduced pressure to give a yellow solid which was purified by flash chromatography (silica, ethyl acetate/hexanes) followed by passage through a column of Sephadex with methanol as eluant to give the (S)—N-(3-(1-(6-(benzylamino)pyrazin-2-ylamino)ethyl)phenyl)-3-methylbenzamide (13 mg, 20%) as an unstable blue oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:24])[CH2:21][C:22]#[N:23])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[Cl:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:24])[C:21](=[CH:27][N:28]([CH3:30])[CH3:29])[C:22]#[N:23])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:4]1
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1
Product: CN(C)C=C(C#N)C(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1
Reaction time: 1.5 h

Procedure:
A solution of 20 g (0.0585 mol) of the above propanenitrile in 75 ml of N,N-dimethylformamide dimethylacetal was refluxed and stirred for 90 mins, and evaporated to dryness. The oil was triturated with ice water which was decanted, and the residue was partitioned between 150 ml of dichloromethane and 150 ml of water. The organic layer was dried with sodium sulfate, concentrated, and filtered through 150 g of Florisil. The column was eluted with ether which was evaporated, and the resulting oil was crystallized from ethanol to give end product. A sample was recrystallized from dichloromethane/ether to give white prisms, mp 107°-110° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([O:38][C:39]([F:42])([F:41])[F:40])[CH:9]=[C:10]([C@H:11]3[CH2:15][O:14][C@:13]4([CH2:21][CH2:20][C@H:19]5[NH:22][C@@:16]4([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH:18]5S(C4C=CC=CC=4)(=O)=O)[CH2:12]3)[C:4]=2[O:3]1.P([O-])([O-])(O)=O.[Na+].[Na+]>[Na].[Hg].CO>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([O:38][C:39]([F:42])([F:40])[F:41])[CH:9]=[C:10]([C@H:11]3[CH2:15][O:14][C@:13]4([CH2:21][CH2:20][C@H:19]5[NH:22][C@@:16]4([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:18]5)[CH2:12]3)[C:4]=2[O:3]1
Reactant: CC1Cc2cc(OC(F)(F)F)cc([C@H]3CO[C@]4(CC[C@H]5N[C@@]4(c4ccccc4)CC5S(=O)(=O)c4ccccc4)C3)c2O1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: CO
Product: CC1Cc2cc(OC(F)(F)F)cc([C@H]3CO[C@]4(CC[C@@H]5CC[C@]4(c4ccccc4)N5)C3)c2O1
Yield: 69.5 %

Procedure:
Sodium amalgam (10%, 2 g) was added in small portions to stirred mixture of (1R*,2R*,4S*,5R*)-2′,3′,4′,5′-tetrahydro-4′-[(2RS)-2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran-7-yl]-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Example 18; 160 mg, 0.26 mmol), disodium hydrogen orthophosphate (500 mg), methanol (10 ml) at +5° C. After reaction went to completion, the mixture was quenched with saturated aqueous NaHCO3, decanted and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (83 mg, 67%).
Reaction SMILES: COC(C1CC2C(=CC=C(S)C=2)C1)=O.[CH3:15][O:16][C:17](=[O:47])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29]CC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)[CH:25]=2)[CH2:20]1>>[CH3:15][O:16][C:17](=[O:47])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([SH:29])[CH:25]=2)[CH2:20]1
Reactant: COC(=O)CN1CCc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2C1
Agent: COC(=O)C1Cc2ccc(S)cc2C1
Product: COC(=O)CN1CCc2cc(S)ccc2C1
Yield: 74 %

Procedure:
10C was prepared analogously to compound 1C. 74% yield. MS: 238 (M+1)+. Preparation of {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic acid methyl ester (Compound 10D)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [F-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(-c3ccccn3)ccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
3,4-Dihydro-6-trifluoromethylsulfonyloxy-1(2H) -naphthalenone (2.40 g, 8.17 mmol) was dissolved in 25 ml of N,N-dimethylformamide in an argon atmosphere, and 3.65 g (9.91 mmol) of 2-pyridyltributyltin, 1.04 g (24.5 mmol) of lithium chloride and 0.29 g (0.41 mmol) of bistriphenylphosphinepalladium chloride were added to the solution. The mixture was stirred at 120° C. for 4 hours. The reaction product was cooled to room temperature. Ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 30% ethyl acetate and hexane) to obtain 0.93 g of the above-mentioned compound (yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(Cl)c(Cl)cc21
Product: CC1c2cc(Cl)c(Cl)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dichloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R )-2-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-ethylamine as a light yellow oil; MS: 560 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:14]1[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[N:16][CH:15]=1)O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:14]1[NH:18][CH:17]=[N:16][CH:15]=1
Reactant: OC(c1ccccc1)(c1cccc(C(F)(F)F)c1F)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1c(C(c2ccccc2)c2cnc[nH]2)cccc1C(F)(F)F
Yield: 62 %

