Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution containing carbazole (20 g; 0.12 mol) in DMF (130 ml) was added portionwise sodium hydride (50% suspension) (6.9 g; 0.14 mol); the suspension thus obtained was stirred at room temperature for 30 minutes and then heated to 60° C. A solution containing ethyl 2-bromoacetate (24 g; 0.14 mol) in DMF (20 ml) was added dropwise, and the resulting mixture was stirred for 16 hours. The mixture was poured into H2O (0.5 L) and filtered, and the solid obtained was crystallized from hexane to give ethyl 9H-carbazol-9-ylacetate (20 g).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C(Cl)Cl>[OH:14][CH:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)CCC(=O)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)CCC(O)Cc1ccccc1
Yield: 60.4 %

Procedure:
A 100-ml stainless steel autoclave purged with nitrogen in advance was charged with 5 g (0.0261 mol) of 6-phenyl-2,5-hexanedione and 10 ml of methanol. A solution of 0.185 g (0.13 mmol) of RuI(p-cymene)((R)-T-BINAP)]I3 in 2 ml of methylene chloride was added thereto, thereby conducting reaction at a reaction temperature of 50° C. for 36 hours under a hydrogen pressure of 50 kg/cm2. After distilling off the solvent, the residue was purified by column chromatography on a silica gel using a developing solvent of hexane/ethyl acetate (5/1) to obtain 3.03 g of (-)-5-hydroxy-6-phenylhexane-2-one (yield: 60.2%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[CH:17][C:16]=2[F:30])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:32].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH2:29])=[O:32])[CH:23]=3)=[CH:17][C:16]=2[F:30])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C#N)c3)cc2F)ncn1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)ncn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.4 %

Procedure:
A mixture of 1-(6-tert-butylpyrimidin-4-yl)-3-[4-(2-cyanopyridin-4-yloxy)-2-fluoro-phenyl]urea (141 mg, 0.35 mmol) and sodium percarbonate (with 25% H2O2) (218 mg, 1.4 mmol, 4.0 eq) in 2:1 v/v acetone/water (11 mL) was stirred at 60° C. for 16 h. The reaction was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Trituration from methanol afforded the title compound (63 mg, 43%) as a white solid. 1H-NMR (DMSO-d6) 10.32 (broad s, 1H), 10.08 (broad s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.23 (t, J=9.3 Hz, 1H), 8.12 (broad s, 1H), 7.71 (broad s, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.36 (dd, J=11.4, 2.4 Hz, 1H), 7.18 (dd, J=5.7, 2.7 Hz, 1H), 7.08 (ddd, J=9.0, 2.7, 1.5 Hz, 1H), 1.26 (s, 9H); LC-MS m/z 425 [M+H]+, RT=3.16 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[H-].[Na+].[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[N:8][C:6]=2[N:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
To a slurry of 1.00 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 in 15 mL of DMF was added 0.15 g sodium hydride (60% in mineral oil) portionwise and the mixture stirred for 1 hour. Propanesulfonyl chloride (0.39 mL) is added dropwise, and the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture is filtered to remove a small amount of insoluble material and the filtrate evaporated in vacuo. The product is purified by medium pressure liquid chromatography (MPLC) using silica gel and eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1) to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH2:27][CH3:28]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [F:1][C:2]([F:12])([S:9]([O-:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].O.OO.S([O-])([O-])=[O:24].[Na+].[Na+]>CC(C)=O>[F:12][C:2]([F:1])([S:9]([O-:24])(=[O:11])=[O:10])[C:3]([F:7])([F:8])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: O=S([O-])C(F)(F)C(F)(F)CCO
Reactant: O=S([O-])[O-]
Agent: CC[NH+](CC)CC
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)CCO
Temperature: 40 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A 500 mL reactor was charged with 65 g (93% purity, 0.194 mole/1.0 equivalent) of triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfinate obtained in Example 2-1 by purification, 200 g of water and 46 g (0.40 mole/2.1 equivalents) of 30% hydrogen peroxide at room temperature, followed by 6 hours of stirring at 40° C. Upon confirming the termination of the reaction, the reaction liquid underwent cooling, and 7.5 g of sodium sulfite was added to the reaction liquid, followed by stirring. Thereafter, 350 g of acetone was added to a liquid obtained by distilling the solvent out of the reaction liquid, followed by 1 hour of stirring at room temperature. Thereafter, filteration was performed in the use of a filter paper. An obtained filtrate was concentrated and dried, thereby obtaining 65.6 g of a target triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfonate. It exhibited a purity of 92% and a yield of 95% at this time.
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:24][CH2:25][CH2:26][NH2:27])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=O)C>O.N>[NH2:27][CH2:26][CH2:25][CH2:24][CH:13]([CH2:12][SH:11])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-(2-Acetylthiomethyl-5-aminopentanoyl)-L-proline trifluoroacetate (1 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonia (12 ml.) under a blanket of argon. The solution is stored twenty minutes at room temperature concentrated to 5 ml. and applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. The column is washed with water and N-(5-amino-2-mercaptomethylpentanoyl)-L-proline is eluted with a buffer of pyridine-acetic acid at pH 6.5.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:54]([NH:58]C2C=CC(OC)=CC=2)[CH:55]([F:57])[F:56])=[C:33]([CH:53]=1)[CH2:34][NH:35][C:36](=[O:52])[C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:51])[C@@H:43]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[OH:44]>O.CC#N>[CH:45]1([C@@H:43]([OH:44])[C:42]([N:38]2[CH2:39][CH2:40][CH2:41][C@H:37]2[C:36]([NH:35][CH2:34][C:33]2[CH:53]=[C:29]([Cl:28])[CH:30]=[CH:31][C:32]=2[CH:54]([NH2:58])[CH:55]([F:57])[F:56])=[O:52])=[O:51])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)C2CCCCC2)C(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: NC(c1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1)C(F)F
Temperature: 25 °C

