Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]([NH2:30])[CH3:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:28]([CH3:29])[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC(C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC(C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methoxypropan-2-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6.82 Hz, 3 H) 2.44 (s, 3 H) 3.29 (s, 3 H) 3.30-3.33 (m, 1 H) 3.44 (dd, J=9.47, 6.44 Hz, 1 H) 4.15-4.32 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.19 (br. s., 1 H) 8.43 (d, J=6.82 Hz, 1 H) 8.50 (d, J=7.83 Hz, 2 H) 8.87-8.96 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 392.2
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:2].C1(C)C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH:27]=[N:26][CH:25]=2)=[N:9][CH:10]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)nc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(-c2cnco2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
In methanol (5 mL) was dissolved 5-(diethoxymethyl)picolinaldehyde (148 mg, 0.707 mmol) obtained in Step 1. To the solution were added toluene-4-sulfonylmethylisocyanide (345 mg, 1.77 mmol) and potassium carbonate (244 mg, 1.77 mmol) and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 5-(5-(diethoxymethyl)pyridin-2-yl)oxazole (161 mg, 92% yield).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCCl.CN(C1C=CN=CC=1)C>[F:36][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:43](=[O:45])[CH3:44])=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(NCc3ccccc3)nc2)cc1OC(F)F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1ccccc1)c1ccc(C(Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cn1
Reaction time: 24 h
Yield: 26.9 %

Procedure:
To a solution of 4-(2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(benzylamino)3-pyridyl]ethyl)pyridine from Example 1 (100 mg, 0.2 mmol) in 3 mL of 1,2-dichloroethane, was added 0.077 mL (0.96 mmol) of pyridine followed by 0.012 mg (0.1 mmol) of DMAP and 0.056 mL (0.6 mmol) of acetic anhydride. The solution was stirred 24 h at reflux, quenched with water and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Gradient 100% ethyl acetate to 10% EtOH/ethyl acetate) to afford 29 mg (27%) of the acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1Cl
Product: O=C(Cl)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 3-chloroisonicotinic acid (413 mg, 2.62 mmol) was added thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was stirred at room temperature for about 20 hours. The solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 hour to give 3-chloro-isonicotinoyl chloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-phenylalanine methyl ester hydrochloride (4.31 g), p-anisaldehyde (2.45 ml), anhydrous magnesium sulfate (5.19 g) and triethylamine (2.9 ml) were added to methylene chloride (200 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, ethyl acetate (150 ml) was added to the residue. The solid was separated again by filtration, and the solvent was distilled off under reduced pressure to quantitatively obtain desired N-(p-methoxyphenylmethylene)-L-phenylalanine methyl ester (5.94 g).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:36]2[CH:35]=[CH:34][C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CNC(=O)Cc1cccc(Br)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: Cc1ccccc1
Product: CNC(=O)Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 2-(3-bromophenyl)-N-methyl-acetamide (0.244 g, Example 24a)), 2M aqueous sodium carbonate (0.265 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction was heated at 110° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) was added and the solution stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure the residue was neutralised using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil which was converted to the oxalic acid salt by treatment with a saturated ethereal solution of oxalic acid to give the title compound as a gum (0.123 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7]Cl)[CH:6]=1.[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24])[CH:6]=1
Reactant: FC(F)(F)C(F)(F)c1nn(CCl)cc1Br
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)c(C(F)(F)C(F)(F)F)n1
Yield: 74.6 %

Procedure:
6.84 g of 4-bromo-1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole and 3.54 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 60 ml of N,N-dimethylformamide. 6.08 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 7.15 g of [(4-bromo-3-(pentafluoroethyl)-1H-pyrazole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (37), hereinafter) shown by below formula.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][OH:14].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:9]([C:2]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:14][CH2:13][CH2:12][O:1]1)[CH2:10][CH3:11]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CCCC1(CC(=O)OCC)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A mixture of ethyl 3-oxohexanoate (5 g, 31.6 mmol), ethylene glycol (3.92 g, 63.2 mmol) and triethyl orthoformate (4.68 g, 31.6 mmol), and p-toluenesulfonic acid monohydrate (544 mg, 2.86 mmol) was stirred at room temperature for 29 hours and 10 minutes. To the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (6.2 g, 97%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(F)c2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2cccc(F)c2)n1
Yield: 116.8 %

