Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[CH:32][CH:33]=[O:34])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C1CCCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:33]([OH:34])[CH:32]=[CH:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: c1ccc2scnc2c1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OC(C=CC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (0.243 g, 1.8 mmol) in 5 ml of dry THF was treated with 1.5M lithium diisopropylamide in cyclohexane (1.45 ml) at -78° C. and stirred at that temperature for 15 minutes. A solution of 3-[1-(phenylmethyl)-4-piperidinyl]propenal (452 mg, 1.97 mmol) in 3 ml of dry THF was added at -78 ° C. and stirred at that temperature for 30 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give a thick yellow oil in a quantitative yield.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15]O)=[NH:14])=[CH:11][C:10]=1[CH3:20]>N1C(C)=CC(C)=CC=1C>[Br:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]2[N:14]=[C:5]([CH3:6])[O:7][N:15]=2)=[CH:11][C:10]=1[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=N)NO)cc(C)c1Br
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1nc(-c2cc(C)c(Br)c(C)c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.35 mL) is added to a solution of 4-bromo-N-hydroxy-3,5-dimethyl-benzamidine (0.30 g) in collidine (3 mL) at room temperature. The solution is stirred at room temperature for 1 h and then at 120° C. for 3 h. After cooling to room temperature, the mixture is concentrated, the residue is taken up in water and acetonitrile, and the resulting mixture is filtered. The filtrate is chromatographed on reversed phase (HPLC; acetonitrile/water/trifluoroacetic acid) to give the title compound. LC (method 11): tR=1.20 min; Mass spectrum (ESI+): m/z=267/269 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:13]([OH:15])=[O:14].[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:13]([O:15][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1)=[O:14]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Product: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylic acid and 3-phenoxy-benzyl alcohol were reacted to obtain 3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([C:37](=[N:39]O)[NH2:38])[CH:33]=[C:34]([F:36])[CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:37]2[N:39]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:38]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: NC(=NO)c1cc(F)cc(F)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cc(F)cc(F)c3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 3,5-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 75 mg (68% of theory)
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[NH2:7][CH2:8][C@@H:9]([SH:11])[CH3:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14]>CCOCC.O>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:7][CH2:8][C@@H:9]([SH:11])[CH3:10])=[O:14])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: C[C@H](S)CN
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C[C@H](S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
Saturated aqueous NaHCO3 (8 ml) was added dropwise to an ice-cold, stirring mixture of (S)-(+)-1-amino-2-propanethiol hydrochloride (363 mg, 2.85 mmol) in Et2O (75 ml) and H2O (8 ml) and the resulting slurry was stirred in the cold for 30 min. A solution of p-nitrobenzyl chloroformate (693 mg, 3.21 mmol) in Et2O (25 ml) was then added dropwise over 35 min. After having been stirred in the cold an additional 50 min., the reaction mixture was transferred to a separately funnel and the layers were separated. The organic portion was washed with ice-cold 0.025N HCl and brine, dried with MgSO4, filtered, and evaporated under a vacuum to a yellow oil (886 mg) which solidified on standing. The crude product was purified by preparative TLC on four 0.1×20×40 cm silica gel GF plates using 30:1 CH2Cl2 -EtOAc as developing solvent. The product band provided a yellow oil (667 mg) which crystallized on scratching. Recrystallization from Et2O-petroleum ether offorded the title compound B3) in two crops; crop 1 consisted of tiny, white crystals (216 mg) having mp 55.5°-60.5° and crop 2 afforded larger, off-white crystals (284 mg) having mp 55.5°-62°, [α]D +21.5° (Cl.32 in CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (2.6 g, 10 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (10 mL) at 0° C. After the addition, the solution was stirred at room temperature overnight, and then the solvent was removed in vacuum to give benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate. Then it was added to a solution of ethyl 3-amino-2-hydroxybenzoate (1.34 g, 8 mmol) and triethylamine (3 g, 30 mmol) in anhydrous dichloromethane (20 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 2:1) to give benzyl 4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (2.63 g, yield 80%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.46-1.56 (m, 2H), 1.79-1.82 (d, J=11.6 Hz, 2H), 2.75-2.87 (m, 3H), 3.92 (s, 3H), 4.04-4.07 (d, J=11.2 Hz, 2H), 5.08 (s, 2H), 6.90-6.94 (t, J=8 Hz, 1H), 7.30-7.40 (m, 5H), 7.54-7.56 (m, 1H), 8.09-8.11 (d, J=7.2 Hz, 1H), 9.34 (s, 1H), 10.99 (brs, 1H); LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: [CH2:1](OC(ON1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C1.[CH3:28][NH:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][NH:29][CH3:28])=[CH:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: c1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCc1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 86 %

