Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][N:25]([CH3:38])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].SC1C=CC(C(O)=O)=CC=1.O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][NH:25][CH3:38])=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 45 °C
Yield: 68.2 %

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (293 mg, 0.38 mmol) in DMF (3.8 mL) was added K2CO3 (371 mg, 2.69 mmol) and 4-mercaptobenzoic acid (207 mg, 1.34 mmol). The reaction mixture was heated in microwave synthesizer at 45° C. for 55 min. After the reaction, water was added, and the mixture was extracted with EtOAc three times. The organic layers were combined and washed with water three times. The combined organic layer was dried over sodium sulfate, filtered off, and concentrated in vacuo. The residue was purified with flash chromatography eluting with EtOAc (containing 20% MeOH and 0.5% ammonia in water)/DCM to provide 150 mg of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide. LCMS (m/z): 578, 580 (MH+), 0.64 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.80 (s, 1H), 7.76-7.68 (m, 1H), 7.59 (dd, J=1.6, 7.8 Hz, 1H), 7.53 (dd, J=1.2, 11.7 Hz, 1H), 7.37 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.11 (d, J=9.4 Hz, 1H), 5.27-5.10 (m, 1H), 4.42-4.13 (m, 1H), 3.65-3.49 (m, 1H), 2.97-2.88 (m, 1H), 2.87-2.79 (m, 1H), 2.74 (t, J=11.7 Hz, 1H), 2.35 (s, 3H), 2.22-2.11 (m, 1H), 2.04-1.92 (m, 1H), 1.85-1.68 (m, 2H), 1.55 (dq, J=3.1, 12.9 Hz, 1H), 1.46-1.33 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:27](/B(O)O)=[CH:28]\[CH3:29].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2/[CH:27]=[CH:28]/[CH3:29])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Reactant: C/C=C/B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccc(F)cc2C1
Yield: 50.9 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and trans-1-propen-1-ylboronic acid (294 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (153) as white solid (165 mg, 51%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.O.[Cl-].[NH4+]>CO.[Zn]>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A solution of 2-(5-nitro-pyridin-2-yl)-malonic acid dibenzyl ester in a mixture of methanol, tetrahydrofuran, and water was treated with ammonium chloride (25 eq.) and zinc dust (>10 micron,10 eq.). The mixture was stirred at 25° C. for 40 min. At this time, the reaction was filtered through celite. The filtrate was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(5-amino-pyridin-2-yl)-malonic acid dibenzyl ester as a yellow viscous oil (89%); LRMS for C22H20N2O4 (M+H)+ at m/z=377.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[CH2:32]([O:34][C:35](=[O:44])[CH2:36][N:37]1[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]1)[CH3:33]>C1C=CC=CC=1>[CH2:32]([O:34][C:35]([CH2:36][N:37]1[C:41](/[CH:42]=[C:10]2\[CH2:9][N:8]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][C:11]\2=[O:14])=[CH:40][N:39]=[CH:38]1)=[O:44])[CH3:33]
Reactant: CCOC(=O)Cn1cncc1C=O
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Yield: 18.5 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (3.66 g) in benzene (40 ml) was added pyrrolidine (0.97 ml), and the mixture was heated under reflux for 3.5 hours. To this mixture was added a solution of ethyl(5-formyl-1H-imidazol-1-yl)acetate (1.95 g) in benzene (10 ml) under cooling using an ice bath. Then, the whole was heated further under reflux for 8.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography using hexane and ethyl acetate (1:3) as an eluent to afford the title compound (1.0 g, yield: 19%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (304 mg) in DMF (5 mL) was added sodium hydride (68 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-4′nitroacetophenone (348 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an orange colored solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22]I)[CH:5]=1)([O-:3])=[O:2].[O:24]1CC[CH2:26][CH2:25]1>C(O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:25]([O:24][CH2:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]2[C:11]1=[O:21])[CH3:26]
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CI
Reactant: C1CCOC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The starting material is prepared as follows: The solution of 2 g of N-(4-nitro-2-iodomethylphenyl)-4-chlorophthalimide in 25 ml of tetrahydrofuran and 25 ml of ethanol, is stirred with 8.7 g of freshly prepared silver carbonate for 20 hours, with protection from light. The mixture is filtered and the filtrate evaporated, to yield the N-(2-ethoxymethyl-4-nitrophenyl)-4-chlorophthalimide.
Reaction SMILES: C[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[C:3]=1[CH2:22][CH2:23][CH3:24].C1C=C[NH+]=CC=1.[Br:31][Br-]Br>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[Br:31][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[C:3]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(C)c2ccc(C(N)=O)cc2n1Cc1ccccc1Br
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Br)c2ccc(C(N)=O)cc2n1Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a stirred solution of methyl 1-(2-bromobenzyl)-2-propylindole-6-carboxamide (52 mg) in a mixture of dichloromethane (3 ml) and pyridine (1 ml) was added pyridinium bromide perbromide (50 mg), and the mixture was stirred at 0° C. for 1.5 hours. The resulting mixture was diluted with ethyl acetate and washed with diluted hydrochloric acid, aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of hexane and diisopropyl ether to give 3-bromo-1-(2-bromobenzyl)-2-propylindole-6-carboxamide (33 mg) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([S:35]([N:38]3[CH2:43][CH2:42][NH:41][CH:40]([CH2:44][CH3:45])[CH2:39]3)(=[O:37])=[O:36])[S:32][C:31]=2[CH:46]=1.[Cl-].[NH4+]>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:41]2[CH2:42][CH2:43][N:38]([S:35]([C:33]3[S:32][C:31]4[CH:46]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=4[CH:34]=3)(=[O:37])=[O:36])[CH2:39][CH:40]2[CH2:44][CH3:45])=[O:10])=[N:4][CH:3]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CCC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1C(=O)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N,N-dimethylformamide (0.15 ml) was added to a methylene chloride solution (25 ml) of 5-bromopyrimidine-2-carboxylic acid (455 mg) was added and the resulting mixture was ice cooled. Oxalyl chloride (564 mg) was added and the resulting mixture was stirred for 30 minutes under ice cooling. The resulting solution, together with diisopropylethylamine (2.7 ml), was added to a methylene chloride solution (25 ml) of 1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-3-ethylpiperazine (255 mg), followed by stirring at 0° C. for 1 hour. The reaction mixture was added successively with a saturated aqueous solution of ammonium chloride and distilled water. The water layer was extracted three times with methylene chloride. The organic layers were combined, washed three times with distilled water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:100), whereby the title compound (308 mg) was obtained as a pale yellow oil.
Reaction SMILES: [B:1]([O:3][O-:4])=[O:2].[Na+].[Cl-].[Cl-].[Ca+2:8].[OH2:9]>>[B-:1]1([OH:9])([OH:4])[O:2][O:9][B-:1]([OH:2])([OH:3])[O:4][O:3]1.[Ca:8]
Reactant: O
Reactant: [Ca+2]
Reactant: O=BO[O-]
Agent: [Cl-]
Agent: [Na+]
Product: O[B-]1(O)OO[B-](O)(O)OO1
Product: [Ca]

