Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:24][CH2:25][CH3:26])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 70 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
To a solution of 6-nitro-2,3,4,9-tetrahydro-1H-carbazole (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 mmol) in DMF (8 mL) was added 1-bromopropane (0.263 mL, 2.89 mmol), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was cooled, and to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 55% ethyl acetate/hexane) to give 6-nitro-9-propyl-2,3,4,9-tetrahydro-1H-carbazole (279 mg, 1.081 mmol, 93%) as a yellow powder.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:26](=[O:27])[C:22]3([CH2:25][CH2:24][CH2:23]3)[N:21]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([NH2:39])=O)=[CH:30][CH:29]=3)[C:20]2=[S:40])=[CH:15][C:14]=1[C:41]([F:44])([F:43])[F:42])#[N:12]>ClCCl>[C:37]([CH2:36][CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([N:21]2[C:20](=[S:40])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([C:41]([F:44])([F:42])[F:43])[CH:15]=3)[C:26](=[O:27])[C:22]32[CH2:23][CH2:24][CH2:25]3)=[CH:33][CH:32]=1)#[N:39]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMSO (0.01 mL, 0.12 mmol) in dry dichloromethane (1 mL) was added to a stirred solution of oxalyl chloride (0.01 mL, 0.09 mmol) in dry dichloromethane (2 mL) at −78° C. After 15 min, a dichloromethane solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (35 mg, 0.07 mmol) was added to the reaction mixture. Stirring was continued for 20 min at −78° C., and then biethylamine (0.03 mL, 0.22 mmol) was added. After 30 min at −78° C., the reaction mixture was warmed to room temperature and then reaction was quenched with saturated aq. NH4Cl solution. The reaction mixture was diluted with dichloromethane, and extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4-(5-(4-(3-Cyanopropyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile, RD170 (Formula 53) (29 mg, 87%) as a viscous oil. 1H NMR δ 7.98 (d, 1H, J=1.8 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.86 (dd, 1H, J=8.3, 1.8 Hz), 7.43 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=8.4 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.63-2.73 (m, 2H), 2.52-2.62 (m, 2H), 2.42 (t, 2H, J=7.3 Hz), 2.18-2.30 (m, 1H), 2.07 (p, 2H, J=7.3 Hz), 1.63-1.73 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][C:8]=1[CH3:18])[CH3:2].[N:20]1[N:21]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[OH:36])[N:22]=[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][O:36][C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[N:21]2[N:22]=[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[N:20]2)=[CH:9][C:8]=1[CH3:18])[CH3:2]
Reactant: Oc1ccc(Cl)cc1-n1nc2ccccc2n1
Reactant: CCOC(=O)COc1ccc(SCCCBr)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCCCOc2ccc(Cl)cc2-n2nc3ccccc3n2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
To a mixture of [4-(3-bromo-propylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (139 mg, 0.4 mmol) and 2-benzotriazole-2-yl-4-chloro-phenol (108 mg, 0.44 mmol) in MeCN (3 mL) was added Cs2CO3 (156 mg, 0.48 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was filtrated through Celite and washed with ethyl acetate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel to give 145 mg of the desired ester.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Yield: 100 %

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (1.0 g, 11.2 mmol), triethylamine (1.7 mL, 12.2 mmol) and N-(benzyloxycarbonyloxy)-succinimide (3.1 g, 12.4 mmol) in THF (100 mL) at 0° C. were reacted for 0.5 hours then at room temperature for an additional hour. The reaction was concentrated and extracted with ethyl acetate (100 mL). The organic extract was washed sequentially with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-20%) to give the title compound as a colorless oil (2.5 g, quantitative).
