Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:47][C:48](=[NH:68])[C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[CH:51]=[CH:52][N:53]=[C:54]2[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:47]=[C:48]([C:49]3[CH:58]=[CH:57][CH:56]=[C:55]4[C:50]=3[CH:51]=[CH:52][N:53]=[C:54]4[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[N:68]=2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(F)c(C#N)c4)n3)cccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
3-Cyano-4-fluorobenzoic acid (D31; 0.288 g, 1.744 mmol) was stirred at room temperature in 5 ml of DMF with HATU (0.723 g, 1.903 mmol) and DIPEA (0.831 ml, 4.76 mmol) for 10 mins. 1,1-Dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36, 0.5 g, 1.585 mmol) and 5 ml of DMF were added, and the resulting mixture was stirred in a Biotage Initiator microwave at 120° C. for 30 mins. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane, to give the title compound as a white solid (67 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:17][O:18][C:19](=[O:34])[C:20]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=1.Cl>ClC(Cl)C>[CH3:17][O:18][C:19](=[O:34])[C:20]1[CH:29]=[C:28]([S:30](=[O:31])(=[O:32])[NH:4][C:3]2[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=2[F:10])[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Reactant: Nc1c(F)cc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Temperature: 0 °C

Procedure:
2.94 g (20 mmol) of 2,4,6-trifluoroaniline is dissolved in 50 ml of dichloroethane with exclusion of moisture, 3.16 g (40 mmol) of pyridine is added and the solution is cooled to 0° C. With this temperature being maintained, a solution of 5.85 g (20 mmol) of 5-chlorosulfonylisophthalic acid dimethyl ester in 50 ml of dichloroethane is instilled. It is stirred for 30 more minutes at 0° C. and 5 more hours at room temperature. The suspension is shaken out three times with 2N hydrochloric acid and twice with water, the organic phase is dried on sodium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. The fractions, concentrated by evaporation, of corresponding polarity yield 6.34 g (15.72 mmol)=78.6% of the theoretical yield is obtained as a partially crystalline product.
Reaction SMILES: CCN(CC)CC.[C:8]1([C:14]2[N:15]=[C:16]([C:19]3([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)#[N:28]>C(Cl)Cl>[C:27]([C:29]1[CH:30]=[C:31]([S:35]([NH:26][CH2:25][C:19]2([C:16]3[S:17][CH:18]=[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:15]=3)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)#[N:28]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
Et3N (0.15 mL, 1.43 mmol) was added dropwise to an ice cold solution of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (130 mg, 0.48 mmol) in dry CH2Cl2 (3 mL). The resulting reaction mixture was stirred at 0° C. for 5 min, then a solution of 3-cyanobenzene-1-sulfonyl chloride (105 mg, 0.52 mmol) in dry CH2Cl2 (2 mL) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford compound 3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide (0.13 g, yield 61%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.03-7.98 (m, 2H), 7.85-7.76 (m, 3H), 7.59-7.54 (m, 1H), 7.50-7.38 (m, 4H), 3.87-3.79 (m, 2H), 3.74-3.66 (m, 2H), 3.36 (s, 2H), 2.27-2.19 (ddd, J=13.5 Hz, 6.7 Hz, 3.5 Hz, 2H), 2.01-1.93 (ddd, J=13.8 Hz, 7.5 Hz, 3.7 Hz, 2H). MS (ESI) m/z: Calculated for C22H21N3O3S2: 439.10. found: 440.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:18][C:19]1[N:20]([CH2:40][CH3:41])[C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[N:24]=[C:23]([C:37]#[N:38])[C:22]=2[N:39]=1>CN(C=O)C>[CH2:40]([N:20]1[C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[N:24]=[C:23]([C:37]#[N:38])[C:22]=2[N:39]=[C:19]1[CH2:18][NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:41]
Reactant: Nc1ccncc1
Reactant: CCn1c(CCl)nc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(CNc2ccncc2)nc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Temperature: 80 °C
Yield: 48.2 %

