Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[CH:5]1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:10][C:9]([F:12])([F:11])[C:7]1[N:6]=[CH:5][N:4]([CH2:3][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:8]=1
Reactant: FC(F)(F)c1cn(CCl)cn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)F)c1
Yield: 27.7 %

Procedure:
2.90 g of 1-(chloromethyl)-4-(trifluoromethyl)-1H-imidazole hydrochloride and 2.11 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 39 ml of N,N-dimethylformamide. 3.59 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.12 g of {[4-(trifluoromethyl)-1H-imidazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (38), hereinafter) shown by below formula.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-])=O)[CH:33]=2)=[C:4]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:5]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:7]=1.[S-2].[Na+].[Na+]>C(O)C.O.C(OCC)(=O)C>[NH2:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:30][C:3]1[C:2]([Br:1])=[CH:7][C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])=[CH:5][C:4]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc([N+](=O)[O-])c2)c(NS(C)(=O)=O)c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(N)c2)c(NS(C)(=O)=O)c1

Procedure:
A mixture of N-[3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-nitro-benzyloxy)-phenyl]-methanesulfonamide (950 mg) and sodium sulfide (350 mg) in ethanol (12 ml) and water (250 μl) was heated at reflux for 2 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][CH2:19][O:18]1)=[O:16])[CH3:13]>C1COCC1>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][C:21]([OH:23])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:20][CH2:19][O:18]1)=[O:16])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)C1CC(=O)CCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(O)(C#C[Si](C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A cold (−78° C.), stirred solution of (trimethylsilyl)acetylene (1.80 g, 18.24 mmol) in anhydrous THF (30 mL) was treated with nBuLi (7.3 mL in hexane, 18.24 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62 g, 15.2 mmol) in anhydrous THF (30 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water (30 mL). After removal of THF, the product was extracted with EtOAc (2×60 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 2.50 g (61%) of yellow oil: 1H NMR (CDCl3) δ 0.17 (s, 9H), 1.30 (t, 3H), 1.76-1.90 (m, 3H), 2.25 (m, 1H), 3.66 (tt, 1H), 4.11-4.21 (m, 2H), 4.24 (q, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
A suspension of 0.7 g (1.6 mmole) of ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-3-carboxylate , 6 ml of 10% aqueous sodium hydroxide and 2 ml of ethanol was refluxed for three hours. The reaction was filtered through a fiber glass pad to clarify and acidified to pH 1.5 with 6.0M hydrochloric acid and lyophilized. The residue was dissolved in 10 ml of ammonium hydroxide and the solution concentrated in vacuo. The precipitate which formed was removed by filtration, washed with aqueous ethanol, ether and dried in vacuo to give 0.04 g, mp 274°-276° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[O:10][N:9]=[C:8]([C:11]([NH:13][C@@H:14]([CH3:31])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28]#[N:29])=[C:23]([Cl:30])[CH:22]=3)=[N:17]2)=[O:12])[CH:7]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:8]3[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[O:10][N:9]=3)=[O:12])[CH3:31])[N:17]=2)[CH:26]=[C:25]([F:27])[C:24]=1[C:28]#[N:29]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Sodium borohydride (0.012 g, 0.308 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide (0.064 g, 0.154 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted below 7 and the mixture was evaporated. 5% of DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 81%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 1.40 (dd, 3H), 4.32 (d, 2H), 4.45 (m, 1H), 4.86 (m, 1H), 5.78 (dd, 1H), 6.53 (dd, 1H), 7.00 (d, 1H), 7.84 (d, 1H), 7.86 (m, 1H), 7.98 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: [C:1]([NH2:5])([NH2:4])=[N:2][NH2:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=O)=[CH:10][CH:9]=1>C(O)C>[NH2:4][C:1]1[N:2]=[N:3][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[N:5]=1
Reactant: NN=C(N)N
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CCO
Product: COc1ccc(-c2nnc(N)nc2-c2ccc(OC)cc2)cc1
Yield: 65 %