Procedure:
3-IN-(Benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole) and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.S.[Na].O>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: S
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(N=Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A suspension of 88.1 g of 4-nitro-4'-(dimethylamino)azobenzene in 1080 ml of ethanol was heated to slight reflux while stirring, treated dropwise within 35 minutes with 1017 g of 25% sodium hydrogen sulphide solution and then stirred at slight reflux for another 1 hour. The mixture was cooled to room temperature, treated with 2120 ml of water and suction filtered. The residue was washed with water/ethanol (vol. 3:1) and dried at 50° C. in vacuo, yielding 55.7 g of 4-amino-4'-(dimethylamino)azobenzene; m.p. 182.5°-187.4° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20](O)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.Cl.[OH:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20]([N:28]3[CH2:29][CH:26]([OH:25])[CH2:27]3)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2
Reactant: OC1CNC1
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2)N1CC(O)C1
Temperature: 75 °C
Yield: 66 %

Procedure:
Example 1 (100 mg, 0.23 mmol) was added to a suspension of 3-hydroxyazetidine hydrochloride (50 mg, 0.46 mmol), HATU (132 mg, 0.35 mmol), and N-methylmorpholine (0.13 mL, 1.15 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 5 hours and then concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified via preparative HPLC (25/70 acetonitrile/water) to give 74 mg (76%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.59 (dd, 1H, J=10.6, 1.8 Hz), 7.72 (dd, 1H, J=8.6, 1.7 Hz), 6.88 (t, 1H, J=8.3 Hz), 5.32 (s, 1H), 4.31-4.48 (m, 2H), 4.05-4.15 (m, 1H), 3.98 (t, 2H, J=6.6 Hz), 3.83-3.94 (m, 1H), 3.72 (m, 1H), 3.50 (m, 1H), 2.89-3.06 (m, 2H), 2.06-2.12 (m, 2H). MS (ES) [m+H] calc'd for C18H16F2IN3O3, 488. found 488.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:12]1[C:11]([C:9]([OH:10])=[O:8])=[CH:16][N:15]=[CH:14][N:13]=1
Reactant: O=C(OCc1ccccc1)c1cnc(Cl)nc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: O=C(O)c1cncnc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-chloro4-trifluoromethyl-5-pyrimidine carboxylic acid benzyl ester in cyclohexene (3 mL, 30 mmole) and ethanol (9 mL) was treated with 10% palladium on carbon and the resulting mixture was heated to reflux for 1 h. The mixture was cooled to room temperature and filtered through a pad of Celite and concentrated to give a quantitative yield of a gummy, off-white solid. LR ES MS (C6H3F3N2O2): 191 (M−H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:12][O-:13].[Na+]>CO>[F:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([CH2:2][O:13][CH3:12])[CH:10]=1
Reactant: C[O-]
Reactant: N#Cc1ccc(F)cc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1cc(F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
A solution of 2-(bromomethyl)-4-fluorobenzonitrile (501 mg, 2.3 mmol) in methanol (5 mL) was treated with sodium methoxide (5.6 mL of 0.5 M solution in methanol, 2.81 mmol) and stirred for 1 hour at room temperature then heated to 55° C. for 2 hours. The mixture was cooled to room temperature, condensed to dryness and directly purified by normal phase flash column chromatography on a 20 g silica gel column (5-60% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield 4-fluoro-2-(methoxymethyl)benzonitrile (110 mg, 0.66 mmol, 28% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (dd, J=8.46, 5.50 Hz, 1H), 7.46 (dd, J=9.53, 2.55 Hz, 1H), 7.39 (td, J=8.59, 2.69 Hz, 1H), 4.58 (s, 2H), 3.37 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCC1CC1
Reaction time: 2 h

