Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl.[Cu]=O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Brc1ccccc1
Reactant: CC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(c2cn(-c3ccccc3)c3ccccc23)CC1
Yield: 77.5 %

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)indole (10.0 g), bromobenzene (6.48 g), potassium carbonate (5.70 g) and copper(II) oxide (0.26 g) in anhydrous N,N-dimethylformamide (10 ml) was refluxed for 30 minutes. The reaction mixture was cooled and diluted with chloroform, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was subjected to column chromatography on alumina (400 g) followed by elution with a mixture of toluene and ethyl acetate (20:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure to give 3-(1-acetyl-4-piperidyl)-1-phenylindole (10.19 g).
Reaction SMILES: [Br:1][C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:18][Br:19].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:37]1[CH2:42][O:41][CH:40]=[CH:39][CH2:38]1.O>C(Cl)Cl>[Br:1][C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:40]3[CH2:39][CH2:38][CH2:37][CH2:42][O:41]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:18][Br:19]
Reactant: C1=COCCC1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c(CBr)c(Br)sc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(CBr)c(Br)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 g, 6.1 mmol) and PPTS (153 mg, 0.61 mmol) in DCM (25 mL) at 0° C. was added DHP (2.00 g, 24.5 mmol) dropwise. The reaction was stirred at RT for 18 h, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:1) to give 6-bromo-5-(bromomethyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 56.7% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH:10]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: Cc1cnn(C2CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-methyl-pyrazol-1-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][N:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][N:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(Br)c1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 6-benzyl-3-methyl-5-propyl-6H-isothiazolo[4,5-d]pyrimidin-7-one (method 59) (208 mg, 0.69 mmol) and sodium acetate (0.5 g, 5 mmol) in acetic acid (10 mL) at 100° C., a solution of the bromine (0.232 g, 1.46 mmol) in acetic acid (20 mL) was added dropwise [The next drop of Bromine was added only after the previous drop had reacted completely by monitoring the decolorization] over a period of 30 min. The reaction mixture was cooled after the addition and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×30 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (30 mL), water (50 mL), brine (50 mL) and dried (Na2SO4). Concentration of the organic layer provided the product and it was pure enough to be used in the next step. Yield 260 mg (99%). 1H NMR (300 MHz) δ 0.77 (t, 3H), 2.20-2.54 (m, 2H), 2.70 (s, 3H), 4.67 (t, 1H), 4.95 (d, 1H), 6.25 (d, 1H) 7.10-7.19 (m, 2H), 7.30-7.39 (m, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH:20][C:11](=[O:13])[CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[S:18][CH:19]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cccc2nccn12
Product: O=C(Cc1cccc2nccn12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamide was synthesized from 2-(imidazo[1,2-a]pyridin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=7.958, method [6], MS(ESI) 403.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.46 (b s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 8.08-7.96 (m, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.16 (s, 1H), 4.64 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12
Reactant: CS(=O)(=O)OCc1ccccn1
Product: O=C(c1cn(Cc2ccccn2)c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine] (prepared according to example 8) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound. ES-MS m/e (%): 457.2(M+H+).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:21]([OH:22])[C:20]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:19]=2[S:18][C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: COc1ccc(Sc2cc(F)ccc2F)c(C=O)c1
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Sc2cc(F)ccc2F)c(C(O)C2CCN(C)CC2)c1
Yield: 99.5 %

Procedure:
A solution of a Grignard reagent is prepared by a reaction of 6.7 g of 4-chloro-1-methylpiperidine with 1.25 g of magnesium in 40 ml of tetrahydrofuran and is treated while stirring for 10 minutes with a solution of 9.35 g 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde in 20 ml of tetrahydrofuran, added dropwise. The mixture is refluxed for 3 hours and, after cooling, it is decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 12.6 g (100%) of crude oily α-(1-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-methoxybenzyl alcohol which is used in this state for the next reaction. For characterization the crystalline hydrogen oxalate may be prepared by neutralization of a sample with oxalic acid; it is purified by crystallization from acetone and melts at 160°-163° C.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N:11]1([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][CH3:20])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 1884.4 %