Reaction SMILES: C(O[K])(C)(C)C.C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH2:20]([N:27]1[CH:31]=[C:30]([CH:32]=O)[C:29]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH2:20]([N:27]1[CH:31]=[C:30]([CH2:32][C:16]#[N:17])[C:29]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: COCCOC
Product: N#CCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
To a mixture of t-butoxy potassium (11.2 g) and dimethoxyethane (50 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (10.3 g) in dimethoxyethane (50 ml) at −78° C. and the mixture was stirred for 5 min. Then a solution of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (14.6 g) in dimethoxyethane (50 ml) was added. After stirring at said temperature for 1 hr, the mixture was stirred for 1 hr. while raising the temperature to room temperature. To the obtained mixture was added methanol (150 ml), and the mixture was refluxed for 1 hr. After cooling, the reaction solution was poured into saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetonitrile (13.1 g, yield 86%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:35]1[C:44]2[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([O:45][CH3:46])[CH:43]=2)[N:38]=[CH:37][N:36]=1>C1COCC1>[CH3:46][O:45][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][C:41]=1[O:47][CH3:48])[N:38]=[CH:37][N:36]=[C:35]2[O:27][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:24])([F:25])[F:26])[CH:13]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C(Nc1ccc(F)c(O)c1)Nc1cc(C(F)(F)F)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
After a mixture of 1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.22 g, 0.58 mmol) and Cs2CO3 (0.325 g, 1 mmol) in THF (10 mL) was stirred at room temperature for 1 hour, to it was added 4-chloro-6,7-dimethoxyquinazoline (0.13 g, 0.58 mmol). It was stirred at 40° C. for 14 hours. The mixture was quenched by water and extracted with DCM. Extracts were dried over MgSO4 and concentrated. It was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.064 g, 19% yield). 1H NMR (300 MHz, DMSO-d6) 3.99 (s, 3H), 4.00 (s, 3H), 6.87 (s, 1H), 7.24 (m, 1H), 7.36 (t, 1H), 7.42 (s, 1H), 7.59 (m, 6H), 7.67 (dd, 1H), 8.56 (s, 1H), 8.83 (s, 1H), 9.32 (s, 1H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])[CH:2]=1.[CH:15]([O-])([O-])OC>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:11][CH3:15])/[CH3:12])[CH:2]=1
Reactant: CC(=O)CC(=O)Nc1cccc(C)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(C)c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 46.6 %

Procedure:
A mixture of 80 g of N-(m-tolyl)-acetoacetamide, 80 g of methyl orthoformate, 100 ml of methanol and 1 g of p-toluene sulfonic acid was refluxed with stirring for 6 hours and the volatile material was distilled off under reduced pressure. 300 ml of toluene and 1.5 ml of quinoline were added and the mixture was heated to about 140° C for 3 hours and then the rest of the toluene was evaporated. The residue was chromatographed over silica gel with a mixture of 9-1 methylene chloride-ethyl acetate as eluant to obtain 40 g of N-(m-tolyl)-3-methoxy-crotonamide melting at 106° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]=O>>[CH2:1]([N:8]([CH3:25])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Reactant: C=O
Product: CN(Cc1ccccc1)c1ccc(-c2cc(COC(N)=O)on2)cc1

Procedure:
An experiment was performed using carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.46 mmol) in Example 74 as a starting material and formaldehyde (20 μl, 0.70 mmol) in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-methyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8]([C:10]1[NH:11][C:12](=[S:16])[NH:13][C:14]=1[CH3:15])=[O:9])[CH3:6].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CCO>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[C:12]([S:16][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])[NH:13][C:14]=1[CH3:15])=[O:9])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(SCC(OCC)OCC)[nH]c1C
Temperature: 25 °C

Procedure:
A solution of sodium ethoxide (5.37 mmol) in EtOH (3.3 mL) is added to a solution of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (5.37 mmol) in EtOH (7.0 mL). Bromoacetaldehyde diethyl acetal (5.37 mmol) is added and the mixture is stirred at reflux for 12 h. After cooling to RT the mixture is filtered and concentrated in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.70 min; [M+H]+=303.4.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1>C(Cl)Cl>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: C1CNC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Reaction time: 0.33 h
Yield: 61 %

Procedure:
Azetidine (0.62 mL, 9.2 mmol, Aldrich) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.76 g, 4.16 mmol, prepared in the manner outlined in Example 47, Step A) in methylene chloride (39 mL). and the reaction was stirred for 20 minutes. Solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with a gradient from 0-5% MeOH in DCM to afford product (0.74 g, 61%); LCMS (M+H)+: 290.0.
