Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])O.[Na+]>O>[CH2:21]([N:27]1[CH2:2][CH:3]2[CH:5]([C:4]2([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:6]1=[O:8])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 20 g, 67.2 mmol) in hexylamine (36 ml, 270 mmol) was added sodium hydrogen carbonate (5.64 g, 67.2 mmol), and the mixture was heated at 100° C. for 16 h. The mixture was cooled, diluted with water (80 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with a gradient of 2:1 to 1:2 hexane/ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (14.2 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:34](=[O:33])[CH2:35][OH:36])[CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2C(=O)CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (180 mg, 0.43 mmol), acetoxyacetyl chloride (51 μL, 0.47 mmol), triethylamine (119 μL, 0.86 mmol) and tetrahydrofuran (3.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (130 mg, 64%) as a white solid. 1H NMR (400 MHz, (DMSO) δ 7.9 (d, J=8.2, 1H), 7.6 (q, J=8.5 and 6.9 Hz, 1H), 7.3 (t, J=8.7 Hz, 1H), 7.1 (t, J=7.9 Hz, 1H), 6.9 (s, 2H), 6.5 (s, 1H), 5.25 (s, 2H), 4.1 (d, J=5.5 Hz, 2H), 3.9 (t, J=8.6 Hz, 2H), 3.42 (t, J=5.4 Hz, 1H), 3.35 (t, J=4.8 Hz, 1H), 3.2 (t, J=8.5 Hz, 2H), 2.3 (s, 3H) ppm. ES-HRMS m/z 475.1220 (M+H calcd for C24H22ClF2N2O4 requires 475.1231).
Reaction SMILES: [ClH:1].[C:2]([NH:6][C:7]1([CH3:24])[CH2:10][N:9](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8]1)([CH3:5])([CH3:4])[CH3:3]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[C:2]([NH:6][C:7]1([CH3:24])[CH2:10][NH:9][CH2:8]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)NC1(C)CNC1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a slurry of N-tert-butyl-1-benzhydryl-3-methylazetidin-3-amine hydrochloride (1.69 g, 4.91 mmol) in ethanol (30 ml) was added 10% Palladium hydroxide on carbon (160 mg) and the mixture degassed three times with nitrogen and three times with hydrogen. The mixture was then stirred under a hydrogen atmosphere 40° C. (warm water bath) for 3 h and then at room temperature for a further 12 h. The reaction was degassed with nitrogen and filtered through celite and concentrated. The compound was used crude in subsequent chemistry. 1H NMR (MeOH) 1.50 (9H, s), 1.99 (3H, s), 4.19 (2H, d), 4.91 (2H, d).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19]2[C:6]=1[C@@:7]1([CH3:31])[C@H:16]([CH2:17][S:18]2(=[O:27])=[O:26])[C@:15]2([CH3:28])[C@H:10]([C:11]([CH3:30])([CH3:29])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]1)=[O:4].O[Li].O>CO.O>[CH3:31][C@@:7]12[CH2:8][CH2:9][C@@H:10]3[C@:15]([CH3:28])([CH2:14][CH2:13][CH2:12][C:11]3([CH3:29])[CH3:30])[C@H:16]1[CH2:17][S:18](=[O:26])(=[O:27])[C:19]1[C:6]2=[C:5]([C:3]([OH:4])=[O:2])[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=1
Reactant: COC(=O)c1cc(C(=O)O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Temperature: 90 °C
Yield: 103.6 %

Procedure:
A mixture of (1R,10R,11S,16S)-3-(methoxycarbonyl)-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (84) (0.1 g, 0.2 mmol) and LiOH.H2O (0.1 g, 4 mmol) in MeOH (5.0 mL) and water (5.0 mL) was heated at 90° C. for 72 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and acidified with 1 M HCl. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo-[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-dicarboxylic acid (85) (0.09 g, 94%) as a white solid. 1H NMR (CD3OD): δ 8.43 (d, 1H), 8.07 (d, 1H), 3.56 (m, 2H), 2.92 (d, 1H), 2.18 (d, 1H), 1.90-1.38 (m, 11H), 1.30-1.17 (m, 2H), 1.08-0.96 (m, 5H), 0.90 (s, 3H), 0.87 (s, 3H). MS m/z 433 (O23H30O6S−H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:21]([O:33][CH3:34])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1.O>[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:2][C:3]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:4]=3[CH:5]=[N:6][N:7]4[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:30][CH:31]=2)=[C:21]([O:33][CH3:34])[CH:20]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2cnn3C2CCCCO2)cc1
Yield: 52.5 %