Procedure:
To a stirred 0° C. solution of 683 mg (6.0 mmol) of 4-cyclopropylbutanol and 1.25 mL (9.0 mmol) of triethylamine in 10 mL of CH2Cl2 was added 697 μL (9.0 mmol) of methanesulfonyl chloride dropwise under Ar. The cold bath was allowed to expire over a 2 h period at which time the reaction mixture was diluted with CH2Cl2, washed with cold 1M HCl, water, sat. NaHCO3, brine, dried over MgSO4 and the solvents removed to give the title compound as a yellow oil:
Reaction SMILES: C(OP([CH2:9][C:10]1[S:11][C:12]([Br:15])=[CH:13][CH:14]=1)(=O)OCC)C.[H-].[Na+].[CH3:18][C:19]([CH3:21])=O.O>O1CCCC1>[Br:15][C:12]1[S:11][C:10]([CH:9]=[C:19]([CH3:21])[CH3:18])=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: CCOP(=O)(Cc1ccc(Br)s1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1ccc(Br)s1
Temperature: 25 °C
Yield: 2.7 %

Procedure:
(5-Bromothiophen-2-ylmethyl)phosphonic acid diethyl ester described in Preparation Example 142 (3.13 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (0.40 g, 10 mmol, 60% in oil) was added to this solution under stirring at room temperature. The solution was stirred for 30 minutes at 60° C., then, acetone (1 g, 17.2 mmol) was added, and the solution was further stirred for 30 minutes. Water (100 mL) was added to the reaction solution, which was then extracted with hexane (50 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane), and the title compound (60 mg, 0.27 mmol, 2.7%) was obtained as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[C:7]([C:24]#[N:25])[C:6]3[N:26]=[C:3]([CH2:2][NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[NH:4][C:5]=3[CH:10]=2)=[CH:12][C:13]=1[C:20]([F:23])([F:22])[F:21])[CH3:19]
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Reactant: Nc1cccnc1
Product: CCOc1ccc(-c2cc3[nH]c(CNc4cccnc4)nc3c(C#N)n2)cc1C(F)(F)F

Procedure:
A solution of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5,c]pyridine-4-carbonitrile (20 mg, 0.052 mmol), diisoproplylethylamine (28.4 uL,0.16 mmol) and 3-aminopyridine (9.8 mg, 0.1 mmol) dimethylsulfoxide (500 μL) was heated in the Creator microwave at 120° C. for 5 minutes. The mixture was filtered and purified by preparative HPLC to afford the title compound. 1H NMR (MeOH) δ 8.3-8.2 (m, 5H), 7.76-7.74 (m, 2H), 7.27 (d, 1H), 6.07 (s, 2H) 4.23 (q, 2H) 1.45 (t, 3H) MS m/z 439.1 (m+1).
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[NH:13][O:14][CH3:15].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC1c2ccccc2CCCC1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1c2ccccc2CCCC1F
Temperature: 20 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a stirred solution of N-(6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (0.100 g; 0.48 mmol), prepared as described in example P2b and triethylamine (0.073 ml; 0.53 mmol) in dichloromethane (1 ml) under nitrogen at 0° C. was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.093 g; 0.48 mmol). The reaction mixture was stirred at 20° C. for 15 h under nitrogen. The solvent was removed in vacuo to afford a sticky oil which was subject to flash chromatography (eluant: c-hexane/ethyl acetate 95:5 to 0:100) to afford 0.134 g (76% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([CH:16]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)CS(C)(=O)=O)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:27][OH:28]>>[ClH:2].[CH:27]1([O:28][CH:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[CH:16]2[CH2:17][NH:18][CH2:19]2)[CH2:7][CH2:8][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(C(CS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)C1
Reactant: CO
Agent: Cl
Product: Clc1ccc(C(OC2CCCC2)C2CNC2)cc1Cl
Temperature: 60 °C
Yield: 97 %

