Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.51 g (2.7 mmol) of 2,6-dichlorobenzamide and 0.41 g (3.2 mmol, 1.2 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2,6-dichlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.86 g (2.7 mmol) of 4,5-dibromo-2-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.28 g (Yield 43%) of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[CH:5][CH:4]=1)#[N:2].[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:11]1[C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][S:14][C:10]1=[N:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: N#Cc1ccc(N=C2NC3(CCCC3)CS2)cc1
Product: CC(C)CN1C(=Nc2ccc(C#N)cc2)SCC12CCCC2

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method C1a to give 2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:22])[C:9]2[S:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2sc(-c3ccccc3)nc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (2.10 g, 7.01 mmole), N-bromosuccinimide (1.31 g, 7.36 mmole) and benzoyl peroxide (84.9 mg, 0.35 mmole) in carbon tetrachloride (40 ml) was refluxed for 2 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (1.89 g). MS: (+) m/z 379.18, 381.18 (M+1, 79Br/81Br).
Reaction SMILES: O[N:2]=[C:3]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)=O>CO.[Zn]>[NH2:2][CH:3]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)c1ccc2cc(OC)ccc2c1
Agent: [Zn]
Solvent: CO
Solvent: O=CO
Product: CCOC(=O)C(N)c1ccc2cc(OC)ccc2c1
Yield: 61.9 %

Procedure:
2-Bromo-6-methoxynaphthalene was converted to the 2-lithio derivative by reaction with n-butyllithium. Diethyl oxalate was then reacted with the 2-lithio-6-methoxynaphthalene to afford ethyl α-keto-6-methoxy-naphth-2-ylacetate. The latter compound was reacted with hydroxylamine hydrochloride and sodium acetate to provide ethyl α-hydroxyimino-6-methoxynaphth-2-ylacetate. A solution of 17.55 g of the oxime in 600 ml of methanol containing 5.3 g of zinc metal dust and 135 ml of 50% (v/v) aqueous formic acid was stirred at 0° C. for three hours. After filtering the reaction mixture, the solvent was removed by evaporation to give 10.3 g of ethyl α-amino-α-(6-methoxynaphth-2-yl)acetate.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Sc1ccccc1
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A solution of cinnamoyl chloride (14.6 g, 87.68 mmol) in dichloromethane (100 mL) was added to a solution of thiophenol (9.55 g, 86.68 mmol) and pyridine (7 mL) in dichloromethane (150 mL) in an ice-water bath. After 18 hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid (100 mL, 1N), brine (100 mL), dried (MgSO4) and was concentrated to afford 19.0 g (91%) of the desired thioester as a crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: CCc1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](OOC(C)(C)C)(C)(C)C>ClC1C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH3:21])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: Clc1ccccc1
Product: CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 51.5 %

Procedure:
A solution of 20.0 grams (72 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 10.5 grams (72 mmol) of di-tert-butyl peroxide, and 30 ml of chlorobenzene is heated for six hours in a Fischer-Porter pressure bottle (nitrogen atmosphere, bath temperature 145°-150° C.). The crude reaction product is purified by flash chromatography (silica gel; 50:1 heptane:ethyl acetate) and then recrystallized from methanol to afford 10.8 grams (51% yield) of the title compound, a white solid melting at 67°-68° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([S:16][Na])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)(=O)C>[CH:13]([S:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)S[Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC(C)C)cc1
Temperature: 80 °C
Yield: 67.3 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (390 mg, 2.32 mmol) and isopropylsulfanylsodium (273 mg, 2.78 mmol) in DMF (2.5 mL) was heated at 80° C. for 36 h. The reaction mixture was diluted with ethyl acetate before being washed with 1N NaOH and then brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give ethyl 4-isopropylsulfanylbenzoate (350 mg).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[CH:19](OCC)=[O:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH2:10][CH2:11][NH:12][CH:19]=[O:20])=[CH:17][CH:18]=1
Reactant: NCCc1ccccc1CCc1ccc(Br)cc1
Reactant: CCOC=O
Product: O=CNCCc1ccccc1CCc1ccc(Br)cc1

Procedure:
A solution of 0.60 g. (0.00197 mole) of 2-(4-bromophenethyl)-phenethylamine in 20 ml. of ethyl formate is heated to refluxing for about 19 hours. The solution is evaporated to dryness under reduced pressure and the residue dissolved in dry benzene. Evaporation of the solvent under reduced pressure leaves the product as the residual yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](F)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5][CH:4]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CS(C)=O>[C:34]([O:33][C:32](=[O:38])[NH:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([N:17]3[C:11]4[CH:10]=[C:9]([C:7]5[CH:6]=[N:5][CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=5)[N:14]=[CH:13][C:12]=4[CH:15]=[N:16]3)[N:19]=2)[CH2:26]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)n1
Solvent: CS(C)=O
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 95 °C
Yield: 69.5 %