Procedure:
To a solution of N-Cbz-proline (140 g, 562 mmol) in methanol (850 mL) was added p-toluenesulfonic acid monohydrate (5 g, 26 mmol). The solution was heated to reflux and stirring continued for 12 h. The heating mantle was removed, and after cooling to room temperature, the solvent was removed by rotary evaporation. The residue was dissolved in ethyl acetate (500 mL), and washed twice with saturated aqueous NaHCO3 (300 mL), twice with brine (200 mL), dried with MgSO4 filtered and concentrated to give a colorless oil (129 g, 88% yield)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)[CH3:10]
Reactant: ClCc1cncnc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cncnc1

Procedure:
prepared by reaction of the 5-chloromethyl-pyrimidine (Russell M. G. N et al J. Med. Chem. 2005, 48, 5, 1367-1383) with 2M ethylamine in THF.
Reaction SMILES: [Cl:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[CH:29]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][CH2:34][S:35][CH3:36])=[O:30]>>[Cl:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][S:18][C:37](=[O:38])[CH:32]([NH:31][CH:29]=[O:30])[CH2:33][CH2:34][S:35][CH3:36])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@@]21C
Yield: 43.6 %

Procedure:
The title compound (0.51 gm) was prepared from 9-chloro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.85 gm) and N-formyl-L-methionine (1.15 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>CN(C1C=CN=CC=1)C.CN(C=O)C.C1COCC1>[CH:26]1([CH2:25][C@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:16])([CH3:15])[CH3:14])[C:22]([N:3]([CH3:4])[CH3:2])=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
Solid EDC.HCl (4.62 g, 24.1 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (5.08 g, 19.0 mmol), diisopropylethylamine (10.0 mL, 57 mmol), HOBt (0.38 g, 2.8 mmol), DMAP (0.16 g, 1.3 mmol), dimethylamine (15 mL of a 2 M THF solution, 30 mmol), and anhydrous DMF (50 mL). The resultant clear light yellow solution was stirred at rt and the reaction progress was followed by LC-MS. After 5 h, the solvent was removed (50° C., 150 Torr). The residue was taken up in ether (200 mL) and washed with satd aq NaHCO3 (3×25 mL). Hexanes (100 mL) was added to the Et2O extract and this was washed with water (5×10 mL) and brine (3×10 mL), dried (Na2SO4), decanted and stripped. The crude material was purified using 40 g SiO2 with an eluent of hexanes to EtOAc. Combining appropriate fractions and removal of solvent gave (S)-tert-butyl 3-cyclohexyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (3.85 g, 69%) as a white solid. MS ESI+ve m/z 321 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][N:22]([CH2:33][CH:34]=O)[C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:34][CH2:33][N:22]([CH3:21])[C:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:32])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN(C)C(=O)OCc1ccccc1

