Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2([OH:28])[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[CH:14][CH:13]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]2([OH:28])[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[CH:16][CH:17]=1
Reactant: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccc(/C=C/C2(O)CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
A 1M solution of lithium aluminium hydride in tetrahydrofuran (10 ml) was added over a period of 20 minutes to a stirred solution of 3-[2-{4-(2-methoxyethoxy)phenyl}ethynyl]quinuclidin-3-ol (3.01 g) in dry tetrahydrofuran (100 ml) under an atmosphere of argon at 40° C. The reaction mixture was then stirred at ambient temperature for 16 hours. Water (0.4 ml) and 2M aqueous sodium hydroxide solution (0.8 ml) was then added to the reaction mixture dropwise followed by a further quantity of water (1.2 ml). The resulting precipitate was collected by filtration and the filtrate was evaporated. The residue from the filtrate was crystallised from acetonitrile to give 3-[(E)-2-{4-(2-methoxyethoxy)phenyl}vinyl]quinuclidin-3-ol (2.54 g) as a solid, mp 164-166° C., microanalysis, found C,71.4; H,8.6; N,4.5%; C18H25NO3 requires: C,71.3; H,8.31; N,4.62%; NMR ([CD3 ]2SO): 1.15-1.32 (1H, m), 1.38-1.52 (1H, m), 1.62-1.74 (2H, m), 1.95-2.1 (1H, m), 2.58-2.6 (5H, m), 2.82-2.92 (1H, d), 3.3 (3H, s), 3.6-3.67 (2H, m), 4.03-4.1 (2H, m), 4.66 (1H, s), 6.38-6.45 (1H, d, J=16.67), 6.51-6.58 (1H, d, J=16.67), 6.86-7.12 (2H, d) and 7.32-7.38 (2H, d); m/z 304 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([NH2:16])[C:10]=2[CH:9]=[CH:8]1.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1I.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[NH:16][C:15]1[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]=2[N:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)ccnc21
Reactant: O=[N+]([O-])c1ccc(I)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 120 °C

Procedure:
50 mg (0.19 mmol) of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine, 61 mg (0.23 mmol) of 2-fluoro-1-iodo-4-nitrobenzene and 26 mg (0.27 mmol) of sodium tert-butoxide are initially charged in 1 ml of toluene. The mixture is degassed. 8.7 mg (0.01 mmol) of tris(dibenzylideneacetone)dipalladium and 9.1 mg (0.02 mmol of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine are then added. The mixture is heated in a sealed vessel at 120° C. overnight. The mixture is then filtered through an Extrelut cartridge (mobile phase: dichloromethane/methanol 10:1) and purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=[O:18])[N:3]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]([OH:20])=[O:18])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=O)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(=O)O)n1

Procedure:
This compound was prepared from the compound of Example 46 reaction with potassium permanganate, mp. 227° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].Cl[C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1nc(C(=O)N2CCCC(C)C2CN)c(-c2ccccc2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2nc3ccccc3o2)c(-c2ccccc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2Cl2 was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et2O/hexanes to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 447.03 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44]1([CH2:50][C:51](Cl)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:50]([C:51]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.310 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise phenylacetyl chloride (0.12 mL, 0.94 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to an oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.176 g colorless crystals. Mp 168° C. Mass spectrum, m+ =447. Anal (C28H35N5O6) theory C, 62.56; H, 6.56; N, 13.03; found C, 62.61; H, 6.65; N, 12.83.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31]([F:42])=[C:32]([C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=3[F:42])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(C(F)(F)F)ccc(Cl)c1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1c(Cl)ccc(C(F)(F)F)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-chloro-2-fluoro-6-trifluoro methyl-benzaldehyde. MS (ESI) m/z 587.
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH3:9][C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[C:18]=1[CH:17]=[N:16][NH:15][C:14]2=[O:19]>C1C=CC=CC=1>[CH3:1][N:15]1[C:14](=[O:19])[N:13]2[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:11][C:10]([CH3:9])=[C:18]2[CH:17]=[N:16]1
Reactant: Cc1nc(-c2ccccc2)n2c(=O)[nH]ncc12
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: Cc1nc(-c2ccccc2)n2c(=O)n(C)ncc12
Yield: 100 %

