Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.Cl.[C:21]([NH:25]N)([CH3:24])([CH3:23])[CH3:22].C(O)C>O>[C:21]([N:25]1[C:4]([C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Cl:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[N:13]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccccc1Cl
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A mixture of 2.82 g of ethyl 2-(2-chlorobenzoyl)-3-(N,N-dimethylamino)acrylate (a compound described in JP-A 7-101940), 1.25 g of tert-butylhydrazine hydrochloride and 10 ml of ethanol was heated to reflux for 8 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.48 g of ethyl 1-tert-butyl-5-(2-chlorophenyl)-1H-pyrazole-4-carboxylate of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:22]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH2:28][CH2:29]2)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)C(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of trans-4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (8.5 g, 32.8 mmol) in DCM (100 mL) 1,1-carbonyldiimidazole (4.87 g, 30.1 mmol) was added and the reaction was left stirring for 2 hours. Then isobutyryl-piperazine (6.95 g, 27.3 mmol) was also added and the reaction was left stirring for 16 h at room temperature. The mixture was diluted with 50 mL of H2O, the organic phase collected and the solvent removed under reduced pressure. The residue was washed with 1N NaOH solution and the precipitate was filtered, affording 8.7 g (21.9 mmol) of [4-(4-Isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester. The product obtained was dissolved in 100 mL of DCM and H2SO4 (2.92 mL, 54.9 mmol) was added. The reaction was stirred for 18 hours and the mixture was washed with 50 mL of 15% NaOH solution, the organic phase was collected and concentrated under reduced pressure. 3.85 g of the titled product were obtained (yield=48%).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].O.O.[F-].[K+].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH2:9].[CH3:8][C:7]1[NH:6][C:5](=[O:9])[NH:4][C:3](=[O:10])[C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Agent: [F-]
Agent: [K+]
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccccc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 20.5 g (0.10 mole) of 5-bromo-6-methyl-2,4(1H, 3H)-pyrimidinedione and 10.3 g (0.11 mole) of potassium fluoride dihydrate in 150 ml of 1-phenylpiperazine was heated under reflux at 105° for 72 hours and cooled. The reaction mixture was poured into 200 ml of ice water. The solid was collected, washed with water, and recrystallized from methanol to give 7.12 g of the product as a white solid, mp>300° C.
Reaction SMILES: C1COCC1.[H-].[Na+].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:27])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)[CH:12]=O.[CH3:28][CH2:29][O:30][C:31]([CH3:33])=[O:32]>O>[CH3:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:33]/[C:31]([O:30][CH2:29][CH3:28])=[O:32])[CH:14]=[C:15]([CH3:27])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C=O)cc(C)c1Oc1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cc(C)c(Oc2ccc([N+](=O)[O-])cn2)c(C)c1
Reaction time: 1 h

Procedure:
To a THF (100 mL) solution of triethyl phosphonoacetate (44.0 mL) was slowly added NaH (60% dispersion in mineral oil, 8.8 g) at 0° C. After stirring for 1 hour, a THF (200 mL) solution of 3,5-dimethyl-4-[(5-nitropyridin-2-yl)oxy]benzaldehyde (54.5 g) was added to the reaction mixture. After stirring at room temperature for 2 hours, AcOEt and H2O were added to the reaction mixture. The resulting precipitate was collected to give ethyl (E)-3-{3,5-dimethyl-4-[(5-nitropyridin-2-yl)oxy]phenyl}prop-2-enoate as a white powder (40.9 g).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(O)C>CCOCC>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Br)cc1
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)CNc2ccc(Br)cc2)cc1
Reaction time: 16 h

Procedure:
p-Cyanophenacyl bromide (29.8 g, 0.138 mole) and p-bromoaniline (47.13 g, 0.266 mole) were combined with 53.2 g of absolute ethanol and stirred 16 hours. The solution was then diluted with ether and the resulting slurry filtered. The filter cake was repulped in 500 ml ether, filtered, repulped in 400 ml acetone and again filtered to yield title product: 17.14 g (40.9%); m.p. 154°-157°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:19]([Si:23]([CH3:26])([CH3:25])[Cl:24])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[ClH:24].[C:19]([Si:23]([CH3:26])([CH3:25])[O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCC1CCNCC1
Product: Cl
Temperature: 0 °C
Reaction time: 21 h
Yield: 79.5 %

