Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:46][CH3:47])[C:30]1[C:39]([N:40]2[CH2:44][CH2:43][O:42][C:41]2=[O:45])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([N:40]4[CH2:44][CH2:43][O:42][C:41]4=[O:45])=[C:30]([CH:29]([O:46][CH3:47])[O:28][CH3:27])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COC(OC)c1nc2c(cc1N1CCOC1=O)CCCN2
Reactant: COCCNc1cc(N)ncc1C#N
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCOC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 629 mg, 3.271 mmol) in anhydrous DMF (5 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (596 mg, 2.86 mmol) and DMF (5 ml) cooled at 0° C. After stirring for 1 h at 0° C. the reaction mixture was allowed to warm to room temperature and a solution of 3-(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxazolidin-2-one (intermediate 335, 685 mg, 1.635 mmol) in DMF (5 ml) was added. The suspension was allowed to warm to room temperature, was continued to stir for 18 h and quenched by the addition of MeOH. The reaction mixture was diluted with water, filtered to remove solid impurities and the filter cake was washed with EtOAc. The filtrate was diluted with brine and EtOAc, phases were separated and the water phase was extracted with EtOAc (2×). The combined organic phases were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (containing 0.3% of aqueous NH3, 0-4%) in DCM, followed by another purification on silica gel eluting with a mixture of MeOH (containing 0.3% of aqueous NH3)/DCM (98/2). Fractions containing the product were combined, concentrated. The solid was suspended in EtOAc, sonicated, filtered and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.86 min, ESI-MS 512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.27 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 6.88 (t, 1H), 5.49 (s, 1H), 4.47 (t, 2H), 3.98-3.87 (m, 4H), 3.53 (t, 2H), 3.43-3.28 (m, 11H), 2.85 (t, 2H), 1.96-1.86 (m, 2H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH2:15][F:16])=[O:12].ClCCl.Cl.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[C:38]([O:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[N:37]=[CH:36][N:35]=1)[CH2:29][CH2:28]2)(=[O:24])=[O:23]>O>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[N:35]=[CH:36][N:37]=[C:38]([O:40][CH:41]3[CH2:46][CH2:45][N:44]([C:11]([O:13][CH2:14][CH2:15][F:16])=[O:12])[CH2:43][CH2:42]3)[CH:39]=1)[CH2:29][CH2:28]2)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: O=C(Cl)OCCF
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OCCF)CC2)ncn1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 36.2 %

Procedure:
Diisopropylethylamine (178 μL, 0.997 mmol) and (2-fluoroethyl) chloroformate (33 μL, 0.350 mmol) were added at 0° C. to a dichloromethane (2 mL) suspension of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline hydrochloride (188 mg, 0.396 mmol) produced in Reference Example 27, and the mixture was stirred at room temperature for 80 minutes. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:dichloromethane=1:1, V/V; (ii) hexane:ethyl acetate:dichloromethane=2:1:2-1:1:1-2:2:1, V/V; (iii) ethyl acetate:dichloromethane=1:1, V/V] to obtain the title compound as white powder (58.8 mg, yield: 38%).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[C:6]1=[O:15]
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)O1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
Sodium hydride (60% in oil, 191 mg, 4.70 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985; 1511–16, 450 mg, 2.27 mmol), in anhydrous DMF (6 mL) at 0° C. over a period of 5 min keeping the internal temperature at <10° C. The reaction was stirred for a further 30 min before addition of [2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate (J. Med. Chem. 35, 1992, 1650–62; 528 mg, 2.50 mmol) and the reaction has then heated to 80° C. for a period of 5 hours The reaction was then cooled and evaporated before addition of sat. aqueous NaHCO3 (20 mL) and EtOAc (50 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM 1:19) to afford the title compound (330 mg, 53%) as colourless oil.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH2:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:26][CH2:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: NCc1cccs1
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCc4cccs4)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 24 h
Yield: 125.6 %

Procedure:
To a solution of 25 mg mitomycin A (0.071mmol) in 2 ml. of anyhdrous methanol, 16.2 mg 2-aminomethylthiophene (0.143 mmol) was added with stirring. The progress of the reaction was checked periodically by TLC and the reaction appeared to be complete in 24 hours. Removal of the solvent by evaporation under reduced pressure gave a dark-blue residue. The residue was purified by preparative thin-layer chromatography using a pre-coated silica-gel plate (2 mm thickness) and acetone as developing solvent. The product was further purified by recrystallizing from a mixture of chloroform and hexane to give 20 mg (65% yield) of the desired product having a melting point of 92°-94° C. and providing the following analysis:
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[C:6]([CH2:20][CH:21]=[CH2:22])[CH:5]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:26])=[O:15])=[C:6]([CH2:20][CH:21]=[CH2:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3.06 g of 6-(4-acetyl-5-hydroxy-2-allylphenoxy)hexanoic acid, 1.74 ml of oxalyl chloride, 100 ml of methylene chloride, and ten drops of dimethylformamide was mixed at 0° C. and allowed to warm to room temperature. After stirring for 4 hours, the solvents were removed by evaporation to provide the desired title product. NMR.
Reaction SMILES: [CH3:1][OH:2].[Li+].[OH-:4].Cl.[CH2:6]1[CH2:10]O[CH2:8][CH2:7]1>O>[CH2:7]([C:6]1[CH:10]=[C:8](/[CH:10]=[CH:6]/[C:7]2[CH:8]=[CH:7][CH:6]=[CH:10][CH:8]=2)[CH:7]=[CH:6][C:10]=1[C:1]([OH:4])=[O:2])[CH3:8]
Reactant: C1CCOC1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Product: CCc1cc(/C=C/c2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of ester (E)-ethyl 4-styrylbenzoate (600 mg, 2.3 mmol) in THF (5 mL) was added MeOH (2 mL) and a solution of LiOH (360 mg, 10 mmol) in water (25 mL). The reaction was stirred at room temperature and for 4 h. The reaction was acidified with 1 N HCl (10 mL) and isolated (E)-ethyl 4-styrylbenzoic acid (440 mg, 83%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 8.11 (d, J=8.0 Hz, 2H), 7.75-7.68 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.62-7.56 (m, 2H), 7.52-7.47 (m, 1H), 7.43-7.36 (m, 3H), 6.97 (d, 1H), 6.88 (d, 1H); LCMS (214 nM) 3.22 min (>98%); MS (ESI) m/z=225.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:13]2[S:29][C:16]3[C:17]4[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=4[O:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[N:10][NH:11][CH:12]=1.[Cl-].[NH4+].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:13]2[S:29][C:16]3[C:17]4[CH:25]=[CH:24][C:23]([C:26]([NH2:33])=[O:27])=[CH:22][C:18]=4[O:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[N:10][NH:11][CH:12]=1
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2

Procedure:
Following Example 47, 2-(4-(2-chlorophenyl)-1H-pyrazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid and ammonium chloride were coupled with HATU and DIPEA in DMF to give 274.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.CO[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[N:34]1([C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:9])=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)=[O:24])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: C1CCNC1
Product: O=C(c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1)N1CCCC1

Procedure:
The title compound is prepared starting with (4-Bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone and 4-methoxycarbonylphenyl boronic acid perform procedures significantly analogous to those found in Procedures BB, V′, W′ (with pyrrolidine in place of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine) and Q. MS (m/e): 432.4 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:28]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[OH:36])[CH2:29]1>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:33]1[CH2:34][CH2:35][C:30]2([CH2:29][CH2:28]2)[C@H:31]([OH:36])[CH2:32]1
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 70 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the pure title compound in 70% yield as light yellow foam. MS: 484.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:16][OH:17])[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[C:18](=O)([O-])[O-].[K+].[K+].Cl.Cl[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: Cc1cccc(Cl)n1
Reactant: COC(=O)NCc1cc(C(C)=NO)ccc1C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(C(C)=NOCc2cccc(C)n2)ccc1C
Temperature: 95 °C
Yield: 48.3 %

Procedure:
0.43 g of methyl N-[2-methyl-5-(1-hydroxyiminoethyl)benzyl]carbamate was dissolved in 15 ml of N,N-dimethylformamide, 0.75 g of potassium carbonate and 0.32 g of 2-chloro-6-methylpyridine hydrochloride were added thereto, followed by stirring under heating at from 90 to 100° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=4/1) to obtain 0.30 g of methyl N-{2-methyl-5-[1-(6-methylpyridin-2-yl methoxy)iminoethyl]benzyl}carbamate (m.p. 72-75° C.) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18](=[O:24])OC(C)(C)C)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH:7]=1.Cl.CCN(CC)CC.[CH2:33]([N:35]1[C:39]2=[N:40][C:41]([CH2:64][CH3:65])=[C:42]([CH2:51][NH:52][C:53]([C:55]3[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=3)C(O)=O)=[O:54])[C:43]([NH:44][CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[C:38]2[CH:37]=[N:36]1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[CH2:33]([N:35]1[C:39]2=[N:40][C:41]([CH2:64][CH3:65])=[C:42]([CH2:51][NH:52][C:53]([C:55]3[CH:63]=[CH:62][CH:61]=[C:57]([C:18]([NH:17][CH2:16][C:4]4[CH:5]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[O:15])[CH:9]=5)[CH:7]=[C:2]([F:1])[CH:3]=4)=[O:24])[CH:56]=3)=[O:54])[C:43]([NH:44][CH:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[C:38]2[CH:37]=[N:36]1)[CH3:34]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)cc(-c2cccc(C=O)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(F)cc(-c3cccc(C=O)c3)c2)c1
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a clear solution of 1,1-dimethylethyl [(5-fluoro-3′-formyl-3-biphenylyl)methyl]carbamate (486 mg, 1.48 mmol) in DCM (2 mL) was added 4N HCl in dioxane (1 mL). Solid precipitated out from the solution after 30 min but stirring was continued at RT for another 1 h. The mixture was then concentrated under vacuum to get rid of solvent. The resulting residue was re-dissolved in DCM. Et3N (1.14 mL, 8.20 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (400 mg, 0.82 mmol) and HBTU (830 mg, 8.20 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The organic layer was then washed with water followed by a brine wash. The organic layer was concentrated under vacuum to give a crude residue. It was purified with CombiFlash chromatography, eluting with 90% ethyl acetate in hexane to obtain N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(5-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (300 mg, 55%). LC-MS m/z 664 (M+H)+
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([CH:9](O)[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=1.[Br:15]C(C1C=CC=CN=1)CCC>>[Br:15][CH:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:8]=1)[CH2:10][CH3:11]
Reactant: CCC(O)c1cccc(C(F)(F)F)n1
Reactant: CCCC(Br)c1ccccn1
Product: CCC(Br)c1cccc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 1-(6-(trifluoromethyl)pyridin-2-yl)propan-1-ol (Example 238, Step A) following a procedure similar to the one described for the synthesis of 2-(1-bromobutyl)pyridine (Example 231, Step B). Mass Spectrum (ESI) m/z=268.0 (M+1) and 269.9 (M+1).
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[N:10][CH:11]=1.[C-:13]#[N:14].[Na+]>O.CCOC(C)=O>[Br:5][C:6]1[CH:7]=[N:8][C:9]([C:13]#[N:14])=[N:10][CH:11]=1
Reactant: Clc1ncc(Br)cn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ncc(Br)cn1
Yield: 82.5 %

Procedure:
To a room temperature DMSO solution (20.0 mL) of 5-bromo-2-chloropyrimidine (1.02 g, 5.27 mmol) was added sodium cyanide (0.284 g, 5.80 mmol). After 70 minutes the reaction mixture was diluted with water (300 mL) and EtOAc (150 mL). The organic layer was washed three times with half brine, then once with brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue, which was subject to silica gel chromatography. Collection of the product containing fractions and removal of solvent provided 5-bromopyrimidine-2-carbonitrile (0.800 g) as a white crystalline solid, giving proton NMR and LC/MS data consistent with theory.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[S:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]([NH2:20])=[S:19]>>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[S:8][C:9]=2[CH3:10])[N:17]=1
Reactant: NC(N)=S
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(=O)CBr
Product: Cc1sc(C(=O)OC(C)C)cc1-c1csc(N)n1
Yield: 107.1 %

Procedure:
A solution of 260 mg (0.85 mmol) of isopropyl 4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate was reacted with 65 mg (0.85 mmol) of thiourea in a manner similar to Example 8, step (a) to give isopropyl 4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxylate (257 mg, quantitive yield) as a white solid. 1H-NMR (DMSO-d6; 300 MHz) δ7.90 (s, 1H), 6.93 (s, 1H), 5.09 (septet, 1H, J=6.2 Hz), 2.61 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C12H14N2O2S2 283.1 (M+H), found 283.1
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[NH2:26][CH:27]1[C:36]2[C:31](=[C:32]([O:39][CH3:40])[CH:33]=[CH:34][C:35]=2[O:37][CH3:38])[CH2:30][CH2:29][CH2:28]1>>[CH3:40][O:39][C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[C:36]2[C:31]=1[CH2:30][CH2:29][CH2:28][CH:27]2[NH:26][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[N:9]=1
Reactant: COc1ccc(OC)c2c1CCCC2N
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: COc1ccc(OC)c2c1CCCC2Nc1ccc2c(NS(=O)(=O)c3ccc(F)cc3)cccc2n1

Procedure:
The title compound, MS: m/e=508.4 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonyl chloride and rac-1-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-naphthalene (CAS 784988-69-8).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[NH2:20]N>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][NH:15][N:20]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)C=CN(C)C)cc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc[nH]n2)cc1Cl
Temperature: 77.5 °C

Procedure:
To a suspension of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester (13.67 g) in ethanol (53 ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80° C. for one hour. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield the title compound as a crude solid (12 g). A purified sample had a melting point of 130-131° C.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=[N:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(NN=Cc2cc(I)ccc2F)cc1
Yield: 98.1 %

Procedure:
4-hydrazinylbenzoic acid (1.54 g, 10 mmol), 2-fluoro-5-iodobenzaldehyde (2.52 g, 10 mmol) and caesium carbonate (3.27 g, 10 mmol) was stirred in DMF (10 mL) at r.t. for 70 min. Water (40 mL) was then added and the clear solution was acidified with aqueous HCl (1.7 M). The light yellow precipitate that formed was collected by filtration, washed with water and dried in vacuo to give 4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (3.77 g, 98%)
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.CCOCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2([OH:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3]2)=[CH:20][CH:19]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 51.42 g (333.3 mmoles) of 3,3,5,5-tetramethylcyclohexanone in 200 ml of tetrahydrofuran (THF) was added dropwise to an ice cold solution made up of 200 ml of a 2M ether solution of 4-fluorophenyl magnesium bromide (400 mmoles) and 100 ml of THF. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then poured onto ice and 500 ml of 1N HCl. After stirring for 0.5 hour, the layers were separated. The aqueous layer was extracted once with ether and the combined organic layers were evaporated in vacuo to obtain the title compound in the form of an oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[NH2:21][CH2:22][CH2:23][OH:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][NH:21][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[N:17]=1)=[O:20]
Reactant: NCCO
Reactant: O=C(O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.5 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (1.00 g, 3.5 mmol) was dissolved in DMF (20 ml). 2-Aminoethanol (0.51 g, 8.3 mmol), WSC (1.34 g, 7.0 mmol) and HOBt (0.95 g, 7.0 mmol) were added thereto, and the mixture was stirred at 80° C. for 6 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (4:1, v/v) were collected, concentrated and recrystallized from diisopropyl ether-methanol to give the titled compound (0.12 g, 10%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[CH3:10][NH2:11].CC1(C)C(C)(C)OB([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][CH3:10])[C:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][N:3]=1
Reactant: CN
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Product: CNc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodopyrimidine, methylamine and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.