Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Solvent: Cc1ccccc1
Product: Nc1ncc(Br)nc1-c1ccccc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A mixture of 3,5-dibromopyrazin-2-amine (214 mg, 0.83 mmol) and phenyl boronic acid (100 mg, 0.8 mmol) in toluene (8 mL) was degassed and backfilled with nitrogen 3 times. Pd(PPh3)4 (46 mg) was added followed by 2M K3PO4 (0.8 mL) and EtOH (1 mL). The mixture was heated at reflux for 18 h. The solution was cooled to room temperature, partitioned between EtOAc (25 mL) and water (5 mL). The layers were separated and the organic layer dried over Na2SO4, filtered and concentrated to an oil which was purified via silica gel chromatography (15% EtOAc/heptane) to afford the product (187 mg, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:12]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:22](=[O:23])[C:21]3[CH:32]=[CH:33][C:18]([C:17]([F:16])([F:34])[F:35])=[CH:19][CH:20]=3)=[CH:25][CH:26]=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (754 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 15 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (448 mg, yield 47%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13]=1[CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:23]([O:21][CH2:20][CH2:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[C:13]1[CH3:22])(=[O:25])[CH3:24]
Reactant: CC1=C(CCCCOC2CCCCO2)CCCC1CCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCCCC1CCCC(CCCCOC2CCCCO2)=C1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 8.2 g (25.6 mmole) of [R-(R*,S*)]-3-[4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl]-2-methyl-2-cyclohexene-1-propanol in 30 ml of dry pyridine at 0° C. was added slowly 4.8 ml (51.3 mmole) of acetic anhydride followed by a catalytic amount of 4-dimethylaminopyridine. The solution was stirred at 0° C. for 3 hours and then quenched with iced water. The mixture was extracted with 3×150 ml of CH2Cl2. The organic extracts were acidified with 1N H2SO4, washed with sat'd NaHCO3, dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column (5:1, hexane/EtOAc), to give 7.3 g (81%) of [R-(R*,S*)]-3-[4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl]-2-methyl-2-cyclohexene-1-propanol acetate as an oil. [α]D25 =-11.09° (CHCl3 c=1.28). IR (CHCl3): 1730 cm-1. 1H NMR (200 MHz): δ1.25 (m, 1H), 1.60-1.72 (m, 18H), 1.61 (s, 3H), 1.80-2.05 (m, 4H), 2.05 (s, 3H), 3.38 (m, 1H), 3.50 (m, 1H), 3.72 (m, 1H), 3.88 (m, 1H), 4.05 (m, 2H), 4.58 (t, J=2.6 Hz, 1H). Mass Spectrum: M+ (352). Anal. for C21H36O4 : Calc. for C, 71.55; H, 10.29. Found: C, 71.16; H, 10.41.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[C:26]([O:30][C:31](=[O:38])[CH:32]([CH2:36][NH2:37])[CH2:33][CH2:34][CH3:35])([CH3:29])([CH3:28])[CH3:27].C[O-].[Na+]>CO>[C:26]([O:30][C:31](=[O:38])[CH:32]([CH2:36][NH:37][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[CH2:33][CH2:34][CH3:35])([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCCC(CN)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Yield: 21.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (138 mg), 2-aminomethyl-pentanoic acid tert-butyl ester HCl salt (96 mg) and NaOMe in MeOH (0.85 mL, 0.5 M solution) in MeOH (1 mL) was microwaved at 150° C. for 2 h. The mixture was cooled, concentrated with HOAc (0.1 mL), the residue was directly column purified to give the desired product (44 mg). LC MS ESI+: 476 (M+1)+.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]2[C:14]=1[CH:15]1[C:20](=[CH:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33]Br)[CH3:30].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:12][C:13]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]2[C:14]=1[C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=1[CH:21]2[CH2:33][CH:32]([O:35][CH2:36][CH3:37])[O:31][CH2:29][CH3:30]
Reactant: COc1c(C)cc(C)c2c1C=C1CCCCC12
Reactant: CCOC(CBr)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(CC1C2=C(CCCC2)c2c(C)cc(C)c(OC)c21)OCC
Reaction time: 0.67 h

