Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[N:6]=1)=[O:4].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1B(O)O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:26]2[CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:25]=2[O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(C2=C(Br)CCC2)n1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Product: COC(=O)c1cccc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)n1

Procedure:
Prepared by general procedure 3 but using 6-(2-bromocyclopent-1enyl)pyridine-2-carboxylic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-benzyloxy-5-trifluoromethylphenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[OH-].[Na+]>ClCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:40](=[O:42])[CH3:41])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:17]=2)[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A solution of crude 5-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (200 mg, 0.42 mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (2 ml) at room temperature was treated with acetic anhydride (0.79 ml, 8.4 mmol) via dropwise addition over 4 minutes. The mixture was stirred at room temperature for 20 hours. The mixture was cooled (0° C.) and treated with 1N NaOH and stirred for 30 minutes. The aqueous layer was extracted with dichloromethane. The combined organic phases were washed with 1N HCl, dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (eluent, 2:1 n-hexanes:ethyl acetate) provided 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (144 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH2:15](C(CC)(CC)C([O-])([O-])[O-])[CH3:16]>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:15]([CH3:16])[NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[S:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=S)n2CC(C)C
Temperature: 130 °C
Yield: 95 %

Procedure:
A mixture of 5,6-diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (Example 6 (c), 0.70 g, 3.26 mmol) and triethylorthoacetate (10 mL) was heated at 130° C. for 2 h and 40 minutes. Then the reaction mixture was cooled on an ice-bath, the solid filtered off and washed with ethanol (4×2 mL). The solid was dried in vacuo yielding the title compound (0.71 g, 95%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[NH2:18].C(OCC)(=O)C>CN1CCCC1=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: OCCn1ccc2ncnc(Cl)c21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (130 mg) in 1-methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethyl acetate (20 mL) was added. The resultant precipitate was recrystallized from a mixed solvent of hexane/methanol (3/7), collected by filtration and dried under reduced pressure to give the title compound (206 mg) as pale purple crystals.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:17][C:18](=O)[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)OC.O.[NH2:25][NH2:26]>>[C:19]([C:18]1[N:25]=[N:26][C:2]2[CH:1]3[CH2:8][CH2:7][CH:4]([C:3]=2[CH:17]=1)[CH2:5][CH2:6]3)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1C(=O)C2CCC1CC2
Reactant: NN
Reactant: COP(=O)(CC(=O)C(C)(C)C)OC
Solvent: O
Product: CC(C)(C)c1cc2c(nn1)C1CCC2CC1

Procedure:
White solid MS (ESI): 217.1 (MH+). Prepared from bicyclo[2.2.2]octane-2,3-dione, (3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13](O)=[O:14].[CH3:21][NH:22][O:23][CH3:24].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([N:22]([O:23][CH3:24])[CH3:21])=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)ccc1Br
Reaction time: 3 h

Procedure:
N,N-diisopropylethylamine (1.10 mL, 6.36 mmol) was added to a stirred solution of 2-bromo-5-chlorobenzoic acid (0.500 g, 2.12 mmol), N,O-dimethylhydroxyl-amine.HCl (0.310 g, 3.18 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (1.21 g, 3.18 mmol) in N,N-dimethylformamide (8.5 mL) at ambient temperature. After 3 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-25% ethyl acetate/hexanes as eluent) gave the title compound as a colorless solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
To a suspension of 4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (216 mg, 0.53 mmol) and 2,6-dichlorobenzoyl chloride (120 mg, 0.57 mmol) in THF (6 mL) was added DIEA (210 μL, 1. 19 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 18 h. Then, the mixture was diluted with ethyl acetate (50 mL). The ethyl acetate solution was washed successively with 0.5 N HCl (50 mL), saturated NaHCO3 solution (50 mL) and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was dissolved in ethyl acetate (˜3 mL) and hexanes (˜3-4 mL) was added and stored in the refrigerator. The solid was collected and washed with hexanes. After drying under high vacuum, 270 mg (93.5% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester was obtained a white solid: mp 170-173° C. ES-HRMS m/e calcd for C25H21Cl2F3N2O4 (M+Na) 563.0724 found 563.0730.
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1Cl>C(O)(C)C>[ClH:12].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nn1ccc2ccccc21
Reactant: Clc1ccncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Clc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 100° C. for 4 hours in substantially the same manner as in Example 1, m.p. >230° C.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]#[N:7].C[O-].[Na+].[Cl-:11].[NH4+:12]>>[ClH:11].[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6](=[NH:12])[NH2:7]
Reactant: N#Cc1nncs1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Product: Cl
Product: N=C(N)c1nncs1