Procedure:
A solution of CAN (0.0647 g, 0.12 mmol) in water (0.4 mL) was added to a stirred solution of N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (0.0332 g, 0.06 mmol) in CH3CN (1.5 mL) at 0° C. and the solution was warmed to ambient temperature. After 4 h the solution was partitioned between EtOAc and 10% aqueous NH4OH. The resulting two phase suspension was filtered and the EtOAc layer was washed with 10% sodium sulfite solution and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica (eluting with 1-10% of 10% ammonium hydroxide in methanol/chloroform gradient) to give the title compound as a gum: LC-MS m/z=458.4.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[CH3:28]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: Cc1cc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, off-white solid (69 mg, 86%), MS (ISN) m/z=320.4 [(M+H)+], mp 290° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:12]=[C:9]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:10]1=2
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
To a solution of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone (15.3 g, 94.3 mmol) in N,N-dimethylformamide (150 mL) were serially added ethyl bromoacetate (16.5 g, 99.0 mmol) and potassium carbonate (13.7 g, 99.0 mmol) and the mixture was stirred at 60° C. for 6 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to provide 19.5 g of the title compound. Yield 83%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[NH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH2:32][CH:28]([NH2:27])[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reactant: NC1CCNC1
Product: Nc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 71 %

Procedure:
The condensation of 5-amino-1-(2′,4′-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-aminopyrrolidine was carried out in a similar manner as described in example 1, gave the titled product. Yield 71%, m.p 268° C. (d), C20H16F4N4O3, m/z 437 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)C1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)C1

Procedure:
Prepared as described in Example 5c) using (+/−)-2-chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-benzoic acid (Example 7b, 0.070 g), N,N′-carbonyldiimidazole (0.033 g), 1-adamantanemethylamine (0.036 ml) and dimethylformamide (3 ml) to give the subtitle compound as a gum.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCC(=O)OC(C)(C)C)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), tert-butyl 3-aminopropanoate hydrochloride (7.94 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC. LCMS m/z=505.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][C@@H:14]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH2:13]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][C@@H:14]([O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:21])[CH3:20])[CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (R)-1-(2-Methoxy-4-nitro-phenyl)-3-triisopropylsilanyloxy-pyrrolidine (12 g, 30.4 mmol) in EtOH (200 mL) and add 5% Pd/C (1.26 g). Purge the black mixture with hydrogen (1 atm) and stir overnight under a hydrogen atmosphere at ambient temperature at 60 psi. Filter the black mixture through Celite® and wash the solids with additional EtOH (100 mL). Concentrate the filtrate to give the title compound as a dark brown oil. 1H NMR (400 MHz, CDCl3): δ 6.76 (d, 1H, J=8.8 Hz), 6.31 (d, 1H, J=2.6 Hz), 6.25 (dd, 1H, J=8.8, 2.6 Hz), 3.74 (s, 3H), 1.34 (s, 9H). Note: title compound decomposed rapidly. Store compound in freezer immediately after use. MS (ES+) 365.2 (M+1)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:27]=[CH:26][C:25](CC(O)=O)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(CC(=O)Cl)cc3)c2cc1OC

