Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:35]([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dichloromethane (0.1 M solution) was added imidazole (1.1 equiv.), DMAP (0.1 equiv.), and TBDMSCl (1.1 equiv.) sequentially. The reaction mixture was stirred at room temperature for 20 h. After worked up with dichloromethane, the crude material was purified by silica column chromatography (10% to 20% EtOAc in hexanes) yielding (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (76%). LCMS (m/z): 365.2 [(M-Boc)H+]; LC Rt=6.05 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]OS(C(F)(F)F)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Br-:23]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][Br:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(=O)(=O)C(F)(F)F)C1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CBr)C1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 3-trifluoromethanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.85 g, 13.8 mmol) and LiBr (3.61 g, 42 mmol) in dry acetone (30 mL) was refluxed overnight. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The residue was dissolved in CH2Cl2 and washed with water, dried and concentrated under reduced pressure to give 6 g of the crude product. Purification by flash chromatography (Heptane/EtOAc: 1/0→68/32) afforded of 3-bromomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 g, 78%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:36])([F:38])[F:37]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 4-fluoro-3-(trifluoromethyl)benzaldehyde in the presence of cesium carbonate to give the title compound as an off-white solid. MS (m/e)=548.1 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[NH2:11][C:12]1[S:13]C=CN=1.C(N=C=S)(=O)C1C=CC=CC=1>>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:12]([NH2:11])=[S:13]
Reactant: Nc1nccs1
Reactant: NCCCNc1nccs1
Agent: O=C(N=C=S)c1ccccc1
Product: NC(=S)NCCCNc1nccs1

Procedure:
By the procedure of Example 46, reacting 2-(3-aminopropylamino)thiazole (prepared from 2-aminothiazole by the method of Example 53) with benzoyl isothiocyanate gives N-benzoyl-N'-[(3-(2-thiazolylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2-thiazolylamino)propyl]thiourea.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][N:18](C(OC(C)(C)C)=O)[C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][C:27]=3[CH3:36])[C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:12]=1[CH2:44][O:45][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][NH:18][C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][C:27]=3[CH3:36])[C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:12]=1[CH2:44][O:45][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(-c2cc(N(Cc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)C(=O)OC(C)(C)C)ccc2C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)c1ccc(-c2cc(NCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 g (1.4 mmol) of 2-benzoyloxymethyl-5-{[tert-butoxycarbonyl(6,2′-dimethyl-4′-propionyl-biphenyl-3-yl)amino]methyl}benzyl benzoate are dissolved in 50 ml of dichloromethane. 1,1 ml (14 mmol) of trifluoroacetic acid are added and the medium is stirred at room temperature for 6 hours. After extraction with water/dichloromethane, the desired product is obtained in the form of a yellowish oil (m=820 mg, Y=95%).
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](O)(O)[CH2:6][CH2:5][N:4](C(=O)C(F)(F)F)[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:7]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1([F:1])[F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(N1CCC(O)(O)C(F)(F)C1)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: FC1(F)CNCCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
In a 100 mL flask, 2.00 g (8.0 mmol) of 3,3-difluoro-4,4-dihydroxy-1-trifluoroacetylpiperidine 13 (J. Org Chem. 2010, 75, 929-932) and 2.15 g (20.0 mmol; 2.5 equiv) of benzylamine were dissolved in 50 mL of toluene. The mixture was heated under reflux with a Dean Stark trap during 15 hours. After cooling to room temperature, the solvent was removed in vacuo. The resulting oil was dissolved in 25 mL of absolute methanol and 0.56 g (8.8 mmol; 1.1 equiv) of sodium cyanoborohydride and 0.48 g (8.0 mmol; 1 equiv) of acetic acid were slowly added at room temperature. The solution was stirred during 4 hours at room temperature. After removing the solvent under vacuum, the crude oil was redissolved in 50 mL of dichloromethane and poured in 50 mL of a saturated aqueous NaHCO3 solution and was subsequently extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Filtration of the solids and evaporation of the solvent resulted in a crude oil which was purified via flash chromatography (EtOAc, Rf=0.03) yielding 1.32 g (5.8 mmol; 73% yield) of benzyl-(3,3-difluoro-piperidin-4-yl)amine 14 as a yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: NCCCCCCl
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCCl
Yield: 72.5 %

Procedure:
A solution of 20.6 g (0.139 mole) of phthalic anhydride, 20 g (0.126 mole) of 5-chloropentylamine hydrochloride and 17.6 ml (0.126 mole) of triethylamine in 250 ml of toluene was heated to 130° C. for 4 hours. The obtained mixture was evaporated to dryness. The residue was taken up into 200 ml of water and extracted with ethyl acetate. The phases were separated and the organic phase was dried over sodium sulfate and evaporated to dryness. From the crude product, 23 g of the title product were obtained as an oil having the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([NH2:22])=O)[NH:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20](=[S:32])[NH2:22])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.80 g), Lawesson's reagent (0.90 g) and tetrahydrofuran (15 ml) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.75 g, yield 91%) as yellow crystals. melting point 228-230° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[B-](F)(F)F.[H+].[Br:18]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Br:18])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of 4-hydroxy-benzoic acid methyl ester (10.0 g, 65.7 mmol) in acetonitrile (110 mL), which has been cooled to at least −5° C. using an ice/acetone bath under a nitrogen atmosphere, was slowly added tetrafluoroboric acid (54% by wt. in diethyl ether, 6.35 g, 72.3 mmol) while maintaining the temperature less than −5° C. After complete addition, a solution of N-bromosuccinimide (12.9 g, 72.3 mmol) dissolved in acetonitrile (55 mL) was slowly added to the reaction mixture such that the temperature did not rise above 10° C. The ice bath was then removed and the reaction mixture was allowed to warm to room temperature and stir for 3 hours. The reaction was quenched by the addition of saturated sodium bisulfite solution until the yellow color was gone. The reaction mixture was extracted with two portions of diethyl ether. The combined organics were washed with one portion of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using methylene chloride/hexanes (gradient from 80/20 to 100/0) to give 3-bromo-4-hydroxy-benzoic acid methyl ester (13.5 g, 89%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 8.18 (s, 1H), 7.91 (d, 1H), 7.04 (d, 1H), 6.02 (bs, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[S:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:13]=3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49](O)N=[N:47][C:45]=2[CH:46]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:47][C:45]1[CH:46]=[CH:41][CH:42]=[CH:43][C:44]=1[NH:49][C:20]([C:18]1[S:17][C:14]2[CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:12][C:13]=2[CH:19]=1)=[O:22]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCc3sc(C(=O)O)cc3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCc3sc(C(=O)Nc4ccccc4N)cc3C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (1.0 eq) obtained from step IV in DMF was added Et3N (2.2 eq.), EDCI (1.2 eq) and HOBt ((1.2 eq) and reaction was stirred for 1 h Phenylene diamine was added and reaction was stirred for overnight. Reaction was then quenched with water and extracted with ethyl acetate. Organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[C:15]1[CH:19]=[C:18]([SH:20])[N:17]([CH3:21])[N:16]=1.[F:22][C:23](I)([F:25])[F:24]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:7]=[C:6]([Cl:14])[C:5]=1[C:15]1[CH:19]=[C:18]([S:20][C:23]([F:25])([F:24])[F:22])[N:17]([CH3:21])[N:16]=1
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S
Reactant: FC(F)(F)I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.13 g of 60% oily sodium hydride in 10 ml of anhydrous tetrahydrofuran was added dropwise 0.7 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-mercaptopyrazole (2) in 2.0 ml of anhydrous tetrahydrofuran at 0° C., and the mixture was stirred at room temperature for 1 hour. Subsequently, with addition of an excess of trifluoromethyl iodide, the mixture was stirred for 4 hours as contained in a sealed container. Ice water was added to the reaction mixture, the mixture was thereafter extracted with ethyl acetate, and the extracts were combined together, washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5), giving 0.6 g of the desired compound in the form of a colorless oil (yield 48.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[C:12]([C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[N+:21]([CH3:23])[CH3:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(C1C=CC(C=O)=CC=1)(C)(C)C.CNC>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]([N:21]([CH3:23])[CH3:22])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:24][CH:25]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[N+](C)=Cc1ccc(C(C)(C)C)cc1
Reactant: Cn1ccc2ccccc21
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: CNC
Agent: [Cl-]
Product: CN(C)C(c1ccc(C(C)(C)C)cc1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (4-tert-butyl-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 4-tert-butyl-benzaldehyde and dimethylamine.
Reaction SMILES: C(OC([NH:8][C:9](=[NH:47])[C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[NH:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[NH:40][CH2:41][C:42]([OH:44])=[O:43])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[C:9]([C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[NH:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[NH:40][CH2:41][C:42]([OH:44])=[O:43])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)(=[NH:8])[NH2:47]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCNC(=O)NCC(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCNC(=O)NCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 60 %

Procedure:
A suspension of {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid ((Example 196: step b) 0.025 g, 0.035 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1.00 mL) and stirred at room temperature 1.2 h. Solvents were removed in vacuo. Preparatory HPLC (10–80% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3-(2-{3-[3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid trifluoroacetate (0.013 g, 60%) as a white glassy solid. 1H NMR (CD3CN): δ 8.099 (s, 1H), 8.048 (d, 1H, J=9.6 Hz), 7.815 (t, 1H, J=1.6 Hz), 7.709 (t, 1H, J=8.0 Hz), 7.575 (d, 1H, J=7.6 Hz), 7.498 (d, 1H, J=8.0 Hz), 7.295 (t, 1H, J=7.6 Hz), 7.161 (d, 1H, J=8.0 Hz), 3.756 (s, 2H), 2.979 (s br, 4H), 2.681 (s, 3H), 2.079 (s, 3H).
