Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][CH:17]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29])(=[O:21])=[O:20])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:29]([CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 26.7 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2 g), 1-{2-[(1-methylethyl)sulfonyl]phenyl}methanamine hydrochloride (2.55 g) and potassium carbonate (2.94 g) were stirred in ethanol (50 ml) at 90° C. for 16 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.46 g).
Reaction SMILES: ClC1N=C2C(=CC=1)C=C1N2[C@H](C)CNC1=O.[C:17]([O:21][C:22]([N:24]1[CH2:36][C@@H:35]([CH3:37])[N:34]2[C:26](=[CH:27][C:28]3[C:33]2=[N:32][C:31]([Br:38])=[CH:30][CH:29]=3)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([BH3-])#N.[Na+]>>[C:17]([O:21][C:22]([N:24]1[CH2:36][C@@H:35]([CH3:37])[N:34]2[C@H:26]([CH2:27][C:28]3[C:33]2=[N:32][C:31]([Br:38])=[CH:30][CH:29]=3)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Br)nc3n21
Agent: C[C@@H]1CNC(=O)c2cc3ccc(Cl)nc3n21
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21

Procedure:
This compound was prepared in analogy to Example 2, intermediate b) from (R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyano borohydride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]1.C(C1C=C(C(C)(C)C)C=C(/C=N/C(C(C)(C)C)C[OH:42])C=1O)(C)(C)C.OO.S([O-])([O-])(=O)=S>C(Cl)(Cl)Cl.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[V].O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:14])[F:13])=[O:42])=[CH:4][C:3]=1[N:15]1[CH:19]=[N:18][C:17]([C:20]([F:22])([F:23])[F:21])=[N:16]1
Reactant: CC(C)(C)c1cc(/C=N/C(CO)C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1cc(C)c(-n2cnc(C(F)(F)F)n2)cc1SCC(F)(F)F
Agent: [V]
Agent: CC(=O)/C=C(/C)O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1-n1cnc(C(F)(F)F)n1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
In a three-neck flask, 10.3 g (27.54 mmol, 95% pure) of 1-{2,4-dimethyl-5-[(2,2,2-trifluoroethyl)sulphanyl]phenyl}-3-(trifluoromethyl)-1H-1,2,4-triazole and 145.8 mg (0.55 mmol) of vanadium acetylacetonate were dissolved in 36 ml of chloroform and stirred for 10 minutes. Subsequently, 275.8 mg (0.825 mmol) of (S)-(2,4-di-tert-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutan-2-yl)imino]methyl}phenol were added. After 10 minutes, 5.66 g (50 mmol) of 30% H2O2 were metered in over 6 hours. The progress of the conversion was monitored by means of HPLC. After 4 h of reaction time, a further 145.8 mg (0.55 mmol) of vanadium acetylacetonate and 275.8 mg of (2,4-di-tert-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutan-2-yl)imino]methyl}phenol in 4 ml of chloroform were metered in. Subsequently, 40 ml of chloroform, 20 ml of water and 20 ml of thiosulphate solution were added successively. After the aqueous phase had been removed, the organic phase was washed with water and dried over Na2SO4, and the solvent was evaporated under reduced pressure. This gave 10.84 g of grey-brown crystals of (+)-1-{2,4-dimethyl-5-[(2,2,2-trifluoroethyl)sulphinyl]phenyl}-3-(trifluoromethyl)-1H-1,2,4-triazole (98% yield, 93.1% HPLC purity) with 2.81% sulphone content. The enantiomeric excess was determined by means of HPLC on a chiral phase (Daicel Chiracel OJ-RH 150) with a ratio of 16.34:83.66.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:14]1[C:22]2[CH:21]=[CH:20][C:19](I)=[C:18]3[CH2:24][C@@H:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:26][C@H:16]([C:17]=23)[CH2:15]1)(=O)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC>C(OCC)(=O)C.CCCCCC.[OH-].[NH4+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:19]1[CH:20]=[CH:21][C:22]2[NH:14][CH2:15][C@@H:16]3[CH2:26][C@H:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:24][C:18]=1[C:17]=23
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ccco3)ccc3c2[C@H](CN3)C1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a sealable tube with threads containing 13 ml of dry tetrahydrofuran were added 1.2 g (2.46 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 968 mg (2.71 mmol) of 2-(tributylstannyl)furan and 200 mg of bis(triphenyl-phosphine)palladium(II) chloride. The resulting mixture was then deaerated with argon for 15 minutes. After deaeration, the tube was sealed with a teflon cap and the contents thereof were heated to 100° C. for 24 hours. After 24 hours, the reaction mixture was cooled, filtered through a celite pad and the resulting filtrate was then concentrated in vacuo to provide a viscous orange oil. Flash chromatography of this oil over silica gel with 60% ethyl acetate/hexane plus 0.5% ammonium hydroxide as eluent gave the protected analog of the title compound in 61% yield.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.N1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C1CCNCC1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Product: CCCCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.41 g (7.5 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 1.41 ml (7.5 mmol) of decylaldehyde in 50 ml of ethanol, 0.08 ml (0.8 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/2) to yield 2.59 g (75.1%, light yellow oily substance) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]4[CH:25]=[CH:26][CH:27]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:28][CH3:29].[I-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>ClCCCl>[CH3:29][O:28][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]3([O:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]4[CH:25]=[CH:26][CH:27]=[C:16]34)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[O:1][CH2:39][C:40]([O:42][CH3:43])=[O:41]
