Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([OH:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[Cu](C#N)C#N.[Cl-].[Na+].CN(C)[CH:41]=[O:42]>>[CH:41]([O:14][CH:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH2:10][N:11]([C:15]2[N:20]=[CH:19][N:18]([CH2:21][C:22]3[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[C:17](=[O:31])[N:16]=2)[CH2:12]1)=[O:42]
Reactant: CN(C)C=O
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(C(F)(F)F)s1
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Na+]
Product: O=COC1CN(c2ncn(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CC=C1c1ccc(F)cc1
Yield: 2 %

Procedure:
To a crude product synthesized using 4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (50.0 mg, 0.111 mmol) synthesized in Synthesis Example 190 in a similar manner to Reference Synthesis Example 68, N,N-dimethylformamide (1.0 mL) and copper cyanide (49.3 mg, 0.550 mmol) were added and the resultant mixture was stirred at 100° C. for 1 day. After the completion of the reaction, to the reaction solution, saturated sodium chloride aqueous solution was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1) to obtain the title compound (0.8 mg, yield: 2%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=1.P(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:36][C:37]1[N:42]=[CH:41][C:40]([N:43]([CH:44]([CH3:46])[CH3:45])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:39][CH:38]=1
Reactant: CC(C)Nc1ccc(Cl)nc1
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: ClP(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a solution of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (30 mg, 0.06 mmol) and (6-chloro-pyridin-3-yl)-isopropyl-amine (Preparation 2(A)) (10.1 mg, 0.06 mmol) in benzene (2 mL) was added PCl3 (2.0 M in CH2Cl2, 0.1 mL, 0.198 mmol) and the reaction was heated at reflux for 24 hours. The reaction was cooled to room temperature and was diluted with CH2CO2. The organic solution was washed consecutively with aqueous NaHCO3 (1×), water (1×), 1N HCl (1×), and water (1×). The organic solution was dried (MgSO4) and the volatiles were concentrated in vacuo. The residue was purified by medium pressure chromatography eluting with 10% EtOH in CH2Cl2 to yield 5 mg of N-(6-chloro-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.26 (s, 1H), 8.17 (s, 1H), 7.76-7.29 (m, 11H), 7.06 (m, 3H), 6.83 (d, 1H), 5.04-4.87 (m, 1H), 4.45-4.15 (m, 1H), 3.94-3.82 (m, 3H), 3.72 (m, 1H), 0.06 (s, 6H); MS 616.6 (M+1), 614.5 (M−1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.N1C=CC=CC=1.[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH2:32][CH:31]1[C:40](Cl)=[O:41]>ClCCl>[CH3:17][N:12]1[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:40]([CH:31]3[O:30][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH2:32]3)=[O:41])[S:3][CH:4]=2)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14](=[O:16])[O:13]1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: O=C(Cl)C1COc2ccccc2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(NC(=O)C2COc3ccccc3O2)n1)c1ccccc1
Reaction time: 8 h
Yield: 106.4 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (120 mg, 0.362 mmol, 1 eq.) and pyridine (0.044 ml, 0.543 mmol, 1.5 eq) in dry dichloromethane (2.0 ml) at room temperature was added 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride (108 mg, 0.543 mmol, 1.5 eq) and stirring was allowed overnight. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in EtOAc and 0.5 ml of 1N NaOH was added. The solution was filtered through a chemelut pad and washed with EtOAc. After concentration, the residue was purified by chromatography on silica gel to give N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide (190 mg, 99% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I>O1CCCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([I:18])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nccc2ccc(I)cc12
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Into a 50 mL round-bottom flask, was placed 7-bromo-1-chloroisoquinoline (as prepared in the previous step, 520 mg, 2.15 mmol, 1.00 equiv) and tetrahydrofuran (10 mL). This was followed by the addition of n-BuLi (0.85 mL, 1.25 equiv) dropwise with stirring at −78° C. in 2 min. The resulting solution was allowed to react, with stirring, for an additional 40 min at −80° C. To this was added a solution of I2 (541 mg, 2.14 mmol, 1.25 equiv) in tetrahydrofuran (3 mL) dropwise with stirring at −78° C. in 1 min. The reaction mixture was allowed to react, with stirring, overnight at 25° C. The reaction was then quenched by the addition of 1 mL of water.
Reaction SMILES: C(O)(=O)C.[C:5]([OH:16])(=[O:15])[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[OH:12][C:11]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:5]([OH:16])=[O:15])=[CH:14][C:13]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reaction time: 4 h