Procedure:
4-Bromomethyl-1-(tetrahydro-pyran-2-yl)-1H-indazole (0.5 g, 1.69 mmol), 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (0.4 g, 1.69 mmol) and potassium carbonate (0.23 g, 1.69 mmol) in 15 mL THF/3 mL DMF was heated to 70° C. overnight. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-25% ethyl acetate in hexanes to yield 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1-(tetrahydro-pyran-2-yl)-1H-indazole as a white solid (400 mg, 52.5%). HR-MS (ES) calculated for C26H24F2N2O3, 473.1646; found m/z 473.1647 [M+Na]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH:11]([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:12])=[CH:8][CH:7]=1>C(OC(=O)C)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([C:13]2[S:17][C:16]([N:18]=[C:1]=[O:2])=[N:15][N:14]=2)[CH3:12])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: CC(Oc1ccc(Cl)cc1)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Cl)cc1)c1nnc(N=C=O)s1
Reaction time: 17 h

Procedure:
A 500 millileter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condensor/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). Additional 100 ml. of ethylacetate was added; (8.9 grams of 5-[1-(4-chlorophenoxy) ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) at a temperature from 0° C. to room temperature was added. The resulting solution was stirred for 17 hours with formation of an emulsion, and then the flask was purged with nitrogen until no COCl2 was detected. The solution was filtered through a Whatman #42 filter paper to yield a slightly cloudy solution which was topped at 60 degrees centigrade with a roto-vac to form 9.2 grams of a pale yellow goop of 5-[1-(4-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4)[C@H]3[C@@H]1CCC2=O

Procedure:
A solution of 1.0 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 10 ml of dimethylformamide is stirred with 0.24 ml of pyrrolidine for 2 hours at a bath temperature of 100° C. Then, it is added to saturated sodium bicarbonate solution, extracted three times with methylene chloride, dried on magnesium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol/triethylamine. 367 mg of 11β-fluoro-3-hydroxy-7α-(5-pyrrolidin-1-yl-pentyl)-estra-1,3,5(10)-trien-17-one is obtained as a foam.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl>>[O:10]1[CH2:9][CH:8]1[CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: C1CCNC1
Product: C1CCN(CC2CO2)C1

Procedure:
By using pyrrolidine (3 ml) and (±)-epichlorohydrin (2.9 ml) as starting materials, the title compound (2.10 g) was obtained in the same manner as that of Reference Example 33.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([O:26]CC)=O.O.[NH2:30][NH2:31]>C(O)C>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([NH:30][NH2:31])=[O:26]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of ethyl (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate (0.35 g, 0.92 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.15 mL, 1.84 mmol) and the solution was heated at reflux for 16 h. Upon being allowed to cool to ambient temperature a solid precipitate formed. The solid was filtered and washed with ethanol (2 mL) to afford 2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide (0.285 g, 84%) as a colorless solid: MS (ES+) m/z 367.9 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:25][C:26]1[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:28]=[CH:29][N:30]=1)[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.[CH:41]1([N:47]2[CH2:56][CH2:55][C:50]3([CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:41]1([N:47]2[CH2:48][CH2:49][C:50]3([CH2:54][N:53]([C:20](=[O:21])[C:19]4[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH:13]([CH2:12][C:8]5[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:39])[CH3:40])[CH:11]=[CH:10][N:9]=5)[CH2:25][C:26]5[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:28]=[CH:29][N:30]=5)=[CH:17][CH:18]=4)[CH2:52][CH2:51]3)[CH2:55][CH2:56]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCC(N2CCC3(CCNC3)CC2)CC1
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(COc1ccc(C(=O)O)cc1)Cc1nccn1COCC[Si](C)(C)C
Product: C[Si](C)(C)CCOCn1ccnc1CC(COc1ccc(C(=O)N2CCC3(CCN(C4CCCCC4)CC3)C2)cc1)Cc1nccn1COCC[Si](C)(C)C
Yield: 80.1 %

Procedure:
Except for using the compound (50 mg) produced in Example 103 in place of the compound produced in Example 68 and using 8-cyclohexyl-2,8-diazaspiro[4.5]decane (38 mg) in place of the compound produced in Example 91, the same operation as in Example 92 was performed to obtain the title compound (54 mg) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH:11]2[CH:5]([CH:6]([CH3:13])[CH2:7][C:8](=[O:12])[CH2:9][CH2:10]2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Agent: [Pd]
Solvent: CCO
Product: CC1CCC2C(C)CC(=O)CCC12