Procedure:
Dimethylformamide dimethyl acetal (0.73 ml; α= 0.897, 0.005 mole) is added slowly to a slurry of 8-methyl-6-phenylimidazo[1,5-d]-as-triazin-4(3H)-one (1.13 g, 0.005 mole in benzene (25 ml). The reaction mixture is stirred, refluxed for 24 hours, cooled and filtered. The filtrate is evaporated to yield 1.4 g (100%) product. Recrystallization from methyl cyclohexane yields yellow crystals, found to be identical (ir: nmr) to the product obtained by Method A.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]([CH3:25])[CH3:24])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>C(O)(C(F)(F)F)=O>[Br:26][C:21]1[C:22]([N:23]([CH3:25])[CH3:24])=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:27]
Reactant: CN(C)c1c(Br)cc2c3c(cccc13)C(=O)N(OCc1ccccc1)C2=O
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1c(Br)cc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 91.8 %

Procedure:
Following the procedure of Example 52, 2-benzyloxy-5-bromo-6-dimethylamino-benzo[de]isoquinoline-1,3-dione (0.17 g, 0.39 mmol, from Example X1) in TFA and a 1.0 M solution of boron tris(trifluoroacetate) in TFA (2 mL) were reacted to give 0.12 g of the title compound, mp 185-187° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:24][CH:23]3[C:25](=[O:26])[CH:20]([CH2:21][CH2:22]3)[CH2:19][C:18]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C(Cl)Cl>[N:50]1([CH2:49][CH2:48][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:24][CH:23]4[C:25](=[O:26])[CH:20]([CH2:21][CH2:22]4)[CH2:19][C:18]=3[CH:27]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1C2CCC1Cc1cc(OCCN3CCOCC3)ccc1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
Diethyl azodicarboxylate (1.07 g, 6.16 mmol) in DCM (5 ml) was added at a dropwise rate to a stirred solution of 2-hydroxy-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (J. Org. Chem. 1982 4329, 829 mg, 4.10 mmol), triphenylphosphine (1.61 g, 6.16 mmol) and 4-(2-hydroxyethyl)morpholine (806 mg, 6.16 mmol) in DCM (45 ml). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The crude product was purified by column chromatography on silica eluting with 40:1 DCM: 2M ammonia in methanol. The chromatographed material was taken up in the minimal volume of ethyl acetate and diluted with diethyl ether. 1M HCl in diethyl ether was added. The precipitate was filtered washing the solid with ethyl acetate and diethyl ether. The white solid was taken up in DCM and washed with 1M sodium hydroxide (aq). The organic phase was dried over sodium sulphate, filtered and concentrated to dryness to give 5-(2-morpholin-4-yl-ethoxy)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one as a colourless oil 740 mg (57%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH:33]([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, d, J=8 Hz), 8.50 (1H, s), 7.77 (1H, s), 7.32 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, m), 4.98 (1H, t, J=5 Hz), 4.11 (2H, s), 4.03 (1H, m), 3.45 (2H, m), 3.12 (3H, s), 2.82 (3H, s), 1.15 (3H, d, J=7 Hz); HRMS calcd for C23H25FN4O5+H+: 457.18817. Found: 457.18872.
Reaction SMILES: [C-:1]#[N:2].[K+].O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25]Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25][C:1]#[N:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 80 %

Procedure:
A mixture of 4.57 g (70.2 mmol) of potassium cyanide and 10 ml of water is heated to reflux. When the potassium cyanide has dissolved, 17 g (54 mmol) of the chloride obtained in Step b dissolved in 10 ml of ethanol are added slowly. When the addition is complete, the mixture is heated under reflux for 3 hours. After evaporation of the solvent, the mixture is taken up in chloroform and washed with water until the pH is neutral. The chloroform phase is dried over magnesium sulfate, filtered and evaporated off. The resulting residue is crystallised from hexane and yields 13.2 g of white crystals.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:16][CH3:17])[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:16][CH3:17])([CH2:14][CH2:13][OH:12])[C:11]([NH:1][NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC1(c2ccc(F)cc2)CCOC1=O
Solvent: CCO
Product: COC(CCO)(C(=O)NN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
A solution of hydrazine (29 mg) in ethanol (0.5 mL) was added to a solution of 3-(4-fluorophenyl)-3-methoxydihydrofuran-2-one (37 mg) in ethanol (1.2 mL), and the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain 41 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH4+:14].[OH-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: [NH4+]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1S(N)(=O)=O
Reaction time: 2 h

