Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(O)Cl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred overnight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8].C(OC(=O)C)(=O)C>>[C:2]([C:3](=[CH:10][O:9][CH2:7][CH3:8])[C:4]#[N:5])(=[O:1])[CH3:6]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(C)=O
Temperature: 25 °C

Procedure:
3-Oxo-butyronitrile (4.94 g, 60.9 mmol), triethylorthoformate (15.0 mL, 90.2 mmol), and acetic anhydride (0.3 mL, 2.7 mmol) were warmed to about 95-115° C. for about 1 hours, over which time a distillate was collected and discarded. After cooling the resultant mixture to room temperature, hexanes were added and a precipitate formed. The resultant mixture was filtered and the solids washed with hexanes, to yield the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:8][C:4]2[CH:3]=[C:2]([O:1][C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:9][CH3:10])=[CH:20][CH:19]=3)[CH:7]=[CH:6][N:5]=2)=[O:17])=[CH:14][CH:13]=1)[CH3:10]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Product: CCOc1ccc(C(=O)Oc2ccnc(OC(=O)c3ccc(OCC)cc3)c2)cc1
Yield: 6 %

Procedure:
The general procedure of Example 16 was followed using 1.00 g of 4-hydroxy-2-pyridone and 3.32 g of 4-ethoxybenzoyl chloride to produce 220 mg of the title compound in a yield of 6%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH2:10])[C@H:2]1[OH:11].CCN(CC)CC.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:11]1[C@H:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C@H:3]2[NH:10][C:20]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N[C@@H]2c3ccccc3C[C@@H]2O1
Temperature: -60 °C

Procedure:
(1R,2S)-cis-1-amino-2-indanol (0.980 g, 6.569 mmol) was placed in a round-bottomed flask and a dry Ar atmosphere was established. Dry CH2Cl2 (50 mL) and Et3N (1.9 mL, 13.63 mmol) were added, and the resulting solution was cooled to −60° C. On addition of triphosgene (0.64 g, 2.157 mmol), the cooling bath was removed, and the reaction was allowed to warm to 20° C. over one hour. The reaction was then poured into CH2Cl2 (100 mL) and H2O (50 mL) and the aqueous phase was extracted with CH2Cl2 (3×100 mL). After drying with MgSO4, the organic layer was evaporated under reduced pressure to give (3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one, (R)-24 (1.15 g, quantitative) as white crystals, which was of sufficient purity for the next step in the reaction sequence. An analytical sample was recrystallized from CH2Cl2/hexanes. mp 205.5-206.5° C.; [Ghosh et al. (1992) J. Chem. Soc. Chem. Commun. 1673-1674 for enantiomer mp 205° C.]; [α]25D=+107.7 (c 1.25, CHCl3); [Id. for enantiomer [α]25D=−79.4 (c 1.4, CHCl3)]. IR (KBr) 3255, 1752, 1707 cm−1; 1H NMR (acetone-d6) δ 7.24-7.43 (4H, m), 5.39 (1H, t, J=7.5 Hz), 5.21 (1H, d, J=7.0 Hz), 3.42 (1H, dd, J=17.7, 6.2 Hz), 3.20 (1H, d, J=17.9 Hz), 2.90 (1H, br s); 13C NMR (acetone-d6) δ 159.1, 142.5, 141.0, 129.7, 128.3, 126.2, 125.8, 80.8, 61.7, 39.3; HRMS (FAB+) m/z: calcd for C10H9NO2+H, 176.0771; found, 176.0681.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1.Br[C:16]1C=CC(N)=NC=1C>>[CH3:16][C:9]1[C:4]([CH:2]2[CH2:3][O:1]2)=[CH:5][CH:6]=[C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:8]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: c1cc(-n2cnnn2)ncc1C1CO1
Product: Cc1nc(-n2cnnn2)ccc1C1CO1

Procedure:
2-Methyl-3-(oxiran-2-yl)-6-(1H-tetrazol-1-yl) pyridine was prepared in a similar fashion to that described for the synthesis of 5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine (INTERMEDIATE 32) starting from 5-bromo-6-methylpyridin-2-amine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[OH-].[K+].Cl[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: COC(=O)C(C)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Reaction time: 0.5 h

Procedure:
At 22° C., 100 g (0.522 mol) of 2-chloro-4-fluoro-5-nitrophenol were added with stirring to a solution of 34.5 g (0.522 mol) of 85% strength potassium hydroxide in 500 ml of methanol, and the mixture was stirred for another 30 min. At 40° C., the reaction mixture was then concentrated under reduced pressure. The residue was dried at 50° C. in a vacuum cabinet overnight. The pulverulent residue was then, at 40° C., dissolved with stirring in 1 l of dimethylformamide (DMF), 70.7 g (0.574 mol) of methyl 2-chloropropionate were added dropwise at 50° C. over a period of 30 min and the mixture was stirred at 80° C. for another 2 h. The solvent was removed under reduced pressure, the residue was introduced into 700 ml of water and undissolved components were filtered off. The aqueous phase was extracted three times with in each case 300 ml of methyl tert-butyl ether. The combined organic extracts were washed with about 500 ml of saturated sodium chloride solution and dried over magnesium sulfate. Concentration gave 106 g (73.1% of theory) of the title compound as a colorless resin.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18](O)=[O:19])=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:27]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:19][N:36]=[C:25]([C:26]5[CH:27]=[C:28]([S:32]([NH2:33])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=5)[N:24]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)c1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (202 mg, 83%). MS (ISP) 486.3 [(M+H)+]; mp 288° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:22][N:21]2[CH:40]=1>>[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:32][CH:33]=3)[C:23]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:22][N:21]2[CH:40]=1
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)cn6cc5-c5ccccc5)cc4)C3)n[nH]2)n1

Procedure:
The compound is prepared in analogy to example 37.0. 306 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 200 mg (0.64 mmol) 4-(2-methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde. After the usual work-up and purification 146 mg (42.6%) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH2:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH2:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)[C:11]([C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2)=[O:13]
Reactant: Clc1ccc(CCNCc2cc3ccccc3o2)cc1Cl
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)cc2cc[nH]c12)N(CCc1ccc(Cl)c(Cl)c1)Cc1cc2ccccc2o1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a solution of 72 mg (0.37 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 118 mg (0.37 mmol) of benzofuran-2-ylmethyl-[2-(3,4-dichloro-phenyl)-ethyl]-amine in DMF (5 ml) were added 131 mg (0.41 mmol) of TBTU and 126 μl (0.74 mmol) of N,N-diisopropylethyl amine and the mixture was stirred over night at RT. Then the reaction mixture was diluted with ethyl acetate and washed with water, brine, sat. NaHCO3 solution, 1N HCl and again with brine. The organic layer was then dried (MgSO4) and concentrated. The remaining residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 9:1) to yield the title compound as a yellow oil (145 mg, 79%). MS (ISP) 497.3 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:18])=[CH:8][C:9]([C:12](N(OC)C)=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:18])=[CH:8][C:9]([CH:12]=[O:13])=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: CON(C)C(=O)c1cc(C)c(OCC2CC2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C=O)ncc1OCC1CC1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (495 mg, pale orange solid) from 5-(cyclopropylmethoxy)-N-methoxy-N,4-dimethylpicolinamide (622 mg, 2.49 mmol, Step-4) and lithium aluminum hydride (47 mg, 1.2 mmol) in a similar manner to Step-2 of Amine-3.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[CH3:27][CH:28]([NH2:33])[C:29]([F:32])([F:31])[F:30]>>[F:30][C:29]([F:32])([F:31])[C@@H:28]([NH:33][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4])[CH3:27]
Reactant: CC(N)C(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Product: C[C@H](NC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C)C(F)(F)F
Yield: 17 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine instead of isopropylamine, to the title compound (21 mg, 17%) which was obtained as a colorless gum. MS: m/e=459.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[N+:21]([O-])=O)[CH:7]=1>C(O)C.C(O)(=O)C.C(OCC)C.[Fe]>[NH2:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]#[C:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1ccc(F)cc1C(C)(C)CC(O)(CC#Cc1cccc(F)c1[N+](=O)[O-])C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(F)cc1C(C)(C)CC(O)(CC#Cc1cccc(F)c1N)C(F)(F)F
Temperature: 80 °C
Yield: 91.2 %

