Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:6][C:7]([C:10]2[S:11][C:12]([C:16](=[O:18])[CH3:17])=[C:13]([CH3:15])[N:14]=2)=[N:8][CH:9]=1>C1COCC1.CO>[Cl:3][C:4]1[C:5]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:6][C:7]([C:10]2[S:11][C:12]([CH:16]([OH:18])[CH3:17])=[C:13]([CH3:15])[N:14]=2)=[N:8][CH:9]=1
Reactant: CC(=O)c1sc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)sc1C(C)O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
NaBH4 (46 mg, 1.2 mmol, 3.0 equiv.) was added to a solution of 1-(2-(5-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-4-methylthiazol-5-yl)ethanone (Compound 297 (150 mg, 0.4 mmol, 1.0 equiv.) in THF (2 mL) and methanol (2 mL) at rt. The mixture was stirred for 0.5 h, then, concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The residue was recrystallized with methanol and isopropyl ether to afford 1-(2-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-4-methylthiazol-5-yl)ethanol (Compound 296) (120 mg, 80%). LC-MS (m/z)=377.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.70-0.78 (m, 2H), 0.95-1.03 (m, 2H), 1.41 (d, J=5.2 Hz, 3H), 1.89-1.96 (m, 1H), 2.38 (s, 3H), 5.04-5.08 (m, 1H), 5.75 (d, J=2.8 Hz, 1H), 6.62 (s, 1H), 8.47 (s, 1H), 9.51 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:52][OH:53])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=1[F:51]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Reaction time: 3 h
Yield: 45.7 %

Procedure:
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 3n (550 mg, 0.74 mmol) was dissolved in 20 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of o-dichlorobenzene (0.84 mL, 7.4 mmol) and Palladium/carbon (300 mg, 10%). The mixture was exchanged with H2 three times and stirred for 3 hours. Thereafter, the reaction mixture was filtered after a small amount of ethyl acetate was added. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 3 (160 mg, white solid), yield: 45.7%. MS m/z (ESI): 472.2 [M+1]. 1H NMR (400 MHz, CDCl3): δ 7.43-7.37 (m, 3H), 6.80-6.76 (m, 2H), 4.16-4.07 (m, 5H), 3.85-3.70 (m, 2H), 3.70-3.51 (m, 4H), 1.34 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1>CCO>[O:23]=[C:15]1[NH:14][C:22]2[C:17](/[C:16]/1=[CH:1]\[C:3]1[CH:11]=[C:10]3[C:6]([C:7]([C:12]#[N:13])=[N:8][NH:9]3)=[CH:5][CH:4]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: N#Cc1n[nH]c2cc(C=O)ccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1n[nH]c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Temperature: 75 °C
Yield: 81.9 %

Procedure:
To a mixture of 6-formyl-1H-indazole-3-carbonitrile (1.10 g, 6.4 mmol) and 2-oxindole (871 mg, 6.5 mmol) in EtOH (25 mL) was added piperidine (0.1 mL, 1 mmol). The resulting mixture was refluxed (oil temp. 75° C.) for 90 min, then cooled to rt. The resulting precipitate was collected by suction filtration and dried to give the title compound as an orange solid (1.5 g, 82%) 1H NMR (400 MHz, DMSO-d6) δ 14.6 (s, 1H), 10.66 (s, 1H), 8.09 (s, 1H), 8.01 (d, J=8.5 Hz, 1H) 7.78 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.83 (t, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:20])=[O:5]
Reactant: CO
Reactant: N[C@H](CC(=O)O)c1cccc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1

Procedure:
(R)-3-amino-3-(3-nitrophenyl)propionic acid is esterified in analogy to Example 2 by activation with thionyl chloride and reaction with methanol under standard conditions to give methyl 3-amino-3-(3-nitrophenyl)propionate, which is reacted with BOC-Gly-OH and 4-(4-methylpyridin-2-ylamino)butyric acid. Cleavage of the ester results in (R)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid. Use of an excess of NaOH results in the sodium salt of (R)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid. Preparative HPLC results in (R)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid trifluoroacetate, RT* 16.89 min, FAB-MS (M+H)+ 444.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[O:9][C:5]=2[CH:4]=1)#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([C:1]#[N:2])[CH:14]=[CH:13][C:6]=4[CH:7]=3)=[O:12])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: N#Cc1ccc2cc(C(=O)O)oc2c1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: N#Cc1ccc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)oc2c1

