Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:14]1[C:15]2[CH:22]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:20][C:16]=2[N:17]=[CH:18][N:19]=1>C1COCC1>[CH3:3][N:4]([CH3:12])[CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:14]2[C:15]3[CH:22]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Reactant: CN(C)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(Oc2ncnc3sc(CCNC(=O)OC(C)(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
Sodium hydride (80 mg, 2.00 mmol, 4.83 equiv, 60% dispersion in mineral oil) was treated with trans-4-(dimethylamino)cyclohexan-1-ol (80 mg, 0.56 mmol, 1.35 equiv) in 10 mL of distilled THF for 30 min at 0° C. under nitrogen. Then a solution of tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (130 mg, 0.41 mmol, 1.00 equiv) in 3 mL of THF was added and stirred at room temperature for 12 hours. After cooling to 0° C., the reaction was quenched with water and extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (4:1) to give 140 mg (80%) of tert-butyl N-[2-(4-[[4-(dimethylamino)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate as a white solid. MS (ES): m/z 421 (M+H)+.
Reaction SMILES: C(O)(=O)C[CH2:3][C:4]([CH3:6])=O.[CH3:9][CH:10]([CH3:17])[N:11]=[C:12]=NC(C)C.[CH2:18](Cl)Cl>>[CH3:18][CH2:12][N:11]([CH:4]([CH3:3])[CH3:6])[CH:10]([CH3:17])[CH3:9]
Reactant: CC(=O)CCC(=O)O
Reactant: ClCCl
Reactant: CC(C)N=C=NC(C)C
Product: CCN(C(C)C)C(C)C

Procedure:
addition of activated levulinic acid (activated as the symmetric anhydride with 0.5 equivalents of DIC in DCM for 5-10 min)
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[F:19][C:20]1[C:25]([CH:26]=[O:27])=[C:24]([F:28])[CH:23]=[CH:22][C:21]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]>CO>[F:19][C:20]1[C:25]([CH:26]([OH:27])[C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=3)[NH:14][CH:15]=2)=[C:24]([F:28])[CH:23]=[CH:22][C:21]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]
Reactant: c1ccc(Nc2cnc3[nH]ccc3c2)cc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Nc4ccccc4)cc23)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To phenyl-(-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine (70, 17.0 mg, 0.09 mmol) in methanol (5.0 mL) were added potassium hydroxide (92.0 mg, 1.6 mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (73, 19.0 mg, 0.072 mmol, prepared as described in Example 7) under an atmosphere of nitrogen. The reaction was stirred for 12 hours at room temperature. The reaction was concentrated and purified by silica gel column chromatography eluting with 1% methanol in dichloromethane to give the compound (71, 17 mg, 50%). MS (ESI) [M+H+]+=473.5.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[C:27](Cl)(=[O:29])[CH3:28].CCN(CC)CC>C(Cl)Cl>[C:27]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a mixture of 1-(4-amino-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (140 mg, 1.0 eq) in DCM (8 mL) was added acetyl chloride (1.5 eq) and Et3N (2.0 eq), the mixture was stirred at room temperature overnight. At the end of reaction, the mixture was concentrated and water was added then extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, filtrated and evaporated until the aim product precipitated, filtrated and washed with some DCM to afford 1-(4-acetamido-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (90 mg, 59%). MS (ESI) 389.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.56 (s, 1H), 8.77 (d, J=3.9 Hz, 2H), 8.51 (d, J=4.2 Hz, 1H), 8.27 (d, J=3.9 Hz, 2H), 7.72 (m, 2H), 7.23 (t, J=4.5 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.55 (t, J=4.2 Hz, 1H), 6.57 (t, J=4.2 Hz, 1H), 3.05-3.15 (m, 1H), 2.90-3.05 (m, 1H), 2.60-2.75 (m, 1H), 2.05-2.15 (m, 1H), 2.11 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][C:7]=1[CH3:26])([OH:5])[CH3:4].C1C(=O)N([Cl:34])C(=O)C1>CN(C)C=O.CO>[Cl:34][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[C:7]([CH3:26])[CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-methylbenzamide (40 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.57 mL) to give a light yellow solution. NCS (14 mg, 0.10 mmol) was then added at room temperature. The mixture was heated mixture at 60° C.; after 3 hr, another 15 mg of NCS was added, and the reaction completed after 1 hr. The mixture was diluted with MeOH (1 ml) and then purified by preparatory HPLC (basic mode, 20-70% ACN in water). Product-containing fractions were combined, concentrated and freeze-dried to obtain the title compound as a tan colored solid (10 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.20 Hz, 3 H) 1.48 (s, 3 H) 2.58 (s, 3 H) 3.58-3.64 (m, 2 H) 4.19 (q, J=7.24 Hz, 2 H) 4.77 (br. s., 1 H) 4.92 (br. s., 1 H) 7.55 (d, J=8.34 Hz, 1 H) 7.68 (s, 1 H) 7.76-7.88 (m, 2 H) 8.36 (d, J=0.76 Hz, 1 H) 8.59 (d, J=1.01 Hz, 1 H) 10.58 (s, 1 H); ESI-MS: m/z 388 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7](CC#N)[CH:8]=1.