Procedure:
A stirred solution of 6-(5-fluoro-2-methylphenyl)-1-(3-fluoro-2-nitrophenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (1.05 g, 2.4 mmol) in 6 mL of absolute ethanol and 2 mL of glacial acetic acid was treated with iron powder (800 mg, 14.3 mmol). The resulting mixture was heated at 80° C. for 2 hours, cooled to room temperature, diluted with diethyl ether, filtered through a pad of CELITE® filter aid, and concentrated in vacuo. The residue was dissolved in diethyl ether, treated with anhydrous potassium carbonate, filtered, and concentrated in vacuo to give 900 mg of 1-(2-amino-3-fluorophenyl)-6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol as a light brownish oil (92% yield), which was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](N)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Br:12])[N:3]=1.N([O-])=O.[Na+].[ClH:17]>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:17])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Br:12])[N:3]=1
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1c(Cl)cc(Br)nc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,6-Dibromo-4-amino-5-nitro-pyridine (3 g) was taken up in concentrated hydrochloric acid (20 mL) and cooled to 0° C. Sodium nitrite (3.5 g) was added and the reaction mixture was allowed to stir at 0° C. for 1 h. The ice bath was removed and the reaction allowed to warm to room temperature over 3 h, and was then quenched by the addition of ethyl acetate (50 mL) and water (100 mL). The organic layer was separated, dried over MgSO4 and filtered and evaporated in vacuo to a pale yellow oil, which was purified by column chromatography using 35:1 pentane:EtOAc as eluant to give the title compound (2.2 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][CH:6]=2.[CH3:13][O-:14].[Na+]>CO.[Cu]>[CH3:13][O:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][CH:6]=2
Reactant: Nc1ccc2ncc(Br)cc2c1
Reactant: C[O-]
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(N)cc2c1
Temperature: 135 °C
Yield: 59.8 %

Procedure:
A suspension of 3-bromo-quinolin-6-ylamine (9.0 g, 40.3 mmol, 1.0 eq), sodium methoxide (10.9 g, 201.7 mmol, 5.0 eq) and copper powder (7.7 g, 121.0 mmol, 3.0 eq) in methanol (240 mL) is heated at 135° C. for 15 hours. The reaction mixture is then filtered and the filtrate is concentrated to give a yellow residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:triethylamine, 2:1:0.05, v/v/v) to afford 3-methoxy-quinolin-6-ylamine as a yellow solid (4.2 g, 59% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[N:5][N:6]2[CH:11]=[C:10]([C:12](OCC)=[O:13])[CH:9]=[N:8][C:7]=12)#[N:2].[BH4-].[Na+]>C(Cl)Cl.CO>[OH:13][CH2:12][CH:10]1[CH2:11][N:6]2[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:3]([C:1]#[N:2])=[C:7]2[NH:8][CH2:9]1
Reactant: CCOC(=O)c1cnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
To a solution of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (250 mg, 0.65 mmol) in DCM (5 mL) and CH3OH (5 mL) was added NaBH4 (250 mg, 6.5 mmol). After stirring at RT for 16 hr, the mixture was partitioned between DCM/CH3OH (100 mL/5 mL) and brine (100 mL). The organic layer was separated from aqueous layers, dried over Na2SO4 and concentrated to afford 250 mg (100%) of 6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile. MS (ESI) m/e [M+1]+346.9.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=O)[OH:14])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:14])[O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Reactant: OCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCC(F)(F)F