Procedure:
Aminoguanidine (2.450 g, 2.21 mmol) is added to a solution of 1,2-bis(4-methoxyphenyl)-ethane-1,2-dione prepared according to example 1 (5 g, 18.5 mmol) in ethanol (50 ml). The mixture is heated at reflux for 12 hours. After returning to ambient temperature, the precipitate obtained is filtered, washed with ethanol and is dried to yield a yellow solid. The residue is purified by chromatography on a silica gel (dichloromethane/triethylamine 0.5%) to yield 3.7 g (65%) of a yellow solid. δH (200 MHz, CDCl3), 3.88 (s; 6H), 5.51 (s; 2H), 6.92 (m; 4H), 7.41 (m; 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:21].N1C=CN=C1.[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].O>CN(C)C=O.C(OCC)(=O)C>[Si:31]([O:20][CH2:19][CH2:18][C:14]1[C:13](=[O:21])[N:12]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 g (346 mmol) of the compound from Example 61A (alternative synthesis) and 30.7 g (450 mmol) of imidazole are dissolved in 1 l of anhydrous N,N-dimethylformamide. A solution of 117 g (416 mmol) of tert-butyl(chloro)diphenylsilane in 150 ml of N,N-dimethylformamide is added dropwise, and the mixture is stirred at RT for 3 h. Water and ethyl acetate are then added, the phases are separated and the organic phase is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is triturated with petroleum ether/diethyl ether (10:1). After filtration, the residue is washed with petroleum ether and then air-dried. This gives 150 g (82% of theory) of the desired product.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(OCC)(=O)C>CO.Cl.O>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: c1cc(N2CCOCC2)ccc1C1OCCO1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-[1,3]dioxolan-2-yl-phenyl)-morpholine (690 mg, 2.933 mmol) in methanol (5 mL) was treated with 10 drops concentrated aqueous hydrochloric acid. The mixture was stirred at room temperature for 1 hour. To this solution was added 5 drops of water and stirring was continued for 2 hours at ambient temperature. The solution was then poured into ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2×50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 4-morpholin-4-yl-benzaldehyde as a tan waxy solid (550 mg, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[CH3:13][NH:14][CH3:15]>C(O)C.Cl.[Pd]>[CH3:13][N:14]([CH3:15])[CH:10]([CH3:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CNC
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(CCc1ccc(O)cc1)N(C)C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 4-(4-hydroxyphenyl)-2-butanone (100 g) in 500 ml of ethanol with anhydrous dimethylamine (300 ml) and 5% palladium on sulfide carbon (100 g) was placed in a high pressure reaction vessel and kept under 1000 psi of H2 at 175° C. for 8 hours. The resultant solution was then filtered and the solvent removed in vacuo to give an oil which was dissolved in 1N hydrochloric acid (100 ml) and extracted with two 100 ml portions of ether. The aqueous layer was adjusted to pH7 with 2N sodium hydroxide and extracted with an additional two 100 ml volumes of ether. The organic extract was retained and dried and reduced in volume to give 55 g (47% yield) of the desired subtitled intermediate.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cccc(CO)n1)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccc(CCl)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 530 mg of (6-hydroxymethylpyridin-2-yl)morpholin-4-ylmethanone and 614 mg of diisopropylethyl-amine in 10 mL of methylene chloride at ice temperature, 0.28 mL of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (methylene chloride-ethanol=50:1) to give 570 mg of (6-chloromethylpyridin-2-yl)morpholin-4-ylmethanone as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12].[Li+].[BH4-]>C1COCC1.CCOC(C)=O.Cl>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: COC(=O)c1ccccc1OS(C)(=O)=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccccc1CO
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methanesulfonyloxybenzoic acid methyl ester (1.0 g, 4.3 mmol) in THF (10 mL) is added LiBH4 (375 mg, 17.2 mmol) in portions. The mixture is heated at 45° C. for 2 h then at 60° C. for 2 h. The mixture is diluted with EtOAc and ice and 1N HCl is added. The organic phase is separated and washed with 1N HCl and brine then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=[O:6].[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:43])[C:22]([NH:24][CH2:25][C:26]1[S:30][CH:29]=[C:28]([N:31]2[C:35]([C:36](O)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)[CH:27]=1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH:8][C:36]([C:35]1[N:31]([C:28]2[CH:27]=[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:43])[S:30][CH:29]=2)[N:32]=[C:33]([C:39]([F:40])([F:42])[F:41])[CH:34]=1)=[O:37])=[O:6]
Reactant: COc1ccccc1C(=O)NN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccccc1C(=O)NNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxybenzhydrazide (0.040 g, 0.238 mmol) and compound 7 (preparation described in scheme 2 example 1c, step 7) (0.11 g, 0.238 mmol) in dichloromethane (2 mL) under nitrogen was added EDC (0.046 g, 0.238 mmol) followed by DMAP (5.81 mg, 0.048 mmol). The reaction was left to stir for 16 hours at room temperature. Another portion of EDC (20 mg, 0.104 mmol) was added and the reaction continued for 4 hours. The solvent was then removed on the rotary evaporator and the crude purified by silica gel column chromatography with a Biotage 12M column and a gradient of 0-5% methanol in dichloromethane to give compound 16 as a yellow crust (73.7 mg, 51%). LRMS (ESI): calc. 610.2; found 511.2 (MH-Boc)+, 633.3 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:29]([Cl:39])[CH:28]=1)=[N:7]2.[C:40](=O)([O-])[O-].[Na+].[Na+].CB1OB(C)OB(C)O1.C(Cl)Cl>CN(C=O)C>[Cl:39][C:29]1[CH:28]=[C:27]([NH:26][C:6]2[N:5]=[CH:4][C:3]3[C:8](=[C:9]([O:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)[CH:10]=[CH:11][C:2]=3[CH3:40])[N:7]=2)[CH:32]=[CH:31][C:30]=1[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Nc4ccc(N5CCOCC5)c(Cl)c4)nc23)CC1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Nc3ccc(N4CCOCC4)c(Cl)c3)ncc12
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-(5-bromo-2-(3-chloro-4-morpholinophenylamino) quinazolin-8-yloxy)piperidine-1-carboxylate (See example 45 for synthesis) (1 eq) in DMF was added 2M sodium carbonate solution, trimethylboroxine (3 eq) and Pd (dppf)2Cl2.CH2Cl2 (0.05 eq). The reaction mixture was micro waved for 10 min at 120° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified by semi-preparative HPLC to provide pure product. ES/MS m/z 554.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>CC(C)=O>[CH3:29][C:28]([CH3:30])=[CH:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Nc2cccc(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2cccc(OCC=C(C)C)c2)n1
Yield: 55 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxyphenylamino)thiazole-4-carboxylate (182 mg, 0.69 mmol) and K2CO3 (105 mg, 0.76 mmol) in acetone (6.9 mL) was treated with 4-bromo-2-methyl-2-butene (0.096 mL, 0.83 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 55% yield (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]1([N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]1([N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N(c1ccccc1)c1ccccc1

