Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([CH:31]=1)[CH:29]=[O:30].C(O)(=O)C>O1CCCC1>[OH:30][CH:29]([C:28]1[CH:31]=[C:24]([O:23][CH2:22][O:21][CH3:20])[CH:25]=[CH:26][C:27]=1[N+:32]([O-:34])=[O:33])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1cc(OCOC)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 135.8 %

Procedure:
1.5N butyllithium (14.9 ml, 22.4 mmole) was added under the argon atmosphere to a solution of diisopropylamine (3.3 ml, 23.8 mmole) in tetrahydrofuran (40 ml) at -78° C., and the mixture was stirred for 1.5 hours. Next, a solution of ethyl propiolate (2.7 ml, 26.8 mmole) in tetrahydrofuran (10 ml) and a solution of 5-methoxymethoxy-2-nitrobenzaldehyde (3.15 g, 14.9 mmole) in tetrahydrofuran (10 ml) were added in this sequence, and the reaction mixture was stirred at -78° C. for further 1 hour. After a solution of acetic acid (2.6 ml, 46.2 mmole) in tetrahydrofuran (10 ml) was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(5-methoxymethoxy-2-nitrophenyl)-2-butynoate as an oil (6.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:22][O:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:18]=1[O:19][CH3:20])[O:6][CH2:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: COc1cc(OCC(=O)N2CCNCC2)cc(OC)c1OC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(OCC(=O)N2CCN(Cc3ccc(C#N)cc3)CC2)cc(OC)c1OC
Yield: 70.5 %

Procedure:
To a solution of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonylpiperazine (0.22 g, 0.70 mmol) in 1% acetic acid in methanol (6 mL) was added 4-cyanobenzaldehyde (0.33 g, 2.5 mmol) and sodium cyanoborohydride (0.093 g, 1.4 mmol). The resultant mixture was stirred at ambient temperature for 1.5 hours and the mixture was then concentrated of volatiles in vacuo. Residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 solution, water, and then brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.21 g of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-4-(4-cyanobenzyl)piperazine, a compound of formula (Ib), as a clear oil: NMR (CDCl3) 7.6 (d, 2), 7.4 (d, 2), 6.2 (s, 2), 4.6 (s, 2), 3.8 (s, 6), 3.75 (s, 3), 3.6 (m, 4), 3.5 (s, 2), 2.2 (m, 4) ppm.
Reaction SMILES: FF.[C:3]([OH:8])(=[O:7])[C:4]([CH3:6])=[CH2:5].[F:9][C:10](=[C:15]([F:17])[F:16])[CH2:11][CH2:12][CH2:13]O>>[C:3]([O:8][CH2:13][CH2:12][CH2:11][C:10]([F:9])=[C:15]([F:17])[F:16])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)O
Reactant: OCCCC(F)=C(F)F
Agent: FF
Product: C=C(C)C(=O)OCCCC(F)=C(F)F
Yield: 43 %

Procedure:
A fluorine based polymer was also tested to provide a plasma reactive functionality. The fluorine based monomer used to form the polymer was synthesized by the reaction of methacrylic acid and 4,5,5-trifluoropent-4-en-1-ol to yield 4,5,5-trifluoropent-4-enyl methacrylate. This yield was about 43%. The chemical structure of 4,5,5-trifluoropent-4-enyl methacrylate is shown in Formula (IV):
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1.C(N(CC)CC)C.[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH:39][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:13]1)=[O:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CCNC(=O)c1ccccc1)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (80 mg, 0.13 mmol) prepared in Example 121a was reacted with triethylamine and benzoyl chloride (22 mg, 0.16 mmol) in tetrahydrofuran, followed by the reaction with aqueous HCl solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%)
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.C([NH2:18])=O.C[O-].[Na+].CCCCCC>Cl>[CH3:15][C:11]1[CH:12]=[N:13][C:14]2[CH:5]([C:3]([NH2:18])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: NC=O
Reactant: COC(=O)C1CCCc2cc(C)cnc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Reaction time: 1 h

Procedure:
A mixture of methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (25 g., 0.13 m), formamide (11.6, 0.26 m) and sodium methoxide (from 2.99 g., 0.13m sodium) was heated with stirring in an oil bath at 120° for 1 hour. The reaction mixture was further heated at 100° for 3 hours under reduced pressure (15 mm Hg). The cooled reaction mixture was diluted with 2N HCl to give an acidic solution which was extracted with ethylacetate (2 × 50 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 9.0 with solid Na2CO3, saturated with NaCl and extracted with chloroform (3 × 100 ml.). The combined extracts were dried and evaporated to give a pale yellow oil which solidified on trituration with n-hexane. Recrystallisation from ethylacetate gave the title compound as colourless cubes (18.6 g., 88%) m.p. 110°. Found: C, 69.6; H, 7.4; N, 14.4%. C11H 14 N2O requires: C, 69.5; H, 7.4; N, 14.7%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:18]=O.Cl.[CH3:21][NH:22][CH3:23]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[O:14][C:15]([CH2:21][N:22]([CH3:18])[CH3:23])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)Nc1ccc(CCc2ccco2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CCc2ccc(CN(C)C)o2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(4-acetamidophenyl)ethyl]furan (0.50 g), 37% formalin (0.26 ml) and dimethylamine hydrochloride (0.27 g) in acetic acid (5 ml) was stirred at ambient temperature for 1 hour and at 50° C. for further 1 hour. The solvent was evaporated in vacuo. The residue was mixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 2-[2-(4-acetamidophenyl)ethyl]-5-dimethylaminomethylfuran (0.57 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1>>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:42][C:41]1[CH:40]=[CH:39][C:38]([C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:47][CH:48]=2)=[CH:37][C:36]=1[C:33]1[CH:34]=[CH:35][N:30]=[N:31][CH:32]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Yield: 79.1 %

Procedure:
Prepared according to Preparation 22 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 19, 165 mg, 0.379 mmol) and 3-Pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-ol (Preparation 8, 120 mg, 0.379 mmol) to afford the title compound as a solid (219 mg, 79%).
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][CH3:21])=[N:17][CH:18]=1>C(Cl)Cl.P(Cl)(Cl)(Cl)=O>[Cl:1][C:18]1[C:13]([Cl:12])=[CH:14][CH:15]=[C:16]([CH2:19][O:20][CH3:21])[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCc1ccc(Cl)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
3-chloroperbenzoic acid (80%, 4.83 g, 13.96 mmol) was added portion-wise to a solution of 5-chloro-2-(methoxymethyl)pyridine (Preparation 57, 2 g, 12.69 mmol) in DCM (50 mL) at 0° C. The reaction was stirred for 18 hours at room temperature. The reaction mixture was quenched with 2M aqueous sodium hydroxide (25 mL) and brine (25 mL) and stirred vigorously. The organic layer was collected, washed with 2M aqueous sodium hydroxide (2×10 mL), water (10 mL), dried over sodium sulfate and concentrated in vacuo. A portion of the residue (100 mg, 0.576 mmol) was stirred in phosphoryl chloride (2 mL) at 80° C. for 2 hours. The reaction was concentrated in vacuo and vigorously stirred in DCM (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) for 5 hours. The organic layer was collected dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM to afford the title compound (38 mg, 34%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][N:2]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(S(C)(=O)=O)cc1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (100 mg, 0.287 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (150 mg, 0.861 mmol) and K2CO3 (158 mg, 1.142 mmol) in DMF (2 mL) was stirred at 120° C. overnight and then cooled to ambient temperature, poured into water, and extracted with EtOAc. The EtOAc layer was concentrated, purified by preparative TLC to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:27][N:28]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=3)[CH2:29]2)=[CH:23][CH:22]=1
Reactant: CNC(=O)c1cccc(Nc2ccnc(Cl)n2)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ccnc(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Yield: 75.8 %

Procedure:
To 3-(2-chloropyrimidin-4-ylamino)-N-methylbenzamide (90.0 mg, 0.343 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (73.3 mg, 0.360 mmol) in a disposable sealed tube in 2-propanol (2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.028 mmol). The resulting reaction mixture was heated at 84° C. for 48 h, cooled to RT, filtered, rinsed with IPA, and concentrated under reduced pressure to afford 3-(2-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide (102.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[H-].[Na+].[N+:31](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.[C:45](=[O:52])(OCC)[O:46][CH2:47][CH3:48]>>[CH2:47]([O:46][C:45]([C:10]1([NH2:31])[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:21][N:22]=[C:11]12)=[O:52])[CH3:48]
Reactant: CCc1cc2c(s1)-n1c(nnc1C1CCCCC1)CN=C2c1ccccc1Cl
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1(N)N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C3CCCCC3)nnc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
4-(2-Chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (3.4 g) and sodium hydride (0.56 g) were added to diethyl carbonate (50 ml) and the mixture was heated. After refluxing for 1 hour, the reaction mixture was cooled to 20° C., and O-(2,4-dinitrophenyl)-hydroxylamine (2.1 g) was added thereto. The mixture was stirred for 2 hours. After the reaction, the reaction mixture was poured into ice water, and the diethyl carbonate layer was separated. The diethyl carbonate layer was washed twice with water, and dried over anhydrous magnesium sulfate. Diisopropyl ether was added to the residue obtained by distilling away diethyl carbonate under reduced pressure. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 2.1 g of ethyl(6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate having a melting point of 140°-145° C. Ethyl(6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate (1.8 g) was dissolved in a mixture of ethanol (60 ml) and water (20 ml) and barium hydroxide 8 hydrate (1.14 g) was added thereto. The mixture was stirred at room temperature for 24 hours. The solvent was distilled away under reduced pressure and water (50 ml) was added thereto. The mixture was adjusted to pH 2 with 1N hydrochloric acid and stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography. The solvent was distilled away and the crystals obtained were recrystallized from diisopropyl ether to give 1.0 g of 6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine having a melting point of 175°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:23]=[C:17]1[CH:16]([N:15]2[C:5](=[O:7])[C:4]3[C:3](=[C:2]([CH3:1])[CH:12]=[CH:11][C:10]=3[CH3:13])[C:8]2=[O:9])[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1ccc(C)c2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
2-(2,6-Dioxopiperid-3-yl)-4,7-dimethylisoindoline-1,3-dione was prepared by the procedure of Example 1 from 3,6-dimethylphthalic anhydride (220 mg, 1.25 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (204 mg, 1.24 mmol) and sodium acetate (110 mg, 1.34 mmol) in acetic acid (10 mL). The product is a white solid (200 mg, 56% yield): mp 263.0-265.0° C.; 1H-NMR (DMSO-d6) δ 2.01-2.07 (m, 1H, CHH), 2.50-2.89 (m, 9H, CH3, CHH, CH2), 5.10 (dd, J=5.1, 12.4 Hz, 1H, NCH), 7.52 (s, 2H, Ar), 11.12 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 16.82, 22.02, 30.97, 48.59, 128.01, 135.04, 136.58, 167.68, 169.98, 172.83.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[O:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]([NH2:17])=[S:16].CS(C)=O.Cl>O1CCCC1.C(OCC)(=O)C>[NH:17]=[C:15]1[N:14]([CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][O:8]2)[C:4]([CH3:5])=[C:3]([C:2](=[O:7])[CH3:1])[S:16]1
Reactant: NC(=S)NC[C@H]1CCCO1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1sc(=N)n(C[C@H]2CCCO2)c1C
Temperature: 40 °C

Procedure:
To a solution of pentane-2,4-dione (451 mg, 4.5 mmol) and the product from Example 278A (786 mg, 4.5 mmol) in tetrahydrofuran (5 mL) was added a mixture of dimethylsulfoxide (0.64 mL, 9.0 mmol) and concentrated HCl (0.75 mL, 9.0 mmol). The reaction mixture was heated at 40° C. for 12 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic extract was dried (Na2SO4), filtered and concentrated to afford the title compound. MS (ESI) m/z 241 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:5]1[C:10](=[O:11])[N:9]2[C@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C@:14](N=[N+]=[N-])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[C:32]([O:36][C:37](=[O:80])[CH2:38][C@@]1(C)C2=NC=C(N(CC=C)C(OCC3C=CC=CC=3)=O)C(=O)N2[C@@H](C(N(C(OC(C)(C)C)=O)C2C=CC=CC=2)=O)C1)([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([N:4]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C@:14]([CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:80])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)C[C@@]2(C)N=[N+]=[N-]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)O)C[C@@]2(C)CC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
According to the procedure for the preparation of 18f, intermediate 38b (413.9 mg, 0.62 mmol) was deprotected to afford 273.9 mg (89%) of intermediate 38c. MS (ESI) 498.4 (M+H+), 496.2 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.CCO.[NH3:28].[NH4+].[Cl-]>C(Cl)(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]([NH2:28])=[NH:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N=C(N)c1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reaction time: 72 h

Procedure:
4-[3-(2-Chloro-pyrimidin-4-yloxy)-phenoxymethyl]-benzonitrile (169 mg; 0.5 mmol; Example 6; Stage 6.1) is dissolved in CHCl3 (5 mL) and EtOH (0.5 mL) and cooled to 0° C. At this temperature, HCl gas is gently bubbled through during 20 min. The reaction mixture is kept at 4-5° C. for 72 h. After this time, pentane (10 mL) is added and stirring is continued for 1 h at 0° C. The supernatant is removed by decantation, and the residue (intermediate product) is suspended in MeOH (2 mL). At 0° C., NH3 (0.375 mL 2M solution in MeOH; 0.75 mmol) and NH4Cl (27 mg; 0.5 mmol) are added and the mixture is stirred at rt for 5 h 15 min. More NH3 (0.375 mL 2M solution in MeOH; 0.75 mmol) is added, as well as diethyl ether. After removal of the solvents under reduced pressure, the residue is taken up in EtOAc/water, extracted with water and brine and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to obtain a small amount of the title compound as free base. Since most of the product is in the aqueous layer, the latter is lyophilized and the residue purified twice over reversed phase silica (Lichroprep RP18; 15-25 μm), eluting with H2O/acetonitrile (0->43%) (0.1% TFA in both). After concentration of the solution, the title compound is isolated by lyophilization as TFA salt; ES-MS: [M+H]+; m/z=355; HPLC: AtRet=3.43 min.
Reaction SMILES: CC([N:5]([C:9]([CH3:29])([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[CH3:27])=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:28])([CH3:29])[NH2:5])=[CH:14][CH:15]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cc2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
1,1-dimethylethyl[2-({4-[(2,3-dimethylphenyl)oxy]phenyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 75, 109 mg) was dissolved in 4.0 mL of dichloromethane and then TFA (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the removal of the volatiles, the residue was charged on a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M solution in MeOH). Evaporation afforded 68 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1>[Ni].CO>[C:2]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1)#[N:1].[NH3:1]
Reactant: NCCc1cccc(Nc2ncnc3[nH]nc(Nc4ccccc4)c23)c1
Agent: [Ni]
Solvent: CO
Product: N
Product: N#CCc1cccc(Nc2ncnc3[nH]nc(Nc4ccccc4)c23)c1

Procedure:
There is obtained from 4-(3-cyanomethyl-phenylamino)-3-phenylamino-1H-pyrazolo[3,4-d]pyrimidine (see Example 8), by reduction with Raney nickel in a solution of ammonia in methanol, 4-(3-[2-amino-ethyl]-phenylamino)-3-phenylamino-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[F:16][C:17]([F:27])([F:26])[C:18](=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:17]([F:16])([F:26])[F:27])[NH:10][C:11]3=[N:12][NH:13][CH:14]=[C:15]23)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1cccc(Cl)c1

Procedure:
The title compound was prepared from 3-chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.