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:19]=2)[C:11]([O:16]C)=[C:12]([CH:14]=[O:15])[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]>ClCCl>[C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]([OH:16])=[C:12]([CH:14]=[O:15])[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1cc(C=O)c(O)c(-c2cccc(S(N)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
N-acetyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (100 mg, 0.21 mmol), prepared as in Reference 19, was dissolved in dichloromethane (10 mL). The solution was flushed with nitrogen for 5 minutes and then boron tribromide (1.0 mL, 1M solution in dichloromethane) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under by evaporation under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was passed through a short silica plug with pure ethyl acetate to give N-acetyl 5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH2:33]([N:36]([CH3:38])[CH3:37])[C:34]#[CH:35].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH3:37][N:36]([CH3:38])[CH2:33][C:34]#[C:35][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:5]([C:8]([F:11])([F:9])[F:10])=[N:6][CH:7]=1
Reactant: C#CCN(C)C
Reactant: O=C1Cc2cnc(Nc3cc(Cl)cnc3C(F)(F)F)nc2-c2ccc(C(F)(F)F)cc2N1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)CC#Cc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
A mixture of 2-{[5-chloro-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.058 g, 0.12 mmol), propargyl(dimethylamine) (0.016 mL, 0.15 mmol) and cesium carbonate (0.080 g, 0.25 mmol) in DMF (0.60 ml) was degassed for 15 min with argon. To the suspension were added bis(acetonitrile)palladium(II) chloride (0.0020 g, 0.0061 mmol) and Xphos (0.0076 g, 0.016 mmol). The suspension was purged three times with nitrogen and was then allowed to stir at 150° C. for 48 h. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography to give 2-{[5-[3-(dimethylamino)prop-1-yn-1-yl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.042 g, 66%) as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OC(=O)C)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CCCCCCC(O)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCC(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of a commercially available racemic 2-hydroxyoctanoic acid mixture (1.00 g, 6.2 mmol.) in HPLC-grade ethylacetate (30 ml), there are added in succession benzyl bromide (2.22 ml; 18.7 mmol.), triethylamine (2.6 ml, 18.7 mmol.) and tetrabutylammonium iodide (1.15 g; 3.12 mmol.). The solution is stirred for 18 hours at room temperature and the solvent is thereafter evaporated. The residue is taken up into ether and the organic layer is then washed with a saturated solution of NaHCO3 and H2O (2×). The organic layer is dried over MgSO4, filtered and evaporated to yield crude benzyl 2-hydroxyoctanoate (Rf=0.57 in a 3/1 petroleum ether/EtOAc mixture; phosphomolybdinium compound and U.V. color development agent)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([N:16]3[CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)=[CH:14][NH:13][N:12]=2)=[C:7]([O:32]CC2C=CC=CC=2)[CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[CH:14][NH:13][N:12]=2)=[C:7]([OH:32])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2n[nH]cc2N2CCN(C(=O)OCc3ccccc3)CC2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(-c2n[nH]cc2N2CCNCC2)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
A solution of 3-[4-acetamido-2-benzyloxyphenyl]-4-[4-(benzyloxycarbonyl)piperazin-1-yl]-1H-pyrazole (70 mg, 133.2 μmol) in MeOH (7 mL) was degassed (3× vacuum/nitrogen) and palladium (10% on carbon; 10 mg, cat.) added. The reaction mixture was again degassed (3× vacuum/nitrogen) and the atmosphere replaced with one of hydrogen (3× vacuum/hydrogen). The mixture was shaken at room temperature for 18 hours. The catalyst was removed by filtration through a small pad of celite and washed with further MeOH (15 mL). The solvent was removed in vacuo to give crude product, which was purified by preparative HPLC to give 3-[4-acetamido-2-hydroxyphenyl]-4-(piperazin-1-yl)-1H-pyrazole (16.3 mg, 41%) as a white solid; δH (MeOH-d4) 8.47 (1H, s), 7.80 (1H, br s), 7.68 (1H, s), 7.26 (1H, s), 7.11 (1H, dd, J=8.5, 2.1 Hz), 3.34-3.29 (4H, m), 3.11-3.07 (4H, m), 2.12 (3H, s); LCMS retention time 1.26 min, M+H+ 302.3.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5](C(OCC)=O)[CH:6]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH:7](C(OCC)=O)[C:8]([O:10]CC)=[O:9])C>Cl>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:6]([CH2:7][C:8]([OH:10])=[O:9])[CH2:5][C:4]([OH:32])=[O:3])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc([N+](=O)[O-])cc1)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
A suspension of 7.32 g (16.1 mmol) of 2,4-bis-ethoxycarbonyl-3-(4-nitro-phenyl)-pentanedioic acid diethyl ester (as prepared in the previous step) in concentrated HCl (15 mL) was heated to 100° C. for 22 h. The mixture was cooled to RT, and the resulting precipitate was filtered, washed with cold water, and air-dried to afford 3.58 g (88%) of the title compound as an off-white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 2H, J=8.8 Hz), 7.58 (d, 2H, J=8.8 Hz), 3.77-3.68 (m, 1H), 2.87-2.66 (m, 4H).