Procedure:
10 kg batches of sodium perborate were treated in a series of experiments with CaCl2 in a two-stage spray process using in the first stage 1.5 kg of 30% by weight CaCl2 solution and in the second stage 1.5 kg of water, giving a perborate having a calcium content of 1.6% by weight.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1.N1C=CC=CC=1.Cl[C:42]([O:44][CH3:45])=[O:43]>ClCCl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:6][N:7]([C:42]([O:44][CH3:45])=[O:43])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1
Reactant: FC(F)(F)c1cc(CN[C@@H]2C[C@H](C3CC3)Nc3c(Br)cc(C(F)(F)F)cc32)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
cis-4-[(3,5-bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 100B) (420 mg, 0.75 mmol) and pyridine (148 mg, 1.88 mmol) were dissolved in anhydrous dichloromethane (15 mL) and cooled to 0° C. Methyl chloroformate (142 mg, 1.5 mmol) was added over 1 min. The reaction was stirred at 0° C. for 1 h, then at room temperature for 24 h. The reaction mixture was then diluted with 50 mL of dichloromethane, and washed twice with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title product (400 mg) which was used without further purification. MS m/z 618.8 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](SC)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl.Cl.[NH2:19][CH:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.C(N(CC)CC)C>O1CCCC1>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[CH:20]([NH:19][C:13]([NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])=[NH:14])[CH2:21]2
Reactant: NC1CN2CCC1CC2
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CN2CCC1CC2
Temperature: 80 °C
Yield: 15.1 %