Procedure:
176 mg of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 15 ml of ethanol with 175 mg of palladium-on-carbon (5%). After hydrogen uptake was completed the mixture was filtered off from the catalyst, the filtrate evaporated and distilled in vacuum. There was obtained pure 1,4-dimethyl-6-oxo-perhydroazulene; b.p.0.05 60°; IR(film):νmax = 1700, 1460, 1375, 1335, 1250, 1180, 980, 850 cm-1. The compound has a camphorous, herby, woody odour.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13]C(OC(C)(C)C)=O)[CH:7]=1>O1CCOCC1.Cl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:21][CH:22]([CH3:23])[CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1
Reactant: COC(=O)[C@H](Cc1cccc(CNC(=O)OC(C)(C)C)c1)OC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1cccc(CN)c1)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
1.034 g of 3-[3-(t-Butoxycarbonylaminomethyl)phenyl]-2(S)-isopropoxypropionic acid methyl ester was dissolved in 20 ml of hydrogen chloride 1,4-dioxane, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 653 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.CC(C[AlH]CC(C)C)C.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)N1CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1CN1CCCCC1
Reaction time: 1.5 h

Procedure:
(2-Methoxy-4-nitro-phenyl)-piperidin-1-yl-methanone (Stage 87.3; 200 mg, 0.76 mmol) is dissolved in THF (8 ml) at −20° C. DIBAH (1 M in THF: 2.3 ml) then is added. After 90 min at −20° C., another portion of DIBAH (0.8 ml) is added and stirring continued for 2 h. Then the reaction mixture is hydrolysed by water (30 ml) and a saturated solution of sodium potassium tartrate (25 ml) and extracted 3 times with AcOEt. The organic phases are washed with brine, dried (Na2SO4) and concentrated. The crude product is dissolved in AcOEt, SiO2 is then added and the solvent evaporate off in vacuo. The resulting powder is put on top of a chromatography column (SiO2; AcOEt) and the title compound eluated with AcOEt: 1H-NMR (DMSO-d6): 7.83 (dd, 1H), 7.73 (d, 1H), 7.60 (d, 1H), 3.91 (s, H3CO), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m, 4H), 1.39 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:12]O)[CH2:7][CH2:6]2.N>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH2:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=NO
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc2c(c1)CCC2N
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
5-Methoxy-2,3-dihydromden-1-one (Ig, 6.17 mmol) was added to a solution of hydroxylamine HCl (730 mg, 10.5 mmol) in 10 ml of water. The mixture was brought up to 70° C. and a solution of sodium acetate (1.4 g, 16.7 mmol) in 7 mL of H2O, 14 ml of MeOH, 3 ml of THF was added. After stirring for 1.5 h at 70° C., 10 ml of H2O was added to produce a precipitate and the suspension was allowed to stir for 2 h. The precipitate was collected by filtration to give 5-methoxy-2,3-dihydroinden-1-one oxime almost quantitatively and was used in the next step without further purification. The oxime (0.5 g, 2.82 mmol) was dissolved in MeOH and a catalytic amount of Raney nickel and 25 mL of ammonia solution in MeOH (7N) was added. The reaction was stirred at r.t. overnight under H2. The slurry was filtered over celite and concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude title amine (yield, 45%). The crude amine was used without further purification.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25]1([CH:31]=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C@H:31]([OH:32])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CC1CCCCC1
Reactant: C#CC(C)(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@@H](O)C1CCCCC1
Yield: 80 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 61 μL (0.50 mmol) cyclohexane-carboxaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 80% yield (78 mg, 0.40 mmol). [α]D20=−27.7 (c=0.13, CHCl3, 96% ee); 1H NMR (CDCl3, 500 MHz): δ 0.92-0.97 (m, 2H), 1.01 (s, 9H), 1.11-1.26 (m, 4H), 1.41 (m, 1H), 1.64 (m, 2H), 1.73 (m, 2H), 1.86 (br d, 1H, J=12.6 Hz), 3.75 (t, 1H, J=7.0 Hz), 5.35 (dd, 1H, J=15.6, 7.5 Hz), and 5.62 (d, 1H, J=15.7 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 26.1, 26.2, 26.6, 28.76, 28.84, 29.6, 32.9, 43.8, 77.9, 126.2, and 143.9 ppm; IR (neat): 3351, 2953, 2926, 2853, 1655, 1473, 1450, 1387, 1362, 1305, 1260, and 1204 cm−1; HRMS-CI m/z 195.1743 [(M−H)+; calcd for C13H23O: 195.1749].
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][CH:9]([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC.FC(F)C(OCC)=O>C(O)C.C(OCC)(=O)C>[CH2:1]([O:4][CH:5]=[C:11]([C:10](=[O:17])[CH:9]([F:18])[F:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CC(=O)OC(C)=O
Agent: CCOC(=O)C(F)F
Solvent: CCO
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
365.2 g of acetic anhydride (3.54 mol) were initially charged in the stirred vessel and heated to 110° C. Within 2 hours, 356.3 g of crude ethyl 4,4-difluoroacetoacetate from synthesis example 7 (26.5% ethyl 4,4-difluoroacetoacetate solution in ethanol/ethyl acetate) and 154.4 g (1.02 mol) of triethyl orthoformate were metered in in parallel. After about half had been fed in, reflux set in at 106° C. At the end of the metered addition, the internal temperature was 92° C. The mixture was stirred for a further 5 hours at reflux temperature and then cooled to 25° C. At a pressure of 150 mbar, the low boilers (ethyl acetate, acetic acid, acetic anhydride, triethyl orthoformate) were distilled off at internal temperature from 40-90° C. To complete the removal, the pressure is lowered to 5 mbar at 90° C., and the distillation bottoms are then stirred at 95° C./5 mbar for 1 hour. The resulting distillation residue (127.5 g) comprised 90.7% by weight of the desired ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate. This corresponds to an overall yield over the two synthesis stages of 86.6% (based on the ethyl difluoroacetate used in working example 7).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:30])[C:9]1[N:29]=[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26](O)=[O:27])=[O:19])=[CH:16][N:11]2[N:10]=1>>[CH3:7][N:8]([CH3:30])[C:9]1[N:29]=[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:27])=[O:19])=[CH:16][N:11]2[N:10]=1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Reactant: C1COCCN1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)cn2n1

