Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([NH:25][C:26]3[C:29](=[O:30])[C:28](=[O:31])[C:27]=3OC(C)C)[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1.[CH2:36]([NH2:39])[CH2:37][CH3:38].CN(C=O)C>CO.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([NH:25][C:26]3[C:29](=[O:30])[C:28](=[O:31])[C:27]=3[NH:39][CH2:36][CH2:37][CH3:38])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)Nc1c(OC(C)C)c(=O)c1=O
Reactant: CCCN
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1c(NC(Cc2ccc3nc(-c4c(Cl)cccc4Cl)ccc3c2)C(=O)OC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[(2-isopropoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propanoate 116 (690 mg) in CH3OH (20 ml) are added 132 μl of n-propylamine. After addition of DMF (15 ml), the solution is stirred at RT overnight. The evaporation of CH3OH gives a DMF residue that is diluted in water (200 ml) and stirred overnight. The solid is filtered, washed with water then with MeOH, diluted in DMF, and n-propylamine (150 μl) is added to drive the reaction to completion. The solution is stirred at RT for 48 h, then poured into water. DMF is evaporated and the resulting solid is filtered, washed with water and dried. The product is purified by HPLC/MS (eluent: CH3CN/water/TFA, 8 minutes gradient from respectively 5/95/0.1 to 95/5/0.1). CH3CN is evaporated and water is added to the residue. The resulting solid is filtered and dried to give methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-{[3,4-dioxo-2-(propylamino)-1-cyclobuten-1-yl]amino}propanoate 123.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Br)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Br)cc1
Yield: 84.8 %

Procedure:
Using 3.86 g of (4-bromobenzyl)malononitrile, 25 ml of N,N-dimethylformamide, 0.72 g of sodium hydride (60% in oil), and 3.20 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 4.61 g of 2-(4-bromobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (9)).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](NCCCC)[N:13]=2)[CH2:9]1)(C)(C)C.C(OC(=O)NC1CN(C2C=CN=C(Cl)N=2)C1)(C)(C)C.[CH2:43]([NH2:47])[CH2:44][CH2:45][CH3:46]>CC(O)C>[NH2:7][CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:46][CH2:45][CH2:44][CH2:43][NH2:47])[N:13]=2)[CH2:11]1
Reactant: CCCCNc1nccc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Reactant: CCCCN
Agent: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Solvent: CC(C)O
Product: NCCCCc1nccc(N2CC(N)C2)n1
Temperature: 95 °C
Yield: 92 %

Procedure:
[1-(2-Chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester To a flask containing 2,4-dichloropyrimidine (1.6 g, 10.7 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) in i-PrOH (40 mL) was added azetidin-3-yl-carbamic acid tert-butyl ester monohydrochloride (2.1 g. 12.2 mmol). The reaction mixture was heated to 70° C. for 72 h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by flash chromatography on SiO2 (100% hexane increasing gradient to 60% EtOAc-Hexane) to yield two isomeric products. The minor upper Rf product was obtained as a white solid (326 mg, 11%), and the desired major lower Rf product was also obtained as a white solid (2.1 g, 69%). [1-(2-Butylamino-pyrimidin-4-yl)azetidin-3-yl]-carbamic acid tert-butyl ester. To a solution of [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in i-PrOH (3.0 mL) was added butylamine (600 μL, 6.0 mmol). The reaction mixture was heated to 95° C. in a sealed tube for 36-48 h followed by cooling to room temperature. The reaction mixture was then concentrated and the crude residue purified by flash chromatography on SiO2 using (100% EtOAc increasing the gradient gradually to 5% 2M NH3-MeOH) to yield the desired product (260 mg, 92%). [4-(3-Amino-azetidin-1-yl)-pyrimidin-2-yl]-butyl-amine. To a solution of [1-(2-butylamino-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in formic acid (4 mL) was added 6N HCl (300 μL). The reaction mixture was stirred at room temperature for 15-30 minutes. Then, MeOH (10 mL) was added and stirred for 10 minutes. The contents were then concentrated and the crude residue purified by flash chromatography on SiO2 using an increasing gradient of (0 to 10% NH3/MeOH in CH2Cl2) to yield the desired product (225 mg, 98%) as the free base. MS (ESI): mass calcd. for C11H19N5, 221.3 m/z found, 222.2 [M+H]+. 1H NMR (CD3OD): 7.61 (d, J=7.3, 1H), 5.99 (d, J=7.1, 1H), 4.6-4.7 (m, 2H), 4.28-4.48 (m, 3H), 3.40 (bs, 1H), 1.54-1.62 (m, 2H), 1.31-1.41 (m, 2H), 0.90 (t, J=7.4, 3H). The compounds in Example 85 through Example 94 were prepared using methods analogous to those described for Example 84.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[CH:32]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K26) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].B(F)(F)F>C(O)(=O)C>[OH:19][C:18]1[N:20]=[C:21]([OH:22])[C:23]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:2]=2[Cl:1])=[CH:24][N:17]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1Cl
Agent: FB(F)F
Solvent: CC(=O)O
Product: Oc1ncc(C(c2ccccc2)c2ccc(Cl)cc2Cl)c(O)n1

