Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10]([NH:25][C@H:26]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27]3)[C:11]3[CH:16]=[CH:15][N:14]([CH2:17][O:18]CC[Si](C)(C)C)[C:12]=3[N:13]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:18][CH2:17][N:14]1[C:12]2[N:13]=[C:8]([NH:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:9]=[C:10]([NH:25][C@H:26]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27]3)[C:11]=2[CH:16]=[CH:15]1
Reactant: C=CC(=O)N[C@H]1C[C@H](Nc2nc(Nc3cnn(C)c3)nc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)N[C@H]1C[C@H](Nc2nc(Nc3cnn(C)c3)nc3c2ccn3CO)C1
Reaction time: 3 h

Procedure:
N-{trans-3-[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}prop-2-enamide (18 mmol) was dissolved in DCM (5 mL) and TFA (0.5 mL) was added. After stirring for 3 hrs, the solvents were removed and chromatography eluting with a gradient of 2%-20% EtOH in DCM to afford N-[trans-3-({7-(hydroxymethyl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]prop-2-enamide. To this N-hydroxymethyl intermediate, was added EtOH (5 mL) and K2CO3 (100 mg) dissolved in water (2.5 mL). The reaction was allowed to stir for 6 hrs and the solvents were removed. Water (3 mL) was added and the product was extracted into 2-methyl-THF (four×3 mL). After drying the organic extract over MgSO4, filtering, and concentrating, the white residue was carefully precipitated from DCM/MeOH/heptane (1:1:1) to afford the title compound (16 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.8 (br. s., 1H), 8.52 (d, J=6.80 Hz, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.45 (s, 1H), 6.87 (s, 1H), 6.72 (br. s., 1H), 6.64 (s, 1H), 6.18-6.29 (m, 1H), 6.12 (d, J=1.76 Hz, 1H), 5.60 (dd, J=10.07, 2.01 Hz, 1H), 4.68 (d, J=6.29 Hz, 1H), 4.40 (d, J=6.55 Hz, 1H), 2.37 (br. s., 3H), 2.18 (s, 2H). m/z (APCI+) for C17H20N8O 353.1 (M+H)+.
Reaction SMILES: C(#N)C.C[O:5][C:6]1[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]2[C:7]=1[N:8]=[CH:9][CH:10]=[N:11]2>[Ag].O>[N:8]1[C:7]2[C:6](=[O:5])[CH:15]=[CH:14][C:13](=[O:16])[C:12]=2[N:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(OC)c2nccnc12
Agent: [Ag]
Solvent: CC#N
Solvent: O
Product: O=C1C=CC(=O)c2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 22 g. of the silver catalyst prepared above, 148 ml. of acetonitrile, and 32 ml. of water was added over a 30 minute period to 2.0 g. of 5,8-dimethoxyquinoxaline. The reaction was stirred for two hours at room temperature. The catalyst was filtered off and washed with methylene chloride. Water was added to the filtrate and the filtrate was then extracted with the methylene chloride used to wash the catalyst. The methylene chloride was dried over sodium sulfate and evaporated to give the title compound as a brown powder which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11](N)=[C:12]([F:16])[CH:13]=2)[N:8]([CH2:18][CH3:19])[CH:7]=1)=[O:5])[CH3:2].N([O-])=O.[Na+].[C-:24]#[N:25].[K+].[OH-].[NH4+]>Cl.O>[CH2:1]([O:3][C:4]([C:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:24]#[N:25])=[C:12]([F:16])[CH:13]=2)[N:8]([CH2:18][CH3:19])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(CC)c2cc(N)c(F)cc2C1
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1=CN(CC)c2cc(C#N)c(F)cc2C1
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
To a suspension of 2.78 g (10 mmole) of 7-amino-1,4-dihydro-1-ethyl-6-fluoro-3-quinolinecarboxylic acid ethyl ester in 40 ml of 1N HCl at 8° was added a solution of 0.72 g (10.5 mml) of sodium nitrite and 5 ml of water portionwise keeping the temperature at 8° C. The orange solution was stirred at 5° to 8° C. for 0.5 hours. To a solution of 1.07 g (12 mmol) of cuprous cyanide, 2.28 g (35 mmol) of potassium cyanide and 25 ml of water at 45°-50° C. was added the diazonium solution over 10 minutes. The foaming mixture was heated with stirring at 50°-60° C. for 1.25 hours, then treated with 10 ml of 29% ammonium hydroxide and stirred at 50° C. for 20 minutes. The solution was cooled with ice and the solid collected by filtration. The solid was recrystallized from acetonitrile to give 0.28g of the title compound, mp 205°-207° C. The acetonitrile filtrate was evaporated to dryness and the residue was triturated with ethers to yield an additional 0.63 g of product.
