Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[F:19][C:20]([F:25])([F:24])[CH2:21][NH:22][NH2:23]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:22]([CH2:21][C:20]([F:25])([F:24])[F:19])[N:23]=1
Reactant: NNCC(F)(F)F
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(CC(F)(F)F)n1

Procedure:
1.38 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one boiled under reflux for 0.5 h with 1.6 of 2,2,2-trifluorethylhydrazine in 20 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from methanol/water. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 154-156° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=[O:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])=[CH2:2].[BH4-].[Na+]>O1CCCC1.C(O)C.C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][OH:21])[CH:9]=1)([CH3:3])=[CH2:2]
Reactant: C=C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
5′-Isopropenyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.0 g) is dissolved in a mixed solvent of tetrahydrofuran (100 ml), ethanol (30 ml) and methylene chloride (10 ml), and thereto is added sodium borohydride (646 mg) and the mixture is stirred at room temperature for 10 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→4:1) to give (5′-isopropenyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (4.73 g). MS (m/z): 307 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:17][CH3:18])=[N:10][C:11]([CH3:16])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C2C(OC)=NC(C)=C(C=2)C#N)C=CC=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:19][CH2:13][C:12]1[C:11]([CH3:16])=[N:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: COc1nc(C)c(C#N)cc1-c1cccc(Cl)c1
Reactant: COc1nc(C)c(C=O)cc1-c1cccc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 72 %

Procedure:
5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. To a cooled solution, −78° C., of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinonitrile (500 mg, 1.9 mmol) in DCM (15 mL), under nitrogen, was added diisobutylaluminum hydride (1 M in hexanes, 4.8 mL, 4.8 mmol) drop-wise, over 3 minutes. The reaction mixture was stirred at −78° C. for 1 h. The reaction was carefully quenched by addition of saturated sodium fluoride (1 mL). After stirring for 30 minutes the suspension was filtered and the filtrate concentrated under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound (358 mg, 72%). [M+H]=262.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.Cl.[N:18]#[C:19]N.[OH-].[Na+]>O.CN(C)C=O.ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:19]2[NH2:18])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NCc1ccc(F)cc1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 9.5 %

Procedure:
To a stirred mixture of 23.5 parts of N-(4-fluorophenylmethyl)-1,2-benzenediamine and 14.4 parts of concentrated hydrochloric acid were added dropwise 9 parts of cyanamide at 100° C. After stirring for 3 hours at 100° C., there were added dropwise 10.5 parts of a sodium hydroxide solution 50%. Upon completion, stirring was continued overnight at reflux temperature. The reaction mixture was cooled and taken up in a mixture of water, trichloromethane and N,N-dimethylformamide. The organic phase was separated, dried, filtered and evaporated. The residue was stirred in trichloromethane. The product was filtered off and crystallized from trichloromethane, yielding 2.5 parts (9.5%) of 1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine; mp. 189.5° C. (int. 31).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Br)C.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:22]([C:24]2[N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[N:26][CH:25]=2)=[O:23])[CH:15]=[CH:14][CH:13]=1>ClCCl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:22]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[N:12]=[CH:13][CH:14]=[CH:15]2)([C:24]1[N:28]([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[N:26][CH:25]=1)[OH:23]
Reactant: O=C(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1ccccn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1ccccn1)(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-iodo-pyridine (commercially available) (307 mg, 1.5 mmol) in dichloromethane (20 mL) at room temperature was treated with ethyl magnesium bromide (0.50 mL, 1.5 mmol, 3M in ether) and allowed to react for 45 m. A solution quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 13) (465 mg, 1.00 mmol) in dichloromethane was added via syringe at room temperature and the reaction mixture was then stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and a sat. solution of ammonium chloride (20 mL). The residue was isolated in a typical aqueous to give pyridin-2-yl(quinolin-8-yl)(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 14) (385 mg, crude).
Reaction SMILES: O.[Na+].[N:3]1(S([O-])(=O)=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[C:4]1=[O:5].P(Cl)(Cl)([Cl:20])=O.O.C1[S:28](=[O:30])(=[O:29])CCC1>>[O:5]=[C:4]1[C:6](=[O:7])[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([S:28]([Cl:20])(=[O:30])=[O:29])[CH:9]=2)[NH:3]1
Reactant: O=S1(=O)CCCC1
Reactant: O=C1C(=O)N(S(=O)(=O)[O-])c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 66 %

Procedure:
A mixture of isatinsulfonic acid sodium salt hydrate (10.00 g, 39.7 mmol ) and phosphorous oxychloride (18.5 mL, 199 mmol, 5 eq) in tetramethylene sulfone (50 mL) was heated at 60° C. for 3 hours under a dry N2 atmosphere. The reaction was cooled in an ice bath to 0 C. and water was cautiously added drop-wise, keeping the internal temperature below 6° C. The resulting green solid was collected by filtration and was washed well with water. The solid was dissolved in ethyl acetate (200 mL) and washed again with water (3×50 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product in 85% yield. The solid was recrystallized from ethyl acetate: hexanes with hot filtration to give the title compound (5.81 g, 66% yield). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(N)cn1
Reaction time: 0.67 h

Procedure:
To a solution of 12-2 (6.0 g, 22.0 mmol) in 50 mL DMF at 0° C. was added NaH gradually. After the mixture was stirred for 40 min, CH3I (3.4 g, 24.0 mmol) was added in one portion. The reaction mixture was stirred for 5 hr, treated with 300 mL water and extracted three times with ethyl ether. The combined organic layers were washed with brine and dried over Na2SO4. After solvent removal, the residue was purified by silica gel flash chromatography (CHCl3 /hexanes 6:1) to afford the desired product 12-3 as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][OH:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(C)(C)C.[CH2:25]([N:27]([CH2:30][C:31]1[S:35][C:34]([C:36](O)=O)=[CH:33][C:32]=1[CH3:39])[CH2:28][CH3:29])[CH3:26]>Cl.O1CCOCC1.O>[NH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:23]=[C:36]([C:34]3[S:35][C:31]([CH2:30][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[C:32]([CH3:39])[CH:33]=3)[O:22][N:21]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(C(=N)NO)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCCN)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.5 %

Procedure:
Crude (2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzenesulfonylamino}-ethyl)-carbamic acid tert-butyl ester (156 mg) is obtained starting from {2-[4-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]-ethyl}-carbamic acid tert-butyl ester (277 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol) according to Method A; LC-MS: tR=0.61 min; [M+1]+=550.16. This material (156 mg, 0.284 mmol) is dissolved in 4 M HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The mixture is diluted with water and washed with EA. The organic washing is extracted with water. The combined aq. extracts are neutralised by adding sat. aq. NaHCO3 solution and extracted twice with EA. These organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge, eluting with a gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give the title compound (11 mg) as a pale yellow oil; LC-MS: tR=0.42 min; [M+1]+=449.64.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.Cl.[CH3:23][OH:24]>C(Cl)(Cl)Cl>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[NH:18])[O:24][CH3:23])[N:8]=1
Reactant: CO
Reactant: N#CCCCOc1cccc(NC(N)=NCC(F)(F)F)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCOc1cccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 72 h

Procedure:
A solution of 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-yloxy]butyronitrile in a mixture of CHCl3 (10 ml.) and MeOH (5 ml.) was saturated with HCl gas at 0° and then kept at 0° for 3 days. The solution was evaporated to dryness and the residue shaken with a mixture of CHCl3 and aqueous K2CO3. The CHCl3 phase was dried and evaporated to dryness to give methyl 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-yloxy]butyrimidate (0.8 g.) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)=[CH:30][C:29]=2[F:47])=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:11]2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].NC1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=CC=1F.C(O)(C(F)(F)F)=O.C(Cl)[Cl:77]>>[F:47][C:29]1[CH:30]=[C:31]([CH:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)[CH:32]=[CH:33][C:28]=1[NH:27][C:5]1[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=[C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:26])[C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:11]2)[N:6]=1.[ClH:77]
Reactant: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4F)n3)C2)cc1
Reactant: ClCCl
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCNCC5)cc4F)n3)C2)cc1
Product: Cl

Procedure:
In a similar manner as described in Example 110, (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazin-2-ylamino)-3-fluorophenyl)piperidine-1-carboxylate (200) was prepared using tert-butyl 4-(4-amino-3-fluorophenyl)piperidine-1-carboxylate. It was treated with 1:1 TFA/DCM at RT for 30 min, and (R)-3-(2-fluoro-4-(piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide (201) was isolated as HCl salt using reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases. MS found for C29H34FN7O3 as (M+H)+ 548.2, (M−H)− 546.3. UV: λ=257, 280, 306, 334, 369 nm. Proton NMR (CD3OD): δ 8.34 (1H, m), 7.79 (2H, d, J=9.0 Hz), 7.72 (1H, s), 7.03 (1H, d, J=12.5 Hz), 6.99 (2H, d, J=8.5 Hz), 6.96 (1H, d, J=9.5 Hz), 4.46 (1H, m), 4.18 (1H, m), 4.12 (1H, m), 3.86 (3H, m), 3.45 (1H, s), 3.42 (1H, s), 3.25 (2H, m), 3.08 (2H, m), 2.80 (1H, m), 2.11 (1H, m), 2.01-1.94 (3H, m), 1.81-1.70 (4H, m) ppm.
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:4][N:3]=[C:2]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: ClC(=NN=C(Cl)c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Brc1ccc(-n2c(-c3ccccc3)nnc2-c2ccccc2)cc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
4.5 g (16 mmol) of 1,2-bis(chloro(phenyl)methylene)hydrazine, 2.0 g (16 mmol) of 4-bromoaniline, and 30 mL of N,N-dimethylaniline were put into a 100 mL three-neck flask, and nitrogen substitution was performed on the contents of the flask. The mixture was stirred at 135° C. for 5 hours. After the reaction, a solid was precipitated out with the reactive solution being added to approximately 100 mL of 1 N diluted hydrochloric acid and the mixture being stirred for 30 minutes. Suction filtration was performed on the precipitated solid, and a solid was obtained. The obtained solid was dissolved in toluene and washed with water and a saturated sodium carbonate solution, in the order given. Magnesium sulfate was added to an organic layer, and the mixture was dried. Suction filtration was performed on the mixture to remove the magnesium sulfate, and thus a filtrate was obtained. The solid, which was obtained by condensation of the obtained filtrate, was recrystallized with a mixed solvent of ethanol and hexane, so that 2.3 g of a powdery white solid, which was the object of the synthesis, was obtained at a yield of 38%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([N:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH:41]=O)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[C:35]([O:34][C:32]([N:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH2:41][NH:24][C:23]1[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:31])=[CH:16][CH:15]=2)=[N:19][C:20]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[N:21][CH:22]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Nc1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of Compound 11b (0.55 g; 1.3 mmol) in 1,2-dichloroethane (25 ml) was added Boc-L-prolinal (0.37 mL; 1.9 mmol). To the reaction mixture was then added NaBH(OAc)3 (0.4 g; 1.9 mmol) portionwise, and the reaction mixture was continually stirred at room temperature for 5 h. The resultant mixture was diluted with water. After stirring for 10 min the organic phase was isolated, washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo to afford Compound 11c. The compound was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].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:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1F
Reactant: COc1ccc(F)cc1B(O)O
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Temperature: 85 °C