Procedure:
4-Piperidineethanol (2 g, 15.5 mmol) and N,N-diisopropylethylamine (3.00 g, 4.06 ml, 23.2 mmol) were combined with dichloromethane (50 mL) to give a colorless solution. t-Butyldimethylchlorosilane (2.8 g, 18.6 mmol) in dichloromethane (30 mL) was added to this solution during 15 min at 0° C. The reaction mixture was stirred for 2.5 h at 0° C. and afterwards for 21 h at room temperature. Subsequently the reaction mixture was concentrated in vacuo and the residue was crystallized from ethyl acetate and n-heptane (100 ml, 1:1) to give the title compound (3.45 g, 80%) as light yellow solid; GC-MS (EI) 243.0 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCN(c2ccncc2)CC1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) and triethylamine (0.7 ml) in dry dichloromethane (20 ml) was treated slowly with a solution of 4-bromophenylsulphonyl chloride (0.77 g) in dry dichloromethane (10 ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were washed with water, brine, dried (MgSO4) and evaporated to yield a white crystalline solid which was recrystallised from ethyl acetate to give 1-(4-pyridyl)-4-(4-bromophenylsulphonyl)piperazine (0.84 g) as a solid, m.p. 199-200° C.: microanalysis, found: C, 47.3; H, 4.1; N, 10.9%; C15H16BrN3O2S requires: C, 47.1; H, 4.22; N, 11.0%; NMR: (CDCl3) 3.13(t,4H), 3.42(t,4H), 6.62(dd,2H), 7.67(q,4H), 8.29(d,2H): MS: m/z 382 (MH)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.[CH2:30]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:30][N:26]4[CH2:27][CH2:28][CH:24]([N:23]([CH3:29])[CH3:22])[CH2:25]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CN(C)C1CCNC1
Reactant: C=O
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Solvent: CCO
Product: CN(C)C1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.050 g, 0.18 mmol) obtained in Example A1, Step 1 in ethanol (3.0 mL) was added with 3-(dimethylamino)pyrrolidine (0.025 g, 0.22 mmol), and 37% aqueous formaldehyde (0.020 g, 0.24 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-7-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-6-hydroxybenzofuran-3(2H)-one (0.015 g, 21%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]([OH:38])/[CH:11]=[CH:12]/[C@H:13]1[C@@H:17]([F:18])[CH2:16][C@H:15]([O:19]C2CCCCO2)[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]([OH:38])/[CH:11]=[CH:12]/[C@H:13]1[C@@H:17]([F:18])[CH2:16][C@H:15]([OH:19])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1O
Temperature: 50 °C
Yield: 17.2 %

Procedure:
To a stirring mixture consisting of (Z)-isopropyl 7-((1R,2R,3S,5S)-2-((S,E)-3-(2,3-dihydro-1H-inden-2-yl)-3-hydroxyprop-1-enyl)-3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step I, 15.2 g) in a 10:1 isopropanol-water solution (300 mL) was added p-toluenesulfonic acid (1 g) and the reaction mixture was heated to 50° C. The reaction progress was monitored by TLC. Upon completion of reaction, the reaction mixture was evaporated to dryness and redissolved in ethyl acetate. The organic solution was washed twice with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel. Elution with hexanes-ethyl acetate (9:1) afforded the title intermediate (2.2 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@H]1CC[C@H](O)CC1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(-n2cnc3ccccc32)nc1N[C@H]1CC[C@H](O)CC1

Procedure:
A mixture of trans-4-(2-chloro-5nitropyrimidin-4-ylamino)cyclohexanol (310 mg), benzimidazole (390 mg), and potassium carbonate (0.5 g) was heated in acetonitrile at 60° C. for 2 hours. The mixture was concentrated onto silicon gel and purified by column chromatography (DCM:EtOAc:MeOH 70:22:8) to give 350 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:30]C(=O)OC(C)(C)C)[C:9](=[O:29])[NH:10][C@@H:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13][C@@H:12]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:30][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][C@@H:12]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Yield: 98.7 %

Procedure:
tert-Butyl ((1×)-1-(4-fluorophenyl)-2-oxo-2-{[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]amino}ethyl)carbamate (65a) (202 mg, 0.400 mmol) was dissolved in 5:1 (v/v) dichloromethane: trifluoroacetic acid (4 mL) and kept at ambient temperature for 1 h. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford the title compound (160 mg, 99%) as a yellow oil. MS APCI, m/z=406 (H+1). LC/MS: 1.60 min.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.O.[C:11](=[O:14])([O-])[O-:12].[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.O1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:33]([O:12][C:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:14])[CH2:34][CH2:35][CH3:36]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCNCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Solvent: O
Product: CCCCOC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C

Procedure:
Isonipecotic acid (6.42 g) was dissolved in a 4:1 mixture of tetrahydrofuran:water (100 ml), potassium carbonate (10.3 g) and di-tert-butyl dicarbonate (11.4 g) were added and stirred at room temperature over night. The tetrahydrofuran was removed in vacuo and the residue dispersed between water (100 ml) and ethyl acetate (100 ml), the aqueous phase was extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine and dried (MgSO4). The solution was filtered, evaporated to dryness to afford a white solid of N-butoxycarbonylpiperidine-4-carboxylic acid(11.6 g).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1.Cl[C:19]1[C:20]2[N:28]=[C:27](Cl)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][C:27]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:11][C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:20]=2[N:28]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cn1ccc(N)n1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cn1ccc(Nc2ncnc3ccc(Sc4nc5ccccc5[nH]4)nc23)n1

Procedure:
The compound of Example 62 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 2-mercapto-1H-benzimidazole, 3-amino-1-methyl-1H-pyrazole and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:6][CH2:7][CH3:8].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)=[CH:19][N:18]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)=[CH:19][N:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CCCN(CCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccc3c(c2)OCO3)c(=O)[nH]1
Product: CCCN(CCCNc1ncc(Cc2ccc3c(c2)OCO3)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-propylamino]pyridine (1.0 g) and 2-methylthio-5-(3,4-methylenedioxybenzyl)pyrimid-4-one (1.14 g) were heated together under reflux for 16 hr. After stripping, the residue was crystallised from ethanol/water to give 2-[3-(N-propyl-N-pyrid-2-ylamino)propylamino]-5-(3,4-methylenedioxybenzyl) pyrimid-4-one 1H2O, 1.47 g (81%) mp 86°-92° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][CH:26]([CH3:30])[CH2:27][CH:28]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:28][CH2:27][CH:26]([CH3:30])[CH3:25])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CC(C)CC=O
Solvent: CC(=O)N(C)C
Product: CC(C)CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 71.4 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methylbutanal (0.5 g, 5.8 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.083 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH2:5]2.OS(O)(=O)=O.[N+:25]([O-])([O-:27])=[O:26].[K+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:25]([O-:27])=[O:26])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccncc1N1CCc2cc(F)ccc2C1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccncc1N1CCc2cc(F)c([N+](=O)[O-])cc2C1=O
Yield: 60.1 %

Procedure:
6-Fluoro-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (83A: 350 mg, 1.38 mmol) was reacted with conc. H2SO4 (4 mL) and KNO3 (154 mg, 1.52 mmol) for 4 hours to afford 250 mg of the product (60.0% yield).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:12]=[C:11]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(O)CC>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[S:13][C:11]1[N:12]=[C:5]2[NH:2][N:3]=[C:7]([NH2:8])[C:6]2=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Reactant: NN
Solvent: CCCO
Solvent: O
Product: Nc1n[nH]c2nc(Sc3ccc(F)cc3F)ccc12
Temperature: 80 °C
Yield: 39.1 %

Procedure:
0.561 mL (11.57 mmol) of hydrazine monohydrate is added under nitrogen to a stirring solution of 1.09 g (3.86 mmol) of 2-chloro-6-(2,4-difluorophenylthio)nicotinonitrile in 15 mL of propanol. The reaction medium is heated at 80° C. for 4 hours. A precipitate is obtained when the reaction medium is returned to room temperature. This precipitate is filtered and rinsed with ethanol. The solid is dissolved in an ethyl acetate fraction and washed with a 1N HCl solution. The organic phase is dried on magnesium sulfate and dry evaporated to yield 420 mg (39%) of 6-(2,4-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].CN(C)C(=O)C.C(#N)C.[Cl:36][CH2:37][C:38](Cl)=[O:39]>O>[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:38](=[O:39])[CH2:37][Cl:36])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8])[C:5]=1[I:17]
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
The general procedure for the process of the invention involves reacting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with N,N-dimethylacetamide and chloroacetyl chloride. The resulting product is hydrolyzed with a base (such as sodium hydroxide). A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. Alternately, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is reacted with N,N-dimethylacetamide, acetonitrile, and chloroacetyl chloride. The resulting product is hydrolyzed with a base. A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. This product is combined with an aqueous base and deionized water. 2-Chloroethanol is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. Alternately, N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide plus metal halide and deionized water are combined. Ethylene oxide is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. This product is suspended in water with acetate ions and hydrochloric acid added. This suspended solution can take place at or above atmospheric pressure. Generally about 1 to about 2 atmospheres above atmospheric pressure is used. After adding aqueous sodium hydroxide to, maintain the pH, the reaction yields N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisopthalamide. Finally, salts and low molecular weight impurities are removed.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32][CH2:31]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: c1cnc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cccnc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.42 mmol) 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised. Then the substance was dissolved in DMF and purified again by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.