Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Temperature: 60 °C
Yield: 89.9 %

Procedure:
A mixture of 2-bromo-4-nitrophenol (Description 6; 14 g, 68.6 mmol), benzyl bromide (14.1 g, 82.4 mmol) and potassium carbonate (47.3 g, 0.343 mol) in dimethylformamide (100 ml) was heated at 60° C. for 3 hours. The mixture was cooled to room temperature and poured into a mixture of ethyl acetate and water. The organic phase was washed with water (3 times) and saturated brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give the title compound (19 g). H NMR (250 MHz, CDCl3) δ 8.48 (1H, d, J 2.8 Hz), 8.18 (1H, dd, J 9.08 Hz, 2.8 Hz), 7.46−7.3 (5H, m), 7.0 (1H, d, J 9.2 Hz), and 5.27 (2H, s).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([N+:18]([O-])=O)=[C:14]([O:16][CH3:17])[CH:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([NH2:18])=[C:14]([O:16][CH3:17])[CH:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1cnc([N+](=O)[O-])c(OC)c1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1cnc(N)c(OC)c1)OCC
Yield: 91.9 %

Procedure:
Diethyl[(5-methoxy-6-nitropyridin-3-yl)methyl]phosphonate (Compound 308B, 102.6 mg) was hydrogenated in the presence of 10% Pd/C (20 mg) in MeOH (5 mL) under 1 atmosphere for 4 h. The catalyst was filtered off, the filtrate was concentrated, and the residue (85 mg, 92% yield) was used in the next step without purification. 1H NMR (CDCl3, 400 MHz): δ=1.27 (dt, J=2.0, 6.8 Hz, 6H), 3.02 (d, J=20.8 Hz, 2H), 3.84 (s, 3H), 4.01-4.08 (m, 4H), 4.74 (s, 2H), 6.98 (t, J=2.0 Hz, 1H), 7.52 (t, J=2.0 Hz, 1H). MS (ES+): m/z 275.10 [MH+]. HPLC: tR=0.77 min (UPLC TOF, polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](O)[CH3:9].C(N(S(F)(F)[F:30])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([F:30])[CH3:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl
Solvent: ClCCl
Product: CC(F)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 5-chloro-6-(1-hydroxyethyl)-4-[1-(4-difluoromethoxyphenyl)-ethylamino]pyrimidine, and to the mixture was added dropwise 0.4 g of diethylaminosulfur trifluoride under ice cooling. The mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2C3C(=C(Br)C=CC=3)C=[CH:24][C:23]=2OC)[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.N[C@@H]1C(=O)N(CC2C3[C:61](=[CH:62][CH:63]=[CH:64]C=3)[N:60]([C:67]3[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=3[C:69]#[N:70])[N:59]=2)C2C=CC=CC=2NC1.N(C(OC(C)(C)C)=O)(C)[C@H](C(O)=O)C>>[C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:23]3[C:61](=[CH:62][CH:63]=[CH:64][CH:24]=3)[N:60]([C:67]3[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=3[C:69]#[N:70])[N:59]=2)[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Reactant: N#Cc1ccccc1-n1nc(CN2C(=O)[C@@H](N)CNc3ccccc32)c2ccccc21
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)N[C@H]1CNc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Yield: 72.8 %

Procedure:
In a similar manner to that described for the preparation of {(S)-1-[(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 12), 2-[3-((S)-3-amino-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl)-indazol-1-yl]-benzonitrile trifluoroacetate (step 1 above) (680 mg, 1.30 mmol) and Boc-N-Me-Ala-OH (290.88 mg, 1.43 mmol) were converted to the title compound (570 mg, 72.8%) obtained as white solid. LC-MS: 594 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:43]3[CH2:44][CH2:45][N:40]([C:32]4[N:31]([CH3:30])[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=4)[CH2:41][CH2:42]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][C:44]1=[O:48].OS([O-])(=O)=O.[Na+]>CCO>[O:1]=[C:2]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][C:44]2=[O:48])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCCN1CCCC1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(3-aminopropyl)-2-pyrrolidinone (0.0085 mL, 0.061 mmol) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.0085 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered, washed with EtOH and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.59 (m, 2 H), 1.89-1.96 (m, 2 H), 2.21 (t, J=8.24 Hz, 2 H), 3.08 (t, J=6.59 Hz, 2 H), 3.15-3.21 (m, 2 H), 3.27-3.31 (m, 2 H), 3.87-3.93 (m, 2 H), 4.11 (s, 2 H), 4.55 (s, 2 H), 7.11-7.16 (m, 2 H), 7.35 (td, J=6.46, 2.29 Hz, 2 H), 7.78-7.85 (m, 4 H), 8.15 (s, 1 H), 8.51 (s, 1 H), 9.95 (s, 1 H); ES+ MS: 612 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=2[N:9]=1.[CH3:22][O-:23].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:22][O:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=2[N:9]=1
Reactant: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)ccc21
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a mixture of 0.30 g of 2-(3-fluoropyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole and 10 ml of DMF was added 0.16 g of sodium methoxide under ice cool, then, the mixture was heated up to room temperature and stirred for 1.5 hours. A saturated ammonium chloride aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 2-(3-methoxypyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 8).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[N:13]=[C:12](SC)[NH:11][C:10]2=[N:16][CH:17]=[CH:18][C:9]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Ni]>[CH2:1]([NH:7][C:8]1[N:13]=[CH:12][NH:11][C:10]2=[N:16][CH:17]=[CH:18][C:9]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNc1nc(SC)[nH]c2nccc1-2
Agent: [Ni]
Product: CCCCCCNc1nc[nH]c2nccc1-2