[OH-:15].[Na+].[CH2:17]([OH:19])[CH3:18]>O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7]([CH2:18][C:17]([OH:15])=[O:19])[CH:8]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCc1cc(C(F)(F)F)ccc1I
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C

Procedure:
A solution of 5-trifluoromethyl-2-iodophenylacetonitrile (30 g, 96 mmol) in ethanol (100 mL) is stirred at room temperature. Sodium hydroxide (7.7 g, 192 mmol) dissolved in water (60 mL) is added. The mixture is heated to reflux temperature for 12 hours and then cooled to room temperature. Most of the ethanol is removed using a rotary evaporator and the residual aqueous solution adjusted to pH 4 with 3 N HCl. The solid which forms is isolated by filtration and washed with water (250 mL) and then hexanes (500 mL). Air drying gives 5-trifluoromethyl-2-iodophenylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>C1COCC1.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:27][CH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH3:20])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN1CCC[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCCC1COC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 3-nitrobenzoylchloride (2.5 g; 13.5 mmol) in THF (25 ml) was added triethylamine (1.87 ml; 13.5 mmol), a catalytic amount of 4-(N,N-dimethylamino)pyridine and (S)-(−)-1-methyl-2-pyrrolidinemethanol (1.61 ml; 13.5 mmol). The mixture was heated to reflux for 1.5 hours and left with stirring at ambient temperature overnight. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and diluted hydrochloric acid (4 M). The aqueous phase was rendered alkaline by addition of aqueous sodium hydroxide (4 M) and extracted with dichloromethane. The organic extract was dried over sodium sulphate and evaporated to leave 6r (2.8 g; 78%).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[Cl:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:31])[NH:25]2>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:25]2[C:26]3[C:22](=[C:21]([Cl:20])[C:29]([F:30])=[CH:28][CH:27]=3)[CH2:23][CH:24]2[CH3:31])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: CC1Cc2c(ccc(F)c2Cl)N1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2Cl)N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 91 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 55 mg of 4-chloro-5-fluoro-2-methyl-2,3-dihydro-1H-indole. After purification, 44 mg of 2-[2-(4-chloro-5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:34][CH3:35])[C:26]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]=O>CS(C)=O.COC(C)(C)C.[Cl-].[Na+].O>[CH3:35][O:34][C:25]1[CH:24]=[C:21](/[CH:22]=[C:14](/[C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH3:3])[CH:6]=3)[NH:10][CH:9]=2)\[C:15]#[N:16])[CH:20]=[C:19]([O:18][CH3:17])[C:26]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCOc1c(OC)cc(C=O)cc1OC
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: COCCOCOc1c(OC)cc(/C=C(\C#N)c2c[nH]c3ccc(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a suspension of NaH (60 mg, 80%, 2.5 mmol, 1.7 eq.) in DMSO (5 mL) was added, under an argon atmosphere, a solution of (5-methoxy-1H-indol-3-yl)-acetonitrile (331 mg, 1.8 mmol, 1.2 eq.) and 3,5-dimethoxy-4-(2-methoxy-ethoxymethoxy)-benzaldehyde (400 mg, 1.5 mmol, 1.0 eq.) in a mixture of DMSO (7 mL) and tert-butyl methyl ether (7 mL). The reaction apparatus was protected from light and the mixture was stirred at ambient temperature for 3 hours, and then treated with brine (10 mL). The mixture was extracted with ethyl acetate (3×30 mL), and the organic layer was washed with water and saturated aqueous ammonium chloride solution, and then dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: heptane/AcOEt, 70:30 to 50:50) to afford (Z)-3-[3,5-dimethoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile as a yellow oil (100 mg) used in the next synthetic step without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].[CH3:29][I:30]>CC(C)=O>[I-:30].[CH3:29][N+:23]1([CH2:22][CH:21]([N:10]2[C:9]3[CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CI