Procedure:
Using morpholine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off-white solid (117 mg, 58%). MS: m/z=399 (M+H+). Ames test negative.
Reaction SMILES: Cl.[C:2]([NH2:6])([CH3:5])([CH3:4])[CH3:3].C(N)(C)(C)C.Cl.[Br:13][CH2:14][CH2:15][C:16](Cl)=[O:17].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOCC>[C:2]([NH:6][C:16](=[O:17])[CH2:15][CH2:14][Br:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)CCBr
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)CCBr
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
To a suspension of t-butylamine hydrochloride (prepared by treatment of an Et2O solution of t-butylamine (2.7 mL, 1.9 g, 0.026 mol) with HCl) in a solution of 3-bromopropionic acid chloride (4.47 g, 0.0261 mol) with CH2Cl2 (145 mL) was added N,N-diisopropylethylamine (9.1 mL, 6.8 g, 0.052 mol) over 10-15 minutes at room temperature. The solution was stirred at room temperature for 2.5-3 hours. A few mL's of N,N-diisopropylethylamine were added until the solution became homogeneous. The solution was washed twice with dilute HCl and once with H2O, dried with MgSO4 and evaporated to provide 3.34 g of N-tert-butyl 3-bromopropanamide and N-tert-butyl acrylamide (approximately 36%/64% by weight). The reaction mixture was taken up in EtOH (200 mL), and to the solution of amides was added 1-(2-pyrimidinyl)piperazine dihydrochloride (6.82 g, 0.0288 mol) and sodium acetate (4.72 g, 0.0575 mol). The mixture was refluxed for 8 days. The solvent was evaporated. The residue was partitioned between CH2Cl2 and aqueous Na2CO3. The CH2Cl2 phase was washed with aqueous NaCl and dried with MgSO4. Evaporation of the CH2Cl2 gave 5.61 of crude compound which was purified by HPLC to give 4.13 g of free base. Treatment in EtOH with HCl gave the title compound, 4.48 g (46%), mp 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[N:24]1([C:30]2[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:35]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: OB(O)c1ccnc(N2CCNCC2)c1
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3ccnc(N4CCNCC4)c3)cc21

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (293 mg) was reacted with 2-(piperazin-1-yl)pyridine-4-boronic acid, pinacol ester as in General Procedure 4B to give the title compound as an off-white solid. m.p.=189° C., LCMS: m/z=489.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.98 (4H, m), 3.49 (6H, m), 3.71 (2H, m), 4.61 (2H, s), 5.29 (1H, s), 5.34 (1H, bs), 6.55 (2H, m), 6.64 (1H, dd, J=5.2, 1.4 Hz), 7.36 (1H, d, J=8.1 Hz), 7.52 (1H, s), 7.64 (1H, d, J=8.3 Hz), 7.77 (1H, d, J=2.0 Hz), 8.12 (1H, d, J=5.3 Hz).