Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][NH2:11]>N1C=CC=CC=1>[CH3:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][S:1]1(=[O:3])=[O:2]
Reactant: CNCCCN
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CN1CCCNS1(=O)=O
Yield: 77.2 %

Procedure:
A mixture comprising 30 g (312 mmol) of sulfamide, 27.5 g (312 mmol) of N-methyl-1,3-propanediamine and 300 ml of dry pyridine was refluxed overnight at 130° C. The mixture was left to cool, and then pyridine was distilled off under reduced pressure. To the residue, 200 ml of chloroform was added and insoluble substance was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3) and then subjected to distillation under reduced pressure to obtain 36.2 g of 2-methyl-tetrahydro-1,2,6-thiadiazine-1,1-dioxide (boiling point: 130°-133° C./0.23 mmHg).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2cc(Cl)cc(Cl)c2n1
Product: CC(C#N)(Cn1cc2cc(Cl)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 98) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (80 mg, 76%). MS (ES): M/Z [M+H]=473. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.11 (d, 1H), 5.25 (d, 1H), 7.48 (s, 1H), 7.84-7.91 (m, 3H), 7.95 (d, 2H), 8.54 (s, 1H) and 9.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[C:19]([C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[N+:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=CC(C=O)=CC=1)(C)(C)C.CNC>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH:27]([N:28]([CH3:30])[CH3:29])[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:31][CH:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C[N+](C)=Cc1ccc(C(C)(C)C)cc1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: CNC
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccc(C(C)(C)C)cc2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenylindole and (4-tert-butyl-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 4-tert-butyl-benzaldehyde and dimethylamine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[CH:9][CH:8]=1.[C:18](=O)([O-])[O-:19].[K+].[K+]>CN(C)C=O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH:18]=[O:19])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-n2cccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.3 %

Procedure:
Phosphorus oxychloride (96.5 g) was added dropwise under ice-cooling to dimethylformamide (600 ml) containing 1-(4-fluorophenyl)pyrrole (101 g) over 1 h, and the mixture was stirred for 2 h and at room temperature for one day. The reaction mixture was added to 3 Liters of aqueous solution containing potassium carbonate (130 g) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of toluene-diisopropyl ether (ratio=1:10) to give 1-(4-fluorophenyl)-2-formylpyrrole (43 g), melting point: 82–83° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH3:22].CC1C=C(C)C(C2N=C(C3CCOCC3)NC=2C)=CC=1C(O)=O.Cl.[NH:47]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=3)[CH2:49][CH2:48]2)=[O:7])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:13][C:12]=1[CH3:22]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1C
Agent: Cc1cc(C)c(-c2nc(C3CCOCC3)[nH]c2C)cc1C(=O)O
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(C2CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 164, except 4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid (compound 168.1) was used in place of 2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid (compound 164.2) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) m/z (ES+) 469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[OH2:13]>OO.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([OH:13])[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O
Agent: OO
Solvent: CCO
Product: COc1ccc(Cl)cc1O

Procedure:
A solution of 5-chloro-2-methoxy benzeneboronic acid (1.9 g, 10 mmol) in hydrogen peroxide (2.04 ml, 30% solution) and ethanol 40 ml was refluxed for 30 min. Water was added and the product was extracted with two portions of ethyiacetate. Drying over magnesium sulfate and evaporation of the solvent gave the product as an oil. Yield 1.05 g, 65%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:31][C:32]([F:46])([F:47])[C:33]1[CH:34]=[C:35]([C:28]2[O:27][C:22]3=[C:23]([NH2:26])[N:24]=[CH:25][C:20]([C:18]4[CH:17]=[N:16][N:15]([C@H:12]5[CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]5)[CH:19]=4)=[C:21]3[CH:29]=2)[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine (83 mg, 0.18 mmol), 3,5-bis(trifluoromethyl)benzeneboronic acid (71 mg, 0.28 mmol), (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (13.5 mg, 0.0186 mmol), and potassium carbonate (77 mg, 0.56 mmol) in 1,4-dioxane (1.0 mL) and water (0.30 mL) was degassed 3× with argon and heated in a microwave reactor at 100° C. for 1 h. The mixture was partitioned between EtOAc and brine and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over sodium sulfate and concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:DCM) afforded 104 mg (90%) of the title compound as a foam. 1H NMR (400 MHz, CDCl3): δ 0.06-0.14 (m, 6H) 0.87-0.98 (m, 9H) 1.49-1.64 (m, 2H) 1.85-2.11 (m, 4H) 2.18-2.33 (m, 2H) 3.69-3.82 (m, 2H), 4.17-4.28 (m, 1H), 5.05 (br. s., 1H) 7.34 (s, 1H) 7.70 (s, 1H) 7.82 (s, 1H) 7.92 (s, 1H) 8.00 (s, 1H) 8.31 (s, 2H); MS (ESI): 624.34 [M+H]+; HPLC tR=2.00 min (TOF: nonpolar—3 min).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@H:13]2[NH:14][C:15](=[O:17])[O:16][C@H:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CCOC(C)=O>[C:22]([O:21][C@@H:18]1[C@H:13]2[NH:14][C:15](=[O:17])[O:16][C@H:12]2[CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@H:19]1[O:20][C:9](=[O:8])[C:10]1[CH:19]=[CH:18][CH:13]=[CH:12][CH:11]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 178.8 %