Procedure:
19 Milliliters of a 15% n-butyl lithium n-hexane solution was added dropwise to a tetrahydrofuran solution containing 5.0 g of 5,7-dimethyl-8-methoxy-2,3,4,4a-tetrahydro-1H-fluorene in 50 ml of tetrahydrofuran at -50° C. After stirring at the same temperature for 40 minutes, thereto was added dropwise 6 ml of bromoacetoaldehyde diethyl acetal at the same temperature, followed by stirring at the same temperature for 1.5 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution and this was diluted with diethyl ether, washed with water twice and then with a saturated aqueous sodium chloride solution and then dried with magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:30) to obtain 5.68 g of 5,7-dimethyl-8-methoxy-9-(2,2-diethoxyethyl)-1,2,3,4-tetrahydro-9H-fluorene.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[CH:16]3)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:8]1[C:9]2[C:4](=[C:3]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[CH:16]4)[C:2]([CH3:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(=O)[nH]ccc34)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CNc1ncc2cc(-c3c(C)ccc4c(Cl)nccc34)ccc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
6-Methyl-5-(2-(methylamino)quinazolin-6-yl)isoquinolin-1(2H)-one (13.00 g, 41.1 mmol) was treated with POCl3 (57.5 mL, 616 mmol) and the mixture heated to 100° C. while stirring. After 4 h, the volatiles were removed under vacuum and residual POCl3 was removed by azeotroping with toluene. Crushed ice was added to the residue and the mixture was stirred for 1 h. The resulting free flowing solid was washed with water and and saturated sodium bicarbonate, filtered off and dissolved in a 9:1 mixture of DCM and MeOH. The solution was loaded onto silica gel and purified by column chromatography using a gradient of 2 to 10% MeOH in DCM to give 6-(1-chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (9.34 g, 68%) as a yellow foam. MS (M+H)+ 335.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16](OC)=[O:17].O.[NH2:27][NH2:28]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:27][NH2:28])=[O:17]
Reactant: NN
Reactant: COC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1

Procedure:
A solution of methyl 3-[(2-naphthyl)methoxy]-5-nitrobenzoate (0.97 g, 2.87 mmol) and hydrazine hydrate (0.56 mL, 11.5 mmol) in MeOH (50 mL) was stirred under reflux overnight. Formation of solid hydrazide from a boiling mixture was observed in the morning. Mixture was cooled, solid filtered and air-dried. Greenish-white plates, yield 0.60 g (62%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.15 (br.s, 1H); 8.27 (s, 1H); 8.05-7.91 (m, 6H); 7.63 (d, J=7.5 Hz, 1H); 7.59-7.52 (m, 2H); 5.48 (s, 2H); 4.66 (br.s, 2H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][NH2:58])=[CH:53][CH:52]=1.Cl>C1COCC1>[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][NH:58][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:6]([O:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[N:7][CH:8]=2)=[CH:53][CH:52]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccco2)c1
Reactant: NNc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(NNc1ccc(F)cc1)c1cnc(OC2CCC2)c(-c2ccco2)c1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In a 5 mL round-bottomed flask the above prepared 6-cyclobutoxy-5-furan-2-yl-nicotinic acid (0.050 g, 174 μmol, Eq: 1.00) was combined with THF (2 mL) to give a colorless solution. TBTU (83.6 mg, 260 μmol, Eq: 1.5) and N,N-diisopropylamine (112 mg, 152 μL, 868 μmol, Eq: 5) were added. The reaction mixture was stirred for 10 min at RT before (4-fluorophenyl)-hydrazine hydrochloride (33.9 mg, 208 μmol, Eq: 1.2) was added and the reaction allowed to proceed at RT overnight. The mixture was poured into 15 mL 1 M HCl and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 1 M NaOH, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) to yield 40 mg of the title compound as white solid; MS (EI) 368.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH3:2].[CH3:13][N:14]([CH3:22])[N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[S:21]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:18]2[S:17][C:16](=[S:21])[N:15]([N:14]([CH3:22])[CH3:13])[C:19]2=[O:20])[CH:9]=[CH:10][C:11]=1[OH:12])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CN(C)N1C(=O)CSC1=S
Product: CCOc1cc(C=C2SC(=S)N(N(C)C)C2=O)ccc1O
Yield: 59.3 %