Reaction SMILES: [I:1]I.[CH2:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[I:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14]
Reactant: II
Reactant: C#CCCCCCCCCCCO
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCCCCCCCCCCI
Reaction time: 0.42 h
Yield: 54.6 %

Procedure:
Iodine (43.16 g, 170 mmol, 2.0 eq) was added to a suspension of distilled alcohol 61 (15.50 g, 85 mmol), imidazole (17.36 g, 255 mmol, 3.0 eq), and triphenylphosphine (66.90 g, 255 mmol, 3.0 eq) in dry toluene (425 mL, stored over molecular sieves). The reaction mixture was heated at reflux with vigorous stirring for 25 min, generating a yellow solution with a oily black precipitate. After colling to 25°, saturated aqueous sodium bicarbonate (200 mL) and iodine (23.73 g, 93.5 mmol, 1.1 eq) were added and the reaction was stirred vigorously for 1 h. Saturated aqueous Sodium sulfite (40 mL) was added, quenching the purple color. The reaction mixture was allowed to separate into two layers and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was dissolved in dichloromethane (50 mL) and ether (200 mL) was added. After standing for 30 min, the resulting precipitate (triphenylphosphine oxide) was removed by filtration and washed with ether (100 mL). On further standing, the combined mother liquor and ether wash deposited a second crop of crystals which were removed as before. The combined mother liquors and ether washes were concentrated and dissolved in warm toluene (200 mL). This solution was placed on a silica gel column (500 g) and eluted with toluene (3 L) to afford 13.55 g (55%) of iodide 62 as a pale Yellow mobile liquid. This material was 96% one peak by GC.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20][CH3:21])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O.C1(C)C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20][CH3:21])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: CC(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Reaction time: 0.5 h

Procedure:
Reflux a mixture of 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.8 g.), aluminium isopropoxide (0.36 g.), toluene (26 cc.) and cyclohexanone (8 cc.) under nitrogen for 3 hours. Allow the solution to cool under nitrogen, add water (5 cc.) and shake the mixture vigorously. Add anhydrous sodium sulphate (5 g.), shake the mixture again, and then allow to stand for 30 minutes. Filter the solution, combine the filtrate with ether-washings of the residue, and evaporate, first at 30°/20 mm., then at 50°/0.1 mm. to leave as a crystalline solid 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one; infrared absorption peaks at 5.78, 5.92, 6.01 μ, with no absorption due to hydroxyl.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[C:12](=O)[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)C>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[CH2:12][NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(I)nn2c1C(=O)NC(CO[Si](C)(C)C(C)(C)C)C2
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CNC(CO[Si](C)(C)C(C)(C)C)C2
Temperature: 40 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of Intermediate 351C (1.2 g, 2.503 mmol) in THF (120 ml) was added neat borane dimethylsulfide complex (0.713 mL, 7.51 mmol) dropwise and the resulting solution was heated at 40° C. for 36 h. The reaction mixture was cooled to room temperature and ethanol (10 mL) was added dropwise. The reaction mixture was stirred at 70° C. for 1 h and concentrated to afford Intermediate 351D as a white semi-solid (1.23 g, 95%), which was taken to the next step without further purification. MS(ES): m/z=466 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4]1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[N:10]([CH2:2][CH:3]1[O:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4]1)=[N+:11]=[N-:12]