Procedure:
To a solution of (3aR,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one (2.21 g, 7.00 mmol) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) in pyridine (20 mL) at 0° C. was added benzoyl chloride (3.92 g, 27.9 mmol) dropwise. The mixture was stirred at room temperature for 20 h. The reaction was diluted with EtOAc (300 mL), washed with saturated aqueous NaHCO3 water (2×150 mL), 0.5 N HCl (2×100 mL) and brine and dried over MgSO4. The solvent was evaporated to give the crude product. This was purified by basic alumina column, eluted with 10-30% EtOAc in hexanes to provide (3aS,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (3.29 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.92-7.97 (m, 4H), 7.49-7.53 (m, 2H), 7.35-7.39 (m, 4H), 6.07 (s, 1H), 5.53 (t, J=10.1 Hz, 1H), 5.13 (dd, J=9.6 Hz, 6.6 Hz, 1H), 4.91-4.94 (m, 1H), 3.89 (t, J=7.0 Hz, 1H), 3.79 (dd, J=10.0 Hz, 4.0 Hz, 1H), 3.61 (dd, J=10.0 Hz, 2.6 Hz, 1H), 2.40 (dt, J=15.5 Hz, 3.0 Hz, 1H), 2.27-2.36 (m, 1H), 2.03-2.11 (m, 1H), 0.87 (s, 9H), −0.03 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4Cl)c3c2s1
Yield: 32 %

Procedure:
Prepared from VII and 2,4-dichloroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 32%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3063, 2231, 1736, 1644, 1611, 1577, 1459, 1380, 1355, 1310, 1242, 1173, 1098, 1051, 983, 830, 818; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 7.80 (d, 1H, J=9.0 Hz), 7.63 (s, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz); HRMS calcd for C16H8N5SCl2 (M+H+): 371.9877, found 371.9877.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1.C1CCCCC1>[Pd].C1(C)C=C(C)C=C(C)C=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2cnc3[nH]c4c(c3n2)CCCC4)c1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc(F)c(-c2cnc3[nH]c4ccccc4c3n2)c1
Temperature: 200 °C

Procedure:
A sealed tube containing 2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-indolo[2,3-b]pyrazine (46 mg, 0.155 mmol), cyclohexane (10 equiv., 0.157 mL, 1.55 mmol), Pd black (35 mg) and mesitylene (10 mL) was heated to 200° C. in an oil bath and the contents stirred via a magnetic stir bar. The progress of the reaction was monitored by intermittently opening the cooled tube and taking out an aliquot for TLC analysis (30% ethyl acetate/hexanes eluent; the aromatized product has a slightly larger Rf value than that of the starting material). Upon completion of the reaction, the mixture was filtered through celite and the mesitylene removed using a high vacuum rotary evaporator. Recrystallization from hexanes/ethyl acetate afforded 2-(2-Fluoro-5-methoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 2) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].C(N(CC)CC)C.[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[C:21]([NH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)O)c1C
Yield: 72 %