Procedure:
A solution containing 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (75 mg, 0.23 mmol) and tert-butyl N-[(3S)-3-piperidyl]carbamate (234 mg, 1.17 mmol) in methyl sulfoxide 2.0 mL was heated 95° C. The reaction was quenched with water then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 65% EtOAc) to give (S)-tert-butyl(1-(6-(6-(6-ethylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate (80 mg) in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]O.P(Br)(Br)[Br:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Br:12]
Reactant: BrP(Br)Br
Reactant: COc1cccc(CO)c1
Solvent: C1CCOC1
Product: COc1cccc(CBr)c1
Reaction time: 3 h

Procedure:
A solution of 270 ul of 3-methoxybenzyl alcohol in 2.5 ml of dry tetrahydrofuran is cooled to 0° C. and 120 ul PBr3 added, followed by stirring for three hours. The reaction mixture is extracted with ether and the organic layer washed with saturated sodium bicarbonate and evaporated to give the desired product.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16].Cl>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1](=[O:9])[CH2:14][C:15](=[O:16])[CH3:17])[CH:3]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccnc1
Temperature: 25 °C

Procedure:
A cooled (0° C.) solution of ethyl nicotinate (3.00 g, 2.71 ml, 19.65 mmol) in THF (10 ml) was treated with sodium hydride (60%, 1.572 g, 39.3 mmol) followed by the dropwise addition of a solution of acetone (2.282 g, 39.3 mmol, 2.89 ml) in THF (10 ml). The mixture was heated at reflux for 3 hours and then allowed to cool to RT. The mixture was acidified to ˜pH5 with 2M HCl and partitioned between EtOAc and water. The organic phase was separated and washed with water, brine, dried (MgSO4) filtered and the solvent was removed in vacuo. Purification by chromatography on silica eluting with iso-hexane/EtOAc afforded the titled compound; 1H NMR (CDCl3, 400 MHz) δ 15.97 (1H, s), 9.10 (1H, s), 8.78 (1H, d), 8.22 (1H, d), 7.49 (1H, t), 6.21 (1H, s), 2.25 (3H, s). LCMS Rt=1.13 mins; [M+H]+ 164.21 Method LowpH_v002.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:74][CH2:75][CH2:76][CH2:77][N:78]1[CH:82]=[CH:81][N:80]=[CH:79]1>CN(C=O)C>[N:78]1([CH2:77][CH2:76][CH2:75][NH:74][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:30])[CH:82]=[CH:81][N:80]=[CH:79]1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Reactant: NCCCn1ccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-(3-aminopropyl)imidazole (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with toluene/methanol (8:2), which after evaporation of the solvents under vacuum gave N-{4′-[(3-imidazol-1-ylpropylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (12 mg, 24%). NMR; δH [2H6]-DMSO 10.31,(1H, s), 8.60,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.67,(2H, m), 7.45,(2H, d), 7.30,(1H, d), 7.22,(1H, s), 1.93,(6H, m). LCMS: retention time 2.24 min, MH+509.
Reaction SMILES: [I-:1].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]([CH2:18]Cl)=[CH2:17])=[C:10]([CH:13]=1)[CH:11]=[O:12])(=[O:5])[CH3:4].O>CC(C)=O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]([CH2:18][I:1])=[CH2:17])=[C:10]([CH:13]=1)[CH:11]=[O:12])(=[O:5])[CH3:4]
Reactant: [I-]
Reactant: C=C(CCl)COc1ccc(C(C)=O)cc1C=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(CI)COc1ccc(C(C)=O)cc1C=O
Reaction time: 5 h
Yield: 100.1 %

Procedure:
531 mg (3.54 mmol) of sodium iodide are added to 894 mg (3.54 mmol) of 5-acetyl-2-{[2-(chloromethyl)-2-propenyl]oxy}benzaldehyde in solution in 10 ml of distilled acetone. The medium is brought to reflux and is stirred for 5 hours. Water is added and then the solution is concentrated. After the addition of water and dichloromethane, the phases are separated by settling and then the aqueous phase is extracted with dichloromethane. The combined organic phases are washed, dried and then concentrated under vacuum to give 1.22 g (100%) of 5-acetyl-2-{[2-(iodomethyl)-2-propenyl]oxy}benzaldehyde in the form of a white solid which turns yellow in air; 1H NMR (300 MHz, CDCl3): 10.46 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.15 (dd, J=2.4 Hz and 8.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 5.52 and 5.32 (2s, 2H), 4.86 (s, 2H), 4.01 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: c1ccccc1
Product: O=C1CCC(c2ccc(NC(=O)CCl)cc2)=NN1
Yield: 81.4 %

