Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH2:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[Cl:3][C:1]([O:19][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][CH3:18])=[O:2]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
29 ml of a 20% toluene solution of phosgene (55.98 mmoles) was added to tetradecyl alcohol (4 g, 18.66 mmoles) and the reaction mixture was left to stand for 20 hours under stirring at room temperature. After solvent evaporation, the residue was taken up with hexane and evaporated to dryness (several times) to give 5.1 g product as colourless liquid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[C:6]2[N:22]=[CH:23][CH:24]=[CH:25][C:5]=2[N:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].[OH2:33]>C(#N)C>[O:33]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]2[C:8](=[O:9])[N:7]([C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[CH:14][CH:15]=3)[C:6]3[N:22]=[CH:23][CH:24]=[CH:25][C:5]=3[N:4]=2)[CH2:26][CH2:27]1
Reactant: O
Reactant: CCN(CC)CC
Reactant: O=c1c(CBr)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Solvent: CC#N
Product: O=c1c(CN2CCOCC2)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromomethyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (200 mg) in acetonitrile was added triethylamine (0.14 ml) and morphorine (0.089 ml). The reaction mixture was stirred for 5 hours at 60° C. The mixture was poured into water and extracted by ethyl acetate. The organic layer was evaporated. The crude product was purified by chromatography (SiO2) to obtain 2-(1-morpholinomethyl)-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (110 mg) as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OO.S([O-])([O-])=[O:13].[Na+].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N+:4]([O-:13])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Cl
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(Cl)ccc[n+]1[O-]
Temperature: 90 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
To a solution of 3-chloro-2-cyanopyridine (40 g, 0.29 mol) in 500 mL acetic acid was added hydrogen peroxide (30%, 52 g, 0.45 mol) dropwise. After stirring at 90° C. for 18 h, the reaction is cooled to 25° C. and a solution of sodium sulfite (57 g, 0.45 mol) in H2O was added dropwise. The reaction was concentrated to remove the bulk of the acetic acid and the residue is partitioned between 1M NaOH and CH2Cl2. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc to provide 23 g (51%) of 3-chloro-2-cyanopyridine-N-oxide. The resulting N-oxide (12.2 g, 79 mmol) was dissolved in DMF (160 mL) at 0° C. Methyl thioglycolate (7.1 mL, 79 mmol) was added followed by sodium methoxide (8.5 g, 160 mmol) in portions. The reaction was stirred for 1 h. The reaction was poured onto ice and the resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc. 10.6 g (60%) of methyl 3-amino-thieno[3,2-b]pyridine-4-oxide carboxylate was obtained. The pyridine-N-oxide (10.6 g, 47 mmol) was mixed with phosphorous oxychloride (100 mL). The reaction was heated to 80° C. for 30 min. The reaction was concentrated and partitioned between CH2Cl2 and 5% aq.NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated, and chromatographed (5:1 hex:EtOAc) to yield methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate (8.3 g, 73%): 1H NMR (300 MHz, CDCl3) d 3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H); MS (DCI/NH3) m/e 243 (M+H)+ ; followed by methyl 3-amino-7-chloro-thieno[3,2-b]pyridine-2-carboxylate (2.0 g, 18%): 1H NMR (300 MHz, CDCl3) d 3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H); MS (DCI/NH3) m/e 243 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 103.2 %