Procedure:
To 5-bromo-2-methoxybenzenesulfonyl chloride (45g; 157.6 mmol, from Lancaster Chemical) at 0° C. in THF, was added concentrated NH4OH (42.5 mL) and the reaction mixture was brought to r.t. for 2 h. The reaction mixture was diluted with EtOAc, extracted with NaHCO3 (2×), brine, and the organic phase was dried over MgSO4. The solvent was removed to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][C:11]([OH:13])=[O:12].O>C1(C)C=CC=CC=1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CBr
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a 3-neck 2-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added sodium hydride (60% dispersion in mineral oil) (41.70 g, 1.043 moles) and 1000 ml of toluene under nitrogen. 2,2,2-Trifluoroethanol (52.02 g, 0.520 moles) was added dropwise and this mixture was stirred at room temperature for 0.5 hours. A solution of bromoacetic acid (72.45 g, 0.520 moles) in 100 ml of toluene was then added dropwise and the resulting mixture heated at reflux for 48 hours. After cooling the mixture to room temperature, water (250 ml) was added and the layers separated. The aqueous layer was washed with ether (3×75 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×75 ml), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Distillation of this oil gave 31.6 g of the product as a colorless oil, bp 110°-118° C./16 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). R-(+)-α-Methylbenzylamine (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred overnight at room temperature. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted twice with water, once with brine and dried over MgSO4. Filtration and concentration in vacuo afforded a white foam that was purified by flash column chromatography (84.5:15:0.5 CH2Cl2:acetonitrile:NH4OH) to afford a clear oil. The material was rechromatographed (89.5:10:0.5 CH2Cl2:acetonitrile:NH4OH) to afford the title compound as a clear oil. Wt.: 547 mg (7%). 1H NMR (300 MHz, CDCl3) δ7.31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H); LC/MS m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]=[C:31]=[O:32]>O1CCOCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[NH:30][C:31](=[O:32])[N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-methyl-N′-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine (428.0 mg, 1.5 mmol), 2,6-dichlorophenyl isocyanate (310.2 mg, 1.65 mmol) in dry dioxane (5 mL) is shaken for 1.5 h at 80° C. After evaporation of the solvent in vacuo, the residue is purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CCc1ccc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1ccc(C(=O)OC)cc1Br

Procedure:
3-Bromo-4-ethyl-benzoic acid (D43) (19.40 g) was dissolved in MeOH (200 mL) and then treated with conc. H2SO4 (1 mL). The mixture was heated at reflux overnight, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution, extracting again with EtOAc. The combined extracts were then washed with brine, dried (MgSO4). The solvent was evaporated in vacuo to afford the title compound (15.8 g). 1H NMR (CDCl3) δ 1.24 (3H, t), 2.79 (2H, q), 3.91 (3H, s), 7.29 (1H, d), 7.89 (1H, dd), 8.19 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:17])[C:14]=3[OH:16])[C:10](=[O:18])[N:9]2[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:4][CH:3]=1.[CH3:28]I.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:17])[C:14]=3[O:16][CH3:28])[C:10](=[O:18])[N:9]2[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N2C(=O)c3nn(C)c(O)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Reactant: CI
Agent: N
Product: COc1c2c(nn1C)C(=O)N(c1cc(C)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 76 using 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-hydroxy-2-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Example 73) and methyl iodide. tR: 0.86 min (LC-MS 2); ESI-MS: 399 [M+H]+ (LC-MS 2); Rf=0.33 (1% ammonia/7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3H) 3.34 (s, 3H) 3.59 (s, 3H) 3.67 (s, 3H) 6.24 (s, 1H) 7.19-7.42 (m, 5H) 7.64 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].BrN1C(=[O:22])CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[S:14][CH:13]=[C:12]([CH:15]=[O:22])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(C)csc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(C=O)csc2c1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 3-methyl-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (1.2 g) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (2.4 g) followed by AIBN (50 mg) and the resulting mixture was heated at reflux for 4 hours. The reaction mixture was cooled; the solids were removed by filtrations and copiously washed with carbon tetrachloride. The filtrate was evaporated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (20 mL) and the resulting mixture was heated at 80° C. for 1 hour. The reaction mixture was cooled, diluted with water, basified by addition of a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (acetone/DCM, 5/95) to give 0.8 g of 3-formyl-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1COCC1>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 29, 70 mg, 0.217 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (20.7 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 82% yield (0.088 g, 0.178 mmol).