Procedure:
4-Aminopyridine (26 mg, 0.27 mmol) was added to a solution of diisopropylethylamine (0.24 mL, 1.37 mmol) and 2-chloromethyl-1-ethyl-6-(3-trifluoromethy-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.100 g, 0.27 mmol) in DMF (3 mL). The mixture was heated at 80° C. for 2 hours, than filtered. The precipitate was washed with water, then isopropyl ether, dried to afford the title compound (55 mg, 47%) as a solid (mp=340° C.). 1H NMR (DMSO-d6) δ: 8.84 (s, 1H); 8.6-8.5 (m, 2H); 8.31 (d, J=8 Hz, 2H); 7.9-7.7 (m, 2H); 6.97 (d, J=8 Hz, 2H); 5.98 (s, 2H); 4.51 (q, J=7 Hz, 2H); 1.45 (t, J=7 Hz, 3H). MS m/z: 423 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:19][SH:20]>>[CH3:19][S:20][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:10]([OH:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CS
Reactant: On1c(C(F)(F)C(F)(F)F)nc2nc(Cl)ccc21
Product: CSc1ccc2c(n1)nc(C(F)(F)C(F)(F)F)n2O

Procedure:
5-Chloro-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)-pyridine is reacted with methanethiol to obtain 5-(methylthio)-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)pyridine which is subsequently oxidized to obtain the corresponding 5-(methylsulfonyl)-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)-pyridine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:25])[CH:18]=[C:17]([C@@H:26]([NH:28]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH3:27])[N:16]=1.O>C1COCC1>[Cl:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[C:15]([O:11][CH:8]1[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)=[N:16][C:17]([C@@H:26]([NH2:28])[CH3:27])=[CH:18]2
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: CS(=O)(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(OC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(methylsulfonyl)piperidin-4-ol (618 mg, 3.45 mmol, 1.6 eq) in THF (5 mL) at 0° C., NaH (60% in mineral oil, 173 mg, 4.32 mmol, 2.0 eq) was added and the resulting mixture was stirred for 10 min. To this mixture, (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate 69 (1.0 g, 2.16 mmol, 1.0 eq) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to RT and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)-1-(8-chloro-1-(1-(methylsulfonyl)piperidin-4-yloxy)isoquinolin-3-yl)ethanamine (175).
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21](=O)[CH2:20][CH2:19][CH2:18]2>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([NH2:10])[CH2:20][CH2:19][CH2:18]2
Reactant: COc1cccc2c1C(=O)CCC2
Reactant: NC1CCCc2occc21
Product: COc1cccc2c1C(N)CCC2

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 8-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.13, 6.73, 4.21, 3.87, 2.78–2.72, 1.88; HRMS (FAB) calcd for C11H15NO+H 178.1232, found 178.1232.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11]O)[CH:5]=[C:6]([F:8])[CH:7]=1.P(Br)(Br)[Br:14].O>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[CH2:11][Br:14])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OC/C=C/c1cc(F)cc(Br)c1
Solvent: O
Solvent: CCOCC
Product: Fc1cc(Br)cc(/C=C/CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4.2 g (0.0182 mol) of (E)-3-(3-bromo-5-fluorophenyl)-2-propen-1-ol in 65 ml of anhydrous ether is cooled to 0° C. under a nitrogen atmosphere. 3.3 g (0.0121 mol) of phosphorus tribromide are added dropwise and then the mixture is stirred for 1 h at 0° C. and left to return to room temperature overnight. The mixture is poured into water and extraction with ether, washing with water, drying over sodium sulphate, filtration and concentration under vacuum are carried out.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:16])[C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N1CCCCC1>CN(C=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:16])[C:13]([CH:14]=[C:22]4[S:18][C:19](=[O:24])[NH:20][C:21]4=[O:23])=[C:9]3[N:8]=[C:7]([CH3:17])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(NC2CC2)n2nc(C)c(C=O)c2n1
Reactant: O=C1CSC(=O)N1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cc(NC2CC2)n2nc(C)c(C=C3SC(=O)NC3=O)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-(cyclopropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (0.25 mmol) in DMF was added thiazolidine-2,4-dione (88 mg, 0.75 mmol) and piperidine (25 μl, 0.25 mmol). The mixture was stirred at room temperature overnight. Mixture was prepared by HPLC to yield 5-((7-(cyclopropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=330)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(N)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NS(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 73 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-amine (20 mg, 0.043 mmol, 1 eq.), triethylamine (0.02 mL, 0.129 mmol, 3 eq.), and the methanesulfonyl chloride (0.007 mL, 0.086 mmol, 2 eq.) were stirred in dichloromethane (2 mL) for 16 h. The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 17 mg (74%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 (dd, J=14.60, 7.06 Hz, 2H) 2.05-2.36 (m, 5H) 2.93-3.10 (m, 3H) 3.35-3.76 (m, 2H) 4.45 (br. s., 2H) 4.71 (br. s., 1H) 7.07 (d, J=7.91 Hz, 2H) 7.15 (d, J=7.72 Hz, 1H) 7.20-7.35 (m, 3H) 7.45 (s, 1H); [M+H]+ 541.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:16])[C@H:12]2[CH2:13][O:14][CH2:15][C@H:11]2[O:10][NH:9]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:9][C@@:8]([C@H:12]1[CH2:13][O:14][CH2:15][C@H:11]1[OH:10])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:16]
Reactant: C[C@]1(c2ccccc2F)NO[C@@H]2COC[C@@H]21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@@](N)(c1ccccc1F)[C@H]1COC[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.9 %