Reactant: COC(=O)CBr
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: ClCCCl
Product: COC(=O)COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
To (4-hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (200 mg, 0.512 mmol), sodium iodide (38.4 mg, 0.256 mmol), Cs2CO3 (334 mg, 1.03 mmol), and DCE (5.0 mL) was added methyl 2-bromoacetate (49 μL, 0.51 mmol). The mixture was stirred at 60° C. for 18 h. Additional methyl 2-bromoacetate (1.0 mmol) was added and the mixture was heated for 3 h at 60° C. The mixture was cooled and then filtered. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (0-30% ethyl acetate/DCM) to yield methyl 2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)acetate (140 mg, 59%). ESI-MS m/z calc. 462.2, found 463.5 (M+1)+; Retention time: 2.68 minutes (4 min run).
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([C:18]=2[NH2:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][CH2:7]1.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23].O>O1CCCC1>[CH2:16]1[C:17]2[C:12](=[N:11][C:10]3[C:19]([C:18]=2[NH:20][C:22](=[O:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:13][CH2:14][CH2:15]1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
n Butyllithium, 0.033 mol, is added to a suspension of 6.5g (0.033 mol) of 1,2,3,4-tetra -hydro-9-acridinamine (Petrow, V., Journal of the Chemical Society, pages 634 to 637 (1947)) in 200 ml of tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for 20 minutes, the cooling bath removed and 6.36 g (0.033 mol) of octyl chloroformate added and the solution stirred over the weekend. Water, 200 ml, is added and the mixture extracted with ethyl acetate. The ethyl acetate layer is separated and evaporated to afford a yellow oil. Chromatography (elution with isopropanol-chloroform (5:95)) affords 6.59 g of octyl (1,2,3,4-tetrahydro-9-acridinyl)carbamate, as a yelIow solid; mp 96-99° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.[CH3:27][N:28]=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:29]([NH:28][CH3:27])=[O:30])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: CN=C=O
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N[C@@H](C)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), methyl isocyanate (38.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (51.9 mg).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH:24]1([C@H:30]([NH2:32])[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C@H:30]([NH:32][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:2])[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: C[C@@H](N)C1CCCCC1
Product: C[C@@H](NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2)C1CCCCC1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-[4-carboxybicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and (1R)-1-cyclohexylethylamine (49.7 μL) were used to obtain (2S,4S)-1-[[N-(4-[-N-[(1R)-1-cyclohexylethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.9 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:64])[CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-phenylalanine cyclopentyl ester tosylate. 1H NMR (300 MHz, d3-MeOD) 7.44-7.17 (5H, m), 6.95 (1H, s), 6.34 (1H, s), 5.17, (1H, m), 4.35-4.12 (4H, m), 3.46-3.35 (1H, m), 3.27-2.85 (6H, m), 1.93-1.21, (13H, m), 1.19 (6H, d, J=7.0 Hz). LC/MS: purity 98.4%, m/z 523 [M+H]+
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>CN(C=O)C>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:46]([NH:45][C:42]6[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=6)=[O:47])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.20 mmol). The reaction mixture stirred at −20° C. for 5 min prior to the addition of 4-fluorophenyl isocyanate (9.5 mg, 0.07 mmol) in DMF (0.5 mL). The mixture was left to stir at rt for 1 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as a white solid. MS (ES+): m/z: 485.88 (100) [MH+]. HPLC: tr=2.73 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=2.52-2.56 (m, 2H), 3.31 (s, 1H), 3.70 (t, 2H), 4.20 (s, 2H), 6.94 (m, 1H), 6.86 (d, J=0.8 Hz, 1H), 7.06-7.11 (m, 2H), 7.48-7.51 (m, 2H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.59 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 9.24 (s, 1H), 9.62 (s, 1H).