Procedure:
A reactor was charged with 525 kg of glacial acetic acid and 50 kg vanillic acid. The mixture was heated with warm water gradually to 50° C. in around 75 minutes. Temperature was set to 16° C. Nitric acid, 31.4 kg was then added gradually over a period of 3 hrs. When the administration was complete the mixture was allowed to stir for additional 3.5-4.5 hours.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:17][C:16]([NH:18][C:19]2[N:20]=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][C:14]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:16]2[S:17][C:13]([NH:12][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)=[C:14]([C:29]([NH2:31])=[O:30])[N:15]=2)[N:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1nc(Nc2cc3ccccc3cn2)sc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2sc(Nc3cc4ccccc4cn3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a mixture of p-anisoyl chloride (0.4 mL, 3.0 mmol) in pyridine (2 mL) was added dropwise a solution of 5-amino-2-(isoquinolin-3-ylamino)-thiazole-4-carboxamide (0.20 g, 0.70 mmol) in pyridine (3 mL), and the mixture was stirred overnight at rt. The solvent was evaporated. The residue was triturated with MeOH, and the resulting solids were collected to give 42 mg (28% yield) of the titled compound.
Reaction SMILES: [H-].[Na+].CS([O:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19]2)=[C:11]([NH:42][CH2:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:10]=1)(=O)=O.[N:57]1([CH2:63][CH2:64]O)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1.O>O1CCCC1>[Si:24]([O:23][C@@H:22]1[C@H:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:36])[CH3:37])([CH3:33])[CH3:34])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][O:7][CH2:64][CH2:63][N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)=[N:10][C:11]=2[NH:42][CH2:43][CH:44]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: OCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCCN4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydride (24 mg of an 80% dispersion in mineral oil, 0.81 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (500 mg, 0.63 mmol) (preparation 16) and 2-(1-piperidinyl)-1-ethanol) (105 mg, 0.81 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 24 hr at room temperature and then heated at reflux for a further 8 hr. The reaction mixture was then poured into cold water and extracted with ethyl acetate. The organic phase was separated, washed with brine and dried with anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (101 mg) as an oil. MS: 833 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13](C)([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.BrC1C(F)=CC=C2C=1NC(=O)C(C)=N2.C(N)(C)C>CS(C)=O>[Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][CH:13]([CH3:14])[CH3:15])[C:8]([CH3:17])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Agent: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Solvent: CS(C)=O
Solvent: CC(C)N
Product: Cc1nc2ccc(F)c(Br)c2nc1NC(C)C
Yield: 91 %

Procedure:
This compound (594 mg, 1.99 mmol, 91% yield) as an orange crystalline solid was prepared according to the procedure described for Intermediate 605a, using 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (600 mg, 2.17 mmol) and isopropylamine (0.94 mL, 10.9 mmol) in DMSO (5.0 mL) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (1H, dd, J=9.0, 5.9 Hz), 7.15 (1H, t, J=8.6 Hz), 4.68-4.82 (1H, m), 4.52 (1H, dq, J=13.2, 6.5 Hz), 2.53 (3H, s), 1.39 (6H, d, J=6.5 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −103.43 (1F, s). m/z (ESI, +ve ion) 298.5/300.6 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]([CH3:17])[S:9]([CH2:12][C:13](OC)=[O:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:24]>>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]([CH3:17])[S:9]([CH2:12][C:13]([NH2:24])=[O:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)CS(=O)(=O)N(C)C(c1ccccc1)c1ccccc1
Product: CN(C(c1ccccc1)c1ccccc1)S(=O)(=O)CC(N)=O
Yield: 90 %

Procedure:
The subtitle compound (2.62 g, 90%) was prepared as a white solid from aqueous ammonia solution (10 ml, s.g.=0.88) and methyl (N-diphenylmethyl-N-methylsulfamoyl)acetate (from step (a), 3.05 g, 9.2 mmol), using the method of Example 1(b). m.p. 110-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.O1CCCC1.S([O-])([O-])(=O)=O.[OH:21][NH3+:22].O[NH3+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:22][OH:21]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ON=Cc1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
50.0 g (0.286 mol) of 2,6-dichlorobenzaldehyde were added to 250 ml of tetrahydrofuran and 250 ml of water, and 26.0 g (0.159 mol) of hydroxylammonium sulfate were added. The mixture was then stirred at 40° C. for 3 h, keeping the pH at 4-5 by adding sodium bicarbonate solution. The tetrahydrofuran was then distilled off under reduced pressure, and the residue was extracted with methyl tert-butyl ether, and the solution was dried over sodium sulfate and concentrated under reduced pressure. Yield 54.3 g (99.9%) of solid of melting point 150° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]Br.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Br:16][C:14]1[C:9]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][C:11]([NH2:15])=[N:12][CH:13]=1
Reactant: Cc1ncccc1Oc1ccnc(N)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ncccc1Oc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.1 %

Procedure:
To 4-(2-methylpyridin-3-yloxy)pyridin-2-amine (3.67 g, 18.2 mmol) in acetic acid (50 mL) was added bromine (0.94 ml, 18.2 mmol). The reaction was stirred at ambient temperature for 5 minutes. Ammonium acetate (1.41 g, 18.2 mmol) was added. After 5 minutes, the solution was concentrated and saturated sodium bicarbonate solution was added. The reaction was extracted with ethyl acetate, dried and concentrated to give the title compound (5.0 g, 98% yield) as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16]Cl)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=3)[CH2:23][CH2:22]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN3CCCN(Cc4cccc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-(3,4,5-Trimethoxyphenyl)benzyl chloride (184 mg) and homopiperazine (52 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:25])([F:24])[CH2:11][CH2:12]N1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl.C(NN)(=O)C1C(=CC=CC=1)C([NH:35]N)=O>C(O)C>[CH2:1]([O:8][CH:9]([NH2:35])[C:10]([F:25])([F:24])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Reactant: O=C1c2ccccc2C(=O)N1CCC(F)(F)COCc1ccccc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC(F)(F)C(N)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-(4-benzyloxy-3,3-difluorobutyl)-phthalimide (68.5 g, 198.6 mmoles) and hydrazine hydrate (10 g, 200 mmoles) are stirred and heated overnight in ethanol (200 mL) at 90°-100° C. A mixture of concentrated HCl (94 mL) and ethanol (1130 mL) is added, and heating (90°-100° C.) is continued for 1.5 hours. After cooling (ice bath), phthalhydrazide is removed by filtration, and the filtrate is evaporated. The residue is taken up in water and extracted with ether (2×500 mL). After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals. These are dissolved in ethanol, the solution is filtered (Millipore organic) and the filtrate is evaporated to yield a residue which crystallizes on addition of ether: 34 g (68%). Evaporation of the ether extracts yields a partially crystalline material (20 g) consisting of starting material. Repetition of the hydrazine cleavage upon this mixture yields a second crop of 4-benzyloxy-3,3-difluorobutylamine (9.1 g). Total: 43.2 g (86.5%).
Reaction SMILES: ClC1N=C(Cl)C([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)=CN=1.C[O:20]C(C)(C)C>>[C:11]1([N:10]=[C:9]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(C)(C)C
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Product: O=C=Nc1ccccc1
Temperature: 55 °C

