Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16]Br)[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.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(C(C)=O)C>[C:1]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH2:16][N:33]2[CH2:34][CH2:35][C:30]3([N:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)[CH2:27][NH:28][C:29]3=[O:36])[CH2:31][CH2:32]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(N2CNC(=O)C23CCNCC3)cc1
Reactant: BrCCCN(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(N2CNC(=O)C23CCN(CCCN(c2ccccc2)c2ccccc2)CC3)cc1

Procedure:
A mixture of 940 mg. (0.00325 moles) of 3-[N,N-diphenylamino]-1-bromopropane (prepared according to the procedure of Example 2) and 850 mg. (0.00325 moles) of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 400 mg. of sodium carbonate and 100 mg. of sodium iodide in 15 ml. of methyl ethyl ketone is refluxed for about 16 hours. The preparation of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one is described in U.S. Pat. No. 3,155,670 to Janssen, issued Nov. 3, 1964. Solvent is evaporated and the residue is dissolved in chloroform, washed with water and chromatographed on a column of silica gel. The product fractions are evaporated and the residue is recrystallized from isopropyl alcohol and again from ethanol, giving 470 mg. of 8-[3-diphenylamino)propyl]-1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, mp. 156.5°-157.5° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH:13]=1)[CH:11]=O)([CH3:5])[CH3:4])#[N:2].[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][CH2:11][C:10]2[CH:13]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=[CH:8][C:9]=2[O:14][CH:15]([CH3:17])[CH3:16])[C@@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: CC(C)Oc1ccc(C(C)(C)C#N)cc1C=O
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 41 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:12][CH2:13][C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27]C1C(Cl)=CC=CC=1CCN.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[Cl:27][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1cccc(Cl)c1Cl
Reactant: O=C(O)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
3-((Benzyloxycarbonyl)(3,4-dichlorophenethyl)amino)propanoic acid (0.5 g), prepared according to the procedure of Example 1 step iv), but using 2,3-dichlorophenethylamine instead of phenethylamine, was dissolved in dichloromethane (10 mL) and treated with oxalyl chloride (0.132 mL) and DMF (0.05 mL). The reaction was stirred at room temperature until gas evolution ceased, and the solvent was removed in vacuo to give an oil which was used in step ii) directly.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(I)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of 4-iodophenol (25.0 g), 2-fluorobenzaldehyde (14.14 g), potassium carbonate (31.5 g) and dimethylformamide (500 ml) was heated at 120° C. under nitrogen with stirring for 15 hours. The mixture was cooled to ambient temperature and filtered. Water (500 ml) was added to the filtrate and the mixture was extracted with ethyl acetate to give a solid which was triturated with hot hexane (500 ml). The supernatant liquid was decanted from a residual gum and cooled. The solid which precipitated was collected by filtration to give 2-(4-iodophenoxy) benzaldehyde, m.p. 84.5-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[S:12](=[O:14])(=[O:13])[N:11]([CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][CH2:17]Cl)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)=[CH:4][CH:3]=1.[I-].[Na+].[CH3:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=3[N:11]([C@@H:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][CH2:17][NH:32][CH3:31])[S:12]2(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=S1(=O)N(c2ccc(Cl)cc2)c2ccccc2N1C(CCCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Product: CNCC[C@H](c1ccccc1)N1c2ccccc2N(c2ccc(Cl)cc2)S1(=O)=O
Reaction time: 96 h

Procedure:
1-(4-Chloro-phenyl)-3-(3-chloro-1-phenyl-propyl)-1,3-dihydro-benzo[1,2,5]-thiadiazole 2,2-dioxide (0.12 g) was dissolved in methylamine (8M in ethanol, 20 mL), sodium iodide (58 mg, 0.39 mmol) was added and the mixture stirred for 96 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give (3R)-3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-3-phenylpropan-1-amine as a colorless oil. The freebase was dissolved in methanol (5 mL) and treated with 2N aqueous hydrochloric acid (1.0 equivalent) and concentrated. The residue was dissolved in water and lyophilized to give 130 mg (72%) (3R)-3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-3-phenylpropan-1-amine as hydrochloride salt as a white powder. MS (ES) m/z 427.8.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([S:31][CH2:32][CH2:33][NH2:34])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([S:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCSCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCSCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 72.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethylsulfanyl-ethyl)-amide (72 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylic acid (82 mg), 2-ethylthio-ethylamine (34 mg), HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 497.