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.78 g, 6.5 mmol) and phenylmethyl methyl(2-oxoethyl)carbamate (2.58 g, 12.4 mmol) under nitrogen in glacial acetic acid (300 mL) was treated with sodium triacetoxyborohydride (2.56 g, 12.1 mmol) at ambient temperature overnight. Concentrated the reaction in vacuo then redissolved in glacial acetic acid (100 mL) and treated with another 1 g of sodium triacetoxyborohydride at ambient temperature for 2 h. The reaction was evaporated in vacuo and the residue was chromatographed on silica gel eluting with 98:2-95:5 CH2Cl2:EtOAc to provide a clear viscous oil. The oil was dissolved in CH2Cl2, washed with saturated K2CO3, water, and brine, dried over Na2SO4, filtered and evaporated in vacuo to afford the product as a yellow viscuos oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.09 Hz, 3 H), 2.87 (d, J=5.90 Hz, 3 H), 3.34-3.51 (m, 4 H), 3.89 (d, J=20.22 Hz, 2 H), 4.24 (q, J=7.16 Hz, 2 H), 5.02 (d, J=23.16 Hz, 2 H), 7.09 (t, J=8.84 Hz, 2 H), 7.18-7.39 (m, 7 H), 7.66 (d, J=16.00 Hz, 1 H), 7.77 (s, 1 H); ES+ MS: 466 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24][CH2:23]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([OH:28])=[O:27])[CH2:23][CH2:24][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(SC)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (325 mg, 0.70 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (265 mg) as a white solid. 1HNMR (CDCl3): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.19 (s, 1H), 3.93 (q, 2H); 2.83 (m, 2H), 2.53 (s, 3H), 2.32 (m, 2H), 2.13 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23])(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])(=[O:18])=[O:17]
Reactant: COCCNS(=O)(=O)c1cccc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1cccc(C=O)c1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
To a mixture of 1.71 g of oxalyl chloride and 30 ml of dichloromethane was added dropwise a solution of 2.3 g of dimethyl sulfoxide in 4 ml of dichloromethane at −60° C. for 35 minutes. After stirred at −60° C. for 20 minutes, a solution of 3.0 g of 3-[(2-methoxyethyl)aminosulfonyl]benzyl alcohol in 22 ml of dichloromethane was added dropwise at −60° C. for 1.5 hours. After stirred at −60° C. for 1 hour, 5.1 ml of triethylamine was added dropwise at −60° C. for 25 minutes. After stirred at room temperature for 3 hours, water was added to the reaction solution, and the layers were separated. The organic layer washed with water, dried over anhydrous sodium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to obtain 2.07 g of oily 3-[(2-methoxyethyl)aminosulfonyl]benzaldehyde [Compound No. (r)].
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15](I)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(Cl)Cl.B(O)O>O.O1CCOCC1>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(I)c1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(OC)c2)c1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
To a solution of K2CO3 (4.99 g, 36.1 mmol) in 18 mL H2O was added 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (5.0 g, 12.04 mmol), 145 mL dioxane, and 3-methoxyphenylboronic acid (1.83 g, 12.04 mmol) at room temperature. This mixture was stirred for 5 min then it was degassed. Then [1,1i-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (49 mg, 0.06 mmol) was added. The reaction was stirred for three hours then 98 mg, 0.12 mmol of the catalyst was added and the reaction was allowed to stir for 3 d after which point 182 mg, 1.2 mmol of the boronic acid was added. The reaction was stirred for an additional 7 d before being worked up as in Step 1 of Example 135. There yielded 475 mg, 10% of the monoarylated product; 1H NMR (CDCl3) δ 1.38 (t, J=8.18 Hz, 3H); 1.83 (bs, 1H); 3.41 (t, J=5.43 Hz, 2H); 3.75 (t, J=5.43 Hz, 2H); 4.84 (s, 3H); 4.37 (q, J=8.18 Hz, 2H); 6.94 (dd, J=8.18 Hz, 2.72 Hz, 1H); 7.06–7.14 (m, 2H); 7.35 (t, J=8.18 Hz, 1H); 7.99 (d, J=2.73 Hz, 1H); 8.22 (d, J=2.73 Hz, 1H); 1.3 g, 25% of the bisarylated product and 2.1 g, 42% of recovered SM after the crude material was subjected to prep HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:44])[F:43])[CH:36]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: FC(F)(F)c1cccc(-c2cccc(Br)n2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C(F)(F)F)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH2:21][OH:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[C:36](=[O:37])([O:38][CH3:39])[O:22][CH2:21]/[CH:20]=[CH:19]/[C:10]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:23][O:24][CH3:25]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/CO)c(COC)nc21
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/COC(=O)OC)c(COC)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-ol (44 mg) and diisopropylethylamine (20 mg) in DCM (1 ml) was added methyl chloroformate (13.5 mg) and stirred for 2 hours at room temperature. The solvent was dried up and the residue was purified with silica gel column chromatography (CHCl3-MeOH 0-2%). (2E)-3-[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-yl methyl carbonate was obtained as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[C:19]1([C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:18]=[CH:17][N:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN=C2c2ccccc2)CC1
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ccnc2-c2ccccc2)CC1
Temperature: 100 °C

Procedure:
Tert-butyl-4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate (0.1 g) and nickel peroxide was dissolved in dry benzene (20 ml) and refluxed at 100° C. for over-night. Reaction mixture was allowed to come to room temperature, filtered through a celite pad and washed with CHCl3 (2×20 ml). The organic solvent removed under reduced pressure gave an oil, which was purified by column chromatography using ethyl acetate. Evaporation of solvent gave pure product, tert-butyl 4-(2-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate.