Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]=[CH2:27])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]=[CH2:27])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 83.1 %

Procedure:
4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.034 g, 0.059 mmol) dissolved in DCM (2.5 mL) was treated with TFA (2.5 mL) at 25° C. for 3 days with stirring. The reaction mixture was concentrated to dryness and the residue was purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.022 g, 0.049 mmol, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.28 (br. s., 1H), 7.78 (s, 1H), 7.50 (d, J=8.52 Hz, 1H), 7.44 (s, 1H), 7.35 (t, J=7.62 Hz, 1H), 7.25 (br. s., 1H), 7.15 (br. s., 1H), 5.85-6.03 (m, 1H), 5.09 (d, J=6.46 Hz, 1H), 5.06 (s, 1H), 4.53 (d, J=4.39 Hz, 2H), 3.41 (d, J=6.46 Hz, 2H). LC-MS (ES−) m/z 443.10, 445.17 [M−1]. LC-MS (ES+) m/z 445.05, 447.08 [M+H].
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1.O>C(O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1)[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CBr)cc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C)C(=O)OCC
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
Diethyl malonate (183 mg, 1.14 mmol) was dissolved in ethanol (2 mL). Thereafter, sodium ethoxide (78.0 mg, 1.15 mmol) and an ethanol (2 mL) solution of 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(bromomethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (390 mg, 0.76 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 1.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (300 mg, 67%) in the form of a colorless amorphous product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=2[O:19][CH3:20])=[O:5])[CH3:2].C(O)(=O)C.C(OCC)(=O)C>O1CCOCC1.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=2[O:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
A suspension of zinc powder (0.70 g) was stirred at 20° C. in a solution of 4,5,7-trichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester 26 (364 mg, 1.09 mmol) and acetic acid (2.2 ml) in 1,4-dioxane (15 ml). After 20 minutes, ethyl acetate (20 ml) was added and the resultant mixture filtered through a pad of celite. The filtrate was washed with saturated aqueous sodium chloride solution (10 ml), dried (MgSO4), filtered, and the solvent removed under vacuum. The residue was chromatographed on flash silica (ethyl acetate/hexane, 1:9), yielding 130 mg (39%) of the title compound 27 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 9.51 (d, J=2.0, 1 H), 9.15 (d, J=2.0, 1 H), 7.72 (s, 1H), 4.51 (q, J=7.2, 2 H), 4.18 (s, 3H), 1.47 (t, J=7.2, 3 H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OC(=O)CCNC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)C>>[C:24]([NH:28][C:29]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=3)=[CH:12][N:13]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: CCOC(=O)CCNC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)NC(C)(C)C)CC3)nc2)cc1I

Procedure:
4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butylamide was synthesized from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and tertbutyl isocyanate in a manner similar to the one described in the synthesis of 3-({4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-amino)-propionic acid ethylester above. LCMS calcd for C22H28IN5O2 (m/e) 521, obsd 522 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:10][N:9]=[C:8]([CH2:19][OH:20])[N:7]=1)=[O:5])C.C(O)C>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]([CH2:19][OH:20])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1nc(CO)ncc1-c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc(CO)ncc1-c1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 3.40 g (11.6 mmol) (2-chloro-phenyl)-2-hydroxymethyl-pyrimidine-4-carboxylic acid ethyl ester in 15 ml ethanol 0.69 g (17.42 mmol) NaOH in 15 ml H2O was added and the mixture stirred for 1 hr. The pH of the solution was adjusted to 1 and the solid was filtered off to give after drying 2.80 g (91%) 5-(2-chloro-phenyl)-2-hydroxymethyl-pyrimidine-4-carboxylic acid as a pale brown solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19]C)=[O:18])[NH:5][CH2:6][C:7]1C=CC=CC=1)#[N:2].C(N=C(NC1C=C(C=CC=1)C(OC)=O)NCC)#N>>[C:1]([N:3]=[C:4]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])[NH:5][CH2:6][CH3:7])#[N:2]
Reactant: COC(=O)c1cccc(NC(=NC#N)NCc2ccccc2)c1
Agent: CCNC(=NC#N)Nc1cccc(C(=O)OC)c1
Product: CCNC(=NC#N)Nc1cccc(C(=O)O)c1
Yield: 81 %

Procedure:
The title compound was prepared as described in Example I except that the compound of Example E was replaced with an equivalent amount of the compound of Example H. This afforded the title compound (81%) as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:26]=3[CH2:27][CH2:28][CH3:29])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:25]2[C:26]([CH2:27][CH2:28][CH3:29])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:37])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:23]=[N:24]2)=[CH:31][CH:32]=1
Reactant: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)OC)ccc3c2)cnn1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)O)ccc3c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
1 N NaOH (335 μL, 0.335 mmol) was added under nitrogen to a solution of [6-({[1-(4-chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (150 mg, 0.305 mmol), prepared in the previous step, in 25 mL of MeOH plus 10 mL of water at room temperature. After the addition the reaction was stirred at room temperature for 20 h (overnight). The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the MeOH. The solid present was collected by filtration and dried under reduced pressure to give the title compound (138 mg, 94%) as a pink solid, mp 203-204° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:23]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a solution of morpholine (870 mg, 10 mmol) and triethylamine (1.1 g, 10.8 mmol) in CH2Cl2 (15 mL) was added a solution of 5-fluoro-2-methylbenzoyl chloride (1.72 g, 10 mmol) in CH2Cl2 (5 mL), dropwise, and the mixture stirred for 15 min. The mixture was then washed with water, and the organic phase dried (MgSO4), filtered, and concentrated to obtain 2.19 g (Yield 98%) of the title compound as a solid: 1H NMR (500 MHz, CDCl3) δ ppm: 2.27 (3H, s) 3.24 (2H, d, J=4 Hz) 3.58 (2H, s) 3.79 (4H, dd, J=18, 3.8 Hz) 6.88 (1H, dd, J=8.2, 2.8 Hz) 6.92-7.05 (1H, m) 7.18 (1H, dd, J=8.4, 5.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][C@H:13]([OH:20])[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=O)=[CH:4][CH:3]=1.CO.[ClH:23]>O1CCCC1>[ClH:23].[ClH:23].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][CH2:12][C@@H:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:20])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1)NC[C@H](O)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H](CNCCc1ccc(Br)cc1)c1cccnc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]acetamide (160 g) in tetrahydrofuran (1.6 l) was added dropwise 2M borane-dimethylsulfide complex in tetrahydrofuran (716 ml) below 0° C. over 5 hours. The mixture was warmed up to 60° C. and stirred at the same temperature for 3 hours. The reaction mixture was cooled in ice bath (below 5° C.). To the cooled reaction mixture were added methanol and conc. hydrochloric acid (hydrogen gas was evolved). The mixture was heated and stirred at 60° C. for 1 hour, stood overnight at ambient temperature. The mixture was concentrated in vacuo and water was removed as azeotrope with butanol (480 ml). The concentrate was pulverized with isopropyl ether (1.5l). The precipitate was collected by filtration, washed with isopropyl ether and dried in vacuo to give (1R)-2-[[2-(4-bromophenyl)ethyl]amino]-1-(3-pyridyl)ethanol dihydrochloride (226 g).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[O:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)(=O)C>[O:6]=[C:7]1[N:11]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:10][CH2:9][N:8]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NN1CCNC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1CCN([Si](C)(C)C)C1=O
Reaction time: 8 h
Yield: 91.1 %

Procedure:
While cooling 10.55 g (97.1 mmol) of chlorotrimethylsilane was dropped into a solution of 19.55 g (97.1 mmol) of (2-oxo-1-imidazolidinyl)carbamic acid, 1,1-dimethylethyl ester and 9.83 g (97.1 mmol) of triethylamine in 900 ml of absolute ethyl acetate. After stirring overnight, the salt was filtered off and the filtrate evaporated in vacuo to yield 24.18 g of the title compound; melting point 132.1° C.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=O)[N:7]=1>C1COCC1>[Br:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:10])[NH2:1])[N:7]=1
Reactant: N
Reactant: CCOC(=O)c1csc(Br)n1
Solvent: C1CCOC1
Product: NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
THF (10 ml) and 20 ml of 30% aqueous ammonia were added to 1.51 g of 2-bromo-4-ethoxycarbonylthiazole, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated to give 1.31 g of 2-bromo-4-carbamoylthiazole.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCC(=O)OCc1cc(O)ncn1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCCCCC(=O)OCc1cc(Cl)ncn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 915 mg (4.08 mMol) hexanoic acid 6-hydroxy-pyrimidin-4-ylmethyl ester, 1.48 g (8.98 mMol) Et4NCl and 698 μl (5.44 mMol) N,N-dimethylaniline in 30 ml of acetonitrile, 3.73 ml (40.8 mMol) POCl3 are added. After stirring for 1 h at 60° C., the cooled solution is concentrated in vacuo. The residue is re-dissolved in EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic phases are washed with water, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated, yielding the title compound as an oil: MS: [M+1]+=243/245; TLC(CH2Cl2): Rf=0.20.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[Cl:35])=O)(C)(C)C>Cl>[ClH:35].[Cl:35][C:19]1[CH:20]=[CH:21][C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)=[CH:23][C:18]=1[C:9]1[NH:8][C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[N:10]=1
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4n3C(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Product: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)CC1
Temperature: 25 °C