Procedure:
A stirred solution of ethyl 3-amino-2-methylbenzoate (17.9 g) in chloroform (150 ml), containing triethylamine (15 ml), was treated with a solution of n-hexadecanoyl chloride (28 g) in chloroform (50 ml), during 30 minutes. The temperature of the reaction mixture was maintained at 0°-10° C. during the addition by ice cooling. The mixture was then refluxed for 90 minutes, washed with water (2×150 ml) and was dried over magnesium sulphate. The solvent was removed in vacuo to give a white solid, which was recrystallised from ethanol. The solid was dissolved in warm ethanol (500 ml) and the solution was treated with sodium hydroxide (10 g) in water (50 ml). The mixture was then refluxed for one hour and was poured onto a mixture of crushed ice and dilute hydrochloric acid (150 ml of strength 2N). The solid was collected and was recrystallised from ethanol (1000 ml) to give 3-(n-hexadecanamido)-2-methylbenzoic acid (28 g), in the form of a white solid, m.p. 163°-165° C.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:36]([CH2:40][OH:41])([F:39])([F:38])[F:37]>>[OH:35][C:8]1([C:5]2[CH:6]=[N:7][C:2]([O:41][CH2:40][C:36]([F:39])([F:38])[F:37])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)=[O:20])[CH2:17]2)[CH2:10][CH2:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Reactant: OCC(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(OCC(F)(F)F)nc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a and CF3CH2OH (Sigma) using the procedure described in Example 8.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:48])[CH2:45][CH2:46][CH3:47]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:48])[CH2:45][CH2:46][CH3:47]
Reactant: CCCC(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise butyryl chloride (0.1 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.389 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.149 g colorless crystals. Mp 122° C. Mass spectrum, m+ =399. Anal (C24H35N5O6) theory C, 58.88; H, 7.21; N, 14.32; found C, 58.60; H, 7.15; N, 14.30.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][N+:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=2)=[CH:7][CH:6]=1.[BH4-].[Na+].CCOC(C)=O>CO>[F:2][CH2:3][CH2:4][N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:9][CH2:10]1
Reactant: COc1cc(-c2cc[n+](CCF)cc2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCN(CCF)CC2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To 1-(2-fluoroethyl)-4-[3-(methyloxy)-4-nitrophenyl]pyridinium bromide (2.0 g, 5.6 mmol) in MeOH (10 mL) cooled in an ice bath was added NaBH4 (1.1 g, 28 mmol) at such a rate to control the foaming which occurred. The mixture was stirred for 2 h then rotovaped down. EtOAc (200 mL) was added, and the solution was washed with saturated NaHCO3 solution and H2O. The solution was dried (MgSO4), filtered, rotovaped and purified by silica gel chromatography. The desired fractions were combined and rotovaped to give the title compound of step B (0.90 g, 3.2 mmol, 57%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz, 1H), 7.05-7.00 (m, 2H), 6.22-6.18 (m, 1H), 4.73 (dd, J=5.1, 4.8 Hz, 1H), 4.61 (dd, J=5.1, 4.8 Hz, 1H), 3.97 (s, 3H), 3.36-3.31 (m, 2H), 2.94-2.82 (m, 4H), 2.65-2.57 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:18]OS(C)(=O)=O)[CH2:7]1.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@H:8]([CH2:18][NH:31][CH3:30])[CH2:7]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C[C@H]1COS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@@H]1C[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 (10 volume equivalents) and once with brine (10 volume equivalents). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 119% mass balance; the material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@H:35]1[CH3:47])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@H:35]3[CH3:47])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (R)-tert-butyl 4-((2-bromophenyl)sulfonyl)-3-methypiperazine-1-carboxylate. MS (ESI): mass calcd. for C26H30FN5O4S, 527.20; m/z found, 528.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](N)=[CH:7][C:6]([CH2:10][CH3:11])=[C:5]([CH3:12])[N:4]=1.N([O-])=[O:14].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[C:8]([OH:14])=[CH:7][C:6]([CH2:10][CH3:11])=[C:5]([CH3:12])[N:4]=1
Reactant: O=N[O-]
Reactant: CCc1cc(N)c(OC)nc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1cc(O)c(OC)nc1C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A batch of 2-methoxy-3-amino-5-ethyl-6-methylpyridine (171 mg, 1.05 mmol) was dissolved in 5% aqueous sulfuric acid (4 mL), cooled in an ice bath, then a solution of sodium nitrite (78 mg, 1.13 mmol) in water (1 mL) was added dropwise. After 0.5 hour, the resulting mixture was added dropwise to 5% aqueous sulfuric acid (6 mL) warmed at 110° C. The solution was stirred for 0.5 hour, cooled and the product extracted into chloroform, then dried (Na2SO4), filtered and evaporated to yield 77 mg (43%) of product.
Reaction SMILES: [OH:1][CH:2]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][O:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.CNN.C(OCC)C>ClCCl>[NH2:5][O:4][CH2:3][CH:2]([OH:1])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(O)CON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C(O)CON
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a solution of 2-(2-hydroxy-3,3-dimethylbutoxy)-isoindole-1,3-dione (1.47 g, 5.60 mmol) in dichloromethane (20 mL) cooled to 0° C. was added methylhydrazine (0.31 mL, 5.90 mmol). The white suspension was allowed to stir for 16 hours at room temperature. Diethyl ether (50 mL) was added and the solids were removed by filtration. The filtrate was concentrated, diluted with diethyl ether and the solids were removed by filtration. This procedure was repeated twice more and the final filtrate was concentrated to provide the desired product as a yellow liquid (0.643 g, 86%). 1H NMR (400 MHz, CDCl3) δ 4.87 (br s, 2H), 3.85 (q, 1H), 3.58 (q, 2H), 0.93 (s, 9H).