Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([SH:9])[CH:3]=1.Br[CH:11]([CH2:17]Br)[C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:11]([C:12]([OH:14])=[O:13])[CH2:17][S:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: Cc1ccc(O)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)SCC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 20.0 g of 4-methyl-2-mercaptophenol in 75 ml of acetone was added slowly to a stirred mixture of 40.2 g of ethyl 2,3-dibromopropionate and 10.2 g of potassium carbonate in 400 ml of acetone, at room temperature. The mixture was stirred at room temperature for 10 minutes, then refluxed for 16 hours. The mixture was filtered and the solid was washed with acetone. The acetone filtrate was stripped of solvent; the residue was dissolved in methylene chloride, the solution was washed with water, then dried (MgSO4) and stripped of solvent. The liquid residue was dry column chromatographed (silica gel) using Solvent No. 2 as eluent. The first band (high Rf) was collected and extracted with ether. The solvent was stripped from the extract. The residue was dried (vacuum, 24 hours) and crystallized from hexane to give the ethyl ester of 2,3-dihydro-6-methyl-1,4-benzoxathiin-2-carboxylic acid (2A), as white needles, mp: 41°-43° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:23])[N:14]([CH3:22])[CH:15]([C:18]([O:20][CH3:21])=[O:19])[C:16](=N)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=[O:27])C.OS(O)(=O)=O>CO>[CH2:1]([N:8]1[C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([OH:27])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1C(=N)c2ccn(Cc3ccccc3)c2C(=O)N1C
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(O)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 1-benzyl-4-imino-6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (9.0 g, 28.9 mmol) in Methanol (100 mL) was treated with Water (40 mL) and Acetic Acid (50 mL), followed by H2SO4 (1.575 mL, 29.6 mmol), and the resultant was stirred at 90° C. overnight. The mixture was concentrated, diluted with water and then adjusted to pH>6 with saturated sodium bicarbonate. The mixture was extracted with Ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 1-benzyl-4-hydroxy-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.0 g, 22.4 mmol, 76% yield) as a pale yellow solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 11.23 (s, 1H) 7.20-7.36 (m, 5H) 7.04-7.11 (m, 1H) 6.62-6.70 (m, 1H) 5.86 (s, 2H) 3.98 (s, 3H) 3.67 (s, 3H); LCMS (m/z) ES+=313 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[NH:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH2:63][CH3:64])[CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[NH:58][C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH2:63][CH3:64])[CH:52]=1)=[O:50]
Reactant: CCOc1cc(C(=O)OC)c2nc(N)[nH]c2c1F
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CCOc1cc(C(=O)OC)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Yield: 44 %

Procedure:
0.3 g (1.5 mmol) of isoquinoline-3-carboxylic acid and 0.6 g (1.6 mmol) of HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.25 g (1.0 mmol) of 2-amino-6-ethoxy-7-fluoro-1H benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A to produce 0.18 g (0.44 mmol, 44%) of 6-ethoxy-7-fluoro-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 409 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[O:6][N:5]=1)[CH3:2].[OH:13]S(O)(=O)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4]1[C:8]2[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:7]=2[O:6][N:5]=1)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOc1noc2c1CCCC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOc1noc2c1C(=O)CCC2
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 1a (35 g) in glacial acetic acid (500 mL) at 10° C. was added concentrated H2SO4 (29 mL). A solution of sodium dichromate (71 g) in glacial acetic acid (300 mL) kept at 40-45° C. was added dropwise during one hour at 20-25° C. The mixture was stirred for another 3 hours at 25-30° C. The reaction mixture was poured onto ice and diethyl ether (3 L). pH was adjusted to >10 by addition of concentrated aqueous NaOH. The organic phase was separated and worked up. The remaining crude title compound was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:1). Pure 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one was washed with diisopropyl ether and dried. Yield 27 g. Mp 98-99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].[OH-].[K+].O>COCCO>[NH2:16][C:15]1[N:17]=[C:18]([NH2:20])[N:19]=[C:13]([C:12]2[C:3]([O:2][CH3:1])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:14]=1
Reactant: N#CNC(=N)N
Reactant: COc1cc2ccccc2cc1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: COc1cc2ccccc2cc1-c1nc(N)nc(N)n1