Reactant: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: CC(C)=O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)C[N+]1(C)CCCC1)c1ccccc1S2
Product: [I-]
Reaction time: 0.5 h

Procedure:
A solution of N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (1.1 g), and methyl iodide (0.75 cc) in acetone (40 cc) is stirred for 2 days at a temperature in the region of 20° C. The pale yellow solution thereby obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the light cream-colored meringue-like residue is suspended with stirring for 30 minutes in diethyl ether (50 cc), drained, washed with diethyl ether (3×10 cc) and dried at 40° C. under reduced pressure (5 mm Hg; 0.7 kPa). 1-Methyl-1-[2-(2-propylcarbamoyl-10-phenothiazinyl)propyl]pyrrolidinium iodide, L series (1.2 g), is thereby obtained in the form of a light beige solid, m.p. 155°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1.C(N(CC)CC)C>>[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[C:6](=[O:8])[C:5]5[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=5)=[CH:29][CH:30]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cn1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that commercially available 6-methylnicotinic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.54 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 1.2 equivalents of triethylamine were added as the final reagent to the reaction mixture. The product was purified by chromatography using silica gel eluted with 95:5 chloroform/methanol followed by crystallization from acetonitrile. MS, m/z(M+)=553.2365.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:5])=[O:4].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH3:15])=[O:4]
Reactant: CCCCCC(N)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: CCCCCC(N)C(=O)OC
Product: Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 2.18 g of 2-aminoheptanoic acid in 50 ml of methanol was dropwise added 2.19 g of thionyl chloride (manufactured by WAKO PURE CHEMICAL INDUSTRIES LTD.), and the mixture was stirred overnight at 60° C. Methanol and thionyl chloride were removed by evaporation and the residue was washed with 20 ml of ether to obtain 2.84 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]([C:49]([O:51]C)=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1.Cl.Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@@H:42]([C:49]([OH:51])=[O:50])[CH2:43][C:44]3[N:48]=[CH:47][NH:46][CH:45]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: COC(=O)[C@H](N)Cc1c[nH]cn1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@H](Cc3c[nH]cn3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-D-His-OMe.2HCl (48 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ13.88-14.43 (m, 1 H), 8.96 (d, 2 H), 8.20 (d, 1 H), 7.38 (s, 1 H), 7.26 (m, 5 H), 7.20 (m, 1 H), 7.13 (d, 4 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.43-4.70 (m, 1 H), 4.04 (d, 4 H), 3.14 (m, 1 H), 2.98 (m, 1 H), 2.92 (s, 3 H), 2.39 (s, 3 H), 2.36 (m, 2 H), 2.09 (m, 2 H), 1.71 (m, 2 H); MS (APCI+) m/z 696 (M+H)+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a 25 mL round bottom flask under a nitrogen atmosphere were added 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (195 mg, 0.65 mmol), 4-(trifluoromethyl)-benzylamine (112 mg, 0.65 mmol), acetonitrile (1 mL) and DIPEA (0.34 mL, 1.96 mmol). The mixture was heated to 80° C. for 24 h at which point the reaction was cooled to RT and concentrated to dryness. The resulting residue was washed with water (2×20 mL) and then dissolved in EtOAc, dried over Na2SO4, filtered and then concentrated. The material was used without further purification. MS (ESI): mass calcd. for C24H18F3N3O3, 453.13; m/z found, 454.1[M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:22][OH:23])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1.Cl[C:25]1[CH:26]=[C:27]2[N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=1)[CH2:22][O:23][C:25]1[CH:26]=[C:27]2[NH:34][CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1