Procedure:
3,4-Dichloroaniline (5.35 g, 0.033 mol) was dissolved in 100 ml of chloroform and 7.65 g (0.033 mol) of diphenylcarbamic chloride and 3.33 g (0.033 mol) of triethylamine were added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2cc[nH]c2cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(F)(F)F)NCC2
Yield: 99 %

Procedure:
5 The indole (D8) (67.63 g, 0.315 mol) in glacial acetic acid (500 ml) was treated with sodium cyanoborohydride (40 g, 0.637 mol) at room temperature with stirring. After 3 h at room temperature the reaction mixture was diluted with water (500 ml) and basified with 40% aqueous NaOH with cooling. The mixture was then extracted with dichloromethane (3×500 ml) and the combined extracts were dried (Na2SO4) and evaporated to give the title compound (67.73 g, 99%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]([CH3:29])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]=[C:46]=[S:47])([CH3:38])[CH3:37].O>CN(C)C=O>[OH:1]/[C:2](/[CH3:29])=[C:3](/[C:46](=[S:47])[NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH:36]([CH3:37])[CH3:38])\[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=3)[N:14]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(=O)CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(O)=C(/C(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=S)Nc1ccccc1C(C)C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A portion of the solid from Step 1 (0.50 g, 1.24 mmol) was dissolved in 5 mL of dry N,N-dimethylformamide (DMF) and stirred at ambient temperature while potassium carbonate (0.25 g, 1.81 mmol) and 2-isopropylphenyl isothiocyanate (0.25 g, 1.41 mmol) were added. The solution was stirred for 18 h, then it was poured into 15 mL of water, extracted with ether, and the solvent evaporated. Chromatography of the crude product (0-70% EtOAc-hexanes) gave 350 mg of the title compound as an off-white solid. mp 141-144° C. 1H NMR (400 MHz, CDCl3) δ 15.35-14.58 (m, 1H), 10.93 (s, 1H), 8.57 (m, 3H), 8.31-8.11 (m, 6H), 7.71 (m, 12H), 7.56-7.30 (m, 15H), 5.35 (s, 1H), 3.02 (heptet, J=6.9 Hz, 1H), 2.52 (s, 3H), 1.35-1.11 (m, 6H); ESIMS m/z 582 ([M+H]+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([OH:12])=O)[C@H:7]([CH2:13][CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[NH:15]([C:17]1[N:18]=[C:19]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=1)[NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:13]([C@H:7]1[C@@H:8]([C:10]([NH:16][NH:15][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)=[O:12])[CH2:9][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]1)[CH3:14]
Reactant: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To a mixture of (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (3.03 g, 15.2 mmol) in DCM (90 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol, Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL, 55.4 mmol). After stirring at ambient temperature for about 2 h, the reaction was diluted with water (60 mL). The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide (7.0 g, 90%, 87% purity) as a tan foam: LC/MS (Table 1, Method a) Rt=1.96 min; MS m/z: 485 (M+H)+. To a solution of impure N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-cyclo-pentyl)acetamide (9.40 g, 19.4 mmol) in 1,4-dioxane (100 mL) was added TEA (8 mL, 58 mmol) and thionyl chloride (1.9 mL, 27.1 mmol). The reaction mixture was heated at about 80° C. for about 2 h, and then cooled to about 0° C. and saturated aqueous NaHCO3 and EtOAc (100 mL each) were added. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc/MeOH/Et2NH (90:9:1) in EtOAc to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.00 g, 66%): LC/MS (Table 1, Method a) Rt=2.03 min; MS m/z: 467 (M+H)+.