Procedure:
A mixture of 3.24 grams of 2-methoxy-3-naphthonitrile, 2.23 grams of cyanoguanidine and 0.24 gram of KOH was dissolved in 30 ml of methyl cellosolve with heating and the mixture was heated to reflux for 6.5 hours. After the reaction was completed, the reaction solution was was poured into water, the crystals separated out were taken by filtration, and were recrystallized from ethyl alcohol to give 2,4-diamino-6-(2-methoxy-3-naphthyl)-s-triazine, colourless needles, melting point 243° to 244° C., the yield being 4.12 grams.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:31])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2].BrCC1C2SC=CC=2C(OCCC2N=C(C3C=CC=CC=3)OC=2C)=CC=1.C(OC(=O)CN=C(C1C=CC=CC=1)C1C=CC=CC=1)C.[C:79]([CH2:87][C:88](=O)[CH3:89])(=[O:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:31]/[C:88](/[CH3:89])=[CH:87]\[C:79](=[O:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccccc1
Yield: 85.2 %

Procedure:
0.334 g (0.75 mmol) [rac]-2-Amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester (prepared from 4-[2-(7-bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole [PCT Int. Appl. (2001) WO01/79202] and N-(diphenylmethylene)glycine ethyl ester in analogy to the sequence described in examples 15 a] and 15 b]) and 0.161 g (0.97 mmol) benzoylacetone were dissolved in 25 ml of toluene. Then, 0.21 ml (1.5 mmol) triethylamine and 0.026 g (0.15 mmol) 4-toluene sulfonic acid were added and the reaction mixture was heated at reflux for 2 hours. After removing the solvent under reduced pressure, the residue was diluted in water/sodium hydrogen carbonate solution and the reaction mixture was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Purification of the residue by flash-chromatography (silica gel, eluent: gradient of hexane and ethyl acetate) gave 0.38 g (85%) [rac]-2-[1-methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A solution of 6-chloro-2-nitrophenol (1.7 g.) and ethyl chloroacetate (2.1 ml.) in dimethylformamide (12 ml.) with potassium carbonate (1.5 g.) was stirred at 75°-80° C. for 3 hours. The mixture as poured into water (120 ml.) and extracted with ethyl acetate (4 × 50 ml.) . The organic layer on evaporation yielded 6-chloro-2-nitrophenoxyacetic acid ethyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62]C1C=CC=CC=1C(O)=O)#[N:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62][C:29]1[CH:30]=[CH:31][CH:2]=[CH:3][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])#[N:55]
Reactant: N#Cc1ccccc1Sc1ccccc1C(=O)O
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Sc3ccccc3C#N)nn2)cc(OC)c1OC
Yield: 80 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 2-[(2-cyanophenyl)thio]benzoic acid (217 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 2-[(2-cyanophenyl)thio]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (282 mg, 80%) as a yellow solid. MS m/z 542 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](Cl)=[O:9].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>C(Cl)Cl>[CH2:12]([N:14]([CH2:15][CH3:16])[C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9])[CH3:13]
Reactant: O=C(Cl)c1cc(Cl)nnc1Cl
Reactant: CCNCC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1cc(Cl)nnc1Cl

Procedure:
3,6-Dichloropyridazine-4-carbonyl chloride (2.5 g) was initially charged in DCM (25 ml) at RT. Thereafter, diethylamine (1.5 ml) predissolved in DCM (5 ml) was slowly added dropwise while stirring. After stirring at RT for 3 h, the mixture was admixed with water and extracted three times with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of silica gel (70 g cartridge, n-heptane/EA gradient). 1.8 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20](I)[CH2:21][CH3:22]>C(Cl)(Cl)Cl.[Ag].[Ag]=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:19][CH2:20][CH2:21][CH3:22])[CH3:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CC(=O)c1ccc(-c2ccc(CC(C)O)cc2)cc1
Agent: O=[Ag]
Agent: [Ag]
Solvent: ClC(Cl)Cl
Product: CCCOC(C)Cc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 360 h
Yield: 30.4 %