Procedure:
(2-fluoro-3-(trifluoromethyl)phenyl)(phenyl)(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 8) (2.02 g, 3.49 mmol) in dichloromethane (30 mL) was reacted with TFA: trifluoroacetic acid (5.3 mL, 68 mmol)) and triethylsilane (TES) (2.8 mL, 17 mmol) at room temperature for 24 hours. The mixture was evaporated under reduced pressure and quenched with solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to yield 5-((2-fluoro-3-(trifluoromethyl)phenyl)(phenyl)methyl)-1H-imidazole 700 mg (62%). 1HNMR (CD3OD, 300 MHz): δ 7.54 (s, 1H), 7.52-7.26 (m, 3H), 7.18-7.11 (m, 4H), 6.66 (s, 1H), 5.84 (s, 1H), 5.49 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:28])[C:22]=3[C:21]3=[N:29][O:30][C:31]([CH3:32])=[C:20]3[C:19]2=[O:33])[CH2:13]1>C(O)C>[Cl:28][C:23]1[C:22]2[C:21]3[C:20](=[C:31]([CH3:32])[O:30][N:29]=3)[C:19](=[O:33])[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][CH:12]([NH:11][CH2:10][CH:8]([C:5]4[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:9])[CH2:13]3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Reactant: Clc1ccc(C2CO2)cn1
Solvent: CCO
Product: Cc1onc2c1c(=O)n(C1CCCC(NCC(O)c3ccc(Cl)nc3)C1)c1cccc(Cl)c21

Procedure:
To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7 mmol) in THF (7 mL) was added BH3 (16 mL, 17.1 mmol, 1M in THF) under N2 atmosphere. The reaction mixture was stirred for 5 h. It was quenched with methanol (5 mL) and then concentrated. The crude was dissolved in EtOAc (30 mL), washed with 1N NaOH (15 mL×3), brine, dried and concentrated. Yield: 615 mg (75%) of 6-chloro-pyridin-3-yl-methanol. To this alcohol (615 mg, 4.28 mmol) solution in CH2Cl2 (8 mL) was added Dess-Martin reagent (5.4 mg, 12.8 mmol). It was stirred at rt. for 2 h and then diluted with CH2Cl2. The resulting solution was washed with NaOH (1N, 2×5 mL), brine, dried and concentrated. 516 mg (85%) of yellow solid as the desired 6-chloro-pyridine-3-carbaldehyde. To a solution of above aldehyde (401 mg, 2.82 mmol) in CH2Cl2 (10 mL) was added 50% NaOH solution (9.3 mL), trimethylsulfonium iodide (1.15 g, 5.64 mmol) and tetrabutylammonium iodide (11 mg). It was refluxed for 48 h and poured onto ice water. The organic layer was extracted with CH2Cl2, washed with brine, dried and concentrated. The crude epoxide was chromatographed (gradient, hexanes: EtOAc) and 190 mg (43%) yellow oil was yielded as desired 2-Chloro-5-oxiranyl-pyridine. To the solution of 2-chloro-5-oxiranyl-pyridine (118.4 mg, 0.76 mmol) in absolute ethanol (40 mL) was added a compound from Example 660 (252 mg, 0.76 mmol). The reaction mixture was refluxed for 24 h and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[OH:30])[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].[Cl:31]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:31][C:27]1[CH:26]=[C:25]([F:29])[C:24]([OH:30])=[C:23]([C:4]2[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]3([NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:14]3)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:28]=1
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2O)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cc(Cl)cc(F)c2O)cc1F

Procedure:
To a solution of N-[(1R)-1-(3,3′-difluoro-2′-hydroxy-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide (125 mg, 0.292 mmol) in acetic acid (1 ml) was added N-chlorosuccinimide (39 mg, 0.292 mmol) and the solution was heated to 90 C for 2 h. After this time, the mixture was concentrated in vacuo and purified by column chromatography eluting with a 0-10% EtOAc/CH2Cl2 gradient to give N-[(1R)-1-(5′-chloro-3,3′-difluoro-2′-hydroxy-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide. Low resolution mass spectrometry: (M+H+)=462.9. 1H NMR (400 MHz, CDCl3) δ 7.26-7.34 (m, 3H), 7.12 (dd, 1H, J=9.9 and 2.4 Hz), 7.08 (s, 1H), 6.98 (s, 1H), 6.59 (d, 1H, J=8.6 Hz), 5.38-5.51 (br, 1H), 5.23 (quin, 1H, J=7.2 Hz), 1.55-1.70 (m, 2H), 1.52 (d, 3H, 7.2 Hz) and 1.08-1.21 (m, 2H) ppm.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[ClH:31].[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 79.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.48 ml (4.96 mmol) of 4-t-butylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.20 g of the desired compound (free base) (88.0%, yellow powder).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10](C(=O)C)[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)n1ncc2ncc(Br)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc2cn[nH]c2c1
Reaction time: 5 h
Yield: 85.6 %