Reaction SMILES: C(N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55]C(NC(=O)CC2C=CC=CC=2)=S)[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.[Cl:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([Cl:75])[C:70]=1[CH2:76][C:77]([N:79]=[C:80]=[S:81])=[O:78]>>[Cl:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([Cl:75])[C:70]=1[CH2:76][C:77]([NH:79][C:80](=[S:81])[NH:55][C:41]1[CH:42]=[CH:43][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[CH:52]=[CH:53][S:54][C:47]=23)=[C:39]([F:38])[CH:40]=1)=[O:78]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Product: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 7 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 2-(2,6-dichlorophenyl)acetyl isothiocyanate, title compound 192a was obtained in 7% yield. Characterization of 192a is provided in table 18.
Reaction SMILES: C(OC([N:8]([CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][C:33]([NH:39][C:40](=[O:42])[NH2:41])=[C:34]([C:36](=[O:38])[NH2:37])[CH:35]=2)=[CH:27][CH:26]=1)[C@H:9]([C:14]([O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O.CCCC(C)C>ClCCl>[C:36]([C:34]1[CH:35]=[C:31]([C:28]2[CH:27]=[CH:26][C:25](/[CH:24]=[CH:23]/[CH2:22][NH:8][C@H:9]([C:14]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:30][CH:29]=2)[S:32][C:33]=1[NH:39][C:40](=[O:42])[NH2:41])(=[O:38])[NH2:37]
Reactant: CC(C)C[C@@H](C(=O)OC1CCCC1)N(C/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCC(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](NC/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopentyl N-(tert-butoxycarbonyl)-N-[(2E)-3-{-4-[4-carbamoyl-5-(carbamoylamino)thiophen-2-yl]phenyl}prop-2-en-1-yl]-leucinate (Intermediate 9a) (39 mg, 0.065 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (0.5 ml). The reaction mixture was left to stir at RT for 2 hrs. The reaction mixture was worked up by removal of the solvents in vacuo. The residue was diluted with methanol and captured by SCX chromatography, eluting the product with ammonia in methanol. The ammonia fractions were concentrated in vacuo to afford an oily residue. This was taken up in dichloromethane and isohexane added. After removal of the solvent in vacuo a pale orange solid was obtained (24.3 mg, 0.049 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[N:21]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].Cl>C(O)C.C1C=CC=CC=1.CO>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=3)[C:25]([C:22]3[CH:23]=[CH:24][NH:20][N:21]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(Nc2ccc(CCO)cc2)c(N)c1
Reactant: O=Cc1cc[nH]n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Pb+4]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCO
Product: COc1ccc2c(c1)nc(-c1cc[nH]n1)n2-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A mixture of 2-(4-{[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. After cooling, the mixture was concentrated. A mixture of the residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at room temperature for 16 h. The mixture was 1.37 mmol) in methanol (4 ml) was added 10% HCl in methanol (2 ml) at room extracted with ethyl acetate (150 ml×4). The organic layer was washed with water (100 ml×5), brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 408 mg (16%) of the title compound as an amber solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6](CC(N2CCOCC2)=S)[CH:7]=1.[C:24]([OH:27])(=[O:26])[CH3:25].O.S(=O)(=O)(O)O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH2:25][C:24]([OH:27])=[O:26])[CH:7]=1
Reactant: S=C(Cc1cc(Cl)ccc1Oc1ccccc1)N1CCOCC1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: O=C(O)Cc1cc(Cl)ccc1Oc1ccccc1

Procedure:
To this morpholine residue is added 290 ml of glacial acetic acid, 61 ml of water and 87 ml of sulfuric acid (96%), and the mixture refluxed for a period of 21 hours. On cooling, the reaction mixture is dissolved in ethyl ether, washed with water until the water wash appears neutral and extracted with a 10% sodium carbonate solution. The aqueous alkaline layer is acidified with a 2 N solution of hydrochloric acid and re-extracted into diethyl ether. The ether solution is washed with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered. The solvent is removed by distillation from the filtrate and the remaining residue is crystallized from cyclohexane to yield 30.5 grams of (5-chloro-2-phenoxyphenyl)acetic acid having a m.p. of 119°-123° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 124.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.97 min, m/z=459.1 [M+H]+, m/z=457.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.37 (m, 2H) 1.53-1.61 (m, 1H) 1.82 (d, J=8.56 Hz, 1H) 2.58 (dd, J=12.23, 9.05 Hz, 1H) 2.69-2.78 (m, 1H) 3.34-3.40 (m, 1H) 3.41-3.51 (m, 1H) 3.55-3.62 (m, 1H) 4.73 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.52 (dd, J=7.95, 4.77 Hz, 1H) 7.83-7.89 (m, 2H) 8.02 (dt, J=7.82, 1.83 Hz, 1H) 8.10 (d, J=2.20 Hz, 1H) 8.59 (dd, J=4.65, 1.22 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 8.81 (d, J=1.71 Hz, 1H) 10.29 (s, 1H).