Procedure:
Into a four-necked flask provided with a stirrer and a thermometer, 25.4 g of (-)-4-acetyl-4'-(2-hydroxypropyl)biphenyl (XXIII-43) [0.1 mol, [α]D20 =-11.2° (C=1, CHCl3)], 69.5 g (0.3 mol) of silver oxide and 255 g (1.5 mol) of propyl iodide were charged, and then stirred at room temperature for 15 days. Thereafter, the reaction mixture was diluted with 300 ml of chloroform, and silver salt was filtered off, and thereafter, the filtrate was concentrated under a reduced pressure. The resulting residue was subjected to a silica gel column chromatography (elution medium: toluene/ethyl acetate=10/1) to obtain 9.0 g of (-)-4-acetyl-4'-(2-propoxypropyl) biphenyl (XXII-43) [yield=30.5%, [α]D20 =-10.2° (C=1, CHCl3), m.p.=5320 -55° C.] and 17.4 g of the starting material (XXIII-43) with recovery of 68.5%.
Reaction SMILES: OO.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11]([CH2:13][CH3:14])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19].CC[O:27]C(C)=O>O.C(O)(=O)C>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11]([CH2:13][CH3:14])(=[O:27])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:19])([F:20])[F:21]
Reactant: CCS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reactant: CCOC(C)=O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 95 °C

Procedure:
Hydrogen peroxide (15 ml of a 30 wt. % solution in water) was added to a solution of (R)-N-[4-ethylsulphanyl-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 1) (1.88 g) in glacial acetic acid (26 ml) and the mixture was heated at 95° C. for 1.5 hours then cooled. EtOAc (200 ml) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (4×200 ml) and brine (250 ml) then was dried. Volatile material was removed by evaporation and the residue was purified by chromatography eluting with 0-50% EtOAc/isohexane to give the title compound (1.71 g) as a white solid. NMR: 1.1 (t, 3H), 1.61 (s, 3H), 3.5 (q, 2H), 8.02 (d, 1H), 8.31 (d, 1H); m/z 392.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc(F)c(Cl)c3)n2)cc1Cl

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to yield N2,N4-bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3+CD3OD)): δ 7.81 (d, 1H), 7.60 (m, 1H), 7.58 (m, 1H), 7.38 (m, 1H), 7.19 (m, 1H), 7.0 (m, 2H); LCMS: ret. time: 28.98 min.; purity: 97%; MS (m/e): 385 (MH+).
Reaction SMILES: CO.[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=1.C=O.[CH:20]([O-])=O.[NH4+]>O>[CH3:20][NH:16][C:15]1[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH3:17])[CH:8]=[CH:7][CH:6]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(Nc2ncccc2N)c1
Reactant: O=C[O-]
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CNc1cccnc1Nc1cccc(C)c1
Reaction time: 3 h

Procedure:
600 mL of methanol and 24 mL water were added to a 3-neck 2 L round bottom flask. Nitrogen was bubbled directly into the solution. Palladium on carbon was added (10%, 10.35 g, 9.73 mmol) while bubbling continued. Next, N2-(m-tolyl)pyridine-2,3-diamine (19.38 g, 97 mmol) and formaldehyde (37%, 14.48 mL, 195 mmol) were added. The reaction mixture was stirred under nitrogen for 3 h. Next, nitrogen was bubbled into the solution and ammonium formate (123 g, 1945 mmol) was added slowly. The reaction mixture was stirred under nitrogen overnight at room temperature. The reaction mixture was filtered through Celite® and the Celite® was washed with dichloromethane. The filtrate was washed with water twice, and the organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified using column chromatography eluting with 30% ethyl acetate/hexanes to isolate the desired product. The product was combined with material from other reactions and purified by column chromatography eluting with 30% ethyl acetate/hexanes. A dark reddish-brown solid was obtained. The solid was recrystallized from boiling hexanes with a small amount of ethyl acetate to dissolve the solid. The product was filtered off as needles with some reddish color which were washed with hexanes, obtained 15.1 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=O.Cl.[NH2:17][OH:18]>C(O)C.O>[Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[N:17][OH:18]
Reactant: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)Sc1c(C=NO)ccc(I)c1Br
Yield: 70 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-4-iodo-benzaldehyde (1.5 g, 3.8 mmol) and hydroxylamine hydrochloride in ethanol (20 mL) and water (4 mL) was heated to reflux for 2 h. The reaction mixture was cooled and concentrated. The residue was treated with water (40 mL) and then saturated aqueous sodium bicarbonate solution until the pH was ˜8.0. The mixture was extracted with ethyl acetate (2×40 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (25% ethyl acetate:hexanes) afforded 1.1 g (70%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 9H), 7.41 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.51 (br. s, 1H); MS (ESI): 414, 416 [M+H]+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][CH:5]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Br:1][C:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[C:11]([C:19]([F:22])([F:20])[F:21])[NH:12][C:13]=1[C:15]([F:16])([F:17])[F:18]
Reactant: BrBr
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)c(C(F)(F)F)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1[nH]c(C(F)(F)F)c(-c2ccc(Cl)cc2)c1Br
Yield: 34 %