Procedure:
The title compound (D26) (76 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (50 mg, 0.16 mmol) and 3-(trifluoromethyl)benzyl bromide (0.038 ml, 0.25 mmol). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O.C1C=CC=CC=1>[C:24]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1-c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A stirred mixture of 12.5 g (0.54 mole) of sodium hydride (25 g of a 50% dispersion in mineral oil) in 300 ml of dimethylformamide and 900 ml of benzene was placed under a nitrogen atmosphere and cooled to 0° C. To this mixture, 104.3 g (0.9 mole) of diethyl malonate was added dropwise during a 5 minute period and the mixture was stirred until hydrogen evolution ceased. 2-(Bromomethyl)biphenyl (117 g. 0.47 mole) was then added at 0° C. Upon complete addition the reaction mixture was stirred at 0° C. for 30 minutes, then was allowed to warm to ambient temperature with stirring for one hour. The reaction mixture was poured into 500 ml of water, the layers separated, and the aqueous layer washed with two portions of 250 ml each of diethyl ether. The organic layer was combined with the ether washings, and the whole was washed with one portion of 500 ml of aqueous 5% hydrochloric acid, one portion of 500 ml of water, one portion of 300 ml of a solution saturated with sodium bicarbonate, and finally, one portion of 500 ml of water. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to an oil residue. The oil was distilled under reduced pressure to give 149.0 g of diethyl (2-phenylbenzyl)malonate; b.p. 175°-180° C./0.8-0.9 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:37]=[C:36]1[CH2:35][CH2:34][CH2:33][N:1]1[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN4CCCC4=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A solution of N-{5-[3-(aminomethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide (69 mg, 0.2 mmol) in dichloromethane (5 ml) was treated with triethylamine (40 mg, 0.4 mmol), followed by 4-chlorobutanoyl chloride (32 mg, 0.22 mmol) and the whole mix stirred at room temperature under argon for 1 h. The reaction mix was evaporated under reduced pressure to remove the dichloromethane and then dimethylformamide was added (5 ml) followed by potassium carbonate (60 mg, 0.43 mmol) and the mix stirred at 100° C. for 2 h. The reaction mix was cooled then partitioned between dichloromethane and 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 1 g SCX column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a beige solid (16 mg, 19%).
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Temperature: 0 °C
Reaction time: 0.07 h

Procedure:
6β-Propargyl-5α-hydroxyandrostane-3,17-dione (10) (0.3 mmol) was dissolved in dry pyridine (10 ml), cooled in an ice-bath and thionyl chloride was added. After stirring for 3-5 minutes, the reaction mixture was poured over ice-water, extracted with ethyl acetate, washed (water), dried, and evaporated in vacuo. The residue was subjected to column chromatography (hexane/ethyl acetate). Recrystallization from acetone/hexane gave the title compound (60% of the analytical product); m.p. 159°-160° C.; IR (KBr) 3245, 2120, 1734, and 1662 (C=O) cm-1 ; 1H-NMR (CDCl3) δ 0.93 (s, 3H, 18-CH3), 1.26 (s, 3H, 19-CH3), 2.6-2.8 (m, 1H), 5.84 (s, 1H, 4-H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 30.7 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.041 g, 0.10 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-morpholin-4-yl-benzaldehyde (0.021 g, 0.11 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.30 mL, 0.3 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM, and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.017 g, 30%); 1H-NMR (500 Mz, DMSO-d6): δ 2.63-2.70 (m, 7H), 3.21-3.27 (m, 4H), 3.60-3.68 (m, 6H), 3.76 (m, 4H), 7.07 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.31 (s, 1H, thiazole 5-H), 8.05 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.17 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.22 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.29 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1345, calculated for C25H29BrN7OS (M+H)+: 554.1338.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].Cl[C:7]1[C:16]([C:17]#[N:18])=[C:15]([Cl:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>C(O)(=O)C>[Cl:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:3])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(Cl)nc2ccccc2c1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Temperature: 140 °C
Yield: 94.1 %

Procedure:
Ammonium acetate (2.1 g, 27 mmol) was added to a suspension of Compound 114 (6.0 g, 27 mmol) in glacial acetic acid and heated at 140° C. for 4 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried under vacuum to yield 5.2 g (94%) of white solids. M.P. 302° C. 1H NMR (DMSO-d6): δ 1H-NMR (DMSO-d6): 7.4 (m, 2H), 7.79 (t, J=7.6 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H); EIMS: 205 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:34][C:35](Cl)=[O:36].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2c1
Yield: 83.4 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (0.31 g, 0.70 mmol) produced in Example A32(iv), chloroacetyl chloride 0.45 g, 4.0 mmol), and 1-methylpiperazine (0.40 g, 4.0 mmol), and in the same manner as in Example A31, the title compound (0.34 g, 49%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].O=C(C1C=CC=CC=1)C[O:14][C:15](=[O:43])[C@H:16]([OH:42])[CH2:17][N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:31][CH:30]=1)[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([OH:27])[CH:23]=1)=[O:21].CCN(CC)CC.CC(O)=O>CC(C)=O.[Zn]>[C:15]([C@H:16]([OH:42])[CH2:17][N:18]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:33][CH:34]=1)[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([O:27][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:23]=1)=[O:21])([OH:43])=[O:14]
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Reactant: CCCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCCC(=O)OCOc1cc(C(=O)NN(Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
A mixture of chloromethyl butyrate (20.5 μL, 164 μmol) and NaI (24.5 mg, 164 μmol) in acetone (2.0 mL, 27 mmol) was stirred at 60° C. for 1 hour, then cooled to room temperature and added to a mixture of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (30.0 mg, 54.5 μmol) and Et3N (38.0 μL, 273 μmol) in acetone (1 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated, dissolved in AcOH (2 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and lyophilized. Zinc (178 mg, 2.7 mmol) and AcOH (1.0 mL, 18 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse phase preparative HPLC to yield the title compound (2.5 mg). MS m/z [M+H]+ calc'd for C25H26ClN3O8, 532.14. found 532.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(N(CC)CC)C>ClCCl>[C:38]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:4]([CH3:15])[CH:5]=2)[CH2:14][CH2:13]1)(=[O:40])[CH3:39]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(C)=O)CC5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 46 %