Procedure:
1,3,4-thiadiazole-2-carbonitrile (1.11 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61, Step B to give the title compound as an offwhite solid (1.15 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[CH:14][N:15]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cn2)CC1

Procedure:
4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from N-(4-tert-butyl-phenyl)-6-chloro-nicotinamide and 1-Boc-piperazine following a procedure similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 10-30% EtOAc in hexanes gradient. HRMS m/z calcd for C25H34N4O3 [M+H]+: 439.2704. Found; 4392700.
Reaction SMILES: [CH2:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6](O)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].CS(Cl)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.CCN(CC)CC>[N:29]([CH:6]([Si:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C(O)CC(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C(CC(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 34 (1.68 g, 5.16 mmol) in CH2Cl2 (100 mL) and Et3N (3.6 mL) at 0° C. was added dropwise over 5 min methanesulfonyl chloride (2.96 g, 25.8 mmol), and the solution was allowed to warm to rt over 1 h. After stirring overnight under argon, the mixture was cooled to 0° C. and quenched with water (50 mL). The organic layer was isolated and the aqueous layer extracted twice with 20-mL portions of CH2Cl2. The combined organic extracts were concentrated in vacuo at rt. The crude mesylate was dissolved in DMF (100 mL), and to this solution was added sodium azide (1.68 g, 25.8 mmol). After stirring for 8 h at rt, the mixture was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was isolated and aqueous layer extracted twice with 50-mL portions of EtOAc. The combined organic extacts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 35 as a colorless oil (1.57 g, 87%): Rf=0.90 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=6.7 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 5.00 (dd, J=17.0, 1.5 Hz, 1H), 4.92 (dd, J=10.2, 1.5 Hz, 1H), 3.44 (d, J=12.4 Hz, IH), 2.12 (m, 2H), 1.84 (m, 1H), 1.60 (t, J=12.5 Hz, 1H), 1.30 (m, 3H), 0.92 (d, J=6.7 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 140.7, 135.3, 132.6, 129.9, 128.0, 113.3, 49.2, 38.8, 27.5, 25.9, 23.3, 20.7, 10.5; IR (neat) 3071 (w), 3051 (w), 2995 (w), 2957 (s), 2923 (m), 2866 (m), 2102 (s), 1642 (w), 1473 (w), 1432 (s), 1264 (m), 1188 (w), 1116 (s), 1004 (w), 915 (m), 743 (s), 701 (s) cm−1; MS (FAB) m/e (rel. intensity) 350 (MH+, 18), 323 (32), 322 (100), 321 (27), 320 (16), 315 (42), 306 (42), 252 (17), 251 (23), 237 (18), 236 (73), 223 (26), 208 (17); HRMS (FAB) calcd for C21H28N3Si: 350.2053. found: 350.2040. Anal. Calcd for C21H27N3Si: C, 72.16; H, 7.79; N, 12.02. Found: C, 71.99; H, 7.91; N, 11.60.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([Br:19])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35].Cl>O1CCCC1>[Br:19][C:16]1[CH:17]=[C:18]2[C:10]([C:8]([C:4]3[C:3]([F:20])=[C:2]([NH:1][S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])(=[O:36])=[O:35])[CH:7]=[CH:6][CH:5]=3)=[O:9])=[CH:11][NH:12][C:13]2=[N:14][CH:15]=1
Reactant: Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(c1cccc(NS(=O)(=O)c2ccccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
To (3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (19, 53 mg, 0.159 mmol) in 0.63 mL of tetrahydrofuran, pyridine (0.115 mL, 1.43 mmol) is added, followed by 2-fluorobenzenesulfonyl chloride (20, 46 mg, 0.238 mmol) and the reaction is stirred at room temperature for 48 hours. Hydrochloric acid (1M aqueous) is added to adjust the mixture to pH 4, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (21, 56 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH:9]=O)[CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40]CC)=[O:39])[CH2:34][CH2:33]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][N:32]2[CH2:33][CH2:34][CH:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37]2)[CH:7]=1