Procedure:
Bromine (0.527 g, 0.17 mL, 0.0033 mol) is added to a solution of 3-(p-chlorophenyl)-2,5-bis(trifluoromethyl)pyrrole (0.94 g, 0.003 mol), acetic acid (6 mL) and sodium acetate (0.984 g, 0.012 mol). After 1 hour the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium metabisulfite solution, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a colorless oil. The oil is chromatographed using silica gel and eluted with methylene chloride to give the title compound as a colorless oil (0.4 g, 34%). Identified by IR and NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].[CH3:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([NH:19][CH3:18])=[O:33])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)[CH:5]=1)[CH3:2]
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Product: CCOc1cc(CN2CCN(c3ccc(C(=O)NC)cc3)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 398B and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.37-1.44 (m, 3H) 2.41-2.49 (m, 4H) 2.74 (d, J=4.55 Hz, 3H) 3.24 (d, J=5.05 Hz, 4H) 3.40 (s, 2H) 3.98-4.12 (m, 2H) 4.55-4.65 (m, 1H) 6.51 (d, J=1.77 Hz, 1 H) 6.63 (d, J=1.77 Hz, 1H) 6.94 (d, J=8.84 Hz, 2H) 7.70 (d, J=8.84 Hz, 2H) 8.14 (q, J=4.72 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 439.4 (M+H)+. mp 228.2-233.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1Br.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Nc1ccc2c(c1Br)C(c1ccccc1)Oc1cccc(OC(F)F)c1-2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(c1ccccc1)Oc1cccc(OC(F)F)c1-2
Yield: 79 %

Procedure:
A solution of Example 4 (1.19 g), triethylamine (2.8 mL) and 10% Pd/C (120 mg) in ethyl acetate (100 mL) was shaken under 1.5 atms. hydrogen for 15 minutes. The mixture was filtered and concentrated under reduced pressure. The residue was taken up in toluene (50 mL), washed with aqueous KHCO3, dried (Na2SO4), filtered and concentrated. The resulting material was purified on silica eluting with 25% hexane −75% CH2Cl2 to provide the titled compound (0.763 g, 80%). 1H NMR (300 MHz, CDCl3) δ 3.75 (br s, 2H), 5.95 (s, 1H), 6.14 (d, J=3 Hz, 1H), 6.50 (t, J=75 Hz, 1H, CHF2) 6.71 (dd, J=9 Hz, 3 Hz, 1H), 6.77 (dd, J=9 Hz, 1Hz, 1H), 6.87 (dd, J=9 Hz, 1Hz, 1H), 7.05 (t, J=8 Hz, H), 7.30-7.40 (m, 5H), 8.12 (d, J=9 Hz, 1H). MS (APCI) m/e 340 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dichloromethane (3 mL) at room temperature was added isonicotinoyl chloride (0.4 g, 2.79 mmol) and triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (2×). Combined organic layers were washed with 10% KHSO4, sat. NaHCO3, and brine before drying (MgSO4), and concentration under reduced pressure to provide (4-methyl-1-(pyridine-4-carbonyl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 354 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.69 (d, 2H), 7.40-7.31 (m, 7H), 5.06 (s, 2H), 4.15 (m, 1H), 4.62 (m, 4H), 2.12 (m, 2H), 1.77-1.45 (m, 2H), 1.42 (s, 3H).