Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([CH:7]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]=[C:35]=[O:36].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][C:35](=[O:36])[NH:1][C:2]1[O:6][C:5]([CH:7]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1
Reactant: Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
350 mg of benzyl [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]-carbamate were dissolved in 5 ml of dry dimethyl sulfoxide, treated with 140 mg of potassium carbonate and 140 mg of methyl isocyanate, and stirred at 80° C. for 16 h. The reaction mixture was cooled, treated with ethyl acetate, washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Benzyl {1-[5-(3-methylureido)-[1,3,4]oxadiazol-2-yl]-3-phenylpropyl}carbamate was obtained, which was employed in the next stage (hydrogenolysis) without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH:11]1([CH:16]([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:23]2[CH:22]=[N:21][N:20]([CH:16]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:17][C:18]#[N:19])[CH:24]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (0.68 g, 3.8 mmol), 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (1.0 g, 3.17 mmol), tetrakis(triphenylphosphine)palladium (200 mg, 0.2 mmol), and potassium phosphate (2.0 g, 9.6 mmol) in 1,4-dioxane (9 mL) and water (0.9 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 60% EtOAc-hexanes, to give the desired product (860 mg, 82%). LCMS (M+H) 331.9.
Reaction SMILES: C(O[C@H:5]1[CH2:9][N:8](C(OC(C)(C)C)=O)[C@@H:7]([C:17](O)=O)[CH2:6]1)C=C.Br[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([O:32]C)=O)[CH:29]=1)[C:24]([OH:26])=[O:25].N(O[CH2:37]CCC)=O.C(OC(N1C[C@H](O)C[C@@H]1C(O)=O)=O)(C)(C)C>[Cu](Br)Br.O.C(#N)C>[CH2:7]([N:8]([CH2:9][CH2:5][CH3:6])[C:30]([C:28]1[CH:27]=[C:23]([CH:22]=[CH:21][CH:29]=1)[C:24]([OH:26])=[O:25])=[O:32])[CH2:17][CH3:37]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CCCCON=O
Reactant: C=CCO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Br[Cu]Br
Agent: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Solvent: CC#N
Solvent: O
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Step G (2): 3-bromo-5-(methoxycarbonyl)benzoic acid. To a mixture of copper (II) bromide (5.5 g, 24.6 mmol), n-butyl nitrite (3.17 g, 30.75 mmol) and acetonitrile (300 mL) was added 3-amino-5-(methoxycarbonyl)benzoic acid (Step G (1), 4.0 g, 20.5 mmol) in aceonitrile (300 mL) over 30 min at 0° C. and the mixture was warmed up and stirred at rt for 3 h. H2O was added and acetonitrile was removed. Ethyl acetate (600 mL) was added and the mixture was washed with 3N HCl, H2O, dried over Na2SO4, and concentrated in vacuo to give the title compound (97% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 3.96 (3H, s), 8.41 (1H, s), 8.41 (1H, s), 8.67 (1H, m). MS (ESI) (M−H)− 259.02.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:14]1([CH2:13][O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[O:29][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
4-Trifluoromethylbenzyl bromide (0.17 mL, 1.09 mmol, 1 eq) was added dropwise to a stirred solution of 3-benzyloxy-4-hydroxybenzaldehyde (250 mg, 1.09 mmol, 1 eq) and cesium carbonate (357 mg, 1.09 mmol, 1 eq) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight, then diluted with ethyl acetate (30 mL) and washed sequentially with water (4×30 mL), 0.5M aqueous sodium hydroxide (30 mL), 10% HCl and brine. The organic solution was dried over sodium sulfate and evaporated in vacuo to give the product as a white powder (422 mg, 99%). 1H NMR (CDCl3) δ 9.82 (s, 1H, O═C—H), 5.28 (2H, s, CH2Ar), 5.21 (s, 2H, CH2Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Methyl 4-chloro-3-hydroxybenzoate [Chem. Pharm. Bull. 1994, 42(11),2365-9] (0.73 g), caesium carbonate (1.27 g) and tert butylbromoacetate (0.58 mL) in DMF (6 mL) were heated and stirred at 60° C. for 3 h. Water was added and the product was extracted into ethyl acetate. The extracts were dried over sodium sulphate, filtered and the solvent was evaporated. The resulting oil was purified by flash chromatography, using 1:10 ethyl acetate/isohexane as eluent, to yield the subtitle compound as a colourless oil (1.25 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].C([N:20]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(C)(C)C>CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:36]([O:35][C:33]([NH:20][C@@H:21]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][CH:28]=1)[C:30]([O:32][C:23]([CH3:28])([CH3:24])[CH3:22])=[O:31])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)N(C(=O)OCc1ccccc1)[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 222.7 %

Procedure:
8.29 ml (57.9 mmol) of ethyl 4-bromobutanoate and 28.21 g (86.58 mmol) of cesium carbonate were added to 21.5 g (57.9 mmol) of tert-butyl N-benzyloxycarbonyltyrosine in 280 ml of acetone and the mixture was heated to reflux with stirring. After 2 h, a further 2 ml of ethyl 4-bromobutanoate and 2 g of cesium carbonate were added, after a further 2 h a further 2 ml of ethyl 4-bromobutanoate and 3 g of cesium carbonate were added and after standing at room temperature overnight 9 ml of ethyl 4-bromobutanoate were added again and the mixture was heated to reflux for a further 6 h. After cooling, it was filtered, the residue was washed with acetone and the filtrate was concentrated. The residue was taken up in diethyl ether and the organic phase was washed successively with 3% strength citric acid solution, 3×H20 and saturated NaCl solution. The ether phase was dried over MgSO4, the drying agent was filtered off and the filtrate was concentrated in vacua. The residue was chromatographed on silica gel using CH2Cl2 and CH2Cl2MeOH (99/1). 31.3 g of a pale yellow oil were obtained, which was employed without further purification for the synthesis of (1.2).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])#[N:7].[CH2:26]([O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>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.C(OCC)(=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([C:12]2[C:13]([CH3:14])=[C:8]([C:6]#[N:7])[C:9]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:10]([O:17][CH3:18])[C:11]=2[F:16])[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(F)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 95 °C
Reaction time: 5.5 h
Yield: 73 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (287 mg, 249 μmol) was added to an N,N-dimethylformamide (16.5 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2,2-trifluoroacetamide (I-35) (500 mg, 1.24 mmol), 3-benzyloxyphenylboronic acid (425 mg, 1.87 mmol), potassium phosphate n-hydrate (74-78%, 713 mg, 2.49 mmol), followed by stirring at 95° C. for 5.5 hours. The reaction liquid was cooled, then ethyl acetate (100 ml) was added, followed by washing with saturated brine (50 ml×3), drying over anhydrous magnesium sulfate, concentration under reduced pressure. The residue was purified twice by silica gel column chromatography (n-hexane:ethyl acetate=4:1), (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (415 mg, 73%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[CH2:18](O)[CH3:19]>>[C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:18][CH3:19])=[O:2]
Reactant: CC(C)(CCCCC1CCCC1=O)CC(=O)O
Reactant: CCO
Product: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O

Procedure:
Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure described in Example 3 is productive of the subject compound.
Reaction SMILES: C(O[CH:4]([S:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:5])C.O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1.C1C[O:37][CH2:36][CH2:35]1>>[C:16]1(=[O:17])[N:12]([O:10][C:8](=[O:9])[CH2:7][S:6][CH2:4][CH2:5][O:37][CH2:36][CH3:35])[C:13](=[O:18])[CH2:14][CH2:15]1
Reactant: CCOC(C)SCC(=O)O
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOCCSCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The S-(1-ethoxyethyl)mercaptoacetic acid (5.76 g, 35.1 mmol) is combined with N-hydroxysuccinimide (4.85 g, 42.1 mmol) in 100 mL of anhydrous THF. To this is added a solution of 1,3-dicyclohexylcarbodiimide (8.70 g, 42.1 mmol) in 65 mL of anhydrous THF. The mixture is stirred at room temperature for 2 hours, or until TLC analysis indicates complete formation of the succinimidyl ester. The mixture is then filtered, and the filtrate is concentrated in vacuo to a viscous residue. The residue is dissolved in ethyl acetate, washed with water, brine, and dried (MgSO4). Removal of the solvent leaves the crude succinimidyl ester as an oil, which is further purified by flash chromatography on silica gel, using ethyl acetate:hexanes as the column eluant, to give 5.1 g of S-1-ethoxyethylmercaptoacetic acid succinimidyl ester 8 as a colorless oil.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:4]([I:3])[C:12]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Sodium hydride (60%, 0.138 g, 3.45 mmol) was added to a suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.750 g, 2.87 mmol) in N,N-dimethylformamide (9 mL), and the mixture was stirred at ambient temperature for 1 hour until a homogeneous solution was obtained. Ethyl bromoacetate (0.447 mL, 4.03 mmol) was added, and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 14 hours. The solvent was removed under reduced pressure and the resulting solid was triturated sequentially with water (25 mL) and then ether/petroleum ether (4:1, 50 mL) to yield ethyl 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (0.791 g, 2.28 mmol) as a brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.21 (s, 1H), 5.17 (s, 2H), 4.15 (qt, 2H), 1.20 (t, 3H); RP-HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 6.87 min.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]#[N:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:30][CH2:31]1)[C:21]#[N:22]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Cc1cc(C#N)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 105 °C