Procedure:
A 500-mL, three-necked flask equipped with a mechanical stirrer, thermometer, condenser, and nitrogen-inlet bubbler was charged with [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine (59.6 g, 209.7 mmol) (from Example 1d supra) and tert-butyl methyl ether (300 mL) (Aldrich). After heating to 55° C. to give a clear solution, phenyl isocyanate (27.48 g, 230.7 mmol) (Aldrich) was added and the mixture was heated to reflux for 10 hours. TLC analysis indicated essentially complete reaction. After cooling to room temperature, the resulting solid was collected by filtration, washed with tert-butyl methyl ether (100 mL), and dried by suction to give N-[(2,4-dichloropyrimidin-5-yl)methyl]-N-(4-methoxyphenyl)(phenylamino) carboxamide as white crystals; 98.46% pure by HPLC analysis. (Yield 78.8 g, 91.3%).
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][CH:13]3[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][CH2:14]3)[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCC1COc2ccccc2O1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CC3COc4ccccc4O3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 3 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as an oil in 3% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.31 (m, 5H), 6.88-6.87 (m, 4H), 5.89 (br s, 1 H), 4.57 (d, J=6.0 Hz, 2H), 4.43-4.39 (m, 1H), 4.33-4.28 (m, 1H), 4.17-3.97 (m, 3 H), 3.86-3.53 (m, 4H), 2.63 (s, 3H); MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[C:15]([O:19][C:20]([N:22]1[C@@H:26]([CH2:27][C:28]([CH:31]=O)([CH3:30])[CH3:29])[CH2:25][O:24][C:23]1([CH3:34])[CH3:33])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CCCCCC.O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[C@@H:26]([CH2:27][C:28]([CH3:30])([CH3:29])[CH:31]=[CH2:1])[CH2:25][O:24][C:23]1([CH3:34])[CH3:33])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
255 ml of a 1.6M butyllithium solution in hexane are added to a solution of 85 ml of hexamethyldisilazane in 800 ml of tetrahydrofuran at -40° C. After 15 min, 140 g of methyltriphenylphosphonium bromide are added at 0° C. and the reaction mixture is stirred at 30° C. for 30 min. 77 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-(2-formyl-2-methylpropyl)-1,3-oxazolidine, dissolved in 200 ml of tetrahydrofuran, are then added to the reaction solution at -30° C. The reaction mixture is stirred at room temperature for 1 h, and 600 ml of hexane are then added at 0° C. The triphenylphosphinoxide which has precipitated out is filtered off and, after dilution with 400 ml of saturated ammonium chloride solution, the filtrate is extracted with diethyl ether. The crude product is purified by means of FC (400 g of silica gel, mobile phase G): Rf (D)=0.55, Rf (ethyl acetate)=0.44; [α]D =+4.2 (c=1.25 in CHCl3); MS: (M)+ =283.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[NH:23][C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:25](Cl)[N:26]=1)C1C=CC=CC=1.C(O)=O.[Cl-]>CO.[Pd]>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:24]2[NH:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:26][CH:25]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)OCCn2c1nc(-c1nc(Cl)c(Cc3ccc(F)cc3)[nH]1)c(OCc1ccccc1)c2=O
Agent: [Pd]
Agent: [Cl-]
Solvent: O=CO
Solvent: CO
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)[nH]1)c(O)c2=O
Temperature: 40 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
To a solution of 3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-1H-imidazol-2-yl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.03 g, 0.061 mmol, 1.0 equiv) in MeOH (3 mL) under a nitrogen atmosphere, was added formic acid (0.1 mL, 2.61 mmol, 43 equiv) and 10% Pd/C (0.065 g, 0.061 mmol, 1.0 equiv). The reaction was stirred for 5 h after which LCMS analysis indicated complete benzyl hydrogenolysis but no chloride reduction. The reaction was warmed to 40° C. (oil bath) and stirred 2 h. LCMS analysis now indicated complete chloride reduction. The reaction was cooled to ambient temperature and stirred a further 16 h. The reaction was then filtered through celite and concentrated in vacuo. The residue was added to saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×5). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by silica gel chromatography (7% MeOH/CH2Cl2) to provide the title compound (0.008 g, 36% yield) as a tan solid. 1H NMR (400 MHz, d7-DMF) δ ppm (major imidazole tautomer) 13.14 (s, 1H), 7.48-7.58 (m, 2H), 7.39 (s, 1H), 7.29 (t, J=8.56 Hz, 2H), 4.21-4.25 (m, 2H), 4.15 (s, 2H), 4.08 (t, J=5.16 Hz, 2H), 1.74 (s, 6H); LCMS (ES+, (M+H)+) m/z 371.17.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[N:12]=1
Reactant: CCOC(=O)c1cnn2c1[nH]c(=O)c1cnc3c(cnn3CC)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12

Procedure:
256 g of 8-ethyl-5,8-dihydro-5-oxo-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are refluxed in 1 liter of phosphorus oxychloride for 24 hours. The excess phosphorus oxychloride is decomposed by pouring the solution on ice and the crystallized 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]-pyrimidine-3-carboxylic acid, ethyl ester is filtered off, yield 245 g (91%); m.p. 170°-172° (butyl alcohol).