Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:12]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(F)cc1Br
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Solvent: C1COCCO1
Product: COc1ccc(F)cc1Nc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-4-fluoroanisole (6.0 g), 2-chloro-4-methylsulphonylaniline (9.0 g), cesium carbonate (14.7 g), palladium acetate (0.33 g) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (0.54 g) in dioxane (60 ml) was heated at 100° C. for 20 h. The mixture was cooled, and partitioned between ethylacetate/water. The organics were separated, washed with brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 25% ethylacetate/isohexane. Yield 3.2 g
Reaction SMILES: C(OC(C1NN=C(CCC)C=1)=O)C.ClC1C=C(C=CC=1Cl)CBr.[Cl:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:28][N:29]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]([CH2:37][CH2:38][CH3:39])=[N:30]1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:28][N:29]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]([CH2:37][CH2:38][CH3:39])=[N:30]1.[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:34]([C:33]1[N:29]([CH2:28][C:27]2[CH:40]=[CH:41][C:42]([Cl:43])=[C:25]([Cl:24])[CH:26]=2)[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[CH:32]=1)=[O:36]
Reactant: Nc1nccs1
Agent: CCCc1cc(C(=O)O)n(Cc2ccc(Cl)c(Cl)c2)n1
Agent: CCCc1cc(C(=O)OCC)[nH]n1
Agent: Clc1ccc(CBr)cc1Cl
Product: CCCc1cc(C(=O)Nc2nccs2)n(Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
2-(3,4-Dichlorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid (0.84 g) was prepared from 5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.91 g, 5.0 mmol) and 3,4-dichlorobenzyl bromide (1.32 g, 5.5 mmol) following the general procedures D and E. 2-(3,4-Dichlorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid thiazol-2-ylamide (63 mg) was prepared from 2-(3,4-dichlorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid (78 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: CO[C:3](=[O:22])[C:4](=[C:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]1[CH3:21])[C:5]([F:8])([F:7])[F:6].[CH3:23][C:24]1([CH3:38])[CH2:29][C:28](=[O:30])[CH:27]=[C:26]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:25]1>C(Cl)(Cl)Cl>[CH3:21][C:10]1[NH:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:14])[C:9]=1[C:4]1([C:5]([F:8])([F:7])[F:6])[C:27]2[C:28](=[O:30])[CH2:29][C:24]([CH3:38])([CH3:23])[CH2:25][C:26]=2[N:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:3]1=[O:22]
Reactant: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C)C(F)(F)F
Reactant: CC1(C)CC(=O)C=C(Nc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: Cc1[nH]n(-c2ccccc2)c(=O)c1C1(C(F)(F)F)C(=O)N(c2ccccc2)C2=C1C(=O)CC(C)(C)C2
Reaction time: 14 h

Procedure:
To a chloroform solution (5 ml) of 2-(1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)-3,3,3-trifluoro-propanoic acid methyl ester (565 mg, 1.81 mmol), 5,5-dimethyl-3-phenylamino-2-cyclohexen-1-one (390 mg, 1.81 mmol) was added and the mixture was stirred for 14 hours. After concentrating the liquid reaction mixture under reduced pressure, the residue was purified by silica gel flash column chromatography. Thus, the title compound was obtained as a colorless solid (780 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[CH:16]3)=[C:4]2[CH:10]=[C:9](I)[NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:36][CH:37]=[C:38]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[C:3]([NH:12][C:13]4[CH:14]=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][N:17]=[CH:16]5)=[C:4]3[CH:10]=2)[CH2:39][CH2:40]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1cnc2[nH]c(I)cc2c1Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)c(Br)cnc3[nH]2)CC1

Procedure:
To a mixture of (5-bromo-2-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1H-indazol-5-yl)-amine (25 mg, 0.069 mmol), potassium carbonate (19 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (10 mg, 0.014 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (21.6 mg, 0.069 mmol) was added degassed DMF (3 mL) and water (0.75 mL) and the mixture was heated to reflux for 5 h. Water was added to the reaction and filtered. The precipitate was washed with water and the filtrate was extracted with DCM. The precipitate was dissolved in DCM/MeOH mixture (9:1) and combined with the DCM extract and evaporated. The crude product was purified by preparative TLC using 8% methanol in DCM as eluent to afford the title compound as beige solid. 1H NMR (400 MHz, CD3OD): δ=10.32 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.26 (dd, J=8.8, 1.9 Hz, 1H), 6.69 (s, 1H), 5.95 (bs, 1H), 5.16 (bs, 1H), 3.99-4.03 (m, 2H), 3.42 (t, J=5.4 Hz, 2H), 2.00-2.07 (m, 2H), 1.39 (s, 9H); MS (ES+): m/z 510.89 (100) [MH+]; HPLC: tR=2.63 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of the compound of step 1 (1.0 g; 3.8 mmol) and NH4Cl (0.61 g; 11.4 mmol) in EtOH (30 ml), THF (20 ml) and water (5.0 ml), was added iron powder (0.5 g, 8.9 mmol) under vigorous stirring. The resulting reaction mixture was heated at 80° C. under stirring for 3 hours. The reaction mixture was cooled to 25° C. and filtered through celite and washed with EtOH. The filtrate was concentrated and basified with NaHCO3. The oil separated was extracted with dichloromethane (3×20 ml). The dichloromethane layer was washed with water (2×10 ml) and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was purified by flash chromatography with EtOAc: light petroleum (1:1) to give the title compound of step 2 (0.67 g; 75%). Mass (ES−), 231 (M−1); 1H NMR (DMSO-d6) δ: 1.31 (t, 3H), 4.36 (q, 2H), 5.64 (s, 2H), 6.61 (d, 2H), 7.60 (d, 2H), 7.66 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.5 %

Procedure:
To a solution of Example 12 (0.230 g, 0.556 mmol) in methanol (3.5 ml), lithium hydroxide (0.132 g, 5.56 mmol) in water (0.9 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.130 g, 61%). M.P.: 254-257° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.43 (s, 1H), 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.38 (d, J=7.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.19 (m, 2H), 8.04 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.23 (s, 2H). MS (m/z): 400.01 (M++1).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[C:31]1([CH2:30][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[OH:11])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O[C@H](CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Reaction time: 4 h

Procedure:
A mixture of 2-[bis(phenylmethyl)amino]-1-[3-({3[(phenylmethyl)oxy]propyl}oxy)phenyl]-ethanone, catalyst SK-N003-2z (Naud catalyst, 47 mg) and 1M sodium hydroxide (2.085 mL) in tetrahydrofuran (10 mL) was set under hydrogen at 150 psi for 4 h. The reaction mixture was then filtered through silica gel. The crude filtrate was purified by chromatography eluting with tert-butyl methyl ether-hexane (0-60%) to yield the desired product as a yellow oil.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[C:16]12([CH2:26][O:27][C:28]3[C:40](/[CH:41]=[CH:42]/[CH2:43][O:44][CH3:45])=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[C:30]([F:46])[CH:29]=3)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(=O)(O)[O-].[Na+]>ClCCl>[C:16]12([CH2:26][O:27][C:28]3[C:40]([C@@H:41]4[CH2:1][C@H:42]4[CH2:43][O:44][CH3:45])=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[C:30]([F:46])[CH:29]=3)[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH2:25]1)[CH2:17]2
Reactant: CC[Zn]CC
Reactant: COC/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H]1C[C@H]1c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a mixture of diethylzinc (1.0 M solution in heptane, 6.8 mL, 6.8 mmol) in anhydrous dichloromethane (3 mL) was added a solution of trifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane (2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes at 0° C. A solution of diiodomethane (0.55 mL, 6.82 mmol) in anhydrous dichloromethane (2 mL) was added to the reaction mixture at 0° C. and stirring was continued for 15 minutes at 0° C. To the reaction mixture was then added a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate (1.17 g) in dichloromethane (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. After addition of saturated sodium bicarbonate solution (10 mL), the mixture was diluted with dichloromethane (100 mL). The organic phase was washed with brine (10 mL) dried over sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was treated with trifluoroacetic acid (2 mL) in dichloromethane (20 mL) for 1 hour. After evaporation of all volatiles under reduced pressure, the residue was triturated with diethyl ether (5 mL) to afford the title compound as a colorless solid (0.554 g, 63%): 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 1H), 6.54 (d, J=12.9 Hz, 1H), 3.57 (dd, J=10.3, 6.3 Hz, 1H), 3.55-3.48 (m, 2H), 3.37 (s, 3H), 3.36-3.29 (dd, J=10.3, 7.2 Hz, 1H), 2.07-1.99 (m, 3H), 1.93 (td, J=8.9, 5.1, 5.1 Hz, 1H), 1.82-1.62 (m, 12H), 1.38-1.25 (m, 1H), 1.00 (td, J=8.4, 5.3, 5.3 Hz, 1H), 0.89 (td, J=8.8, 5.2, 5.2 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>CC(C)=O>[OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[N:8]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1
Reactant: CCOC(=O)c1cc(CC(C)O)[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(CC(C)O)n(COCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask containing ethyl 5-(2-hydroxypropyl)-1H-pyrazole-3-carboxylate (15.65 mmol, 3.2 g) in acetone (60 ml), Cs2CO3 (13.7 g, 99.1 mmol), SEM-Cl (9.3 ml, 51.6 mmol) were added and stirred at RT overnight. The reaction mixture was quenched by the addition of H2O and extracted with EtOAc. The organic layer was concentrated and purified by column-chromatography. Yield 3.8 g. 1H-NMR (400 MHz; CDCl3): δ −0.05 (s, 9H), 0.89 (t, 2H), 1.25 (d, 3H), 1.40 (t, 3H), 2.71-2.83 (m, 3H), 3.57 (t, 2H), 4.34 (q, 2H), 5.79 (s, 2H), 6.74 (s, 1H). LC-MS: [M+1]=329.14.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:28][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:24]([F:25])([F:26])[F:27])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (84.1 mg, 0.187 mmol) and triethylamine (33.8 μL, 0.242 mmol) in tetrahydrofuran (1.0 mL) was added acetyl chloride (15.9 μL, 0.224 mmol) at 0° C. After 1 h, triethylamine (18.2 μL, 0.131 mmol) and acetyl chloride (8.0 μL, 0.112 mmol) was added. After 1 hr the reaction mixture was quenched with water, concentrated in vacuo, and purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (93.2 mg, 0.187 mmol, 100%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C>C(O)C.[Pd]>[CH3:15][O:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH3:4]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2[nH]cc(C)c2c1

Procedure:
A solution of 5-methoxygramine (3.96 g) in absolute ethanol (80 ml) with 10% Palladium on carbon (0.40 g) is hydrogenated at atmospheric pressure for 10 hours. The catalyst is removed by vacuum filtration through Hy-Flo and the filtrate is concentrated in vacuo to give an oil which crystallizes on standing to give 5-methoxy-3-methylindole.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:28])([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:28][C:19]([N:18]1[C:8](=[O:16])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([CH3:13])[O:11][CH2:10]1)([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=NC(C)(C)Cc1ccccc1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)Cc2ccccc2)CO1
Yield: 77.3 %

Procedure:
5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g) and N-methylene-1,1-dimethyl-2-phenylethylamine (0.63 g) were reacted at 140° for 30 minutes. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.74 g).
Reaction SMILES: O[C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.CCN(S(F)(F)[F:28])CC>C(Cl)Cl>[F:28][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (400 mg, 1.36 mmol, the first eluting enantiomer E-1 from step E) in DCM (5 mL) cooled to 0° C. was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. The mixture was allowed to warm up to rt and was stirred for 2 h. The reaction was slowly quenched with 50 mL of a 10% aqueous sodium bicarbonate solution and extracted four times with 50 mL of DCM. The combined organic layers were washed with 75 mL of brine, dried, and concentrated under vacuum to yield 390 mg of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate which was used without further purification. LCMS (Method Q) RT 0.92 min, m/z 240.1 (M+H+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Mg]Cl.Cl[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CC1(P(C(C)(C)C)C(C)(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1.O.C1COCC1>[O:24]([C:21]1[CH:22]=[CH:23][C:18]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:19][CH:20]=1)[CH3:25]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: C[Mg]Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 5 °C
Yield: 93.3 %