Procedure:
1 N HCl (3.0 mL) was added to 10 mL of tertiary butyl 3-(1-(3,4-dichlorophenyl)-2-(methylsulfonyl)ethyl)azetidine-1-carboxylate (0.15 g, 0.36 mmol) dissolved in the methanol solution and heated to reflux at 60° C. for one day. Thereafter, the solvent of the reaction mixture was removed by reduced pressure evaporation to obtain the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([SH:32])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu](I)I>[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([S:32][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:30][CH:31]=1
Reactant: COc1cnc(S)cn1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 80 °C
Yield: 75.1 %

Procedure:
A mixture of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (25-1, 173.5 mg, 0.40 mmol), 5-methoxypyrazine-2-thiol (25-2, 170 mg, 17.5 mmol), copper iodide (3.8 mg, 0.02 mmol), and potassium carbonate (165.3 mg, 1.2 mmol) in DMF (2 mL) was heated at 80° C. for 16 h. The solution was added with water and extracted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexanes as eluant) to provide N-{4-(4-(5-methoxypyrazin-2-ylthio)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (25, 135 mg) as yellow solids in 24% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 2 H), 8.28 (s, 1 H), 8.18 (s, 1 H), 7.94-7.95 (m, 2 H), 7.14-7.21 (m, 3 H), 3.88 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 450.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]([CH3:11])[CH:10]=1)=[N:6][CH:5]=[N:4]2.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:9]([CH3:11])=[N:8][C:7]2[N:3]([N:4]=[CH:5][N:6]=2)[C:2]=1[OH:1]
Reactant: BrBr
Reactant: Cc1cc(O)n2ncnc2n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2ncnn2c(O)c1Br
Reaction time: 2 h
Yield: 83 %

Procedure:
A suspension of 4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene (15.0 g, 0.1 mol) in acetic acid (100 ml) was treated dropwise at 20° C. with a solution of bromine (16.172 g, 0.102 mol) in acetic acid (20 ml). As the reaction progressed, the suspended crystals dissolved and new crystals of brominated product were formed. After about 2 hours, the reaction mixture was poured into water (250 ml) and crystals were collected by filtration. The crude product was purified by first converting into its sodium salt by dissolving 22 g in one liter of hot aqueous 0.2N sodium carbonate and then slowly acidifying with dilute hydrochloric acid. The unchanged starting material was converted into a soluble salt by addition of excess of triethylamine. Crystals were then collected and recrystallized from hot water to give 19 g (82%) of Compound TAI-4 as white needles, m.p.=269° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
0.5 g (2 mmole) of 1-(diphenylmethyl)-3-hydroxyazetidine is added to a suspension of 0.06 g (2.3 mmole) of NaH in 20 ml of dry THF, under an argon atmosphere. After agitation for one hour at 23° C., a solution of 0.29 g (2.1 mmole) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is maintained for another 2 hours at 23° C. and the mixture is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, the organic phase is then washed twice with 25 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified on a silica column (eluent: 12% ethyl acetate in heptane). The pure fractions are evaporated in order to produce a colourless oil with a yield of 40%.
Reaction SMILES: [Br:1][C:2]1(F)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.Cl.[F:10][CH:11]([F:15])[CH2:12][NH:13][CH3:14].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[N:3]=[C:4]([N:13]([CH2:12][CH:11]([F:15])[F:10])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(F)F
Reactant: FC1(Br)C=CC=CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(F)F)c1cccc(Br)n1

Procedure:
88.0 mg (0.50 mmol) 2-bromo-2-fluoropyridine, 78.9 mg (0.60 mmol) (2,2-difluoro-ethyl)-methyl-amine hydrochloride and 0.17 mL (1.00 mmol) DIPEA are stirred at 90° C. over night. The reaction is quenched by the addition of water and extracted with DCM. The combined org. layers are dried over MgSO4, filtered and the solvent is removend in vacuo.