Procedure:
Operations are carried out as for Example 7, starting from 1.32 g of 1-(3-fluoro phenyl) isoquinoline 3-carboxylic acid, 0.57 g of triethylamine, 0.62 g of ethyl chloroformate, and 0.47 g of diethylamine in 50 ml of chloroform. 1.86 g of N,N-diethyl 1-(3-fluoro phenyl) isoquinoline 3-carboxamide, melting at 92° C., are obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](I)[CH:18]=1.[CH3:20][S-:21].[Na+]>C1(C)C=CC=CC=1.[Cu](Br)Br>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([S:21][CH3:20])[CH:18]=1
Reactant: C[S-]
Reactant: Brc1cncc(I)c1
Agent: Br[Cu]Br
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CSc1cncc(Br)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 mL, 5.28 mmol) to a solution of 3-bromo-5-iodopyridine (500 mg, 1.76 mmol), (prepared as described in PREPARATION 21), sodium methanethiolate (370 mg, 5.28 mmol) and copper bromide (50.2 mg, 0.35 mmol) in toluene (3 mL). Stir in a sealed flask at 90° C. overnight and then partition between water and ethyl acetate. Separate the organic layer and wash with an aqueous saturated solution of sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with hexane:ethyl acetate, to give the title compound (250 mg, 70%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:27])([CH3:26])[C:19](=O)[CH2:20][C:21](OC)=[O:22])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)([CH3:27])[CH3:26])=[CH:16][CH:17]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)C(C)(C)c1ccc(Cl)cc1
Product: CC(C)(c1ccc(Cl)cc1)c1cc(O)n(-c2cc(C#N)ccn2)n1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(4-chlorophenyl)-4-methyl-3-oxopentanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [O:1]=[C:2]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14](C(OC(C)(C)C)=O)[CH:15]=[C:16]([C:17]([O:19]C)=[O:18])[C:9]=12)[CH2:4][CH3:5].CO.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:9]=12)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Temperature: 53 °C
Reaction time: 16 h
Yield: 9.2 %

Procedure:
To a 20 mL round bottom flask with a stirrer was added (S)-1-tert-butyl 3-methyl 4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (88 mg, 0.198 mmol), MeOH (1 mL) and THF (1 mL). Aqueous NaOH (12N, 1 mL) was added and the reaction mixture was stirred at 53° C. for 16 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 1-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (6 mg, 9.17%). [M+H] calc'd for C17H22N4O3, 331; found, 331.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:29][C:11]3[N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH2:17][CH2:18][CH2:19]OC4CCCCO4)[C:15](=[O:16])[C:10]=3[C:9]=2[CH:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl.O>[F:49][C:48]([F:51])([F:50])[C:46]([O:52][CH2:19][CH2:18][CH2:17][N:14]1[C:15](=[O:16])[C:10]2[C:9]([CH2:30][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[S:29][C:11]=2[N:12]([CH3:28])[C:13]1=[O:27])=[O:47]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 6-(3-chlorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetra hydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 4, Step 2, 50 mg, 0.078 mmol) in TFA (1 mL) was added triethylsilane (0.5 mL). The reaction was stirred at RT for 2 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 80.5% yield) as an oil. LCMS: MH+ 571 and TR=2.327 min. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.C[C:30]1[C:35]([F:36])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][C:31]=1[SH:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:39][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[C:35]([F:36])[CH:30]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S)c(C)c1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1F
Temperature: 70 °C