Procedure:
To a solution/suspension of the product from part (i) (0.55 g), 5-fluoro-2-methoxy-phenylboronic acid (0.3 g) in toluene (6 ml), ethanol (4 ml) and 2M Na2CO3 (3 ml) was added tetrakis(triphenylphosphine)palladium (0.05 g). The mixture was heated to 85° C. for 3 h, concentrated under reduced pressure to give a crude material. The residue was suspended in water, extracted with ethylacetate, washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification using flash column chromatography (eluent 10% diethylether/hexane) gave the subtitle compound, yield 0.39 g.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=1)=[O:5].O1C=CN=C1[Cl:25]>CN(C)C=O.ClCCl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:25])=[O:12])=[CH:9][N:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cn1
Reactant: Clc1ncco1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-(2-methylbenzoylamino)nicotinic acid (0.3 g) in dimethylformamide (0.5 ml) and dichloromethane (2.5 ml) is added dropwise oxazolyl chloride (0.2 ml), and the mixture is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=O)[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[S:24])[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN(C)CC(=O)N1c2ccccc2NC(=O)c2cccnc21
Solvent: c1ccncc1
Product: CN(C)CC(=O)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
A mixture of 6,11-dihydro-11-[(dimethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.14 mole), phosphorus pentasulfide (0.155 mole) and 1200 ml. of pyridine is heated at reflux temperature for 24 hours and the pyridine is then evaporated. Methylene chloride and water are added, and the organic layer is separated (some solid is present), washed with aqueous sodium bicarbonate until only a trace of solid is present, then with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. Trituration of the residue with methanol gives a solid which after crystallization from methylene chloride-methanol gives the product 6,11-dihydro-11-[(dimethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1.[I-].[K+].CCN(C(C)C)C(C)C>CN(C)C=O.O>[NH:20]1[CH:21]=[CH:22][C:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)=[N:19]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A stirred mixture of ethyl 4-chloroquinazoline-2-carboxylate (709 mg, 3 mmol), 3-aminopyrazole (274 mg, 3.3 mmol), potassium iodide (498 mg, 3 mmol), and DIEA (574 μL, 3.3 mmol) in N,N-dimethylformamide (5 mL) was heated at 50° C. for 2 h and then stirred at rt overnight. Water was added to the mixture and the precipitated solid was filtered, washed with water and dried under high vacuum at 50° C. for 3 h to afford ethyl 4-(1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (595 mg, 70%). LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20]2[O:21][C:22]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.CN(C1C=CC=CN=1)C.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(Cl)(Cl)Cl>ClCCl>[C:45]([N:26]([CH2:25][C:22]1[O:21][C:20]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)(=[O:47])[CH3:46]
Reactant: COCOc1cc(CC(=O)OC)c(-c2ccc(CNCCCN3CCOCC3)o2)c(OCOC)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCOc1cc(CC(=O)OC)c(-c2ccc(CN(CCCN3CCOCC3)C(C)=O)o2)c(OCOC)c1
Reaction time: 20 h
Yield: 89.5 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-{5-[N-(3-morpholinopropyl)aminomethyl]furan-2-yl}phenylacetate (46 mg, 0.094 mmol) obtained in Example 247 was dissolved in dichloromethane (1.0 mL), and dimethylaminopyridine (20 mg, 0.16 mmol) and acetic anhydride (0.1 mL, 1.1 mmol) were added thereto and stirred for 20 hours. Chloroform was added to the reaction solution for liquid-liquid separation. The organic layer was washed with 2 mol/L hydrochloric acid, aqueous saturated carbonic acid solution and aqueous saturated sodium chloride solution in order, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (methanol/chloroform=1/9) to obtain methyl 2-{5-[N-acetyl-N-(3-morpholinopropyl)aminomethyl]furan-2-yl}-3,5-bis(methoxymethoxy)phenylacetate (45 mg, 89%).