Procedure:
In a similar manner to Referential Example 12 except for the use of 6-cyanobenzofuran-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.ClC1C=C(I)C=C2C=1O[CH:20]([C:23]([F:26])([F:25])[F:24])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=C2>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[C:4]([Cl:11])[CH:3]=1)[O:10][CH:20]([C:23]([F:24])([F:26])[F:25])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Reactant: O=Cc1cc(Br)cc(Cl)c1O
Product: CCOC(=O)C1=Cc2cc(Br)cc(Cl)c2OC1C(F)(F)F

Procedure:
The ethyl 6-bromo-8-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate was prepared from 5-bromo-3-chloro-2-hydroxybenzaldehyde in an analogous manner to step 2, preparation of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][NH2:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:16])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: CN
Product: CNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 90 %

Procedure:
In an analogous manner to General Procedure A, 4-Bromo-2-trifluoromethylbenzenesulfonyl chloride (0.50 g, 1.54 mmol) and methylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-bromo-N-methyl-2 (trifluoromethyl)benzenesulfonamide (0.44 g, 90%) was provided after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370 nm, 8.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@@:11]2([CH3:30])[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:31](Cl)(=O)[CH2:32][CH2:33][CH3:34]>>[CH3:28][S:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][C@@:11]([CH3:30])([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:31]([CH2:32][CH2:33][CH3:34])[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:29][C:14]3=[CH:15][N:16]=2)[CH2:24][CH2:23]1)(=[O:27])=[O:26]
Reactant: CCCC(=O)Cl
Reactant: C[C@@]1(C2CCN(C(=N)NO)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Product: CCCc1nc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from (S)—N-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (Intermediate 43; the configuration of the stereocenter is arbitrarily assigned) and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 4): tR=1.00 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:42]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis(triphenylphosphino)palladium(O) (0.021 g, 0.018 mmol). The mixture was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via silica gel chromatography (5% methanol/dichloromethane elute) to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=1)=[O:7]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1cccc(Cl)c1Cl)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 4 h
Yield: 93.7 %

Procedure:
28.2 g of 4-hydroxy-N-(2,3-dichlorophenyl)-benzamide, 20.0 g of ethyl bromoacetate and 20.7 g of potassium carbonate were dispersed in 150 ml of N,N-dimethylformamide, and the dispersion was stirred at a temperature of from 120° to 140° C. for 4 hours. After completion of the reaction, the reaction solution was poured into 500 ml of a 2% hydrochloric acid aqueous solution. The crude product obtained by collecting precipitates by filtration, was recrystallized from toluene to obtain 34.5 g of desired ethyl 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetate. Yield: 93.4% Melting point: 126°-129° C.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([S:17][C:18]2([C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=O)[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].OO>C(O)(C)(C)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:21]2([C:18]3([S:17][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:20][CH2:19]3)[CH2:10][O:9]2)=[CH:26][CH:27]=1
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Reactant: COS(=O)(=O)OC
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: Clc1ccc(CCC2(C3(Sc4ccccc4)CC3)CO2)cc1
Reaction time: 14 h
Yield: 81.4 %

Procedure:
21 ml (0.29 mol) of dimethyl sulphide and 32.5 g (0.26 mol) of dimethyl sulphate are added to 40 ml of tert.-butanol and the mixture is allowed to stand at room temperature for 14 hours. A solution of 30 g (0.095 mol) of 4-chlorophenylethyl 1-phenylmercapto-cyclopropyl ketone in 90 ml of tert.-butanol is initially added dropwise to the reaction mixture with stirring and 29.2 g of potassium hydroxide powder are then introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed using water and concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 25.6 g (82% of theory) of 2-(4-chlorophenylethyl)-2-(1-phenylmercapto-cyclopropyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR72##
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](Cl)(=O)[CH:11]([CH3:13])[CH3:12].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(Cl)nn12
Temperature: 90 °C
Yield: 94 %

Procedure:
A mixture of 3-chloro-6-hydrazinylpyridazine (200 g, 1.38 mol) and isobutyryl chloride (175 mL, 1.66 mol) in 1,4-dioxane (2 L) was heated at about 90° C. overnight. The suspension was cooled to about 5° C. in an ice bath and then water (2 L) was added followed by slow addition of Na2CO3 (275 g, 2.59 mol). The resulting solution was extracted with DCM (3×1 L). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum overnight to give the title compound (255 g, 94%): LC/MS (Table 1, Method a) Rt=2.04 min; MS m/z: 197.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)C>Cl.O>[CH:17]1([N:7]2[CH2:8][CH:9]([CH2:15][CH3:16])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCC1CN(C2CCCC2)c2nc(Cl)ncc2N(CC)C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(CC)C1=O
Yield: 62.8 %

Procedure:
A mixture of 0.042 g (0.00013 mole) of (rac)-2-chloro-9-cyclopentyl-7-ethyl-5-ethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-14), 0.026 g (0.00016 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.037 g of (rac)-4-(9-cyclopentyl-5,7-diethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-14) as an off-white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.FC(F)(F)C(O)=O.[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)/C=C\C(O)=O>C(#N)C>[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:11][CH:12]3[O:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[O:14][CH2:13]3)[CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Nc1ncccc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncccc1C(=O)NCC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A stirred mixture of 1,4-benzodioxan-2-ylmethyl toluene4-sulphonate (0.82 g), 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate (0.905 g; prepared in a similar manner to that described in Example 2) and potassium carbonate (1.4 g) in acetonitrile (50 ml) was heated under reflux for 6 hours. After cooling, the solvent was removed in vacuo, water (60 ml) was added to the residue, and the product was extracted with dichloromethane (2×30 ml). The extracts were dried over magnesium sulphate and the solvent was removed in vacuo to give an oil. The oil was purified by flash chromatography on silica eluting with a 9:1 then 1:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvents removed in vacuo to give an oil. Ethereal maleic acid (20 ml) was added to yield a white solid. The solid was collected by filtration, washed with ether and the solvent removed in vacuo to yield 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide 0.5 maleate (95 mg) m.p. 104-106° C.
Reaction SMILES: B.[F:2][C:3]([F:13])([CH2:9][C:10](O)=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]>O1CCCC1>[F:2][C:3]([F:13])([CH2:9][CH2:10][OH:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(F)(F)CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CCO
Reaction time: 18 h

Procedure:
A solution of 123.0 mL (0.123 mol) of 1.0M of borane in tetrahydrofuran was added dropwise at 0° to a mixture of 12.4 g (0.068 mol) of ethyl 2,2-difluoro-3-carboxypropionate in 70 mL of dry tetrahydrofuran. The reaction mixture was stirred at 0° for 18 hr then was quenched by adding 40 mL of water dropwise. The solution was saturated with solid sodium chloride and the product was isolated with ether. The ether layers were washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield ethyl 2,2-difluoro-4-hydroxybutyrate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1Cl
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(Cl)c3)n2)cc1Cl

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-methoxyaniline were reacted to provide N2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](I)[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:11][CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl iodide (17.3. gm; 102 mmol), and potassium carbonate (16.90 gm; 122 mmol) in 2-butanone (100 mL) and reflux. After 17 h, allow the mixture to cool to room temperature, decant the solution and concentrate by rotary evaporation. Partition the residue between diethyl ether (150 mL) and water (150 mL), separate the layers and extract the aqueous layer with diethyl ether (2×100 mL). Combine organic layers and wash with water, 1 N NaOH, and then water, dry over MgSO4, and concentrate to give a residue. Distill the residue to give the title compound: bp: 122–125° C. (15 mm); TLC (10% Et2O/hexanes; Rf 0.35).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH2:24][CH:25](O)C>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:24]([O:23][CH3:22])[CH3:25])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COCC(C)O
Product: COC(C)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared from methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate and propylene glycol monomethyl ether, by a procedure analogous to that of Reference Example 10. White powder with mellting point 73°-74° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1>[C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C1CCCC1N
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCC1NC(=O)CC(C)=O
Temperature: 20 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
4.8 g of diketene were added to a mixture of 9 g of 1-amino-2-carbethoxy-cyclopentane and 90 ml of benzene and after stirring for 72 hours at 20° C., the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 7.7 g of N-(2-carbethoxycyclopentyl)-acetylacetamide with a refractive index of ND22 =1.487. 6.3 g of the latter product and 0.25 g of p-toluene sulfonic acid were added to a mixture of 4.2 g of methyl orthoformate and 60 ml of methanol and after stirring the mixture at 20° C. for 16 hours, the mixture was evaporated to dryness under reduced pressure. The residue was added to toluene and 0.5 ml of quinoline and the mixture was heated at 145° C. for 1 hour while distilling a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 methylene chloride-acetone mixture gave 1.8 g of N-(2'-carbethoxycyclopentyl)-3-methoxy-crotonamide melting at 74° C. The RMN spectra showed it to be the E isomer.