Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[F:20][C:21]([F:36])([F:35])[C:22]([N:24]1[CH2:29][C:28]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:27][CH2:26][CH2:25]1)=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN1CCCC1=O.O.C(O)(=O)C>[F:36][C:21]([F:20])([F:35])[C:22]([N:24]1[CH2:29][C:28]2([CH2:34][CH2:33][N:32]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][OH:12])[C:2]=3[F:1])[CH2:31][CH2:30]2)[O:27][CH2:26][CH2:25]1)=[O:23]
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Reactant: O=Cc1cccc(CCO)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
2-Fluoro-3-(2-hydroxyethyl)benzaldehyde (example 48, step a) (1.05 g) was added to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (2.08 g) and acetic acid (0.33 mL) in N-methyl-2-pyrrolidinone (10 mL). The resulting mixture was stirred for 15 min then cooled in an ice bath. Sodium triacetoxyborohydride (1.81 g) was then added and the mixture stirred overnight. The reaction was poured into a mixture of saturated sodium hydrogen carbonate solution (20 mL) and water (100 mL). The aqueous was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (50 mL) and brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate+5% triethylamine to ethyl acetate+5% triethylamine gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 1.9 g. Used immediately.
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[OH:20][CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:25])[N:11]3[CH2:26][CH2:27][NH:8][CH2:9][C@H:10]32)=[C:14]([C:21]([F:23])([F:24])[F:22])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(CO)cc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C1c2c(cc(CO)cc2C(F)(F)F)[C@@H]2CNCCN12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (14 mg, 0.04 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 10 mg of a white solid. MS (ESI) 287 (M−Cl).
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[N:21][CH:20]=[CH:19]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[N:21][CH:20]=[CH:19]2
Reactant: Brc1ccc2cnccc2c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
Benzophenone imine (445 μL, 2.64 mmol) was added to a mixture of 6-bromoisoquinoline (500 mg, 2.4 mmol), BINAP (60 mg, 0.1 mmol), palladium acetate (12 mg, 0.05 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in THF (10 ml) at room temperature. The mixture was degassed (N2×3) then heated at reflux under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature, partitioned between ethyl acetate (20 ml) and water (20 ml) and the aqueous phase extracted with ethyl acetate (20 ml). The combined organic phases were evaporated then re-dissolved in THF (15 ml). Hydrochloric acid (2N, aqueous, 4 ml) was added, then after stirring for 1 hour the THF was evaporated. The mixture was partitioned between ethyl acetate (20 ml) and 3M HCl (50 ml) and the aqueous phase washed with ethyl acetate (20 ml). The aqueous phase was basified (12N NaOH) then extracted with dichloromethane (3×50 ml). The combined organic phases were dried (Na2SO4) and evaporated to give the title compound (360 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]>>[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COc1ccccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-2-methoxybenzene following the procedure of Example 478: MS (ESI) m/z 514.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCBr

Procedure:
A solution of 4-phenoxy-2-propylphenol (25.0 g, 0.11 mol), 1,4-dibromobutane (70.99 g, 0.33 mol) and cesium carbonate (39.28 g, 0.12 mol) in dry DMF (250 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (1:1) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([CH:32]([CH3:34])[CH3:33])[CH:26]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][C:27]=1[CH:32]([CH3:34])[CH3:33]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1ccc(S)c(C(C)C)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 75°-76° C.). 1H NMR (DMSO-d6) δ1.15 (m, 6H), 2.16 (s, 3H), 2.19-2.36 (m, 3H), 2.62 (m, 1H), 3.21 (m, 1H), 3.44 (q, 2H), 5.82 (d, 1H), 6.40 (dd, 1H), 6.95 (d, 1H), 7.10-7.18 (m, 3H), 7.25 (m, 2H), 7.44 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:42]([NH:41][C:36]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=3)=[O:43])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)cc2)COC1(C)C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (180 mg) in dichloromethane (3 ml) were added sequentially N,N-diisopropylethylamine (0.19 ml) and 3,4-dichlorophenyl isocyanate (137 mg, CAS 102-36-3) and stirring was continued at room temperature for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[3-(3,4-dichloro-phenyl)-ureido]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (267 mg, 93%) as a colourless amorphous solid. MS (ISP): 529.4 ([{37Cl}M+NH4]+), 527.4 ([{37Cl35Cl}M+NH4]+), 525.4 ([{35Cl}M+NH4]+), 512.2 ([{37Cl}M+H]+), 510.2 ([{37Cl35Cl}M+H]+), 508.2 ([{35Cl}M+H]+), 456.2 ([{37Cl}M+H—C4H8]+), 454.2 ([{37Cl35Cl}M+H—C4H8]+), 452.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:34]2)=[O:29]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COC(=O)c1cccc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 26.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 4-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 65 mg of the target compound.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[CH2:16][CH2:17][N:18]3[CH2:26][CH:25]4[CH2:27][CH:21]5[CH2:22][CH:23]([CH2:28][CH:19]3[CH2:20]5)[CH2:24]4)[CH2:7]1)[CH2:13]2>>[Cl:3][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[CH2:16][CH2:17][N:18]3[CH2:26][CH:25]4[CH2:27][CH:21]5[CH2:22][CH:23]([CH2:28][CH:19]3[CH2:20]5)[CH2:24]4)[CH2:7]1)[CH2:13]2