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:15]([N:34]1[CH:38]=[C:37]([CH:39]=[O:40])[N:36]=[CH:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[OH:40][CH:39]([C:37]1[N:36]=[CH:35][N:34]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:38]=1)[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 14.80 mmol of 4-iodobenzonitrile [3058-39-7] in 20 ml of tetrahydrofuran is cooled to −30° C., and 14.80 mmol of i-propylmagnesium chloride (2M in tetrahydrofuran) are added. The mixture is stirred at −30° C. for 60 minutes and a solution, precooled to −30° C., of 11.84 mmol of 1-trityl-1H-imidazole-4-carbaldehyde [33016-47-6] in 30 ml of tetrahydrofuran is added. The mixture is stirred at −30° C. for 30 minutes, and then the reaction mixture is warmed to room temperature and quenched with saturated aqueous ammonium chloride solution. The phases are separated, and the aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried with magnesium sulphate and evaporated. The title compound is obtained as a white solid from the residue by recrystallization from ethyl acetate. Rf=0.23 (CH2Cl2-2M NH3 in EtOH 97:3); Rt=7.32.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][C@H:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][C:14]1=[O:26])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][CH2:7][CH2:8][C@H:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][C:14]1=[O:26])[C:10]([NH:41][C:38]1[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]2[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]2)[N:37]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
In a round bottom flask under argon was placed (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid (190 mg, 0.45 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 105 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL). To this mixture was added N,N-diisopropyethylamine (220 μL, 1.34 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (295 mg, 0.57 mmol) and stirred for 5 h at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and saturated aqueous sodium chloride solution (25 mL) dried over sodium sulfate, and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate/hexanes) afforded (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-butyramide (131 mg, 49%) as a white foam: HR-ES-MS m/z calculated for C29H41N4O6ClSi [M+H]+ 605.2557, observed 605.2559.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][CH:14]([F:21])[C:15](N(OC)C)=[O:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[F:13][CH:14]([F:21])[C:15]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:16]
Reactant: CON(C)C(=O)C(F)F
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1cccnc1)C(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
To toluene (7.0 mL) were added dropwise at −78° C. n-butyllithium (2.76 mol/L solution in n-hexane, 2.60 mL, 7.19 mmol) and a solution of 3-bromopyridine (1.00 mL, 10.4 mmol) in toluene (2.5 mL), and the mixture was stirred at the same temperature for 30 minutes. THF (4.0 mL) was added to the resulting suspension and the mixture was stirred at −78° C. for 15 minutes. To the mixture was added 2,2-difluoro-N-methoxy-N-methylacetamide (1.00 g, 7.19 mmol) and the mixture was stirred for 3 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 2,2-difluoro-1-(pyridin-3-yl)ethanone (868 mg, 91% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1>O.C(#N)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1cc(I)ccn1
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(Nc2cc(I)ccn2)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-4-iodopyridine (1.0 g, 4.48 mmol) and 4-aminobenzenesulfonamide (772 mg, 4.48 mmol) was heated with an oil bath for 3 hours at 150° C. The title compound A4 was obtained from the residue by preparative HPLC (water/ACN gradient). Yield: 135 mg (8%). MS (ES) C11H10IN3O2S requires: 375. found: 376 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([O-])([OH:9])=[O:8].S(=O)(=O)(O)O>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1c[nH]cn1
Agent: O=S(=O)(O)O
Product: Cc1nc[nH]c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
4-Methylimidazole (10 g, 0.12 moles), was cooled in a flask, and fuming nitric acid (11 ml, 0.24 moles) was added dropwise. This was followed by the addition of sulfuric acid (11 ml). The reaction was then heated with stirring at 100° C. for 21/2 hours. The cooled reaction mixture was then added to 500 ml of ice water, and the precipitate was filtered off. The filtrate was neutralized with ammonium hydroxide, and filtered again. The combined precipitates were then recrystallized from water to give 6.35 g of 4-methyl-5-nitroimidazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:22][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: NCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1NCc1cccnc1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethyl-amino)-pyrimidine-5-carbonitrile was treated with 3-picolylamine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as a colorless foam.