Procedure:
To a solution of 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 5.9 mmol) in tetrahydrofuran (20 mL) and methanol (15 mL) was added a solution of sodium hydroxide (0.71 g, 18 mmol) in water (5 mL) at 27° C. After 5 h, the reaction was neutralized with hydrogen chloride acid (2 mol/L, 10 mL), and the resulting mixture was extracted with ethyl acetate (3×50 mL). The collected organic extracts were concentrated in vacuo. Purification by flash column chromatography (15→30% ethyl acetate in petroleum ether) afforded 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 86% yield). 1H NMR (400 MHz, Chloroform-d) δ 10.46 (brs, 1 H), 8.58 (s, 1 H), 8.25 (s, 1 H), 7.98 (s, 1 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][CH3:34])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:43](Cl)(Cl)=[S:44]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:33]([CH3:34])[C:43]2=[S:44])[CH2:19][CH2:18]1
Reactant: S=C(Cl)Cl
Reactant: CNc1ccccc1C(=O)NCCN1CCC(Cc2nc3cccnc3n2Cc2ccco2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=S)n(CCN2CCC(Cc3nc4cccnc4n3Cc3ccco3)CC2)c(=O)c2ccccc21
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a stirred mixture of 8 parts of N-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2-(methylamino)benzamide, 13 parts of N,N-diethylethanamine and 130 parts of dichloromethane was added dropwise a solution of 2.3 parts of carbonothioic dichloride in dichloromethane. Upon completion, stirring was continued for 2 hours. The reaction mixture was evaporated. The residue was crystallized from a mixture of methanol and ethanol. The product was filtered off and boiled in methanol. The product was filtered off and dried, yielding 3 parts (34.3%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-1-methyl-2-thioxo-4(1H)-quinazolinone; mp. 169.2° C. (486).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]([C:13]([OH:15])=O)[CH2:7]1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:13]([CH:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[C:11](=[O:12])[CH2:10][CH2:9]1)=[O:15])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CN2CC(C(=O)O)CCC2=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)CCC2=O)c(OC)c1
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid (3.39 g) in chloroform (15 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (2.04 g), WSC.HCl (2.44 g) and 4-dimethylaminopyridine (706 mg) at room temperature, and the mixture was stirred overnight. This reaction mixture was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=4/1 to 1/1) to give the titled compound (low-polarity component 3.37 g, high-polarity component 2.72 g).
Reaction SMILES: COCCCC[N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O>ClCCl>[Br:16][C:11]1[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=1
Reactant: COCCCCn1cccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)[nH]1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Methyl 1-(4-methoxybutyl)-1H-pyrrole-2-carboxylate (4.5 g) was dissolved in dichloromethane (30 ml), N-bromosuccinimide (4.0 g) was added and the mixture was stirred for 1 hr. The reaction mixture was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object product (2.2 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[CH3:6][CH:1]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:11]=[C:2]1[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2ccccc2C1C
Yield: 74 %

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, methylmagnesium bromide (3.0 mol/l ether solution)(16.9 ml, 50.7 mmol) and dehydrated ether (50 ml) were introduced. To the flask, a solution of 2-methyl-1-indanes (3.70 g, 25.3 mmol)in dehydrate ether (20 ml) was dropwise added at room temperature with stirring. Then, the reaction mixture was stirred for 2 hours and poured into cold water. The resultant mixture was introduced into a separatory funnel to separate an organic phase. The aqueous phase was extracted by ether (100 ml×3) and a combined organic phase was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 1,2-dimethyl-1-hydroxy-indene. The compound thus obtained was dissolved in toluene (30 ml) and, thereto, 0.1 g of p-toluenesulphonic acid was added. The reaction mixture was refluxed for 3 hours to remove water. The organic phase thus obtained was introduced into a separatory funnel and washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After removing a solvent, it was purified by column chromatography (developer: hexane) to obtain 2.70 g (GC 94%) of a pale yellow solution (yield: 74%).