Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][C:8](Cl)=[O:9])=[O:4].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1)#[N:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[C:8](=[O:9])[CH2:7][CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH3:12])[CH3:11])=[CH:25][CH:26]=1)#[N:14]
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)(C)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(C)(C)C(=O)OC
Reaction time: 1 h

Procedure:
The starting material can be prepared, for example, as follows: 2.89 g of 4-methoxycarbonyl-4-methyl-pentanoic acid chloride are added to a solution of 2.50 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine and 2.09 ml of triethylamine in 100 ml of CH2Cl2, and the mixture is stirred for 1 hour. The reaction mixture is washed twice with 50 ml of water each time and the combined aqueous phases are extracted with 50 ml of CH2Cl2. The crude product obtained from the organic phase by the customary procedure is purified by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (98:2) as eluant to yield pure 4-methoxycarbonyl-4-methyl-pentanoic acid N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amide that has an Rf value of 0.56 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: [C:1]([O:6][C@H:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])[OH:19])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])(O)=O.[Na+:29]>O.C(#N)C>[Na+:29].[C:1]([O:6][CH:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[O-:20])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCP(=O)(O)CCCNC(=O)O[C@@H](OC(=O)C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCP(=O)([O-])CCCNC(=O)OC(OC(=O)C(C)C)C(C)C
Reaction time: 0.17 h

Procedure:
Compound 39 was dissolved in a mixture of water and acetonitrile, an aqueous solution of 1 eq. NaHCO3 was added, the mixture stirred for about 10 min, and lyophilized to afford the title compound (213). 1H-NMR (400 MHz, CDCl3): δ 6.55 (d, J=4.8 Hz, 1H), 3.10 (t, J=6.4 Hz, 2H), 2.53-2.56 (m, 1H), 1.97-2.00 (m, 1H), 1.79-1.83 (m, 2H), 1.70-1.74 (m, 2H), 1.53-1.58 (m, 2H), 1.37-1.43 (m, 2H), 1.15 (t, J=6.8 Hz, 6H), 0.90 (t, J=7.2 Hz, 9H). Phosphorus (162 MHz, CD3OD) δ0.36; MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NC=CN=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccc(C)cc2C(=O)O)nc1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, using 2-bromo-5-methylpyridine. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(Cl)(Cl)=O>CCOCC>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
According to the general procedure outlined in J. Med. Chem. 1986, Vol. 30, p. 3575, 15.0 g norleucine (Nle) was mixed with 200 mL benzyl alcohol and cooled to 0° C. Thionyl chloride (25 ml) was added dropwise over 15 min. and the mixture was slowly heated to 90° C. with a fierce evolution of SO2 occurring at about 50° C. After 2 h at 90° C. the mixture was cooled to 0° C. and 25 mL more thionyl chloride was added. The mixture was then heated again at 90° C. for 2 h, cooled, diluted with 1.6 L ether and stored overnight at 0° C. The crystals which formed were filtered, washed with ether and dried to give 23.1 g of a damp solid which was recrystallized from 1:10 ethanol-ether, using 23 mL ethanol. The filtered and dried solid weighed 17.1 g, TLC Rf 0.25 in System C. (the spotted plate was exposed to ammonia vapor and dried prior to elution).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][N:3]=2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2cc(-c3ccccc3)[nH]n2)n1
Temperature: 40 °C