Reaction SMILES: Cl.ClC1C=CC(S[C:10]2[N:15]=[CH:14][N:13]=[C:12]([C@@H:16]([CH3:33])[C@@:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])([OH:24])[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[C:11]=2[F:34])=CC=1.C([O-])=O.[NH4+]>O1CCCC1.O.[Zn]>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@@:17]([OH:24])([C@@H:16]([C:12]1[C:11]([F:34])=[CH:10][N:15]=[CH:14][N:13]=1)[CH3:33])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: C[C@H](c1ncnc(Sc2ccc(Cl)cc2)c1F)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1ncncc1F)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
13.3 g of zinc powder treated with 1N HCl was dissolved in 300 ml of tetrahydrofuran and refluxed for 1 hour. The resulting solution was cooled to 50° C., and 20 g of (2R,3S)/(2S,3R)-3-[6-(4-chloro-phenylsulfanyl)-5-fluoro-pyrimidine-4-yl]-2-(2,4-difluoro-phenyl)-1-[1,2,4]triazol-1-yl-butane-2-ol obtained in Example 1 or 2 was added thereto. 7.71 g of ammonium formate dissolved in 200 ml of water was slowly added to the resulting mixture for 30 min, and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered and washed with 200 ml of ethyl acetate. The resulting residue was washed with 200 ml of saturated ammonium chloride aqueous solution, and the water layer was removed therefrom. The organic layer was washed with 200 ml of sodium bicarbonate and 200 ml of brine, and dried over magnesium sulfate. 200 ml of ethyl acetate and 100 ml of hexane were added to the resulting residue, and 9 ml of concentrated HCl was added thereto for crystallization. 200 ml of ethyl acetate and 200 ml of sodium bicarbonate were added to the obtained solid mixture and stirred for 10 min, and the resulting solid was filtered out by using celite. The resulting organic layer was washed with 200 ml of a 5% sodium hydroxide aqueous solution and concentrated under a reduced pressure to obtain the crystallized title compound (12.7 g, yield: 90%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[N+:34]([C:37]1[CH:38]=[CH:39][C:40]([C@@H:43]([NH:45][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[CH:22]=[C:23]3[CH3:33])=[O:31])[CH3:44])=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:11][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1cccc(CBr)c1
Reactant: CC(C)(O)C(C)(C)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a solution of 3-(bromomethyl)phenyl boronic acid (3.13 g) in ethyl acetate (45 ml) were sequentially added pinacol (1.72 g) and anhydrous magnesium sulfate (15 g) at room temperature, and the mixture was stirred for 8 hours. The insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure to give the titled compound (4.43 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C@@:11]2([CH3:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:3]=1[CH2:24][CH2:25][OH:26].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C@@:11]2([CH3:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12]2)[C:3]=1[CH2:24][CH2:25][O:26][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: CSc1nc(Cl)c(CCO)c(N[C@@]2(C)CCN(C(=O)OC(C)(C)C)C2)n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSc1nc(Cl)c(CCOS(C)(=O)=O)c(N[C@@]2(C)CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.7 %

Procedure:
To a solution of tert-butyl(3S)-3-{[6-chloro-5-(2-hydroxyethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylate (1.37 g, 3.40 mmol) in DCM (57 mL) was added TEA (1.66 mL, 11.9 mmol), methanesulfonylchloride (0.7 mL, 8.5 mmol) and DMAP (25 mg, 0.204 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was transferred to a separatory funnel with the aid of DCM. The solution was washed with water (3 times), dried over Na2SO4 and concentrated to give 1.86 g (>99%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J=18.5 Hz, 1 H), 4.28-4.19 (m, 2 H), 3.82-3.61 (m, 1 H), 3.60-3.42 (m, 1H), 3.41-3.36 (m, 1 H), 3.32-3.23 (m, 1 H), 3.13 (s, 3 H), 3.12-3.06 (m, 2 H), 2.45 (s, 3 H), 2.41-2.26 (m, 1 H), 2.07-1.97 (m, 1 H), 1.46 (d, J=11.4 Hz, 3 H), 1.38 (s, 9 H). m/z (APCI+) for C18H29ClN4O5S2 481.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].C(Cl)(=O)N.C(NC(Cl)=O)C.CN(C)C(Cl)=O.C([S:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:45])=[CH:35][CH:34]=1)[C:30]([OH:32])=[O:31])(=O)N.C(NC(SC(C1C=CC(C2C=CC=CC=2Cl)=CC=1)C(O)=O)=O)C.CN(C)C(SC(C1C=CC(C2C=CC=CC=2Cl)=CC=1)C(O)=O)=O>>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([S:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:45])=[CH:35][CH:34]=1)[C:30]([OH:32])=[O:31])=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: NC(=O)SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1
Agent: CCNC(=O)Cl
Agent: CCNC(=O)SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1
Agent: CN(C)C(=O)Cl
Product: CCN(CC)C(=O)SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
When diethylcarbamylchloride is replaced in the above procedure by carbamyl chloride (prepared in situ from potassium cyanate and anhydrous hydrogen chloride in anhydrous chloroform), ethylcarbamyl chloride or dimethylcarbamyl chloride, then the products prepared are α-carbamylthio2'-chloro-4-biphenylylacetic acid, α-ethylcarbamylthio-2'-chloro-4-biphenylylacetic acid or α-dimethylcarbamylthio-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:19])=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12]([Cl:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(C(=O)O)c1ccc(CC(C)C)cc1
Reactant: O=S(Cl)Cl
Product: CCC(C(=O)Cl)c1ccc(CC(C)C)cc1
Yield: 98.1 %

Procedure:
110 g of 2-(4-isobutylphenyl)butyric acid and 89 g of thionyl chloride are heated on a water bath until the gas evolution ceases. An excess of thionyl chloride is removed by distillation, A residue of 117 g of 2-(4-isobutylphenyl)butyric chloride is obtained.