Procedure:
One method of preparation involves the reaction of, for example, 2,4-dichlorobenzhydrol with uracil in glacial acetic acid in the presence of BF3. This yields the 2,4-dihydroxy-5-(2,4-dichlorobenzhydryl)pyrimidine. Treatment with phosphorus oxychloride in excess yields the 2,4-dichloro-5-(2,4-dichlorobenzhydryl)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([CH:23]=1)[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:16]([NH:15][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[O:14])[CH:17]=[CH:18][C:19]=1[O:24][CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])#[N:22]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Yield: 30.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 5-fluoro-2-methyl-1H-indole-3-carboxylic acid (1 g) and 5-amino-2-neopentyloxybenzonitrile (1.1 g), the title compound (0.6 g) was obtained. melting point: 169-171° C.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>C(O)C>[Br:25][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(Br)c3)cs2)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution (5 mL) of the compound (1.1 g, 5.16 mmol) obtained in Example 1b in ethanol was added 2-bromo-1-(3-bromophenyl)ethanone (1.6 g, 5.67 mmol), and the mixture was heated under reflux for 3 hr. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The obtained crude product was washed with ethyl acetate to give the title compound (1.44 g, 71%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH3:21])[C:10](=[O:22])[C:9]=2[N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH3:21])[C:10](=[O:22])[C:9]=2[N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2c(-c3cccc(Cl)c3)c3ccc(C=O)nc3n(CC)c2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(c2c(-c3cccc(Cl)c3)c3ccc(CO)nc3n(CC)c2=O)CC1
Reaction time: 0.25 h

Procedure:
To an ethanol solution of ethyl 1-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]piperidine-4-carboxylate was added sodium borohydride under ice cooling, followed by stirring for 15 minutes. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain ethyl 1-[4-(3-chlorophenyl)-1-ethyl-7-hydroxymethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]piperidine-4-carboxylate as a yellow oily substance. MS: 470.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br.[Br:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: NCCBr
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCBr)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred mixture of 4-chlorobenzenesulfonyl chloride (5.0 g, 23.7 mmol) and 2-bromoethylamine hydrobromide (5.4 g, 26.3 mmol) in anhydrous methylene chloride (50 mL) at 0° C. was slowly added N,N-diisopropylethyl amine (8.6 mL, 52.1 mmol) and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was washed sequentially with water, 2N aqueous hydrochloric acid, saturated aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo to afford a white solid (7 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, 2H, J=8.7 Hz), 7.52 (d, 2H, J=8.7 Hz), 4.96 (s, 1H), 3.50-3.30 (m, 4H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[NH:43]1[CH:46]([C@@H:47]2[CH2:51][C@H:50]([SH:52])[CH2:49][N:48]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:45][C:44]1=[O:66]>>[NH:43]1[CH:46]([C@@H:47]2[CH2:51][C@H:50]([S:52][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:49][N:48]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:45][C:44]1=[O:66]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 70.9 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (153 mg, 0.27 mmol) and (2S,4S)-2-(2-azetidinon-4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (90 mg, 0.26 mmol, compound of Reference Example 4) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A (128 mg, yield: 70.9%).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][C:11]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:12][C:13](N)=[C:8]3[C:7]([CH3:21])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.N([O-])=[O:23].[Na+].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O.O>[CH:1]1([N:5]2[C:9]3=[N:10][C:11]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:12][C:13](=[O:23])[C:8]3=[C:7]([CH3:21])[NH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(C2CCC2)c2nc(-c3ccncc3)nc(N)c12
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1[nH]n(C2CCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
To a solution of 1-cyclobutyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-amine (1.5 g, 5.3 mmol) in 75% aqueous sulfuric acid (25 ml) cooled in an ice-bath was added sodium nitrite (4.0 g, 58.0 mmol) in water (3 ml). The reaction mixture was warmed to room temperature, stirred for 24 hours and then warmed to 50° C. for 2 hours. The mixture was cooled in an ice-bath and sodium nitrite (4.2 g, 61.0 mmol) in water (5 ml) was added. The reaction mixture was warmed to room temperature and stirred for 24 hours. The mixture was poured onto ice-water and neutralized with K2CO3. The product was collected by filtration and recrystallized from isopropanol to afford 1.2 g (81%) of 1-cyclobutyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. 289°-90° C. when dried at 45° C. in high vacuum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.C1COCC1.[C:16]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>CCN(CC)CC>[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=2)=[O:8])[CH:21]=[CH:22][CH:23]=1)#[CH:17]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Temperature: 55 °C
Yield: 71.9 %

Procedure:
A dry 25 mL flask was charged with 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.135 g, 0.854 mmol) and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.100 g, 0.854 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature. The reaction was extracted twice with EtOAc (5 mL) and water (10 mL) followed by saturated aqueous NaHCO3 (˜10 mL). The combined organic layers were dried over anhydrous Na2SO4 (s) and then concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 60%). The product containing fractions were concentrated to give the title compound as a tan solid (147 mg. 72%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 59.2 %