Reactant: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1c(CCN2CCC(C(=O)O)CC2)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (80 mg) and ethyl 4-piperidinecarboxylate (138 mg) in dichloromethane (DCM) (15 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (74.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was dissolved in isopropanol (10 mL) and water (10 mL), sodium hydroxide (50 mg) was added. Stirring continued for 2 h at room temperature. 1M HCl solution was added until PH=6˜7. Then iPrOH was removed by evaporation. The aqueous layer was extracted by EA/THF/MeCN for 3 times. The combined organic layers were concentrated, and purified by Mass Directed AutoPrep to give 1-{2-[5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylic acid (E13) (45 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 1.57 (2H, m), 1.79 (2H, d), 2.06 (2H, t), 2.19 (1H, m), 2.58 (2H, t), 2.87 (4H, t), 3.80 (3H, s), 4.94 (1H, m), 7.45 (1H, dd), 7.51 (1H, d), 7.88 (1H, dd), 8.23 (1H, d), 8.29 (1H, dd). δF (DMSO-d6, 376 MHz): −117.4, −61.3. MS (ES): C27H29F4N3O4S requires 567. found 568.2 (M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:35])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:35])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a suspension of 60% sodium hydride (800 mg, 20 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (2.4 g, 20 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A52. A solution of 4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1 g, 2.86 mmol) and 1,1′-carbonyldiimidazole (930 mg, 5.71 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B52. Solution B52 was added to Solution A52 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (107 mg, 8%) as a brown solid: MS (ESI) M+1=454.2.
Reaction SMILES: C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:5](C)=O.[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCCl.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:5])=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCCCC1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
0.54 ml of 37% aqueous formaldehyde and then 1.41 g of NaBH(OAc)3 are added to a solution of 0.99 g of the compound obtained in step 5.2, in 11 ml of DCE, and the medium is stirred at AT for 12 h. The medium is diluted in DCM and filtered through cotton wool. The organic phase is washed twice with a saturated NaHCO3 solution, and then with a saturated NaCl solution. After drying over MgSO4 and evaporation of the solvents, 0.84 g of the expected product is recovered.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH:7]=1)=[O:4]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:24])([F:1])[F:23])[CH:11]=[CH:10][CH:9]=2)=[N:14][CH:15]=1
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
2,2,2-Trifluoro-N-{3-[methyl(5-nitropyridin-2-yl)amino]phenyl}acetamide (5.00 g, 14.7 mmol) was dissolved in ethanol (66 mL)/tetrahydrofuran (33 mL), 10% palladium-carbon (500 mg) was added, and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The precipitate was collected by filtration to give the title compound (3.60 g, 79%) as a pale-violet powder.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[O:22][CH3:23].[CH3:24][C:25](O)([CH3:27])[CH3:26]>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:18])=[CH:15][C:14]=1[O:22][CH3:23]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
MgSO4 (4.82 g, 40.0 mmol), DCM (40 mL), and H2SO4 (533 μL, 10.0 mmol) were combined at 0° C. and the mixture was allowed to stir for 30 minutes at 0° C. 4-Bromo-3-methoxy-benzoic acid (2.31 g, 10.0 mmol) and 2-methylpropan-2-ol (4.78 mL, 50.0 mmol) were added and the mixture was allowed to stir at rt overnight. The mixture was filtered to remove the MgSO4 and the filtrate was washed with 1N NaOH. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was removed to yield 400 mg of tert-butyl 4-bromo-3-methoxybenzoate. ESI-MS m/z calc. 286.0. found 287.0 (M+1)+; Retention time: 3.11 minutes (4 min run).