Reactant: OCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E65 using NaH (11.04 mg, 0.276 mmol), (3-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)-phenyl)methanol (56.0 mg, 0.184 mmol) and tertbutyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (50 mg, 0.18 mmol).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17]([CH:20]([CH3:22])[CH3:21])([CH3:19])[OH:18])([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:18][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([OH:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)([CH3:19])[CH:20]([CH3:22])[CH3:21])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)C(C)(O)C12CC3CC(CC(O)(C3)C1)C2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(C(C)C)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A total of 10 mmole of acrylyl chloride was added dropwise to a mixture of 10 mmole of 3-hydroxy-α-isopropyl-α-methyl-1-adamantanemethanol thus obtained, 10 mmole of triethylamine and 40 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. After adding water, the reaction mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 67%.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[C:16]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])#[N:17]>>[C:16]([CH2:18][CH2:19][CH2:20][C:21]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3][CH:2]1[CH3:1])=[O:22])#[N:17]
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Reactant: N#CCCCC(=O)O
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)CCCC#N
Yield: 85 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 4-cyanobutyric acid as described for example 37 step 3 (900 mg, yield 85%) and it was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 8.41-8.40 (dd, J=2.3 Hz, 0.5 Hz, 1H), 7.67-7.63 (dd, J=9.0 Hz, 2.2 Hz, 1H), 6.61-6.58 (d, J=9.0 Hz, 1H), 4.46-4.19 (m, 4H), 3.54-3.36 (m, 2H), 3.16-3.11 (m, 2H), 2.59-2.51 (m, 3H), 2.06-2.01 (m, 2H), 1.26 (m, 3H). MS (ESI) m/z: Calculated for C16H19N6O: 297.16. found: 298.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([N:8]2[CH2:24][CH2:23][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[N:19][CH:20]=[N:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)=[CH:7][C:6]=1[N:8]1[CH2:24][CH2:23][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3cncnc3)ncc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3cncnc3)ncc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-pyrimidin-5-yl-amine (50.0 mg, 0.15 mmol), 3-Trifluoromethylbenzoic acid (28.5 mg, 0.15 mmol), and DIPEA (78 μl, 0.45 mmol) in DMF was added HATU (59 mg, 0.15 mmol), and the reaction mixture was stirred for 3 hour at room temperature. The reaction mixture is diluted with ethyl acetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 49.75 mg (65.6%) of N-{4-Methyl-3-[2-(pyrimidin-5-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl benzamide [17] as a pale yellow solid.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Br:5][C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](N)[CH:17]=2)[N:9]2[C:14]=1[CH:13]=[N:12][NH:11][C:10]2=[O:15].C=O.[C:25](O)(=O)C>C(#N)C>[Br:5][C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:2]([CH3:1])[CH3:25])[CH:17]=2)[N:9]2[C:14]=1[CH:13]=[N:12][NH:11][C:10]2=[O:15]
Reactant: Nc1cccc(-c2nc(Br)c3cn[nH]c(=O)n23)c1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1cccc(-c2nc(Br)c3cn[nH]c(=O)n23)c1
Reaction time: 0.25 h

Procedure:
Sodium cyanoborohydride (1.2 gm., 0.019 mole) is added to a stirred solution of 8-bromo-6-(m-aminophenyl)imidazo-[1,5-d]-as-triazine-4(3H)-one, aqueous formaldehyde (5 ml., 37%) in acetonitrile (110 ml.). The reaction mixture is stirred for 15 minutes then acetic acid is added to adjust the pH of the reaction mixture to 7. The reaction mixture is stirred for 45 minutes while the pH of the mixture is maintained at 7 with acetic acid being added as needed. The solvent is then evaporated in vacuo, the residual oil is added to 2 N potassium hydroxide (150 ml.), and crystallizes. The product is washed with water, and recrystallized from acetone-water, m.p. 206° C.(d).