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (220 mg, 0.45 mmol) and methyl 3-fluoro-4-methoxybenzenethiol (107 mg, 0.68 mmol) were dissolved in 10 mL dimethylformamide in a microwave vessel. Potassium carbonate (94 mg, 0.68 mmol) and copper(I) iodide (129 mg, 0.68 mmol) were added and the mixture was heated overnight at 70° C. The reaction mixture was cooled at room temperature and diluted with ethyl acetate. The organic phase was washed with 2N HCl, 4% sodium bicarbonate solution, water and brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue (0.26 g, 87%) was used in the next synthetic step without further purification. Purity 78%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[Cl:7].[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:29]3[CH:28]=[N:27][CH:26]=[N:25][C:24]=3[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])[C:6]=1[Cl:7]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cn1cnc(Cl)c1Cl
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: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cn3cnc(Cl)c3Cl)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
(4,5-Dichloro-imidazol-1-yl)-acetic acid (25.2 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.4 mg, 0.130 mmol) and DIPEA (51.7 uL, 0.300 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 46% yield, 21.2 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Yield: 98.1 %

Procedure:
2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(C(C)C)CC)(C)C.[CH3:43][CH:44]([CH3:49])[CH2:45][C:46](Cl)=[O:47]>ClCCl>[CH3:43][CH:44]([CH3:49])[CH2:45][C:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)=[O:47]
Reactant: Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(=O)Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.25 h

Procedure:
2-(2-Aminophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 626, 30 mg, 0.069 mmol) and diisopropylethylamine (30 μL, 0.17 mmol, 2.5 equiv) were combined in dichloromethane (1 mL) and treated with 3-methylbutanoyl chloride (9.2 mg, 0.076 mmol, 1.1 equiv). After 15 minutes at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound; 1H-NMR (400 MHz, d6-DMSO) δ 9.72 (1H, br s), 9.33 (1H, s), 8.47 (1H, d, J=2.3 Hz), 8.28 (1H, d, J=7.7 Hz), 7.93 (1H, d, 8.0 Hz), 7.84 (1H, d, J=8.9 Hz), 7.83 (2H, d, J=8.5 Hz), 7.72 (1H, br s), 7.69-7.64 (2H, m), 7.59 (1H, t, J=7.3 Hz), 7.47 (2H, d, J=8.4 Hz), 7.37 (1H, t, J=7.5 Hz), 7.27 (1H, t, J=7.5 Hz), 6.53 (1H, m), 5.83 (2H, s), 2.15 (2H, d, J=7.3 Hz), 2.09-1.94 (1H, m), 0.86 (6H, d, J=6.6 Hz) ppm; high resolution mass spectrometry (ES+) m/z 517.2391 [(M+H)+; calculated for C31H29N6O2: 517.2347].
Reaction SMILES: [CH2:1]=[O:2].[OH-:3].[Na+].[P:5]([OH:9])([OH:8])([OH:7])=[O:6].[NH2:10][C:11]([NH2:13])=[NH:12]>CO>[C:1](=[O:6])([OH:3])[OH:2].[NH2:12][C:11]([NH2:13])=[NH:10].[P:5](=[O:6])([OH:9])([OH:8])[OH:7]
Reactant: [OH-]
Reactant: C=O
Agent: N=C(N)N
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(O)O

Procedure:
189 grams of paraformaldehyde (6 moles) were dissolved in the heat in 298 grams of methanol with 1 gram of sodium hydroxide. Then there were added 2 moles of a hot, concentrated guanidine dihydrogen phosphate solution, which was previously produced from 180 grams of guanidine carbonate (1 mole) and 231 grams of 85% phosphoric acid (2 moles). After about one hour of boiling at reflux there was formed a clear solution to which there were added a further 2 moles of the previously described concentrated guanidine dihydrogen phosphate solution as well as 137 grams of methanol. The mixture was boiled at reflux for a further three hours, cooled and drawn off. It contained 60% solids, 31.5% methanol and 8.5% water.