Reaction SMILES: [Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH2:3]O.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(Cl)(Cl)Cl>[Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH2:3][Br:18]
Reactant: OCC1(Br)C=CC=C(F)C1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: FC1=CC=CC(Br)(CBr)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of 1-bromo-3-fluorobenzyl alcohol (1.61 kg, 7.85 mol) in chloroform (14 L) at 0° C. add pyridine (770 mL, 9.52 mol) in one portion (slight exotherm) and stir at 0° C. for 5 min. Add phosphorus tribromide (900 mL, 9.49) dropwise while maintaining the internal temperature below 20° C. and stir the resulting solution overnight while allowing to warm to room temperature. Cool the reaction to 0° C. and quench slowly with ice water (2 L). Transfer to a 50 L flask, separate the layers and then extract the aqueous layer with chloroform (1 L). Wash the combined organic phases with 5% sulfuric acid (2 L), saturated aqueous sodium bicarbonate (2 L), brine (2 L), dry over magnesium sulfate, filter, and concentrate to obtain the title compound as a yellow oil (1753 g, 83%). 1H NMR (CDCl3) δ 7.43 (d, 1H), 7.21 (m, 1H), 7.09 (t, 1H), 4.68 (s, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])=[O:6])=[N+:2]=[N-:3].[BH4-].[Na+].C(O)(=O)C>CO>[N:1]([CH2:4][C:5]([NH:7][CH2:8][CH:9]([OH:20])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])=[O:6])=[N+:2]=[N-:3]
Reactant: COc1ccc(OC)c(C(=O)CNC(=O)CN=[N+]=[N-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(OC)c(C(O)CNC(=O)CN=[N+]=[N-])c1
Temperature: 0 °C
Yield: 95 %

Procedure:
In a four neck round bottomed flask 32.4 gm (0.11 mole) of 2-azido-N-(β-Oxo-2,5-dimethoxy phenehyl)-acetamide is prepared according to the step (c) and 260 ml methanol is charged and cooled to 0° C. To this 3.24 gm (0.08 mole) sodium boro hydride is added slowly over a period. After completion of the addition, the reaction mass temperature is raised to 10° C. After completion of the reaction, 10 ml of acetic acid is added. Methanol is stripped off under reduced pressure and the residue obtained is extracted with methylene dichloride. Organic layer is washed with water and methylene dichloride is distilled off. The yield was 95%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:19][OH:20])[N:4]=1.I[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COCCOCCOCCI
Reactant: COC(=O)CCNCCOc1cc(CO)nc(CO)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCN(CCOc1cc(CO)nc(CO)c1)CCC(=O)OC
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a solution of 284 mg of methyl 3-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-propanoate in 28 ml of acetonitrile was added 356 mg of 1-iodo-2-[2-(2-methoxy-ethoxy)-ethoxy]-ethane and 330 μl of diisopropylethylamine. The mixture was heated at 80° C. for 3 days and then concentrated under reduced pressure and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-40g), using a gradient of 5 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 165 mg of methyl 3-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate were obtained. LC/MS (B): tr=0.44 min; [M+H]+: m/z 431.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].C([O-])(=O)C.[NH4+].C(O)C>O.Cl>[C:2]1([C:1]([CH2:9][C:10]#[N:11])=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: N#CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CCC(=C(C#N)C#N)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzoylacetonitrile (9.94 g, 0.0685 mole), malononitrile (11.3 g, 0.17 mole), ammonium acetate (5.4 g, 0.07 mole) and ethanol (100 mL) was heated at reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and concentrated hydrochloric acid (7.5 mL) was added dropwise over 5 minutes. The resulting precipitate was collected by filtration and washed with water and ligroin. The yield was 10.0 g (76%), m.p. 92°-98° C.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[F:7][C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20](=[NH:22])[NH2:21])=[N:12]1>C(O)(=O)C>[Br:1][C:2]1[CH:5]=[N:21][C:20]([C:13]2[C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:11]([CH2:10][C:9]3[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=3[F:7])[N:12]=2)=[N:22][CH:3]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: Fc1ccccc1Cn1nc(-c2ncc(Br)cn2)c2cccnc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