Procedure:
3-Ethoxy-4-hydroxybenzaldehyde (45.7 g), N-dimethylaminorhodanine (53.35 g) and fused sodium acetate (92.4 g) were reacted in the manner described in Example 1 to provide 52.92 g of the subtitled intermediate. m.p. 194°-198° C.
Reaction SMILES: [C:1]1(=[O:14])[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][NH:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:2]1[C:1](=[O:14])[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3]1
Reactant: ClCCCBr
Reactant: O=c1[nH]nc2n1-c1ccccc1OC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(CCCCl)nc2n1-c1ccccc1OC2

Procedure:
A solution of 2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one, from step 3 above (14.0 g., 0.074 mole), in 500 ml. of N,N-dimethylformamide (DMF) under a nitrogen atmosphere was treated with 3.91 g. (0.081 mole) of a 50% mineral oil suspension of sodium hydride and warmed on a steam bath for 0.5 hour. The resulting mixture was cooled in an ice bath, treated dropwise with 8.68 ml. (0.081 mole) of 1-bromo-3-chloropropane, and the resulting mixture was stirred 18 hours at room temperature to insure complete reaction and then concentrated in vacuo. The residue was mixed with cold water, extracted with methylene chloride, washed with dilute sodium chloride brine solution, dried over sodium sulfate and concentrated. The residue was chromatographed on 1000 g. of silica gel using 25% ethyl acetate in Skellysolve®B hexane (25:75, v/v) mixture. The product thus obtained was crystallized from ethyl acetate/Skellysolve®B hexanes, as described above to give in two crops 12.09 g., m.p. 77°-78° C., and 3.05 g., m.p. 76°-78° C., of the above subtitled intermediate product. The analytical sample had a melting point of 77.5°-78.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].C([O-])(=O)C.[K+].C([O-])([O-])=O.[K+].[K+].CCO>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][OH:33])([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2(CO)CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 145 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
A 25 mL round bottom flask charged with a mixture of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (900 mg, 1.316 mmol), potassium acetate (388 mg, 3.95 mmol), K2CO3 (182 mg, 1.316 mmol), EtOH (1 ml, 17.13 mmol), N,N-dimethylacetamide (6 mL) and stirred in a pre-heated oil bath (145° C.) for 3 h. After cooling the reaction was quenched with 1 N HCl (3 mL), diluted with EtOAc (100 mL) and washed with water (3×25 mL). The combined aqueous layers were extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to afford a brown solid which was crystallized from ethanol (˜30 mL) to give the title compound (250 mg, 0.448 mmol, 34.1% yield) as white crystals. 1H NMR (500 MHz, CDCl3) δ: 9.59 (1H, t, J=5.95 Hz), 7.24 (1H, d, J=7.63 Hz), 7.16-7.22 (1H, m), 6.94 (1H, t, J=9.00 Hz), 4.76 (1H, d, J=15.26 Hz), 4.58-4.65 (1H, m), 4.42-4.49 (1H, m), 3.48-3.57 (3H, m), 3.37-3.47 (1H, m), 3.05 (3H, s), 3.04 (3H, s), 3.01 (3H, s), 2.26 (3H, d, J=1.53 Hz), 2.08-2.16 (3H, m), 1.77-1.85 (1H, m), 1.67-1.74 (2H, m), 1.41-1.51 (1H, m). LCMS (M+H)=530.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:37][CH2:36][CH2:35][CH2:34][N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(NCCCN3CCN(C)CC3)nc21
Yield: 57 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1142 g (0.726 mmol) of 3-(4-methyl-piperazin-1-yl)-propylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.0712 g (57%) of the title compound: HPLC=96% pure.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([O:29][CH3:30])[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.C(OCC)(=O)C>[N+:26]([C:25]1[C:20]([NH:1][CH:2]([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])=[N:21][C:22]([O:29][CH3:30])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: NC(C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(NC(C(=O)O)C(c2ccccc2)c2ccccc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 20.1 %

