Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[CH3:20][N:21](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[C:20]([C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:5]=[N:6][CH:7]=1)#[N:21]
Reactant: COC(=O)c1cc(Oc2cncc(Br)c2)cc(C)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(Oc2cncc(C#N)c2)cc(C)n1
Temperature: 140 °C
Yield: 81 %

Procedure:
Methyl 4-(5-bromopyridin-3-yloxy)-6-methylpicolinate (313 mg, 0.969 mmol, 1.00 eq), Tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.0969 mmol, 0.1 eq), Zn(CN)2 (125 mg, 1.06 mmol, 1.1 eq), and DMF (5 mL) were added to a microwave vial and heated at 140° C. for 10 minutes. The reaction was filtered and concentrated on silica gel (2 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude solid was purified by flash chromatography on silica gel to afford 210 mg (81%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J=1.5 Hz, 1H), 8.84 (d, J=2.7 Hz, 1H), 8.35-8.34 (m, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H); [M+1]+: 270.1.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:30])[C:28]#[N:29]>CN(C=O)C>[C:28]([CH:27]([N:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:30])#[N:29]
Reactant: CC(Br)C#N
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 1.55 g, 5.91 mmol) in DMF (15 mL) is added potassium carbonate (2.45 g, 17.7 mmol), and the mixture is stirred at room temperature for 20 min. 2-bromopropionitrile (1.05 mL, 11.8 mmol) is added, the mixture is warmed to 80° C., and is stirred overnight. After being cooled to room temperature, the mixture is poured onto H2O, and the aqueous layer is extracted with EtOAc (3×100 mL). The combined organic extracts are dried (MgSO4), filtered, and concentrated. The crude material is purified via flash column chromatography using a gradient elution of 10-50% ethyl acetate/hexanes to afford the title compound as a bright yellow solid (809 mg, 43%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:28]=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:39][N:38]=2)[C:30]2[N:31]([CH:33]=[CH:34][N:35]=2)[CH:32]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[N:28]=[C:29]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)=[CH:39][N:38]=3)[C:30]3[N:31]([CH:33]=[CH:34][N:35]=3)[CH:32]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(N4CCN(C)CC4)cn3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn4ccnc34)nc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
A mixture of 106d (200 mg, 0.92 mmol) and LiOH (300 mg, 10 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (1 mL) was stirred at 50° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with Ethyl acetate (10 mL×2). The combined Ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 106 (45 mg, 20%). LCMS: [M+H]+ 622. 1H NMR (500 MHz, DMSO) δ 9.04 (s, 1H), 8.41 (s, 1H), 8.13-8.10 (m, 2H), 7.98 (s, 1H), 7.71 (s, 1H), 7.47-7.44 (m, 2H), 7.39-7.37 (m, 1H), 6.53 (s, 1H), 5.38-5.36 (m, 1H), 4.37-4.44 (m, 2H), 4.19-3.98 (m, 4H), 3.12 (s, 4H), 2.60-2.58 (m, 2H), 2.50-2.45 (m, 6H), 2.21 (s, 3H), 1.79-1.68 (m, 2H), 1.69-1.67 (m, 2H)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[C:8]1([C:5]2[S:6][CH:7]=[C:3]([CH2:2][OH:16])[N:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1csc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (8.60 g), sodium acetate (10.1 g) and N,N-dimethylformamide (80 ml) was stirred at 80° C. for 6 hours. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (25 ml), tetrahydrofuran (50 ml) and methanol (50 ml) was stirred at room temperature for 5 minutes, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-phenyl-4-thiazolylmethanol (7.05 g, yield 90%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from hexane. Melting point: 71–72° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]CC)=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].[OH-].[Na+].O>C1COCC1>[F:24][C:2]([F:1])([F:25])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 65.2 %

Procedure:
3′-Trifluoromethylsulfonamido-[1,1′-biphenyl]-3-carboxylic acid, ethyl ester (150 mg, 0.40 mmol, 1 eq.) and 1.000 N NaOH (0.80 mL, 0.80 mmol, 2 eq.) were dissolved in THF (5 mL) at room temperature and stirred for 20 hours. Little reaction. Added 100 mg of NaOH and heated at 50° C. for 20 hours. Worked up by adding water then rinsing 2 times with diethyl ether. The aqueous layer's pH was adjusted to 3 with 1N HCl. The acidic aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 3′-trifluoromethylsulfonamido-[1,1′-biphenyl]-3-carboxylic acid (90 mg) of an amber solid. Yield=65%. Mass Spec (ESI) detects (M+H)+=344.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=[O:5])[CH3:2].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:4]([C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]=1[O:15][CH2:16][CH:18]1[O:20][CH2:19]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1[nH]c2c(c1O)CCCC2
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c2c(c1OCC1CO1)CCCC2
Yield: 100.1 %