10.09 g (66.84 mmol) of 2-bromomalonaldehyde are added to a solution of 15.00 g (55.70 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) in 200 ml of glacial acetic acid and stirring at 100° C. for 2 hours. The solvent is removed in vacuo. The residue is purified by chromatography on silica gel (eluent: DCM/methanol 40:1 to 30:1). 9.51 g (44% of theory) of the product are obtained.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+]>CS(C)=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)CC(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 1-bromo-3,3-dimethylbutan-2-one (33.3 g, 0.19 mole) in dimethylsulfoxide (330 ml), sodium p-toluenesulfinate (34.9 g, 0.20 mole) was added in a small portion at 30°-40° C., and stirring was continued at 60°-70° C. for 18 hours. The resultant mixture was poured into ice-cold H2O (2 l), the precipitate was filtered by suction, washed with H2O and dried to give 41.6 g of 1-(p-toluenesulfonyl)-3,3-dimethylbutan-2-one as white crystals.
Reaction SMILES: CN.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13](Cl)=[N:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[CH2:28]([N:30](CC)CC)C>O1CCCC1>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]([NH:30][CH3:28])=[N:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: O=C(NCc1ccc(Cl)nc1)C(Cl)=NNc1ccc(C(F)(F)F)cc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40% aqueous solution of methylamine (78 mg, 1.0 mmol) was gradually added to a solution of N-(6-chloro-3-pyridylmethyl)-2-chloro-2-(4-trifluoromethylphenyl hydrazono) acetic acid amide (Compound No. 5) (0.4 g, 1 mmol) and triethylamine (0.1 g, 1 mmol) in tetrahydrofuran (10 ml) and left at room temperature overnight. Further, 40% aqueous solution of methylamine (10 mg, 0.13 mmol) was added and stirred at room temperature for 1 hour, and thereafter subjected to extraction by adding ethyl acetate and water. The organic phase was washed with a saturated brine, and then dried on anhydrous sodium sulfate. The resulting residue was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-methylamino-2-(4-trifluoromethylphenyl hydrazono) acetic acid amide (Compound No. 191) (0.13 g, 0.34 mmol, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(I)cc2)n1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(-c3ccncc3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A dry flask charged with 1-(4-chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (20 mg, 0.038 mmol), 4-tributylstannylpyridine (14 mg, 0.038 mmol) and tetrakis(triphenylphosphine) palladium (4.4 mg, 0.0038 mmol) is heated at 100° C. overnight. Filtration and concentration followed by purification gives the desired product. 1H NMR (methanol-d4) δ(ppm) 8.69 (d, 2H), 8.49 (s, 1H), 8.04 (d, 2H), 7.81 (m, 4H), 7.60 (m, 4H), 7.51 (m, 1H), 7.35 (m, 4H); HPLC-MS calculated for C28H18ClN5O (M+H+): 476.2. Found 476.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH2:15]O>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[NH:13][CH2:14][CH2:15][S:12]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: NCCO
Solvent: CCOCC
Product: CC(C)c1ccccc1N=C1NCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of (2-isopropylphenyl)isothiocyanate (2.00 g) in diethylether (20 ml) was added 2-aminoethanol (0.69 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. To the obtained oil was added concentrated hydrochloric acid (5 ml). The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into an aqueous solution of 20% sodium hydroxide (25 ml). The mixture was extracted with dichloromethane (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-1,3-thiazolidine (1.80 g, yield: 73%) as a white crystal. M.p. 76-77° C.