Reactant: CC1(C)CCC(CBr)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCC(CN=[N+]=[N-])O1
Temperature: 90 °C

Procedure:
5-(Bromomethyl)-2,2-dimethyltetrahydrofuran (36 g, 186 mmol) in DMF (300 ml) was treated with solid sodium azide (12.73 g, 196 mmol) and heated at 90° C. for 4 hrs. The mixture was allowed to cool to RT and partitioned between water (1.5 l) and ether (2×500 ml). The ether layer was separated and washed with (0.5M) LiCl (500 ml), dried MgSO4, filtered and evaporated to afford the title compound;
Reaction SMILES: [F:1][C:2]1[C:3]([N:17]=[CH:18]N(C)C)=[N:4][C:5]([O:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.Cl.[O:23]1CCOCC1>>[F:1][C:2]1[C:3]([NH:17][CH:18]=[O:23])=[N:4][C:5]([O:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: CN(C)C=Nc1nc(ON=Cc2ccccc2)ncc1F
Reactant: C1COCCO1
Agent: Cl
Product: O=CNc1nc(ON=Cc2ccccc2)ncc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a suspension of N′-{5-fluoro-2-[1-phenylmethylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.035 g, 0.12 mmol) in dioxane (1.2 mL) was added dilute hydrochloric acid (HCl, 1 N, 0.006 g, 0.16 mmol) and the mixture was stirred at 23° C. for 16 h. The reaction mixture was purified by flash chromatography (4 g SiO2; 0→60% EtOAc/hexanes) to give N-{5-fluoro-2-[1-phenylmethylideneaminooxy]pyrimidin-4-yl}formamide (0.007 g, 22%) as a white solid: mp 210-232° C. dec; 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.36 (s, 1H), 8.79 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 7.80 (dd, J=7.7, 1.6 Hz, 2H), 7.52 (m, 3H); ESIMS m/z 261 ([M+H]+), 259 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC1
Reactant: O=C(c1ccc(Cl)nc1)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of (6-chloro-pyridin-3-yl)[1,4]diazepan-1-yl-methanone (255.1 g, 1.06 mol) in dichloroethane (3.0 L) was added cyclobutanone (108.1 mL, 1.45 mol). After a 1 h aging period, sodium triacetoxyborohydride (308.2 g, 1.45 mol) was added in four equal portions over 1.5 h. The resulting mixture was allowed to stir for 20 h, then quenched with 2.5 L of an aqueous solution containing NaOH (141.3 g, 3.53 mol). After stirring for 30 minutes, the layers were separated and the organic dried with magnesium sulfate, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6]([CH3:12])([CH3:11])[C:5]1=[O:13].C(O[Cl:19])(C)(C)C>CO>[Cl:19][N:7]1[C:8](=[O:10])[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:13])[C:6]1([CH3:11])[CH3:12]
Reactant: CC1(C)NC(=O)CN(CCO)C1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(C)C(=O)N(CCO)CC(=O)N1Cl
Reaction time: 0.58 h
Yield: 79.5 %

Procedure:
A solution of 1-(2-hydroxyethyl)-3,3-dimethylpiperazine-2,5-dione (300 mg, 1.61 mmol) in methanol (3 ml) was cooled to 0° C. tert-Butylhypochlorite (272 ul, 2.4 mmol) was added. The resulting solution was stirred for 35 minutes, and then concentrated under reduced pressure. The crude material was purified by column chromatography, eluting the desired product from silica gel with a gradient of 1 to 10% methanol in dichloromethane to give the title compound as a white solid (284 mg, 1.28 mmol, 80%). 1H NMR (D2O, 400 MHz) δ 1.67 (s, 6H), 2.26-2.28 (t, J=5.0 Hz, 1H), 3.59-3.62 (t, J=5.0 Hz, 2H), 3.86-3.90 (q, J=5.0 Hz, 2H), 4.32 (s, 2H); LRMS (ESI/APCI) m/z 221 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)C1CC=C(c2ccc(F)c(Cl)c2)CC1
Temperature: 100 °C

Procedure:
A flask was charged with (3-chloro-4-fluorophenyl)boronic acid (495 mg, 2.84 mmol), ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (686 mg, 2.27 mmol), Pd(PPh3)4 (262 mg, 0.227 mmol), 1M Na2CO3 (6.81 mL, 6.81 mmol), EtOH (2.8 mL), and DME (8.6 mL). The reaction was degassed with N2, the flask was sealed, and the reaction was heated to 100° C. for 2 hours. The reaction was then cooled to room temperature and diluted with hexanes (100 mL) and EtOAc (20 mL). The mixture was washed with water (2×25 mL) and brine (2×25 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 10% EtOAc/hexanes) afforded ethyl 4-(3-chloro-4-fluorophenyl)cyclohex-3-ene-1-carboxylate. Rf=0.25 (5% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.37 (dd, J=7.1, 2.3 Hz, 1H), 7.20 (m, 1H), 7.05 (t, J=8.8 Hz, 1H), 6.05 (s, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.36-2.62 (m, 4H), 2.17 (m, 1H), 1.84 (m, 1H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:40])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:25]([CH3:38])=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:39])[CH2:9]1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl.C(OCC)C>[CH3:40][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:25]([CH3:38])=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C=CC(=O)Nc1cc(Nc2ncc(C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
Acryloyl chloride (0.043 mL, 1M in THF, 0.53 mmol) was added dropwise to a mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 83, 252 mg, 0.53 mmol) and DIPEA (0.103 mL, 0.59 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, and then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). The resulting solution was washed with water and sat. brine. The aqueous washes were re-extracted three times using CH2Cl2. The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave a yellow dry film after concentration of the appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. The resulting mixture was stirred for 30 minutes and then concentrated in vacuo to give the title compound (133 mg, 47%) as a yellow solid; 1H NMR: 1.67-1.81 (1H, m), 2.09 (1H, s), 2.19 (6H, s), 2.35 (3H, s), 2.72 (1H, s), 3.20 (3H, t), 3.30-3.43 (1H, m), 3.84 (3H, s), 3.89 (3H, s), 5.66 (1H, d), 6.16 (1H, d), 6.49 (1H, dd), 6.55 (1H, s), 7.12 (1H, t), 7.22 (1H, t), 7.48 (1H, d), 7.75 (1H, s), 7.92 (1H, s), 8.02 (1H, s), 8.18 (1H, s), 8.40 (1H, d), 9.32 (1H, s); m/z: ES+ MH+ 526.66.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]2=[N:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([NH:57][C:58](=[O:70])[C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([C:68]#[N:69])([CH3:67])[CH3:66])[CH:60]=2)[CH:53]=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[C:68]([C:65]([C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[C:58]([NH:57][C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[C:50]([NH:49][C:13]([C:11]2[S:10][C:8]3=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][N:6]=[C:7]3[CH:12]=2)=[O:15])[CH:51]=1)=[O:70])([CH3:67])[CH3:66])#[N:69]
Reactant: CCOc1cnc2cc(C(=O)O)sc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Temperature: 80 °C
Yield: 7.1 %

Procedure:
A solution of 97 (0.085 mmol, 18.29 mg), N,N-diisopropylethylamine (0.426 mmol, 0.070 ml, 55.1 mg) and HATU (0.128 mmol, 48.6 mg) in DMF (1 mL) was stirred for 5 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (0.085 mmol, 25 mg) was added and stirred at 80° C. over the weekend. The reaction mixture was quenched in citric acid solution and extracted with ethyl acetate (2×). Organic layer was washed with brine, dried and concentrated under reduced pressure. The crude compound was purified with HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-ethoxythieno[2,3-b]pyrazine-6-carboxamide 98 (3 mg, 7%). NMR (400 MHz, CDCl3) 1.48 (t, 3H), 1.78 (s, 6H), 2.36 (s, 3H), 4.51 (q, J=7.0 Hz, 2H), 7.24 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 2H), 7.79 (m, 2H), 7.91 (s, 1H), 7.98 (m, 2H), 8.16 (d, J=2 Hz, 1H), 8.32 (s, 1H). (m/z)=501 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:31][CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:21])([F:20])[F:22])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: NCc1ccccn1