Procedure:
Using the method described in Example V, 130 g of 3-hydroxy-4,5,6,7-tetrahydroindole-2-carboxylic acid ethyl ester, 170 g of epibromohydrin and 172 g of anhydrous potassium carbonate in 500 ml of acetone give 165 g of 1-(2-carboethoxy-4,5,6,7-tetrahydro-indol-3-oxy)-2,3-epoxypropane, of melting point 102°-104° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24][CH2:23]1.[CH3:30][C:31]1([CH3:45])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:38]2[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=2)[O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.O>[CH3:36][C:35]1([CH3:37])[C:31]([CH3:30])([CH3:45])[O:32][B:33]([C:38]2[CH:43]=[CH:42][C:41]([O:29][CH2:28][C@H:25]3[CH2:26][CH2:27][C@H:22]([O:21][CH:16]4[CH2:17][CH2:18][CH2:19][CH2:20][O:15]4)[CH2:23][CH2:24]3)=[CH:40][CH:39]=2)[O:34]1
Reactant: OC[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) was added to a solution of [trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (2.05 g, 9.57 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.3 g, 10.7 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) in THF (150 mL) at 0° C. The reaction was allowed to warm to rt and stirred overnight. Water (200 mL) was added and the reaction was extracted with EtOAc (600 mL). The organics were washed with 1 M aq NaOH (4×100 mL), brine, then dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified via flash chromatography using an eluent of 20% EtOAc in hexanes to afford the title compound as a white solid (1.9 g, 48%). MS (APCI) m/z 417.3 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+].[C:27](OC)(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Reactant: CCCCCCCCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)CCCCCCCCCCCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-octadecylamine (1.0 g, 0.0029 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (0.7885 g, 0.0029 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.59 g). The waxy solid was recrystalized from hot hexane (yield=0.99 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH2:16][CH2:15][C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:20].[Ce+4].S([O-])([O-])(=O)=O>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH2:16][C:15](=[O:20])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Agent: [Ce+4]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2=O
Yield: 29.9 %

Procedure:
To a suspension of 2-Acetylamino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (140 g) in acetic acid (1.5 L) and water (1.5 L) was added gradually cerium (IV) sulfate 4 hydrate (900 g) with vigorously stirring. After the solution was stirred overnight, the solid was removed by filtration and the filtrate was concentrated. The solution was then neutralized with aqueous ammonia and extracted 3 times with ethyl acetate-tetrahydrofuran (=4:1). The organic layers were combined and evaporated in vacuo. The resulting solid was washed with tetrahydrofuran to provide the title compound (44 g) as a pale yellow solid.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-phenylethylamine as the starting materials.
Reaction SMILES: OC1C=C(N2C3C(=NC(OC)=CC=3)N=C2)SC=1C(OC)=O.[OH:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32]3=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=[C:31]3[N:30]=[CH:29]2)[S:25][C:24]=1[C:39]([O:41][CH3:42])=[O:40].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58]>CN(C)C=O>[CH3:38][O:37][C:34]1[N:33]=[C:32]2[N:28]([C:26]3[S:25][C:24]([C:39]([O:41][CH3:42])=[O:40])=[C:23]([O:22][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:57]([F:58])([F:59])[F:60])[CH:27]=3)[CH:29]=[N:30][C:31]2=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3nc(OC)ccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 1.4 g of an isomeric mixture of methyl 3-hydroxy-5-(5-methoxy-1H-imidazo[4,5-b]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)thiophene-2-carboxylate (example C9) and 0.76 g K2CO3 and 1.31 g 1-(bromomethyl)-2-(trifluoromethyl)benzene in 20 ml N,N-dimethylformamide yield compound B7a and compound B7b as crude material. These compounds were used for the next step (examples 22 and 23) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][CH:16]1[CH2:17][O:18]1
Reactant: ClCC1CO1
Reactant: CCC(C)(C)c1ccc(O)c(Cl)c1
Product: CCC(C)(C)c1ccc(OCC2CO2)c(Cl)c1

Procedure:
The title compound was prepared from 2-chloro-4-(1,1-dimethyl-propyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]1[CH2:25][OH:26]
Reactant: [H][H]
Reactant: CC(C)c1nc(CO)n(Cc2cccc([N+](=O)[O-])c2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2cccc(N)c2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 3 h

Procedure:
In ethyl acetate was dissolved 64 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(m-nitrobenzyl)-1H-imidazole (103b), and platinum sulfided carbon was added. After replacement with hydrogen atomosphere, the mixture was catalytically hydrogenated under atmospheric pressure at room temperature. After 3 hours, the mixture was filtered through Celite, the filtrate was distilled off under reduced pressure, and diethyl ether was added. Crystals precipitated were filtered, and 25 mg of Compound I-118 was obtained (yield 42%). mp 145-148° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C@@H:33]2[CH2:37][NH:36][CH2:35][C@H:34]2[OH:38])[CH2:29][CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:36]3[CH2:37][C@@H:33]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[C@H:34]([OH:38])[CH2:35]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CN1CCN([C@@H]2CNC[C@H]2O)CC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](O)[C@H](N4CCN(C)CC4)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R,4R)-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 522, 1H NMR (400 MHz, CD3OD) δ ppm 7.99-7.86 (m, 1 H), 7.84-7.75 (m, 1 H), 7.73 (s, 1 H), 7.64-7.52 (m, 1 H), 7.47 (d, J=8.59 Hz, 1 H), 7.43-7.32 (m, 1 H), 7.27 (d, J=8.59 Hz, 1 H), 6.27-6.09 (m, 1 H), 5.10 (brs, 2 H), 4.50 (brs, 1 H), 4.43-4.33 (m, 1 H), 3.81-3.62 (m, 2 H), 3.56 (dd, J=9.85, 4.55 Hz, 3 H), 3.45-3.35 (m, 1 H), 3.02-2.92 (m, 1 H), 2.84 (brs, 2 H), 2.76-2.62 (m, 3 H), 2.57 (brs, 3 H), 2.39 (s, 3 H), 2.32 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:29][CH2:30][N:31]([CH2:34][CH2:35]Cl)[CH2:32][CH3:33]>C(#N)C>[CH2:30]([N:31]([CH2:34][CH3:35])[CH2:32][CH2:33][N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([C:2](=[O:1])[CH:3]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH3:5])=[CH:22][CH:21]=1)[CH3:29]
Reactant: CCN(CC)CCCl
Reactant: CCC(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(C(=O)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccccc1
Yield: 58 %