Procedure:
Method 3,4—Step e A mixture of 2-[2-Chloro-5-(4-ethoxycarbonyl-piperidin-1-yl)-phenyl]-5-fluoro-benzoimidazole-1-carboxylic acid tert-butyl ester (0.42 g, 0.84 mmol) in 6N HCl (4 mL) was stirred at room temperature for few minutes and then heated in microwave at 120° C. for 15 minutes. Solvent was removed under vacuum to obtain the title compound in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[CH:18][N:19]([CH3:21])[CH3:20]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To 13.2 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in 100 mL of DMF was added 23.8 g of N,N-dimethylormamide dimethyl acetal. The mixture was stirred at 75° C. for 16 hours. The solution was then concentrated and used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.S([O-])([O-])=S.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[N:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1CNc1ccc(CO)cn1
Agent: [Na+]
Agent: [O-]S([O-])=S
Solvent: C1CCOC1
Product: COc1ncc(F)cc1CNc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To {6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-methanol (92, 0.353 g, 1.34 mmol) dissolved in 8 mL of tetrahydrofuran, Dess-Maritn periodinane (0.626 g, 1.47 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was poured into aqueous saturated sodium thiosulfite and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=262.3.
Reaction SMILES: [N+](C1C=C(C=CC=1O)C=O)([O-])=O.[CH3:13][O:14][CH:15]([O:35][CH3:36])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:19]([N+:32]([O-])=O)[CH:18]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:36][O:35][CH:15]([O:14][CH3:13])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:19]([NH2:32])[CH:18]=1
Reactant: CCCCCCCCOc1ccc(CC(OC)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: O=Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCCCCCCCOc1ccc(CC(OC)OC)cc1N
Reaction time: 0.5 h
Yield: 98 %

Procedure:
By the method of example 1 above, 3-nitro-4-hydroxybenzaldehyde is converted into 1-(2,2-dimethoxyethyl)-3-nitro-4-octyloxybenzene. This material (1.83 g) is dissolved in ethanol (20 ml) and to the solution is added ammonium formate (3.5 g) and palladium black (0.30 g), and the mixture is stirred for 30 min. The mixture is filtered through diatomaceous earth and evaporated to dryness in vacuo. The residue is partitioned between water and dichloromethane, and the organic phase is dried over magnesium sulfate, filtered, and concentrated to give 1-(2,2-dimethoxyethyl)-3-amino-4-octyloxybenzene as an orange oil (1.64 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CNC(=O)CCN2C(=O)C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(=O)C(F)(F)F)ncc1Cl

Procedure:
2-{5-Chloro-2-[4-oxo-1-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-benzo[b][1,5]diazocin-8-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 8-Amino-1-(2,2,2-trifluoro-acetyl)-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound isolated as an off-white solid (27 mg, 14%). mp 191-194° C.; LCMS: m/z=548.25 (M+H+), HPLC (98% purity), 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.78 (s, 1H), 8.72 (m, 2H), 8.27 (s, 1H), 7.90 (m, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 4.65 (m, 1H), 4.43 (m, 1H), 3.70 (m, 1H), 3.18 (m, 1H), 2.81 (m, 4H), 2.36 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: ClCCCCn1nnc2ccccc21
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cccc(N2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-cyano phenylpiperazine (5.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.6 g compound (I-41) with a yield of 70.5%. ESI-MS [M+H]+: m/z 360.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:22]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40].[NH2:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])[CH:33]=[CH:34][C:35]=3[CH3:36])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(2-phenylethyl)benzamide (156 mg, 0.28 mmol) in dichloromethane (11 mL) was added 1,1-dimethylethyl (2-aminoethyl)methylcarbamate (75 μL, 0.42 mmol) and triethylamine (78.7 μL, 0.56 mmol). The reaction mixture was stirred at room temperature for 16 hours then applied to the flash chromatograph to afford the titled compound 147 mg (79%). LC-MS m/z 669 (M+H)+; 1H-NMR (MeOD) 1.30 (m, 9 H), 2.31 (m, 3H), 2.65 (m, 2 H), 2.76 (m, 1 H), 2.92 (m, 2 H), 3.22 (m, 2 H), 3.45 (m, 1 H), 3.60 (m, 2 H), 6.35 (m, 1 H), 7.19 (m, 2 H), 7.26 (m, 5 H), 7.43 (m, 1 H), 7.49 (m, 1 H), 7.60 (m, 1 H), 7.74 (m, 1 H), 7.97 (m, 1 H).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].O=[C:10]1[CH2:14][S:13][CH2:12][CH:11]1[C:15](OCC)=[O:16]>C(O)C>[N:3]1[C:10]2[CH2:14][S:13][CH2:12][C:11]=2[C:15]([OH:16])=[N:4][CH:2]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CSCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1ncnc2c1CSC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of formamidine HCl salt (3.70 g, 46.0 mmol) in ethanol (200 mL) was added NaOEt in ethanol (21% wt, 17.2 mL, 46.0 mmol). The mixture was stirred at room temperature for 1 hour. The ethyl 4-oxotetrahydrothiophene-3-carboxylate (8.0 g, 46.0 mmol) was added. The mixture was stirred at room temperature for 4 hours and then refluxed overnight. After cooling, the solvent was removed and the residue was washed with a small amount of water and CH2Cl2 to afford 5,7-dihydrothieno[3,4-d]pyrimidin-4-ol as light brown solid (2.5 g, 35%). 1H NMR (d6-DMSO, 400 MHz) δ 12.59 (s, 1H), 8.13 (s, 1H), 4.12 (s, 2H), 3.96 (s, 2H). MS (APCI+) [M+H]+ 155.