Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][CH:2]1[N:7]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 3-methylpiperazine-1-carboxylate (1.00 g, 4.99 mmol, 1.00 equiv), 4-phenylbenzaldehyde (1.00 g, 5.49 mmol, 1.10 equiv), sodium triacetoxyborohydride (3.18 g, 15.0 mmol, 3.01 equiv), 1,2-dichloroethane (30 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was washed with water (1×120 mL) and extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5) to yield 1.71 g (93% yield) of tert-butyl 3-methyl-4-[(4-phenylphenyl)methyl]piperazine-1-carboxylate as a light yellow solid. LCMS (ESI, m/z): 367 [M+H]+.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:30]2[CH2:31][CH2:32][N:28]([C:26]3[S:25][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([CH3:22])[CH:27]=3)[C:29]2=[O:33])=[CH:16][CH:15]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Yield: 95 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-fluorobenzyl bromide to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 95% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.25 (in, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.15 (s, 1H), 4.44 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.49 (s, 3H), 1.34 (t, J=7.1 Hz, 3H): MS (ES+) m/z 363.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[O:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>ClCCl>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[O:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1)c1ccccc1Cl
Yield: 82.2 %

Procedure:
to a solution of 4-(4-phenyl-5-(trifluoromethyl)oxazol-2-yl)benzenamine (178 mg, 585 μmol) and pyridine (473 μl, 5850 μmol) in 5 mL dichloromethane at room temperature was added 2-chlorobenzoyl chloride (78.0 μl, 614 μmol) all at once by pipet. After one hour the reaction was concentrated under reduced pressure then taken up in 25 mL dichloromethane and washed with 25 mL saturated aqueous sodium bicarbonate solution. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow oil. The product was isolated by chromatography on silica gel, eluting with 15-40% ethyl acetate in hexane, to yield a colorless foamy solid (213 mg, 82%). ESI+ m/z=443.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:20]=[N:19][CH:18]=[C:17]([CH3:16])[CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cncc(C)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)c1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 3-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:26]([OH:28])=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:27]
Reactant: NC(CCc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(CCc1ccccc1)C(=O)O
Yield: 77 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-homophenylalanine to provide the title compound in 77% yield as yellow needles (recrystallization from EtOH).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:28]([O:35][C:36](=[O:40])[CH2:37][NH:38][CH3:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>C(#N)C.C(OCC)(=O)C.CN(C)C=O>[CH2:28]([O:35][C:36](=[O:40])[CH2:37][N:38]([C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNCC(=O)OCc1ccccc1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
N-Boc-(D)-methionine (17.1 g, 68.58 mmole) and sarcosine benzyl ester tosylate salt (24.08 g, 68.60 mmole) were suspended in 110 mL of acetonitrile and 25 mL of dimethylformamide at 0° C., then benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (30.34 g, 68.58 mmole) and N-methylmorpholine (20.83 g, 205.83 mmole) were added. The ice bath was removed after 30 minutes and the reaction was stirred for 18 hours at room temperature. The reaction mixture was reduced in volume under vacuum at 25° C. to give an oil. The oil was dissolved in ethyl acetate (250 mL), then successively washed with 1N hydrochloric acid (1×50 mL), saturated sodium bicarbonate (1×50 mL) and brine (1×50 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated under vacuum to give crude product. The crude product was purified by column chromatography on silica gel, eluting with 60:40 hexane:ethyl acetate to yield 26.07 g (92.6%) of the title compound as an oil. Thin layer chromatography analysis of the title compound showed a single spot with Rf=0.55 (silica, 3:2 ethyl acetate/hexane).
Reaction SMILES: C[O-].[Na+].NC[C:6]([C:8]1[N:9]=[CH:10][N:11]([C@@H:18]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:19]2[F:26])[C:12]=1[N:13]=[CH:14][N:15](C)[CH3:16])=[O:7]>CO>[F:26][C@@H:19]1[C@H:20]([OH:21])[C@@H:22]([CH2:24][OH:25])[O:23][C@H:18]1[N:11]1[C:12]2[N:13]=[CH:14][NH:15][CH2:16][C:6](=[O:7])[C:8]=2[N:9]=[CH:10]1
Reactant: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CNC=Nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F

Procedure:
In step 18, compound (24) is dissolved in methanol and treated with a methanolic solution of sodium methylate at room temperature to effect the ring-formation of the substituents on the imidazole ring of compound (24). Thus, 3-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-6,7-dihydroimidazo-[4,5-d][1,3]diazepin-8(3H)-one [compound (25)] is produced.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])(=O)=O.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([NH:16][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CCCCCOS(C)(=O)=O
Reactant: CC(C)(C)N
Product: C#CCCCCNC(C)(C)C

Procedure:
A solution of 3.5 g of 17b in 30 ml of tert-butyl amine was stirred at ambient temperature for 24 hrs. The reaction mixture was concentrated and the residues were partitioned between ethyl acetate and 5% NaHCO3. The organic layer was dried and concentrated, to provide 3.0 g of 17c as a colorles oil, which was used without further purification in next step.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[C:19]1(/[CH:25]=[CH:26]/[CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]2[CH2:32][CH2:33][N:28]([CH2:27]/[CH:26]=[CH:25]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:29][CH2:30]2)[CH:11]=1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: C(=C/c1ccccc1)\CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCN(C/C=C/c2ccccc2)CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (0.80 g in 40 ml acetonitrile) was added [(2E)-3-phenylprop-2-enyl]piperazine (0.50 g in 10 ml acetonitrile). After 3 hrs, N,N-diisopropylethylamine was added (428 μl in 10 ml acetonitrile) and the reaction stirred for a further 2 hrs after which time a precipitate of the title compound appeared. This was used crude in the next step. m/z (ES+) 448 (MH)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:45][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[N:26]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.195 g, 0.333 mmol) was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.049 g, 0.37 mmol) and EDCl (0.070 g, 0.37 mmol) and N,N-diisopropylethylamine (0.232 mL, 1.33 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.128 g, 1.332 mmol) was added in one portion, and the reaction was stirred room temperature for 20 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the organic layer was washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (Biotage Isolera, 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% methanol in EtOAc) to give the title compound (I8) (0.133 g, 68% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.61 (s, 1H), 7.65-7.56 (m, 2H), 7.44 (s, 1H), 7.26-7.13 (m, 4H), 6.98-6.89 (m, 3H), 3.52-3.41 (m, 6H), 3.13-2.95 (m, 8H), 1.42 (s, 9H). LCMS Method C: rt 6.18 min; m/z 585.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=2)[C:3]=1[OH:17].C(N(CC)CC)C>[Pd].C(O)C>[CH3:12][C:11]1[CH:2]=[C:3]([OH:17])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(S(C)(=O)=O)ccc2c(O)c1Br
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)c2ccc(S(C)(=O)=O)cc2c1
Reaction time: 1.5 h

Procedure:
A mixture of 2-bromo-3-methyl-6-(methylsulfonyl)naphthalen-1-ol (0.500 g, 1.59 mmol), 10% palladium on carbon (0.050 g) and triethylamine (0.331 mL, 2.38 mmol) in ethanol was stirred under a hydrogen atmosphere for 1.5 hours. Celite was added and the mixture was stirred for 10 minutes, filtered through a pad of Celite and the filtrate concentrated. The residue was dissolved in ethyl acetate, washed with dilute HCl/brine, dried (MgSO4), filtered, concentrated, and purified by flash column chromatography (silica gel, 20 to 50% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M−H]− calcd for C12H11O3S: 235.3. Found: 235.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)OCCCCCC=Cc1cccc(Br)c1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CCc1ccc(NCCCCCC=Cc2cccc(Br)c2)cc1

Procedure:
A mixture of 5.0 g. of ethyl 4-aminohydrocinnamate, 10.0 g. of 7-(3-bromophenyl)-1-methanesulfonyloxy-6-heptene (prepared by the method of Example 9), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 80° for 17 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1>C(O)C>[CH3:33][C:31]1[NH:30][N:29]=[C:28]([NH:27][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[S:8][C:4]=4[CH:3]=3)[N:26]=2)[CH:32]=1
Reactant: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Solvent: CCO
Product: Cc1cc(Nc2ccnc(Nc3ccc4nc(NC(=O)c5ccccc5)sc4c3)n2)n[nH]1