Procedure:
4'-(1-Oxo-2-phenylbutyl)methanesulfonanilide (31.7 g., 0.100 mole), potassium carbonate (13.8 g., 0.100 mole), and 2-chlorotriethylamine (13.6 g., 0.100 mole) are mixed together in 1 liter of acetonitrile and refluxed 18 hr. The reaction mixture is clarified by filtration and concentrated under reduced pressure. The residual oil is dissolved in ethyl ether and the product extracted therefrom with 1.5N HCl. The aqueous acid extract is washed with ethyl ether and then basified with 50% NaOH. The organic material which separates is extracted into ethyl ether and the extracts are washed with water and brine, and the solution dried (MgSO4). The ether is evaporated and the solid residue is crystallized from hexane to yield 24.1 g. (58% yield), m.p. 76°-77°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=2[C:4](=[O:15])[CH2:3]1.[H-].[Na+].[OH:19][CH:20]([CH2:32][OH:33])[CH2:21][NH:22][C:23]1[CH:30]=[C:29](F)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26].[NH4+].[Cl-]>CC(N(C)C)=O>[OH:19][CH:20]([CH2:32][OH:33])[CH2:21][NH:22][C:23]1[CH:30]=[C:29]([N:8]2[C:9]3[CH2:10][C:2]([CH3:16])([CH3:1])[CH2:3][C:4](=[O:15])[C:5]=3[C:6]([C:11]([F:14])([F:13])[F:12])=[N:7]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: N#Cc1ccc(F)cc1NCC(O)CO
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)n[nH]c2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(NCC(O)CO)c3)c2C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 6,6-Dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (0.961 g, 4.14 mmol, 1 eq) and NaH (99 mg, 4.14 mmol, 1 eq) in dimethyl acetamide (20 mL) was added slowly 2-(2,3-Dihydroxy-propylamino)-4-fluorobenzonitrile (0.87 g, 4.14 mmol, 1 eq). Then the reaction mixture was stirred at 150° C. overnight, cooled, poured into saturated NH4Cl aq. solution (100 mL), extracted by EtOAc (3×150 mL), dried over Na2SO4, filtered, concentrated. The crude product was purified by flash silica gel chromatography, eluted by EtOAc to give 2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (1.7 g, 97% yield). LCMS (m/z): M+H=423.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[N:34]([C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COCC(=O)Cl
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)N1Cc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CC1C

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol), 2-methoxyacetyl chloride (2.9 mg, 0.027 mmol), and DIPEA (7.0 mg, 0.054 mmol) in DCM (90 μL) was stirred at room temperature for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (4 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.16 (d, J=6.8 Hz, 1.4H), 1.24 (d, J=6.6 Hz, 1.6H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.59 (dd, J=16.9, 10.6 Hz, 1H), 2.97-3.00 (m, 2.4H), 3.09-3.15 (m, 0.6H), 3.35-3.41 (m, 2H), 3.43 (s, 3H), 3.78 (td, J=14.6, 4.3 Hz, 2H), 4.03 (d, J=17.9 Hz, 0.6H), 4.19-4.27 (m, 1.4H), 4.29-4.39 (m, 1H), 4.46-4.52 (m, 1.5H), 4.58-4.62 (m, 0.5H), 5.07 (d, J=18.8 Hz, 0.5H), 5.18 (t, J=5.3 Hz, 0.5H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 511.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=2)=[N:6][CH:7]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=3)=[CH:4][CH:3]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: FC(F)(F)c1cc(COc2ccc(Br)cn2)ccc1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 80 °C

Procedure:
5-Bromo-2-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridine (332 mg, 0.8 mmol), tert-butyl 1-piperazine-carboxylate (178 mg, 0.96 mmol), Pd(dppf)Cl2 (17.5 mg, 0.024 mmol), dppf (20 mg, 0.036 mmol) and sodium tert-butoxide (115 mg, 1.19 mmol) are mixed in toluene (2 mL). The mixture is purged with N2 (g), heated at 80° C. for 14 h, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (180:25:1 hexanes/EtOAc/Et3N) to give 4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester.