Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of BH3 in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq) was added to a stirring solution of 3-(4-phenylpiperidin-1-yl)propionitrile (5.10 g, 24.0 mmol) in anhydrous THF (20 mL) under argon at room temperature. The mixture was heated at reflux temperature for 4.5 hours and then cooled to room temperature. Aqueous 6 N HCl (130 mL) was added and stirring was continued for 2 hours at 50-70° C. The mixture was basified to pH 9 by addition of aqueous 6 N NaOH and extracted with EtOAc (100 mL) and CH2Cl2 (3×100 mL). The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0 M, 50 mL). The solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (60 mL) was added to the resulting white solid, 1 N NaOH was added until pH 10-11 was reached, and then the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined extracts were dried over magnesium sulfate and the solvents were evaporated, giving the desired product (4.50 g, 87%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[CH2:27]1[C:30]2([CH2:33][NH:32][CH2:31]2)[CH2:29][O:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:32]3[CH2:33][C:30]4([CH2:27][O:28][CH2:29]4)[CH2:31]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1NCC12COC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2(COC2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-oxa-6-azaspiro[3.3]heptane oxalate (CAN 1159599-99-1) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1(Br)[CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCC1
Yield: 42429.7 %

Procedure:
Sodium (10.3 g, 0.44 mmol) was dissolved in dry ethanol (300 ml) under a nitrogen atmosphere and to the cooled solution (0° C.) was added diethyl malonate (71 g, 0.44 mmol). After stirring for 15 minutes cyclobutyl bromide (60 g, 0.44 mmol) was added and the solution was heated to reflux overnight. The cooled mixture was evaporated and the residue was partitioned between water and ether. The ether layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was distilled to give diethyl cyclobutylmalonate (40 g, 42%) (bp. 74°-75° C. at 0.5 mm Hg).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].O=[C:13](CCCCCC)[C:14](O)=O>>[O:1]=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CCCCCCC(O)C(=O)O
Reactant: CCCCCCC(=O)C(=O)O
Product: CCCCCCC(=O)C(=O)OCC

Procedure:
The diglycerides and the triglycerides of 2-hydroxyoctanoic acid and 2-ketooctanoic acid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(O[CH:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C>[Cl-].[Cl-].[Zn+2].C(Cl)Cl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@@H:13]1[O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:18])[CH3:17]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
8.9 g of p-cresol, 8.9 g of penta-O-acetyl-D-galactopyranose and 0.56 g of ZnCl2 are mixed, heated to 160° C. and kept at this temperature for 30 minutes, according to HELFERICH's method. After cooling to 60° C., the reaction medium is taken up with 400 ml of CH2Cl2 and washed with twice 400 ml of water and then with a solution of sodium hydroxide (≈1N) until the aqueous phase is practically colourless. The organic phase is finally washed with twice 400 ml of water, dried over anhydrous sodium sulfate and then evaporated to dryness in a water bath (temperature: 35°-40° C.) to give a residue of 7.08 g (yield=70%). Chromatography on a column of 60H silica (solvent: hexane/ethyl acetate: 90/10 v/v) gives 2.9 g of the compound 1 (yield=29%) and 1.17 g of its β anomer (yield=12%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:19](OCC)(OCC)OCC>CN(C=O)C>[CH3:9][N:5]1[C:4](=[O:10])[C:3]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[N:1][C:2]=2[NH:7][C:6]1=[O:8]
Reactant: Cn1c(=O)[nH]c(N)c(NCc2ccccc2)c1=O
Reactant: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2ncn(Cc3ccccc3)c2c1=O
Temperature: 110 °C

Procedure:
To 6-amino-3-methyl-5-(phenylmethylamino)pyrimidine-2,4-dione (24.6 g=0.1 mol) in DMF (125 ml) at 60° C. add triethyl orthoformate (75 ml=0.45 mol). Heat to 110° C. for 5 hr, cool in ice, filter, and wash with methanol, then ether, to obtain the title compound, m.p. 268°-71° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:18]N1C(=O)CCC1=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cool a solution of 5-(tert-butyldimethylsilyloxy)-1H-indazole (300.00 g, 1.21 mol) in DCM (4.00 L) to 10° C. in a 10 L jacketed reactor vessel. To the resulting solution add N-iodosuccinimide (298.89 g, 1.33 mol) in portions over 0.5 hours. Stir the mixture at RT for 3 hours to give complete conversion as indicated by liquid chromatography mass spectrometry (LC-MS) and thin layer chromatography (TLC). Cool the mixture to 10° C. and quench with water (2.5 L). Transfer the mixture to a separatory funnel and extract the aqueous layer into DCM (2.5 L). Wash the combined organic extracts with a 10% aqueous sodium thiosulfate solution (5 L) and brine. Dry the organic solution over magnesium sulfate, filter and concentrate in vacuo to afford the title compound as an orange solid. Yield: 388 g (90%). MS (ES) m/z 375 [M+1]+.
Reaction SMILES: [C:1]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@@H:25]4[CH2:30][C@H:29]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[C@@H:28]([CH2:39][O:40][Si](CC)(CC)CC)[O:27][CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:48])=[CH:3][CH:2]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:26][O:27][C@H:28]([CH2:39][OH:40])[C@@H:29]([O:31][Si:32]([CH2:37][CH3:38])([CH2:33][CH3:34])[CH2:35][CH3:36])[CH2:30]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:48])=[CH:3][CH:2]=1
Reactant: CC[Si](CC)(CC)OC[C@H]1OC[C@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C[C@@H]1O[Si](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC[Si](CC)(CC)O[C@H]1C[C@@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CO[C@@H]1CO
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(((3R,5S,6R)-5-((triethylsilyl)oxy)-6-(((triethylsilyl)oxy)-methyl)tetrahydro-2H-pyran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (99 mg, 0.122 mmol) under nitrogen in DCM (2.0 mL) and methanol (2.0 mL) at −20° C. was added pyridinium-paratoluenesulfonic acid (6 mg, 0.024 mmol). After stirring for 2.5 hours at −20° C., the mixture was poured into saturated aqueous sodium bicarbonate (40 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant oil was chromatographed using a Biotage™ 20 g (2×10 g in series) silica gel cartridge eluted with 0-20% EtOAc in 1:1 Hexane/DCM over 15 column volumes, then 20-100% EtOAc over 10 column volumes. The desired SEM regiosiomeric products were combined and concentrated under reduced pressure to provide the title compound as a clear oil. LC-MS: calculated for C36H50ClN3O5Si2 695.30, observed m/e: 696.23 (M+H)+ (Rt 3.26/4 min, minor isomer), 696.23 (M+H)+ (Rt 3.39/4 min, major isomer).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.061 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH3:29][N:30]([CH2:32][CH2:33][CH2:34][Cl:35])[CH3:31].Cl>CN(C)C=O.O.C1(C)C=CC=CC=1>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:34][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reactant: CN(C)CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In one portion 1.5 g (4.8 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.6 g (5.3 mmol) of potassium t-butoxide in 25 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 5.2 ml (10.4 mmol) of a 2 M toluene solution of dimethylaminopropyl chloride was added. The mixture was warmed to room temperature and stirred for 4 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel, 25 g; eluents, 4:1 ration of methylene chloride:ether followed by 1:2:7 ratio of methanol:ether:methylene chloride) gave a colorless oil. The oil was dissolved in an excess of methanolic hydrogen chloride and the solution was concentrated at reduced pressure. Crystallization of the residue from a mixture of isopropanol and ether gave an orange solid, mp 258°-260°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O.C(Cl)Cl>CN(C)C=O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccn1
Reaction time: 5 h

Procedure:
2-pyrazine carboxylic acid, 104.3 gm, and 105.9 gm thionyl chloride were added to 800 ml methylene chloride and 5 ml dimethylformamide. The system was heated to reflux, at which point gas evolution took place. The system was stirred at reflux until gas evolution ceased, after about 5 hours, to give the 2-pyrazine carboxylic acid chloride. The solution was cooled to room temperature and transferred to a dropping funnel for use in Step (b) without further isolation.
Reaction SMILES: [CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@H:28]2[O:30][C@H:29]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl

Procedure:
A solution of Cryptophycin 27 (6.0 mg) in 1.0 mL of dry acetone was treated with 15 mg of potassium carbonate at 85° C. After 24 h the reaction mixture was filtered and the filtrate was evaporated. The residue was subjected to normal-phase HPLC on silica using 50/50 EtOAc/hexane to give Cryptophycin 39 (3.2 mg).
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[Cl:28]N1C(=O)CCC1=O.C(Cl)Cl>>[Cl:28][C:19]1[N:18]2[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][C:6]#[N:7])[CH:12]=3)=[N:14][C:15]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:16][C:17]2=[N:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2cc3ncc(Cl)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
3-Cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2) (46 mg, 0.13 mmol) and 1-chloropyrrolidine-2,5-dione (26 mg, 0.19 mmol) were suspended in DCM (1.3 mL, 0.13 mmol) and stirred at ambient temperature for 1 hour. This was immediately purified by silica chromatography using a 0-10% MeOH/EtOAc gradient to afford the title compound (18 mg, 34% yield) as a light yellow solid. MS (apci) m/z=393.2 (M+H).
Reaction SMILES: Cl[C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:10]([CH3:16])=[C:11]([C:12](=[O:15])[CH2:13][Cl:14])[C:3]=12.[NH2:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:30][CH2:29][CH2:28][CH:27]([NH:26][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:10]([CH3:16])=[C:11]([C:12](=[O:15])[CH2:13][Cl:14])[C:3]=12)[CH2:31][CH2:32][CH3:33]
Reactant: Cc1cc(C)c(-n2c(C)c(C(=O)CCl)c3c2=NC(C)NC=3Cl)c(C)c1
Reactant: CCCC(N)CCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC(CCC)NC1=c2c(C(=O)CCl)c(C)n(-c3c(C)cc(C)cc3C)c2=NC(C)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of compound (7) (730 mg, 2 mmol), 4-aminoheptane (250 mg, 2.2 mmol) and triethylamine (250 mg, 2.5 mmol) were stirred at ambient temperature for 16 hours. The solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to provide compound (8).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]([CH3:30])[C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])[C:6]=1[N+:27]([O-:29])=[O:28].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38]>C(#N)C>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:9]1[N:8]=[C:7]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])[C:6]([N+:27]([O-:29])=[O:28])=[C:5]([N:4]([CH2:3][C:2]([CH3:32])([CH3:31])[CH3:1])[CH3:30])[N:10]=1
Reactant: CN(C)CCCN
Reactant: CNC(=O)c1ccc(C)c(Nc2nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Solvent: CC#N
Product: CNC(=O)c1ccc(C)c(Nc2nc(NCCCN(C)C)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 3-{6-[(2,2-Dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-5-nitro-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (4.2 mg, 0.01 mmol) and 3-(Dimethylamino)propylamine (0.2 mL) in 2 mL of acetonitrile was heated with stirring at 80° C. for 16 h. The solvent was then evaporated under vacuum and the crude product was purified by flash chromatography to afford 2.8 mg of the product (Yield: 64%). MS (m/z) calcd for C24H38N8O3 (MH+), 487.3, found, 487.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:16].Cl[CH:18](Cl)[O:19]C.C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([CH:18]=[O:19])[C:3]=1[Cl:16]
Reactant: CCOC(=O)C1Oc2ccc(Cl)c(Cl)c2O1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1Oc2cc(C=O)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.52 ml of titanium tetrachloride are added dropwise to a mixture of 4.0 g of ethyl 4,5-dichloro-1,3-benzodioxole-2-carboxylate, 2.12 ml of dichloromethoxymethane and 60 ml of methylene chloride at -60° C. and the mixture is stirred at room temperature for 2 days. 2.1 ml of dichloromethoxymethane and 2.1 ml of titanium tetrachloride are added to the reaction mixture at -60° C. and the mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution, and the organic layer is separated. The organic layer is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 3.21 g of ethyl 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (76 mg, 88%), MS (ISP) m/z=347.5 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][NH:10][CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:13].Cl[CH2:15][CH2:16][S:17][CH3:18].[Br-].[Li+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][N:10]([CH2:15][CH2:16][S:17][CH3:18])[CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: CSCCCl
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSCCN1CCc2[nH]c(=O)n(C)c(=O)c2C1
Yield: 45 %

Procedure:
36.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]-pyrimidine-2,4-dione, 23 g of 1-chloro-2-methylsulfanylethane (97% pure), 17.4 g of lithium bromide and 27 g of ethyldiisopropylamine in 700 ml of dimethylformamide were stirred for 14 h at 50° C. After the reaction mixture had been concentrated under reduced pressure, the residue was taken up with 400 ml of water and 400 ml, of dichloromethane, the pH was adjusted to 8 with sodium bicarbonate, with stirring, and the mixture was worked up by extraction with dichloromethane and water. 23 g of 3-methyl-6-(2-methylsulfanylethyl)-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were obtained from the combined dichloromethane phases after drying, concentration and recrystallization of the residue from isopropanol.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[Cl:1])[CH2:18][CH2:19]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cl
Reactant: COc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1OC
Product: COc1ccc(CCN2CCC(NC(=O)c3ccccc3Cl)CC2)cc1OC

Procedure:
The title compound as its hydrochloride (m.p. 250°-2° C.) was prepared in the same way as for the compound of Example 5 but using o-chlorobenzoyl chloride in place of benzoyl chloride. (Found: C, 60.2; H, 6.1; N, 6.3. C22H26Cl N2O3.HCl requires C, 60.3; H, 6.2; N, 6.4%).
Reaction SMILES: C1C=CC=CC=1.[CH:7]([N:10]1[CH2:13][CH:12](CS([O-])(=O)=O)[CH2:11]1)([CH3:9])[CH3:8].[Na].[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]#[N:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1(C)C=CC=CC=1>[C:29]1([C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH:12]2[CH2:13][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:11]2)[C:27]#[N:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CC(C)N1CC(CS(=O)(=O)[O-])C1
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 1.5 h

Procedure:
The benzene solution of 1-isopropyl-3-azetidinylmethane sulfonate was added dropwise to the stirred refluxing toluene mixture containing the sodium salt of diphenylacetonitrile and refluxing continued for 1.5 hours after addition. The cooled reaction mixture was treated with water, the layers separated, and the organic layer extracted with dilute hydrochloric acid and water. The combined extracts were basified using dilute sodium hydroxide and the base insoluble material extracted with chloroform. The dried extract was concentrated and the residual material was recrystallized from isooctane. The α,α-diphenyl-α-(1-isopropyl-3-azetidinyl)acetonitrile weighed 142 g. (56%) and melted at 93°-95° C.