Procedure:
N-{6-[4-(5-Methylpyrazol-3-ylamino)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 35 mg, 0.13 mmol) and (2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg, 0.143 mmol) in ethanol (3 mL) to 80° C. for 9 h. The precipitate was separated by filtration, washed with ethanol and dried (38 mg, 85 μmol, 66%). LC/ESI-MS: m/z=443 [M+H]+; m/z =441 [M−H]−; Rt=2.80 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC(C2CC(=O)C(=[CH:30][N:31]([CH3:33])[CH3:32])C(=O)C2)=CC=1>>[CH3:30][N:31]([CH:33]=[C:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][C:10]1=[O:15])[CH3:32]
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Reactant: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: CN(C)C=C1C(=O)CC(c2ccc(F)cc2)CC1=O
Reaction time: 0.17 h

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)cyclohexane-1,3-dione (1.0 g, 4.85 mmol), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was run at ambient temperature for 10 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(F)cc(F)c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-difluorobenzaldehyde (2.00 g, 14.1 mmol) in MeOH (20 mL) at 0-5° C. was added NaBH4 (1.06 g, 28.1 mmol) portionwise. The mixture was stirred at 0-5° C. for 1 h, quenched with brine, and then extracted with EtOAc (2×). The combined organic phases were washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure to give sub-title compound as a colorless oil. %). 1H NMR (300 MHz, CDCl3) δ 6.88 (m, 2H), 6.70 (m, 1H), 4.69 (s, 2H), 1.88 (br s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[C:29]([O:32][CH2:33][CH2:34]O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:29]([O:32][CH2:33][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCCO
Reactant: COc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2[nH]c(-c3ccc(OCCOC(C)=O)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-acetoxyethyloxy)phenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.Br[CH:18]([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:13]([C:7]1[CH:6]=[C:5]([N:4]([CH2:3][C:2]([F:15])([F:16])[F:1])[C@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:26])[CH:10]=[CH:9][C:8]=1[C:11]#[N:12])#[N:14]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C#N
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(2,2,2-trifluoroethyl)amino]-1,2-benzenedicarbonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z 354 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cl)cc1C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol 1b (1.2, 17 g, 0.05 mol) and p-TsOH (29.3 g, 0.15 mol) in toluene (300 mL) was heated to reflux for 6 h with water being removed through a Dean-Stark apparatus. The mixture was cooled to room temperature and was washed with saturated NaHCO3 (100 mL×3). The organic layer was dried over Na2SO4 and concentrated to afford 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine 1c as a brown liquid.
Reaction SMILES: CC(OC[C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10](N)[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(Cl)(Cl)Cl>C(N(CC)CC)C>[O:12]=[C:11]1[N:8]2[CH:9]([S:14][CH2:15][CH:6]=[C:7]2[C:16]([OH:18])=[O:17])[CH2:10]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)C1=CCSC2CC(=O)N12

Procedure:
By treating 4 g. of the product of Example 1 (c) with 4.5 g. of 7-aminocephalosporanic acid which has been dissolved in 100 ml. of anhydrous chloroform with 6 ml. of triethylamine according to the procedure of Example 1 (d), 2.8 g. of 3-[(acetyloxy)methyl]-7β-[[(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)phenyl-acetyl[amino[-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained which decomposes between 95° and 100°.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([I:14])[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[F:1][C:2]1[CH:18]=[C:17]([CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([I:14])[S:13][C:6]=12)[NH2:19]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Yield: 99.6 %

Procedure:
To a solution of 399 (2 g, 4.81 mmol) and NH4Cl (220 mg, 4.08 mmol) in 2:1 EtOH/water (75 mL) was added iron powder (2.28 g, 40.8 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to afford 410 (1.85 g, 100% yield), that was used without further purification MS. (m/z): (M+1) 386.8 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=2[CH3:49])[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=2[CH3:49])[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c(C)c1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4C)c3)c2cc1OC
Yield: 83.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate from Step A (120 mg, 0.33 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (141 mg, 0.25 mmol, 83%). 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.39 (s, 1H), 7.36 (t, 1H), 7.23-7.11 (m, 4H), 6.94 (d, 1H), 6.33 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 567 (M+H)+.