Procedure:
A solution of (3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazole (16.72 g, 72.9 mmol) in ethanol (300 ml) was treated with ammonium formate (36.8 g, 583 mmol) and palladium (5% on carbon; 7.76 g). The reaction mixture was stirred at room temperature for 18 hours, then filtered and the filtrate evaporated at reduced pressure. The crude product was triturated with diisopropyl ether (50 ml) and filtered. The filtrate was evaporated at reduced pressure and the (3S,4S)-4-[(S)-rel-1-amino-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (8.69 g, 48% yield) was obtained as a thick colorless oil. MS (ISP): m/z=226.2 [M+H]+. The solid material obtained after filtration, the rel-(3S,4S)-4-[(S)-1-amino-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol formate (8.21 g, 42% yield), was treated with a saturated solution of sodium hydrogencarbonate (100 ml) and with dichloromethane (100 ml) and stirred for 1 hour. The aqueous layer was separated and extracted with dichloromethane, then the combined organic layers were dried over sodium sulphate and evaporated. An additional amount of the rel-(3S,4S)-4-[(S)-1-amino-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (5.6 g, 31% yield) was obtained as a thick colorless oil. MS (ISP): m/z=226.2 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][C:11](=O)[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:21][OH:22]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][C:11](=[N:21][OH:22])[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)N1C2COCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)N1C2COCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (CAS no: 99189-30-7)(1.25 g, 6.82 mmol) in ethanol (40 mL) and pyridine (0.8 mL, 10.2 mmol) with hydroxylamine hydrochloride (0.5 g, 7.23 mmol) was refluxed for 6 h. Cooled to 23° C., evaporated all volatiles, partitioned the residue between dichloromethane and sodium carbonate solution, reextracted the aqueous layer with tetrahydrofuran/ethyl acetate, all combined organic layers were dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a dark brown solid. (1.0 g, 74%); MS: m/e=199.1 (M+H+).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[CH3:9][Mg]I>>[CH3:9][C:2]1([OH:8])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: C[Mg]I
Reactant: O=C1CC2CCC1C2
Product: CC1(O)CC2CCC1C2