Procedure:
3,5-Diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide (Intermediate 3, 250 mg, 0.88 mmol) is dissolved in tetrahydrofuran (20 mL) and to the solution 3-amino-quinuclidine dihydrochloride (211 mg, 1.06 mmol) and triethylamine (0.61 mL, 4.41 mmol) are added. The mixture is heated at 80° C. for 24 hours. The solid is removed by filtration and the is filtrate evaporated and purified by preparative HPLC (5 mM ammonium formate in H2O: CH3CN gradient) obtaining the title compound (45 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([SH:21])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[N:16][CH:17]=1)=[O:11].II>>[CH3:19][N:18]([CH3:20])[C:15]1[N:14]=[C:13]2[S:21][N:9]([CH2:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:10](=[O:11])[C:12]2=[CH:17][N:16]=1
Reactant: CN(C)c1ncc(C(=O)NCCc2ccccn2)c(S)n1
Agent: II
Product: CN(C)c1ncc2c(=O)n(CCc3ccccn3)sc2n1
Yield: 56.3 %

Procedure:
Using the procedure of Example 20, 7.5 g (24.8 mmol) of 2-dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide were treated with 6.4 g (25.2 mmol) of iodine to give 4.21 g of the title compound after recrystallization from isopropanol, mp 134-136° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13].[CH2:14]=O>C(O)(=O)C>[N:1]1([CH2:14][C:10]2[CH:9]=[C:8]([CH:12]=[O:13])[NH:7][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=Cc1ccc[nH]1
Reactant: C1COCCN1
Solvent: CC(=O)O
Product: O=Cc1cc(CN2CCOCC2)c[nH]1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a solution of morpholine (0.38 mole) in acetic acid (120 ml) at 0° C. there is added a solution of 1H-pyrrole-2-carbaldehyde (0.32 mole) in acetic acid (100 ml). Formaldehyde (37% aq., 26 ml) is then added dropwise. The reaction mixture is then stirred for 65 hours at ambient temperature. The mixture is concentrated (about 50 ml) and cooled in an ice bath. The pH of the solution is made alkaline (pH=12) using 20% aqueous sodium hydroxide solution. The product is extracted with dichloromethane (DCM) (3×250 ml). The organic phases are combined. The organic phase obtained is washed with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained (oil) is purified on silica gel (SiO2, gradient DCM/MeOH) to yield the title product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24].[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][C:12]([N:7]1[C:8]2[C:3](=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([CH2:27][OH:26])=[CH:29][CH:30]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH2:6]1)=[O:25]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a degassed solution of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one (0.216 g, 0.537 mmol), 4-(hydroxymethyl)phenylboronic acid (0.122 g, 0.805 mmol) and potassium carbonate (0.223 g, 1.611 mmol) in dioxane (3.00 mL)/water (1.20 mL) was added tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol). Upon completion of addition, the vial was purged with argon, sealed and stirred at 90° C. for 16 h. After this time, the reaction mixture was partitioned between water and EtOAc, and the organic layer was separated. The aqueous phase was extracted with EtOAc and the combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.215 g, 93% yield) as a clear colorless oil. LCMS, [M+H]+=430.2.
Reaction SMILES: CN(C)[C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[C:15]=1[F:25].CC[OH:30]>[OH-].[Na+]>[CH2:11]([C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[C:15]=2[F:25])=[C:5]([CH2:4][C:3]([OH:26])=[O:30])[CH:10]=1)[CH3:12]
Reactant: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)O)c1
Temperature: 80 °C

Procedure:
A solution of the above 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide described in Example 3 (0.9 g, 2.4 mmol) in EtOH (25 mL) and 4N NaOH (12 mL) is heated to 80° C. overnight. After cooling, the reaction is concentrated under reduced pressure and diluted with ice cold EtOAc. The pH of the aqueous layer is adjusted to 1-2 with ice cold 2.5 N HCl. The separated organic layer is dried with Na2SO4 and concentrated to a solid. The solid is purified by trituration with an Et2O/hexane mixture to give the title acid, 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C@H:7]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH:35]([NH2:38])([CH3:37])[CH3:36].O>C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:7]2[C@@H:6]([CH2:5][S:2](=[O:4])(=[O:3])[NH:38][CH:35]([CH3:37])[CH3:36])[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CS(=O)(=O)Cl)[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-7-[(chlorosulfonyl)methyl]-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (95 mg) in ethyl acetate (2.0 mL) were added triethylamine (0.06 mL) and isopropylamine (0.03 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (33 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][CH:16]([CH3:50])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:20][CH:19]=1>O.C(OCC)(=O)C>[CH3:13][O:14][CH2:15][CH:16]([CH3:50])[O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:22][CH:23]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogen carbonate (1.32 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.52 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 41%).