Procedure:
(S)-Methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (20 mg, 0.04 mmol) was dissolved in 2 mL of dichloromethane, followed by addition of acetic anhydride (5 mg, 0.05 mmol) and triethylamine (12 mg, 0.12 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound (S)-methyl 2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 6a (10 mg, yield 47.0%) as a colorless oil.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(F)c1
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Product: CCCc1c(OC)cc(C=Cc2cccc(F)c2)cc1OC

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 3-fluorobenzaldehyde in the same way as described in Example 21.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([O:23]CC)=[O:22].CO.O>C1COCC1>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Lithium hydroxide (0.113 g, 4.72 mmol) was added to a solution of ethyl 3-bromo-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.181 g, 0.472 mmol) in THF:methanol:water/3:1:1 (5 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in water, acidified with 1 N aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.151 g, 77%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (br. s., 1H), 9.27 (br. s., 1H), 7.73 (br. s., 1H), 7.22-7.33 (m, 2H), 1.44-1.54 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Yield: 52.3 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (300 mg, 0.88 mmol) and 4-fluorobenzylamine (165 mg, 1.32 mmol) were dissolved in 20 mL THF, DIEA (0.45 mL, 2.64 mmol) was added dropwise, HATU (401 mg, 1.06 mmol) was added under ice-water-bath, reacted at room temperature for 4 h, to the reaction solution was added 100 mL of water, then extracted with dichloromethane, dried with anhydrous sodium sulfate, dried by rotation, the solid was separated with silica gel separation (dichloromethane:methanol=100:1) to obtain a white solid 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(4-fluorobenzyl)pyrimidine-5-carboxamide 206 mg, yield 52%.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.[Br:12][C:13]1[C:14](N(C(CC)C)CCC(NC)=O)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1>>[Br:12][C:13]1[C:14]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: CNC(=O)CCNCC1CC1
Reactant: CCC(C)N(CCC(=O)NC)c1nc(Cl)ncc1Br
Product: CNC(=O)CCN(CC1CC1)c1nc(Cl)ncc1Br

Procedure:
Using 3-(cyclopropylmethylamino)-N-methyl-propanamide—Intermediate 95 and analogous conditions to Intermediate 88 the title compound was obtained as a white solid (431 mg)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH2:7][CH2:6]1)=[O:4].FC1C=C(F)C=CC=1C1CCNCC1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:54][C@H:51]2[CH2:52][CH2:53][C@H:48]([NH:47][C:44]3[CH:45]=[CH:46][C:41]([N+:38]([O-:40])=[O:39])=[C:42]([C:55]([F:56])([F:57])[F:58])[CH:43]=3)[CH2:49][CH2:50]2)[CH2:6][CH2:7]1
Reactant: O=C(CCl)N1CCC(c2ccc(F)cc2F)CC1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: Fc1ccc(C2CCNCC2)c(F)c1
Agent: O=C(Cl)CCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCC(c2ccc(F)cc2F)CC1

Procedure:
1-[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(2,4-difluoro-phenyl)-piperidine (also known as 2-chloro-1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-ethanone) was prepared from 4-(2,4-difluoro-phenyl)-piperidine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(2,4-difluoro-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (16% yield). The structure was confirmed using Protocol II-A. Calculated mass=542; observed mass=543; HPLC retention time=4.36 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3,4-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.