Procedure:
A mixture of 0.0406 g (0.00013 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.0191 g (0.000138 mole) of 4-aminobenzoic acid, 0.7 mL of ethanol, 2.8 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled and the white precipitate which formed was collected by filtration to give 0.0315 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-50a) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](Cl)[C:19]([CH3:26])=[C:18]([CH3:27])[N:17]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:19]([CH3:26])=[C:18]([CH3:27])[N:17]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(C)OC(=O)NCCOCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (23.1 g, 113 mmol) in N,N-dimethylformamide (100 mL) was added over a 1 hour period to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25.02 g, 113 mmol) in N,N-dimethylformamide (400 mL) containing triethylamine (24 mL, 175 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The N,N-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting sequentially with 3/1 hexanes/ethyl acetate (1.2 L), 2/1 hexanes/ethyl acetate (1.2 L), and 1/1 hexanes/ethyl acetate (1 L)) to provide 20.67 g of tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14]1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.N1C=CC=CC=1.F>C(#N)C>[OH:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc(=O)n(C(C)(C)CO[Si](C)(C)C(C)(C)C)c1
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(=O)n(C(C)(C)CO)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of tert-butyl 1-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridin-3-ylcarbamate (800 mg, 2017 μmol) in ACN (10 mL) was added hydrogen fluoride pyridine (484 μl, 24206 μmol). The reaction mixture was stirred for 1 h and quenched with dry silica. The solvent was removed under reduced pressure and the product purified on silica (40 g) eluting with 0-5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 283. Calc'd exact mass for C14H22N2O4: 282.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:9]1[S:10][C:11]([C:14](OCC)=[O:15])=[CH:12][N:13]=1>C1COCC1>[CH3:7][N:8]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:9]1[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cnc(N(C)C2CCCCO2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1ncc(CO)s1)C1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
LiAlH4 (425 mg, 11.20 mmol) was added to a solution of ethyl 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carboxylate (2.02 g, 7.47 mmol) in THF (20 mL) at 0° C. in small portions. After stirring at 0° C. for 30 min, the reaction was quenched slowly by H2O (1 mL), 5% NaOH (3 mL) and again H2O (5 mL). Then AcOEt was added. The reaction mixture was dried with Na2SO4 and filtered through celite. The filtrate was concentrated and purified by column chromatography (30%-50% AcOEt/PE gradient), yielding (2-(methyl-(tetrahydro-2H-pyran-2-yl)amino)thiazol-5-yl)methanol (1.5 g, 93%) as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[F:13][C:14]([F:22])([F:23])[C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:10](=[O:12])[CH2:9][C:7]#[N:8])=[CH:20][CH:21]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Phosphorus pentachloride (83.3 g; 0.40 mol) is introduced into a solution of cyanoacetic acid (34.0 g; 0.40 mol) in 1,2 l of dichloromethane and the mixture is heated under reflux for 30 minutes. 4-Trifluoromethylaniline (41.0 g, 0.26 mol) is then introduced into said mixture within about 10 minutes and the reaction mixture is heated under reflux for 2 hours. After cooling to 20° C., the reaction mixture is treated with 500 ml of water and then stirred for 30 minutes. The aqueous phase is neutralized with sodium carbonate and the precipitate is filtered off with suction. The filter cake is washed with water and dried. 55.2 g of N-(4-trifluoromethylphenyl)cyanoacetamide are thus obtained in crystalline form. Melting point: 194°-195.5° C.
Reaction SMILES: [CH:1]1([C:9]([O:11]CC)=[O:10])[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[OH-].[Na+]>O>[CH:1]1([C:9]([OH:11])=[O:10])[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: CCOC(=O)C1CC12CCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC12CCCCC2
Temperature: 25 °C

Procedure:
The product from Example 1A in 100 mL of water was treated with NaOH (11.4 g, 0.29 mol) and heated at reflux for 8 hours. The reaction mixture was allowed to cool to ambient temperature and extracted with diethyl ether (2×100 mL). The aqueous layer was acidified to pH 3 by careful addition of concentrated HCl and extracted with diethyl ether (3×100 mL). The ethereal extracts were combined and concentrated under reduced pressure to afford an oil that was distilled under vacuum (120° C., 60 torr) to provide the title compound as a clear oil. 1H NMR (CDCl3, 300 MHz) δ 11.95 (s, 1H), 1.30-1.60 (m, 11H), 1.13 (dd, 1H), 0.90 (dd, 1H); 13C NMR (CDCl3, 100 MHz) δ 179.6, 37.5, 32.1, 28.8, 26.0, 25.9, 25.6, 21.6; MS m/z 172 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][OH:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: NCCO
Reactant: Clc1ncc(I)c(Cl)n1
Product: OCCNc1nc(Cl)ncc1I
Yield: 83 %

Procedure:
In the reaction of 2,4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol) with 2-amino-ethanol (480 mg, 7.9 mmol) according to procedure 2, the desired product is obtained in 83% yield (1.8 g) after chromatographic purification (silica gel, dichloromethane/methanol (0% to 20% methanol)).