Procedure:
[PdCl(π-allyl)]2 (23.1 mg, 0.1 mol %) and cBRIDP (89.0 mg, 0.4 mol %) were placed into a 50 mL, two-necked, round bottomed flask equipped a gas inlet, and the flask was evacuated and filled with nitrogen. Subsequently, to the mixture was added dehydrated THF (8.2 mL, 101.0 mmol, 1.6 equivalents) to prepare a catalyst solution. A 200 mL, four-necked, round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, condenser, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. Carbazole (10.9 g, 65.0 mmol, 1.03 equivalents) and dehydrated xylenes (66 mL) were charged into the flask, and the mixture was cooled to 5° C. using an ice bath. Subsequently, to the mixture was added a THF solution of MeMgCl (3.22 mol/L, 20.0 mL, 64.4 mmol, 1.02 equivalents) dropwise via the dropping funnel at such a rate that the temperature of the reaction solution was kept at 20° C. or lower, and then the dropping funnel was washed with dehydrated xylenes (11 mL). Subsequently, to the solution were added 4-chloroanisole (7.7 mL, 63.1 mmol, 1.0 equivalent) and the catalyst solution (8.2 mL) successively, and the solution was stirred for 1 hour under reflux. After cooling the reaction mixture to room temperature, to the mixture were added water (25 mL) and ammonium chloride (1.7 g). The aqueous layer was separated off, and the organic layer was concentrated under reduced pressure to give solid residue. The residue was dissolved in toluene, and the solution was decolorized by silica gel (1 g) and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the solid, which was recrystallized from toluene/methanol to afford 16.1 g of N-(4-methoxylphenyl)carbazole as a white powder.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35]>>[NH2:20][C:17]1[N:18]=[CH:19][C:14]([C:12]2[N:13]=[C:8]([N:5]3[CH2:4][CH2:3][O:2][CH2:7][CH2:6]3)[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:26][CH2:27][N:28]([C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])[CH2:29][CH2:30]4)=[CH:21][C:10]=3[N:11]=2)=[CH:15][N:16]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Agent: Cl
Product: CN(C)CC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with N,N-dimethylglycine via General Procedure B to generate 38.3 mg of 105. MS (Q1) 498.3 (M)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[C:23]([OH:25])=[O:24])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.[H-].[Na+].ClC1[C:42]2[C:37](=[CH:38]C=C(S(N[C@H]3CCCC[C@H]3C(OC(C)(C)C)=O)(=O)=O)C=2)[C:36](Cl)=CN=1>COCCOC>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[C:23]([O:25][C:37]([CH3:42])([CH3:38])[CH3:36])=[O:24])(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)O)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 17.6 %

Procedure:
(±)-cis-2-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR56## Guanidine hydrochloride (325 mg, 3.4 mmol) was added in one portion to a stirred suspension of NaH (89 mg, 80% dispersion by wt in mineral oil, 2.97 mmol) in DME (5 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of t-butyl (±)-cis-2-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (391 mg, 0.85 mmol) in DME (5 mL) was added and the mixture heated at 90° C. for 6 h. The solvents were evaporated in vacuo, the residue was dissolved with EtOAc, washed with aqueous NH4Cl, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using using toluene-i-PrOH-0.880NH3 (100:0:0 to 90:10:0.05) as eluant to give t-butyl (±)-cis-2-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (75 mg, 0.15 mmol) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=4)[N:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)#[N:31]>>[F:27][C:26]([F:29])([F:28])[C:23]1[N:21]2[N:22]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:34]5[CH:33]=[C:32]([C:30]#[N:31])[CH:36]=[N:35]5)=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCBr)cc4)CC3)nn12
Reactant: N#Cc1cn[nH]c1
Product: N#Cc1cnn(CCOc2ccc(N3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)c1
Yield: 75 %

Procedure:
Obtained in 75% yield by an analogous method to Example 847, starting from 6-[4-[4-(2-bromoethoxy)phenyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 4-cyanopyrazole.