Product: C[C@H](Oc1ncc(C(=O)NCc2ccccn2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1 using (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylic acid (example AH) and 2-pyridinemethanamine (CAN 3731-51-9) as starting materials; MS (ESI): 437.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]1.F[C:34](F)(F)[C:35](O)=O>C(Cl)Cl>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:9][N:8]2[CH2:35][CH2:34][CH2:3][CH2:2][CH2:7]2)[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(CCN4CCCCC4)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
The N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (1.00 g, 2.20 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. with an ice bath. Trifluoroacetic acid (20 mL) was added, the cooling bath removed, and the reaction mixture allowed to warm to ambient temperature over 1 h. The reaction mixture was then concentrated in vacuo and the residue dissolved in H2O (15 mL). The resultant solution was added to Bio Rad AG-1-X8 ion exchange resin (12 mL; OH- form, washed with H2O until neutral), additional H2O (5 mL) was added, and the mixture stirred for 10 min. The mixture was then filtered and the resin washed with additional H2O (3×5 mL). The aqueous filtrate was lyophilized to give 0.559 g (72%) of the title compound as a white solid with mp 108°-112° C. (dec).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]=[C:9]([C:11](OC)=[O:12])[O:8][N:7]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]=[C:9]([CH2:11][OH:12])[O:8][N:7]=1
Reactant: COCCCc1noc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCc1noc(CO)n1

Procedure:
In analogy to the procedure described for example D26 methyl 3-(3-methoxypropyl)-1,2,4-oxadiazole-5-carboxylate (990 mg) and sodium borohydride (386 mg) in MeOH yield the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]3[C:11]4[C:16]([CH2:17][C:7]3([CH3:18])[C:6]=2[C:5]([CH3:19])=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22])=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:23][Li].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:23][C@@:8]12[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][C@:7]1([CH3:18])[C:6]1[C:5]([CH3:19])=[C:4]([O:20][CH3:21])[C:3]([CH3:22])=[C:2]([CH3:1])[C:10]=1[NH:9]2
Reactant: [Li]C
Reactant: COc1c(C)c(C)c2c(c1C)C1(C)Cc3ccccc3C1=N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(C)c(C)c2c(c1C)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (-80° C.) solution of 1.1 g (0.0038 mol) of 9b,10-dihydro-6,7,9,9b-tetramethyl-8-methoxyindeno[1,2-b]indole in 20 ml of dry THF was added 4 ml of 1.6M methyl lithium in ether under argon. The mixture was stirred at -78° C. for 1 hour and then at -20° C. for 1 hour. After attaining 0° C. aqueous NH4Cl and ether was added. The phases were separated, and the organic phase was washed once with water, dried (MgSO4) and evaporated. The resulting crude product was purified by chromatography on silica using ethyl acetate/isooctane (2/10) as eluant. This gave 0.3 g (25%) of the expected product. 1H NMR (CDCl3): 1.41 (3H,s), 1.43 (3H,s), 1.96 (3H,s), 2.07 (3H,s), 2.35 (3H,s), 3.0 (1H,d), 3.55 (3H,s), 3.65 (1H,d), 7.1 (3H,m), 7.25 (1H,m).