Reactant: O=S(Cl)Cl
Reactant: OC12CC3CC(C1)C(CCN1CC4CC5CC(C4)CC1C5)C(C3)C2
Product: ClC12CC3CC(C1)C(CCN1CC4CC5CC(C4)CC1C5)C(C3)C2

Procedure:
Thionyl chloride 5 ml was added to 4-[2-(5-hydroxy-2-adamantyl)-ethyl]-4-azatricyclo[4.3.1.1 3.8 ] undecane 105 mg obtained in example 8 and refluxed for 4 hours. Reaction mixture was concentrated in vacuo and saturated sodium bicarbonate was added to the residue to set to alkaline pH, then extracted with chloroform. The extract was dried by adding ahnydrous sodium sulfate. After removal of drying agent, the filtrate was concentrated in vacuo, and the residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: methanol=50:1-20:1) to obtain the product as a mixture of stereoisomer. (a mixture of stereoisomer 1:1 measured by gas chromatography)
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][N:14]2[CH:18]3[N:19]=[C:20]4[C:25]([N:17]3[N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:15]2=[O:36])=[C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[CH:22][N:21]4[NH2:31])(=O)=O)=CC=1.[F:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:31][N:21]1[C:20]2[C:25]([N:17]3[N:16]([CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:15](=[O:36])[N:14]([CH2:13][CH2:12][O:11][C:41]4[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=4)[CH:18]3[N:19]=2)=[C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[CH:22]1
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(CC3CC3)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCOc3ccc(F)cc3)C(=O)N(CC3CC3)N21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate obtained in step 7 of C1 (0.045 g, 0.088 mmol), 4-fluorophenol (0.018 g, 0.176 mmol) and K2CO3 (0.036 g, 0.22 mmol) were taken in DMF (2 ml) and stirred at 80° C. for 16 hours. To the reaction mixture water (25 ml) was added and extracted with ethyl acetate (3×20 ml). The crude product was purified by column chromatography to 5-amino-1-(cyclopropylmethyl)-3-[2-(4-fluorophenoxy)ethyl]-8-(2-furyl)-[1,2,4]triazolo[5,1-f]purin-2-one (8 mg, 20%) as an off white solid
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1.N([O-])=[O:30].[Na+].S(=O)(=O)(O)O.O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([OH:30])=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:14]=[C:15]([C:23]([F:24])([F:26])[F:25])[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc(O)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
To a solution of 4-amino-2-(3,5-bis-trifluoromethyl-benzoylamino)-benzoic acid methyl ester (1.70 g, 4.18 mmol) in trifluoroacetic acid (25 mL) which has been cooled to 0° C. was slowly added a solution of sodium nitrite (0.35 g, 5.06 mmol in 9 mL of water). In a separate flask, concentrated sulfuric acid (21 m]L) was added to water (50 mL) to make a 30% sulfuric acid solution. After 5 minutes, the trifluoroacetic acid mixture was slowly added to the sulfuric acid solution. After complete addition, the reaction mixture was allowed to stir at ambient temperature for 15 minutes. The reaction mixture was extracted with three portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80) to give 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (1.30 g, 76%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6); δ 11.92 (s, 1H), 10.68 (s, 1H), 8.50 (s, 2H), 8.44 (s, 1H), 8.03 (d, 1H), 7.88 (d, 1H), 6.64 (dd, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:38](Cl)=[O:39])=[N:29][N:30]([C:32]2[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=2)[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=3)[N:29]=2)=[O:39])=[CH:18][C:17]=1[F:23]
Reactant: CCOc1cn(-c2ccn(C)n2)nc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Product: CCOc1cn(-c2ccn(C)n2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X20 was prepared from A2 and 4-ethoxy-1′-methyl-1′H-[1,3′-bipyrazole]-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.36 (t, J=7.0 Hz, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 4.02 (s, 3H), 4.06 (q, J=7.0 Hz, 2H), 6.57 (d, J=2.1 Hz, 1H), 6.88 (d, J=6.2 Hz, 1H), 7.52 (s, 1H), 7.56 (m, 2H), 7.71 (s, 1H), 7.76 (d, J=8.9 Hz, 1H), 8.08 (dd, J=2.1 Hz, J=13.1 Hz, 1H), 8.17 (s, 1H), 8.75 (d, J=6.2 Hz, 1H), 10.34 (s, 1H). MS (ES) C27H25FN6O5 requires: 532. Found: 533 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(Cl)Cl.[OH-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=2[Cl:2])[N:11]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: NNc1ccc(F)cc1Cl