Procedure:
Norbornanone (I) is reacted with methylmagnesium iodide to give 2-methyl-2-norbornanol (II). The compound (II) is reacted with acetic acid and a 75% solution of sulfuric acid to give 2-acetoxy-1-methylnorbornane (III) which is then converted into 1-methyl- 2-norbornanol (IV) with lithium-aluminum hydride. Then the compound (IV) is enzymatically resolved according to the method reported by Christian Triantaphylides et al., Tetrahedron Letters, 26(15), 1857 (1985) to give (1S)-1-methyl-2-norbornanol (V). This optically active alcohol (V) is then oxidized with pyridine dichromate complex to give (1S)-1-methyl-2-norbornanone (VI). The compound (VI) is reacted with methyltriphenylphosphonium bromide in the presence of n-butyllithium to give (1S)-2-methylenenorbornane (VII) which is then treated with peracetic acid to give an epoxy compound. This epoxy compound is treated with a boron trifluoride etherate complex to give (1S,2S)-1-methyl-2-norbornyl aldehyde (VIII) which is then reduced with lithium aluminum hydride to give (1S,2S)-1-methyl-2-hydroxymethylnorbornane (IX).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.Cl.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[OH:29]>ClCCl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H]1CCCC[C@@H]1O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N[C@@H]2CCCC[C@@H]2O)ccc(C#N)c1Cl
Reaction time: 4 h
Yield: 29.6 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), diisopropylethylamine (1.29 mL, 7.37 mmol), and (1S,2R)-2-aminocyclohexanol hydrochloride (670 mg, 4.42 mmol, Acros®) is microwaved using a CEM® microwave at 190° C. for 2 h and 180° C. for 4 h. The mixture is diluted with dichloromethane and washed with 1 N HCl. The aqueous layer is extracted again with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane. The isolated product is recrystallized with ether and hexane to yield the title compound as a white solid (231 mg, 29%). LC-ES/MS m/z 265.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36]([O:38]C)=[O:37])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:12]=2[N:13]=1>C1COCC1.O1CCOCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36]([OH:38])=[O:37])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]([F:21])([F:20])[F:22])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 250-mL round-bottom flask, methyl (1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate (2.53 g, 4.53 mmol) was dissolved in 100 mL of 1:1 THF/dioxane containing 5.0 molar equivalents of 1 N aqueous NaOH. The mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to a volume of about 20 mL. Ethyl acetate (100 mL), water (30 mL), and 5.1 molar equivalents of 1 N aqueous HCl were added to the mixture. The mixture was transferred to a separation funnel. The organic layer was washed with water (1×50 mL), dried (Na2SO4), and concentrated under reduced pressure. The solid was ultrasonicated in 30 mL acetonitrile and filtered to give the desired compound as a white solid (1.96 g, 80%, 94.5% ee). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 10.60 (bs, 1H), 8.70 (t, 1H), 7.60-8.20 (m, 8H), 7.30 (d, 1H), 4.70 (q, 1H), 3.20 (q, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.50-1.90 (m, 4H); LC-MS m/z 545.3 (MH+), ret. time 3.93 min.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][C@H:38]([CH3:42])[CH2:37]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][C@H:38]4[CH3:42])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C[C@@H]1CN(C)CCN1
Product: C[C@@H]1CN(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2-(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,3-(R)-Dimethyl-piperazine following general procedure C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cncc(Br)c1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Fc1cncc(NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 85 °C
Yield: 81.6 %

Procedure:
To a stirred and degassed solution of 3-bromo-5-fluoropyridine (1 g, 5.68 mmol), benzophenone hydrazone (1.23 g, 6.25 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (329 mg, 0.57 mmol) in anhydrous toluene (15 mL) at rt under an argon atmosphere, was added palladium acetate (128 mg, 0.57 mmol). The vessel was sealed and heated at 85° C. for 15 h. The reaction mixture was cooled to rt and partitioned between ethyl acetate and water. The organic layer was separated and washed with water, then brine, then dried over magnesium sulfate and filtered. Concentration under reduced pressure gave a brown solid which was purified via silica gel column chromatography (eluting with a gradient of 12% ethyl acetate in hexanes to 100% ethyl acetate) to afford 3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (1.35 g, 82%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.30-7.65 (m, 11H); LC-MS (ESI) m/z 292 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH:12]=1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].C([O-])(O)=O.[Na+]>C(O)C>[OH:19][CH2:18][CH2:17][N:14]1[CH2:15][CH:16]=[C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1)c1cccs1
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A solution of 2-(4-(5-amino-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.16 g, 0.622 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.355 g, 1.244 mmol) at room temperature and stirred overnight (18 h). The reaction was basified with sat. NaHCO3 solution (50 mL) and product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain N-(3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (0.14 g, 61.4%) as a solid. 1H NMR (DMSO-d6) δ 10.92 (s, 1H), 7.71 (d, 1H, J=3.6 Hz), 7.58 (d, 1H, J=5.1 Hz), 7.33-7.30 (m, 2H), 7.21 (s, 1H), 7.09 (t, 1H, J=3.9 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.23 (brs, 2H), 6.03 (s, 1H), 4.40 (t, 1H, J=5.1 Hz), 3.54 (q, 2H), 3.16-3.10 (m, 2H), 2.66 (t, 2H, J=5.4 Hz), 2.50-2.44 (m, 4H, merged with DMSO-peak); ESI-MS (m/z, %): 367 (MH+, 33), 294 (100).