Yield: 49.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-methyl-4-(piperazin-1-yl)benzonitrile (92 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water (6 mL) and dried in vacuum to afford (S)-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (90.1 mg, 0.224 mmol, 49.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.01 (m, 3H) 2.12-2.21 (m, 1H) 2.24 (s, 3H) 2.43-2.55 (m, 4H) 2.85-2.97 (m, 4H) 3.35-3.44 (m, 3H) 3.53-3.63 (m, 1H) 3.95-4.03 (m, 1H) 6.98 (d, J=2.02 Hz, 1H) 7.05-7.12 (m, 1H) 7.54-7.60 (m, 2H) 7.62 (d, J=1.77 Hz, 1H) 10.44 (s, 1H). [M+H] calc'd for C23H26N6O, 403. found, 403.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[O:20][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:18][C:17]=1[CH2:27][CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:15][C:16]1[O:20][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:18][C:17]=1[CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(Nc2ccccc2)cc1
Reaction time: 5 h
Yield: 62 %

Procedure:
To a solution of 0.50 g 4-hydrox-phenylaniline, 0.83 g of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethan-1-ol and 1.06 g of triphenylphosphine in 20 ml of THF was added at 0° C. a solution of 0.82 g of diisopropyl azodicarboxylate in 10 ml of THF over 30 min and stirring was continued at 22° C. for 5 h. The mixture was evaporated and the residue purified by chromatography (SiO2, n-hexane/AcOEt 6:1) to give 0.62 g of the title compound as a colorless solid. MS: (M+H)+ 371.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O.[C:29](Cl)(Cl)=[S:30].[OH-].[Na+]>O>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]=[C:29]=[S:30])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N=C=S
Yield: 31.7 %

Procedure:
To a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.100 g, 0.4 mmol) in 1 ml H2O and TFA (0.040 g, 0.4 mmol) was added thiophosgene (0.040 g, 0.4 mmol). After 1 h the mixture was neutralized with 2 M NaOH and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(2-isopropyl-5-isothiocyanato-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.042 g, 36%) as brown foam [MH]+=334.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O=[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35])[CH2:30][CH2:29]1>C(O)C>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:39])[Cl:40])=[O:35])[CH2:30][C:29]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Reactant: BrCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2)CCN(C(=O)OCC(Cl)(Cl)Cl)C1
Yield: 21.5 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (10 g, 63 mmol), 2-phenyl ethyl bromide (11.6 g, 63 mmol), triethyl amine (19.4 g, 189 mmol) and 2,2,2-trichloroethyl 4-oxopiperidine-1-carboxylate (452 mg, 2 mmol) were taken in ethanol (10 ml) at 90° C. for 3 h to obtain 200 mg of 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc2c(-c3cccc(F)c3)c(C(C)N=[N+]=[N-])ccc2s1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2c(-c3cccc(F)c3)c(C(C)N)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(1-azidoethyl)-4-(3-fluorophenyl)-2-methyl-1,3-benzothiazole (0.088 g, 0.28 mmol) in tetrahydrofuran (0.8 mL) and water (0.203 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.338 mL, 0.338 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added EtOAc and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue, showing two peaks with the same desired mass, was used directly in next step (74 mg, 91%). LCMS calculated for C16H16FN2S(M+H)+: m/z=287.1; found: 287.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2].[NH4+:20].[OH-].O.[Cl-].[NH4+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](=[O:15])[NH2:20])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
The 2-(3-nitroanilino)-3-chloroformylpyridine was dissolved in tetrahydrofuran (2000 ml) and 70 ml of 30% solution of NH4OH was added dropwise with stirring to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the mixture to dissolve the solid ammonium chloride that was formed. The tetrahydrofuran was removed, and the resulting aqueous slurry was filtered and washed yielding a yellow solid. The solid was washed with water and air dried yielding 64.8 g (250 mmole, 99% yield) of 2-(3-nitroanilino)-3-carbamoylpyridine (mp 240°-241° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](Cl)=[N:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C.CCOC(C)=O>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:31]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5, 100 mg) in N,N-dimethylacetamide (2 ml) were added methyl-6-chloro-nicotinate (68 mg) and cesium carbonate (256 mg). The mixture was stirred at room temperature for 3 h. Methyl-6-chloro-nicotinate (23 mg) was added and the mixture was stirred overnight and then diluted with EtOAc. Water was added. The mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>2:3) to give the title compound (103 mg) as a colorless solid. MS (m/e)=519.2 [M+H+].