Procedure:
Into a flask equipped with a stirring bar and reflux condenser were introduced 4-(n-hexylamino)-2-methylthio-pyrrolo[2,3-d]-pyrimidine (100 mg) and 5 ml of Raney nickel ethanolic slurry (c.a. 0.6 g/ml; 10 months old). The mixture was heated at reflux and additional 5 ml portions of Raney nickel slurry were added at 12 hour intervals for 48 hours at which point tlc (24:1 CHCl3 -MeO) indicated that the reaction was complete. The Raney nickel was removed by filtration through Celite. Evaporation of the solvent afforded a tan solid (79 mg; 95%) which was purified by preparative tlc on silica using a solvent system of 4:1 benzene-ethanol. This purification yielded a white solid, m.p. 147°-148° C.; C12H18N4 (M+ calculated: 218.15314; found: 218.15365);
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:39][CH3:40])=[CH:29][C:30]=2[O:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:39][CH3:40])=[CH:29][C:30]=4[O:32][CH:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1cc(OC2CCOCC2)c2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1
Yield: 28 %

Procedure:
Using the procedure described in Example 92A Step 3, using 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.193 g, 0.7 mmol) from Example 1A, 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline from the previous step (0.212 g, 0.72 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (10 mL) at 60° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yloxy]phenyl}urea as solid (0.104 g, 28%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.58 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.37 (d and s, 2H), 6.95 (d and s, 2H), 6.59 (s, 1H), 5.89 (s, 1H), 4.76 (m 1H), 3.99 (m, 2H), 3.96 (s, 3H), 3.66 (m, 2H), 2.06 (m, 2H), 1.95 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[CH:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH2:12][CH2:13]\1)[CH3:3].[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2C(N)=[CH:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>O>[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:13][CH2:12][C:11]5[N:10]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:9]=[CH:8][C:7]=5[C:6]=4[C:31]=3[CH:30]=[N:29]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CN(C)/C=C1/CCc2c(cnn2-c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2c-4cnn2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
To a mixture of (Z)-5-((dimethylamino)methylene)-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (1 g, 3.74 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3.5 g, 17.2 mmol) was added trifluoroacetic acid (0.8 mL, 10.3 mmol). The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then poured into ice-cooled water (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic extracts were dried using sodium sulfate and concentrated under reduced pressure to give a dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to a residue, which was further purified by crystallization from methanol and isopropanol to give the pure desired product (0.8 g, 15%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.33 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.55-7.49 (m, 4H), 7.41-7.39 (m, 1H), 7.38 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.66 (s, 2H), 3.75 (s, 3H), 3.14-3.09 (m, 4H); LCMS [M+H]: 408.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([CH2:16][C:17]([NH2:19])=[O:18])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][C:17]([NH:19][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:18])[CH2:15][CH2:14]1
Reactant: NC(=O)CC1CC1
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Product: COC(=O)c1cc(C)nc(NC(=O)CC2CC2)c1
Yield: 67 %

Procedure:
The title compound is prepared in 67% yield (316 mg) from methyl 2-chloro-6-methylisonicotinate (350 mg, 1.89 mmol) and 2-cyclopropylacetamide (243 mg, 2.45 mmol) by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: NCCCCCCNC(=O)N1c2ccccc2CCc2ccccc21
Reactant: O=C(O)C=Cc1cccnc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCNC(=O)N1c2ccccc2CCc2ccccc21

Procedure:
Batch size: 2.2 g (14.8 mmol) 3-(3-pyridyl)-acrylic acid, 2.5 g (19.7 mmol) oxalyl chloride, 4.5 g (44.5 mmol) TEA and 5.0 g (13.4 mmol) 6-(10,11-dihydro-dibenzo[b,f]azepin-5-yl-carbonylamino)-hexylamine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])#[N:24]>N1C=CC=CC=1>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([O:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)=[O:29])#[N:24]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(O)C1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cccc(C#N)c2)C1
Temperature: 50 °C

Procedure:
0.1 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol is dissolved in 3 ml of pyridine and, at 0° C., 0.1 g of 3-cyanobenzoyl chloride is added. The reaction mixture is then heated at 50° C. for 10 minutes. The reaction is checked (LCMS), showing the formation of the desired product in addition to unreacted alcohol cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. After addition of a further 0.9 g of 3-cyanobenzoyl chloride and 30 minutes of stirring at room temperature, the reaction is terminated by addition of 5 ml of concentrated hydrochloric acid, the mixture is extracted with ethyl acetate and the organic phase is washed with saturated sodium bicarbonate and sodium chloride solution and dried over magnesium sulfate. Purification by HPLC gives 0.1 g of the compound cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-cyanobenzoate as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:23])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[C:5]1([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH2:22][CH3:24])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:23])[CH2:10][N:9]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COc1cc2c(cc1OC)C(c1ccc(Br)cc1)=NCC(=O)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc2c(cc1OC)NC(=O)CN=C2c1ccccc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 100 mg (0.267 mmol) of 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in 2 ml of anhydrous DMF, add under an inert atmosphere 48 mg (0.35 mmol) of K2CO3. After 30 minutes at room temperature, add dropwise 25 μl (0.4 mmol) of MeI. Allow to stand at room temperature for 12 hours. Add 30 ml of water. Extract three times with 30 ml of EtO2. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt 1/hexane 1). Recrystallize in EtO2. One obtains 78 mg of the abovenamed product as a white powder. Yield: 73%. 1H-NMR (CDCl3, 200 MHz): d 3.40 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.29 (AB system, ? d=1.014, JAB=10.7, 2H, CH2), 6.65 (s, 1H Ar), 6.78 (s, 1H Ar), 7.54 (s, 4H Ar).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[NH2:13])=O.[NH2:14][C:15](N)=[O:16]>O>[OH:16][C:15]1[N:14]=[CH:1][C:3]2[C:4](=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)[N:13]=1
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Reactant: NC(N)=O
Solvent: O
Product: COC(=O)c1ccc2cnc(O)nc2c1
Temperature: 145 °C

Procedure:
To methyl 4-formyl-3-aminobenzoate (1 eq) was added urea (5 eq) and the mixture was heated to 145° C. for 16 h. To the crude was added water and the precipitated solid was filtered to give methyl 2-hydroxyquinazolin-7-carboxylate in quantitative yield. ES/MS m/z 205 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:14][N:13]=[C:12]([CH2:15]Cl)[N:11]=1)=[O:8].[CH3:20][NH2:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:14][N:13]=[C:12]([CH2:15][NH:21][CH3:20])[N:11]=1)=[O:8]
Reactant: CN
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Product: CNCc1nsc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
A solution of 1-(3-Fluorobenzyl)-3-(3-(chloromethyl)-1,2,4-thiadiazol-5-yl)urea (Intermediate XXV) and excess methyl amine (2.0M solution in THF) was heated for 15 min at 60° C. under microwave irradiation. Filtered off insolubles and removed solvent in vacuo to give title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=1.[CH3:21][C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:27][C:24]2[S:25][CH:26]=[C:22]([CH3:21])[N:23]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 89.7 %

Procedure:
Following the method of Example 3, Step B, ethyl 4-chloro-3-(2-chloropyridin-4-yloxy)benzoate (1.64 g, 5.26 mmol), 4-methylthiazol-2-amine (0.60 g, 5.26 mmol), potassium phosphate (1.23 g, 5.78 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.241 g, 0.263 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.228 g, 0.394 mmol), water (4 mL) and toluene (13 mL) were combined to give the desired product (1.84 g, 89.8% yield) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[F:22][C:23]1[C:28](O)=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[F:33]>ClCCl>[F:22][C:23]1[C:28]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[F:33]
Reactant: N#CCC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.25 g. (0.05 moles) of cyanoacetic acid are dissolved in 100 ml. of dichloromethane and a solution of 10.3 g. (0.05 moles) of dicyclohexylcarbodiimide and 9.2 g. (0.05 moles) of pentafluorophenol in 50 ml. of dichloromethane is added. The mixture is stirred at room temperature for 4 hours, cooled to 0° C. and the precipitated dicyclohecylcarbodiimide is removed by filtration, the solvent is removed by distillation and the residue is taken up in petrolether and the precipitated ester is filtered, trituated with petrolether, washed and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)Cl.C(O)(=O)C>[Br:23][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of the crude 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene of Example 2a (12.6 g, up to 30 mmole) in methylene chloride (100 ml) was diluted with 75 ml of acetic acid and cooled to about 5°. A 1M solution of bromine in acetic acid (33 ml, 1.1 equiv) was added and the reaction stirred at about 5°. After 1 hour, additional bromine solution (5 ml) was added. After 2 hours total reaction time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. Recrystallization from ethanol gave the title compound (7.9 g), m.p. 122°-124°. Infrared and NMR spectral data were consistent with the assigned structure.