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cnn(-c2ccc(F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
2-Chloro-4-fluorophenyl hydrazine hydrochloride (CAS 497959-29-2) (25.0 g, 126.9 mmol) was partitioned between DCM (250 mL) and 2M NaOH (100 mL). The organic phase was separated and washed sequentially with water (2×150 mL) and brine (150 mL), dried over MgSO4 and evaporated to give the free base. This oil was dissolved in MeOH (200 mL) under nitrogen at −5° C. and 2-(ethoxymethylene)malononitrile (15.5 g, 127 mmol) was added portionwise. The resulting mixture was stirred at 0° C. for 2 hours then at reflux for a further 2 hours. After cooling, the mixture was evaporated to provide 5-amino-1-(2-chloro-4-fluorophenyl)-1H-pyrazole-4-carbonitrile (28.9 g).
Reaction SMILES: CC(OC([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)C.[CH3:21][C:22]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][C:22]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: Cc1cccc(N)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(NC(=O)[C@@H]2Cc3ccccc3CN2)c1C

Procedure:
N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Bachem) was coupled with 2,3-dimethyl aniline using standard peptide coupling procedures. The product was deprotected using TFA in CH2Cl2 to give the title compound.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][NH:32]C(OC(C)(C)C)=O)[N:26]=1)(=[O:3])[CH3:2].[ClH:40]>>[ClH:40].[ClH:40].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][NH2:32])[N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CCNC(=O)OC(C)(C)C)n1
Agent: Cl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CCN)n1

Procedure:
A solution of (E)-4-(acetylsulfanyl)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (479 mg) in 4 N hydrogen chloride (in dioxane, 8 ml) was stirred at room temperature for one hour. The solvent and hydrogen chloride were removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of in ethanol and dichloromethane (2:98 to 20:80) as eluents to afford (E)-4-(acetylsulfanyl)-3-{[1-(2-aminoethyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine dihydrochloride as a pale brown amorphous solid (450 mg). A part of the above compound (104.2 mg) was dissolved in ethanol (4 ml), and hydrogen chloride gas was passed therethrough with stirring at 0° C., and the resulting mixture was stirred under tightly sealed condition at room temperature for 5 hours. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethanol and dichloromethane (5:95 to 25:75) as the eluent to afford the title compound as a colourless amorphous solid (86.3 mg, overall yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][OH:13])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].I(O)(=O)(=O)=[O:15]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:15])=[O:13])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1sc(CO)cc1C#N
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C(=O)O)cc1C#N
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 3-Cyano-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (0.1342 g, 0.68 mmol) and Periodic Acid (0.34 g, 1.50 mmol) in MeCN (9.5 ml) was stirred for 30 min. A solution of PCC (0.010 g, 0.015 mmol) in MeCN (0.5 ml) was added. After 1 h, the reaction mixture was diluted with EtOAc (50 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 0.13 g (90%) of beige solid.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[SH:39]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:33]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=2[F:31])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: Fc1ccc(S)c(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(F)cc2F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2,4-difluorothiophenol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2,4-difluoro-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless foam. MS: 422.2 [M−H]−.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([N:7]2[C:8]3=[C:9]4[CH:17]=[CH:16][NH:15][C:10]4=[N:11][CH:12]=[C:13]3[N:14]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cnc2[nH]ccc2c1NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1cc2c(ncc3ncn(C4CCCCC4)c32)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
To a solution of N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.084 g, 0.36 mmol) in triethyl orthoformate (1 mL, 6 mmol) was added p-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol). The reaction mixture was heated at about 80° C. for about 1 h. p-Toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol) was added and the reaction mixture was stirred at about 80° C. After about 1 h, p-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol) was added and the reaction mixture was stirred at about 80° C. for about 2 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The reaction was purified by RP-HPLC (Table 1, Method m) to give 1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.002 g, 2%) as a brown solid: LC/MS (Table 1, Method a) Rt=1.90 min; MS m/z 241 (M+H)+.