Procedure:
2.50 g (10.4 mmol) of 2-amino-3,3-diphenylpropionic acid, 0.84 g (4.3 mmol) of 2-chloro-3-nitro-6-methoxypyridine and 0.55 g (5.2 mmol) of sodium carbonate were introduced into 18 ml of DMF and 18 ml of water, and the mixture was stirred at 80° C. for 5 hours. Ethyl acetate and water were then added, and the phases were separated. The aqueous phase was acidified with 6 normal hydrochloric acid and extracted three times with ethyl acetate. After drying with MgSO4 and concentration under reduced pressure, the crude product was recrystallized from isopropanol. 0.34 g (20.1%) of a yellow powder of melting point 172-180° C. was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]([CH2:24][CH3:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:10]=[CH:11][N:12]=[C:13]([N:15]([CH2:24][CH3:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH:14]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CCN(c1cc(Cl)ncn1)c1cccc(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC)c2cccc(F)c2F)ncn1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.06 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.5 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(N-ethyl-N-(2,3-difluorophenyl)amino)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 6-(2-butynyloxy)-4-(N-ethyl-N-(2,3-difluorophenyl)amino)pyrimidine (the present compound (164)).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH:20]=[CH:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH:2]([OH:4])[CH2:3][N:15]1[CH2:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:19][CH2:20]1)[CH:6]=[CH:7]2
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Reactant: Fc1ccc2c(ccn2CC2CO2)c1
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)Cn1ccc2cc(F)ccc21
Yield: 77.9 %

Procedure:
A methanolic solution of 1-N-glycidyl-5-fluoroindole (0.52 g, 3.0 mmole) from example 1 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a light yellow colored solid (0.91 g, 78% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required salt as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][CH2:13][CH:14]([F:16])[F:15])=[C:7]([C:17]#[C:18][Si](C)(C)C)[N:6]=1)=[O:4]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[CH2:17][CH2:18][N:12]([CH2:13][CH:14]([F:16])[F:15])[C:8]2=[N:9][C:10]=1[NH2:11])=[O:4]
Reactant: COC(=O)c1nc(C#C[Si](C)(C)C)c(NCC(F)F)nc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(nc1N)N(CC(F)F)CC2
Temperature: 120 °C

Procedure:
To a solution of 3-amino-5-(2,2-difluoro-ethylamino)-6-trimethylsilanylethynyl-pyrazine-2-carboxylic acid methyl ester (624 mg, 1.9 mmol) in DMF (19 ml) was added Copper(I) iodide (181 mg, 0.95 mmol) and the mixture was heated to 120° C. for 2 h. The reaction mixture was filtered through Hyflo, the residue washed with toluene. The combined organic phases were extracted with water, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 40:60) to provide the title compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:30])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCC[C@@H]3O)c12
Reactant: N
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCC[C@@H]3O)c12

Procedure:
Prepared analogously to example 1.4 from 0.083 g racemic 4-[4-Fluoro-2-((cis)-2-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][S:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:32][CH:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(S(C)(=O)=O)cc2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 83.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (813 mg, 3.0 mmol) and 4-(methylsulfonyl)benzohydrazide (648 mg, 3.0 mmol) were coupled in a procedure analogous to that described for the preparation of intermediate 3b. The crude product was recrystalized from hot chloroform (100 mL to yield product as a white solid (1.16 g, 82%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.83 (br s, 2H), 8.14 (AA′XX′, J=8.5 Hz, 2H), 8.06 (AA′XX′, J=8.5 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 4.40 (m, 1H), 4.14 (dd, J=3.4, 6.9 Hz, 1H), 3.19 (s, 3H), 2.90 (br s, 1H), 2.36 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).