Procedure:
Oxalyl chloride (0.5 ml) was added dropwise to a stirred suspension of 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid (0.2 g) in chloroform (5 ml) at ambient temperature under argon. The resultant mixture was heated to reflux for 30 minutes. The mixture was evaporated to leave 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetyl chloride as a solid. Chloroform (5 ml) and 5-amino-3-methyl-1,2,4 oxadiazole (0.099 g) were added in turn. Pyridine (0.286 ml) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 250 mm length) that was eluted with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.053 g); 1H NMR: (DMSOd6) 2.26 (s, 3H), 3.86 (s, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 6.46 (d, 1H), 7.24 (d, 2H), 7.4 (s, 1H), 7.44 (d, 2H), 7.49 (s, 1H), 8.48 (d, 1H), 11.27 (br s, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=O.[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][CH2:1][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1
Reactant: CSc1ncc(C=O)c(Nc2cccc(CCO)c2)n1
Reactant: Nc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(CNc2ccccc2Br)c(Nc2cccc(CCO)c2)n1
Yield: 90.9 %

Procedure:
A solution of 2.5 g (8.65 mmol) of 5-formyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine in 120 ml of toluene was treated with 1.5 g (9.3 mmol) of 2-bromoaniline and 100 mg (0.5 mmol) of 4-toluenesulfonic acid monohydrate and then heated at reflux with azeotropic removal of water for 1 hour. The cooled mixture was evaporated and the residue was dissolved in 4 ml of tetrahydrofuran. The solution obtained was added dropwise to a solution of 9 ml (9 mmol) of lithium aluminium hydride (as a 1M solution in tetrahydrofuran) in 40 ml of tetrahydrofuran. After 1 hour the reaction was quenched by the cautious dropwise addition of 0.35 ml of water, 0.35 ml of 2M aqueous sodium hydroxide and 1 ml of water. The resulting suspension was filtered through a filter aid and the filtrate was evaporated. The residue was partitioned between 150 ml of ethyl acetate and 50 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 3.5 g (91%) of 5-(2-bromoanilino)methyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine as an orange colored gum. [Mass spectrum (ESI) MH+ =444].
Reaction SMILES: [CH2:1]([C@:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[OH:26])=[CH:11][C:10]=1[Cl:27])[CH2:5][OH:6])[CH:2]=[CH2:3].[OH2:36]>C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C@@:4]([CH2:1][CH2:2][CH3:3])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])=[CH:11][C:10]=1[Cl:27])[CH2:5][OH:6])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: O
Reactant: C=CC[C@@](CO)(CCc1ccc(Sc2cc(C(F)(F)F)ccc2O)cc1Cl)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CCC[C@@](CO)(CCc1ccc(Sc2cc(C(F)(F)F)ccc2OC(=O)OC(C)(C)C)cc1Cl)NC(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A palladium on activated carbon/ethylene diamine complex (100 mg) was added to a solution of the compound of Example 33 (473 mg) in ethyl acetate (9 mL) to form a first reaction solution. This first reaction solution was stirred at normal temperature for 20 hours under hydrogen purging. The first reaction solution was filtrated through Celite, and the solvent was removed by distillation. The resultant residue was dissolved in acetonitrile (9 mL). Triethylamine (145 μL) and di-tert-butoxydicarbonate (284 mg) were added to this solution to form a second reaction solution. This second reaction solution was stirred at normal temperature for 2 hours and then left to stand overnight. Then, water was added to the second reaction solution, and the second reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the target product (434 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:18].O1CCN(CCNC(C2SC3C(OC4C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[S:48])=CC=4F)=NC=NC=3C=2)=O)CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:18][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[S:48]
Reactant: Nc1ccc(Oc2ncnc3ccsc23)cc1Cl
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(C(=O)NCCN4CCOCC4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 9 %

Procedure:
Starting from the amine 172 and following the procedure described above for the synthesis of compound 26a (scheme 4, example 22), title compound 173 was obtained in 9% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.35 (s, 1H), 11.89 (s, 1H), 8.72 (s, 1H), 8.48(d, J=5.6 Hz, 1H), 8.04(d, J=8.8 Hz, 1H), 7.69(d, J=2.8 Hz, 1H), 7.68(d, J=5.6 Hz, 1H), 7.40(dd, J=2.8 and 8.8 Hz, 1H), 7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.84 (s, 2H). LRMS (M+1) (100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([F:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([F:11])([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)=[CH:3][CH:4]=2)[CH2:9][NH2:10])=[CH:13][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: NCC(F)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: NCC(F)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reaction time: 0.08 h

Procedure:
2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine was reacted with 4,4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 except that heating was carried out at 100° C. for 5 minutes using 300 W power in a CEM microwave, to obtain the title compound. LCMS (PS-B4) Rt 6.69 min [M−F−]+296. 1H NMR (Me-d3-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d).