Procedure:
30.2 g (0.16 mole) of 6-(p-aminophenyl)-4,5-dihydropyridaz-3-one, 18.1 g (0.16 mole) of chloroacetyl chloride and 150 ml of absolute benzene are refluxed for 2 hours. The product is filtered off at room temperature, washed first with benzene and then with water, and dried under reduced pressure at 80° C. 34.6 g (81% of theory) of 6-(p-chloroacetylaminophenyl)-4,5-dihydropyridaz-3-one are obtained as a beige solid which, after recrystallization from dimethylformamide/water, melts, with decomposition, at 233° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:14][CH:13]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].C=O.[BH3-][C:33]#N.[Na+].Cl>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:16][CH:17]=2)[CH3:33])=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccc(N(C)Cc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To 3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzonitrile (138 mg, 0.36 mmol) in acetonitrile (14 mL) are added 37% aqueous solution of formaldehyde (140 μL) and NaCNBH3 (69 mg, 1.1 mmol). The pH of the mixture is adjusted to approximately 2 by dropwise addition of 1 N HCl over a 15 min period. The reaction was complete after 1.5 h, during which time the pH of the reaction mixture is monitored every 15 min using pH paper and kept at around 2 by addition of 1N HCl. The reaction mixture is quenched into H2O and basified with saturated aqueous NaHCO3. The mixture is extracted with EtOAc (3×), washed with brine, dried over Na2SO4, and concentrated. Obtained is the title compound as a yellow oil (135 mg, 94%). LC-MS (m/e): 399 (M−1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]4[CH2:20][CH2:19][CH2:18][O:17][CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[N:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]5[CH2:20][CH2:19][CH2:18][O:17][CH2:16]5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cn1c(=O)n([C@H]2CCCOC2)c2c3cc(Br)ccc3ncc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)n([C@H]2CCCOC2)c2c3cc(-c4ccc(F)nc4)ccc3ncc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
Pd(Ph3P)4 (0.160 g, 0.14 mmol) was added to 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (1 g, 2.76 mmol), (6-fluoropyridin-3-yl)boronic acid (0.506 g, 3.59 mmol) and Cs2CO3 (1.799 g, 5.52 mmol) in 1,4-dioxane (23 mL) and water (3 mL) under nitrogen. The resulting mixture was stirred at 100° C. for 3 h then allowed to cool and the solvent removed under reduced pressure. The crude product was purified by FCC, elution gradient 0 to 7% MeOH in DCM to give the desired material (0.905 g, 87%) as a yellow solid. NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.83-1.86 (2H, m), 2.15-2.19 (1H, m), 2.49-2.64 (1H, m), 3.38-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H, d), 4.15-4.26 (2H, m), 4.91-5.10 (1H, m), 7.42 (1H, dd), 7.96 (1H, dd), 8.13 (1H, d), 8.38 (1H, s), 8.44 (1H, td), 8.72 (1H, d), 8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=379.1.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O>N1C=CC=CC=1>[O:3]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=2)[CH:34]=1)[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of 3.0 g of capric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was separated by filtration and washed with a small volume of pyridine. The filtrate and washings were poured into stirred ethyl ether. The precipitated crystals were collected by filtration, washed with ethyl ether, then with acetone, and recrystallized from a methanol-ether mixture to yield 1.2 g of a white powder of 6-amidino-2-naphthyl caprate methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH2:22][C:23]4[N:27]([CH3:28])[C:26]5[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=5[N:24]=4)=[CH:15][C:14]=3[F:33])O)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C(#N)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[C:14]([F:33])=[CH:15][C:16]([O:21][CH2:22][C:23]4[N:27]([CH3:28])[C:26]5[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=5[N:24]=4)=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)c(F)cc1OCc1nc2ccccc2n1C
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1nc2ccccc2n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
(5-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-5-methoxy-4-(1-methyl-1H-benzimidazol-2-ylmethoxy)-phenyl]-methanol (145) (0.140 g, 0.225 mmol) was suspended in acetonitrile (5 ml, 100 mmol). Triethylsilane (1.0 mL, 6.3 mmol) was added followed by trifluoroacetic acid (0.500 mL, 6.4 mmol). After the reaction was stirred at 60-80° C. for 1.5 hours the solvent was evaporated to dryness. Ethyl acetate was added and the organic portion was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography eluting with a gradient of ethyl acetate (20 to 100%) in hexanes gave the desired compound as a white powder (P-2106, 0.034 g, 34%). MS (ESI) [M+H+]+=451.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:6]=2[N:7]=1.[OH:27][CH:28]([CH3:31])[CH2:29][NH2:30]>>[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([NH:30][CH2:29][CH:28]([OH:27])[CH3:31])[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH3:17]
Reactant: CCN(CC)CCSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: CC(O)CN
Product: CCN(CC)CCSc1ncnc2c(N3CCS(=O)CC3)nc(NCC(C)O)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-diethylaminoethyl-thio)-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 146°-148° C.) and 2-hydroxypropyl-amine. Resin.