Procedure:
Using the procedure of Example 53, trifluoroethanol and the product of Step B of Example 57 were reacted to obtain benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+45° (c=0.6% in chloroform).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([C:25]([O:27]CC)=[O:26])[CH:20]=2)[CH2:15][CH2:14]1.O.Cl>C1COCC1>[O:3]=[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]1[CH:13]1[CH2:14][CH2:15][N:16]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.0 mL (36.0 mmol) of a 4M NaOH solution were added to 5.50 g (14.9 mmol) ethyl 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate, 25 mL water in 150 mL THF. After 3 h stirring at RT the THF was eliminated i. vac. The aqueous residue was combined with 9 mL of a 4M hydrochloric acid solution. After 3 h stirring at RT the precipitate was suction filtered and dried in the CAD at 60 C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:9]([OH:32])[CH2:10][N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:42](O)(=[O:44])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C1C=CC(OC)=CC=1>CO.ClC(Cl)C.[OH-].[OH-].[Pd+2]>[CH2:1]([C@H:8]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[C@@H:9]([OH:32])[CH2:10][N:11]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:44][CH3:42])=[CH:30][CH:31]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1ccc(C=O)cc1
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(OC)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of Example 26B (1.2 g, 2.2 mmol) in methanol (7 mL) was treated with Pd(OH)2 (0.24 g), 4N HCl (0.54 mL), stirred under a hydrogen balloon at 25° C. for 16 hrs. The catalyst was filtered, washed with methanol, and the solvents were evaporated to give 1 g (100%) of the crude product used directly for the next step. This material (0.5 g, 1.1 mmol) was dissolved in dichloroethane (4 mL) and treated with acetic acid (0.12 mL, 2 equivalent), sodium triacetoxyborohydride (0.57 g, 2.5 equivalent), and p-anisaldehyde (0.26 mL, 2 equivalents) at 25° C. for 16 hrs. The mixture was quenched with 10% sodium bicarbonate and chloroform. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified using 1% methanol/chloroform to give 0.38 g (60%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([NH2:19])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25].C(O)(=O)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]3[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
A mixture of 8-benzyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (100 mg), 2,5-hexanedione (50 μL), acetic acid (164 μL) and toluene (3 mL) was stirred at 80° C. for 24 hr. The mixture was diluted with ethyl acetate at room temperature, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→100% ethyl acetate/hexane) to give the title compound (60 mg, 46%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:12]3[CH:20]=[C:19](F)[N:18]=[CH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[Cl:9])#[CH:2].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CS(C)=O>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([NH:10][C:11]2[C:12]3[CH:20]=[C:19]([NH:29][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:18]=[CH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:4][C:3]=1[C:1]#[CH:2]
Reactant: COc1ccc(CN)cc1
Reactant: C#Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Cl
Solvent: CS(C)=O
Product: C#Cc1cc(Nc2ncnc3cnc(NCc4ccc(OC)cc4)cc23)ccc1Cl
Temperature: 70 °C
Reaction time: 141 h
Yield: 53.7 %

Procedure:
A mixture of compound 209 (3.07 g, 10.3 mmol) and 4-methoxybenzylamine (13.5 mL, 103 mmol) in dry DMSO (27 mL) was stirred under a nitrogen atmosphere at 70° C. (bath temperature) for 141 h. The mixture was cooled and petroleum ether (300 mL) was added. It was stirred at room temperature for 30 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (300 mL). Water (300 mL) was added and the mixture was stirred at room temperature for 30 min. It was filtered and washed sticky solid with water (4×20 mL). The sticky solid was dissolved in minimum acetone (50 mL) and water (200 mL) added. The mixture was stirred at room temperature overnight (22 h). Sticky solid generated again. Thus, the product was extracted into ethyl acetate, which after washed with water several times, was dried (MgSO) and evaporated. The crude product was applied to a silica column (dichloromethane/MeOH=50:1) to give N4-(4-chloro-3-ethynylphenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (218) (2.30 g, 54%) as a greenish yellow solid, mp 201-203° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 7.96 (dd, J=8.9, 2.5 Hz, 14, 7.56 (d, J=8.9 Hz, 14, 7.39-7.28 (m, 3H), 7.17 (s, 1H), 6.93-6.82 (m, 2H), 4.59 (s, 1H), 4.49 (d, J=6.3 Hz, 2H), 3.71 (s, 34. Anal. Calcd for C23H18ClN5O.0.18hexane: C, 67.04; H, 4.80; N, 16.23%. Found C, 66.76; H, 4.79; N, 15.96%.