Procedure:
The mixture of 3-amino-5-phenylpyrazole (103 mg, 0.65 mmol), 2,4,5-trichloropyrimidine (74.5 μL, 0.65 mmol), and sodium carbonate (68.9 mg, 0.65) in 3 mL of EtOH is heated at 40° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford 2,5-Dichloro-N-(5-phenyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 306.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](I)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([OH:20])[C:18]#[CH:19].O>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[C:10]([C:19]#[C:18][CH2:17][OH:20])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCc2ccccc2)c(I)n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: OCC#Cc1nc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
A mixture of compound 3-(benzyloxy)-6-chloro-2-iodopyridine (2.5 g, 7.2 mmol), prop-2-yn-1-ol (443 mg, 7.9 mmol), Pd(PPh3)2Cl2 (280 mg, 0.4 mmol) and CuI (76 mg, 0.4 mmol) in Et3N (25 mL) was stirred at room temperature for 6 hours. Water (50 mL) was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=2:1) to provide the product of compound 3-(3-(benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-1-ol (1.8 g, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.42˜7.33 (m, 5H), 7.17 (s, 2H), 5.18 (s, 2H), 4.54 (s, 2H). MS (M+H)+: 274/276.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:13]([NH:16][NH2:17])([NH2:15])=[S:14].O>C(O)(=O)C>[OH:1][N:2]=[C:3]([CH3:12])[C:4](=[N:17][NH:16][C:13]([NH2:15])=[S:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNC(N)=S
Reactant: CC(=NO)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=NO)C(=NNC(N)=S)c1ccccc1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
A mixture of 2-hydroxyiminopropiophenone (150 g) and thiosemicarbazine (90 g) in acetic acid (500 ml) was heated at 60° C. for 60 hours with stirring. After cooling, water was added to the reaction mixture. The resultant precipitates were collected by filtration, washed successively with water, methanol and diisopropyl ether, and dried to give 2-hydroxyiminopropiophenone thiosemicarbazone (188.2 g).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][O:13][C@@:14]1([C:22]#[CH:23])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1.[CH:24]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([OH:32])[C:23]#[C:22][C@:14]2([O:13][CH3:12])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(c1ccccc1)C1CCCCCC1
Reactant: C#C[C@@]1(OC)CN2CCC1CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCCCCC2)CN2CCC1CC2
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A 1.6 N solution of BuLi in hexane (41.7 ml, 66.7 mmol) was added dropwise to a solution of (3R)-3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl methyl ether 53 (11 g, 66.7 mmol) in THF (100 ml) cooled at −5° C. After stirring for 10 minutes, the medium was cooled at −15° C., and a solution of cycloheptyl(phenyl)methanone 44 (14.2 g, 70.2 mmol) in THF (50 ml) was slowly added. The cooling bath was removed and the reaction was allowed to gradually warm to room temperature during 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was washed with brine, dried over Na2SO4 and evaporated. The yellowish oil was purified by chromatography over silica gel (CH2Cl2/EtOH/NH4OH 94/6/1). 1-cycloheptyl-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propyn-1-ol 116 was obtained as a white solid (20.35 g, 83%, mixture of diastereomers).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([C:38]2[S:39][CH:40]=[C:41]([CH2:43][NH2:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:44][CH2:43][C:41]4[N:42]=[C:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[S:39][CH:40]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: NCc1csc(-c2ccccc2)n1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1csc(-c2ccccc2)n1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in General Procedure 10 to give the title compound. LCMS: m/z=619.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>ClCCl>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: COc1ccc(C=O)c(O)c1
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Ex-29A: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. using an ice-water bath. Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise to the cooled solution and stirred for 2 h at 0° C. The mixture was warmed to room temperature and stirred for an additional 1 h and the resulting yellow precipitate was collected. Recrystallization (ethyl acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, m.p. 63–64° C. 1H-NMR (300 MHz, CDCl3) δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H), 3.95 (s, 3H). Anal. Calcd. for C8H7BrO3: C, 41.59; H, 3.05. Found: C, 41.86; H, 3.05.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]([Cl:31])([Cl:30])[C:14]1[O:18][N:17]=[C:16]([CH:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:28][CH:27]([NH2:29])[CH2:26]3)[CH2:21][CH2:20]2)[N:15]=1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38]>>[Cl:31][C:13]([Cl:30])([Cl:12])[C:14]1[O:18][N:17]=[C:16]([CH:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:28][CH:27]([NH:29][C:41]([CH2:40][NH:39][C:37](=[O:38])[C:36]4[CH:44]=[CH:45][CH:46]=[C:34]([C:33]([F:48])([F:32])[F:47])[CH:35]=4)=[O:42])[CH2:26]3)[CH2:21][CH2:20]2)[N:15]=1
Reactant: NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1

Procedure:
The title compound was prepared by the EDCI coupling of 1-[4-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-azetidin-3-ylamine (as prepared in the previous step) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet Building Blocks). Purification by HPLC gave cis and trans isomers.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=3)[C:33](OC)=[O:34])[C:26]2=[O:40])=[CH:22][CH:21]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:33](=[O:34])[C:32]1[CH:37]=[CH:38][N:39]=[C:30]([N:27]2[CH2:28][CH2:29][N:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:42][CH:41]=3)[C:26]2=[O:40])[CH:31]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccc(F)c(F)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 34 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 3,4-difluorobenzylamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, N-(3,4-difluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 34% yield: mp 182-183° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.37 (d, J=5.1 Hz, 1H), 7.24-6.99 (m, 9H), 4.55 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.37 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 157.0, 153.0, 148.4, 142.6, 131.9, 129.9, 129.7, 123.9, 117.6, 117.4, 117.0, 116.8, 116.1, 115.9, 115.6, 108.9, 47.2, 43.1, 41.3, 41.1; MS (ES+) m/z 440.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[CH:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>O1CCCC1>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[CH:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: CCOC(=O)CCCCCC(c1ccccc1)c1c(C)c(C)cc(C)c1O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(O)c(C(CCCCCCO)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of ethyl 7-(2-hydroxy-3,5,6-trimethylphenyl)-7-phenylheptanoate (1.12 g) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.17 g) with ice cooling and the mixture was stirred at room temperature for 3 hours. Diluted sulfuric acid was added to the reaction mixture and it was extracted with ethyl acetate. The organic layer was separated, washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by subjecting it to silica gel column chromatography and eluting with ethyl acetate/hexane (1:4) to obtain 7-(2-hydroxy-3,5,6-trimethylphenyl)-7-phenylheptanol (0.81 g) (Compound 5). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>C(O)C>[F:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[F:11])[N:1]=[CH:17][NH:18][C:4]2=[O:5]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2cc(F)c(F)cc12
Yield: 86 %

Procedure:
38.0 g (0.213 mol) of 2-amino-4,5-difluorobenzoic acid and 44.0 g (0.423 mol) of formamidine acetate were suspended in 300 ml of ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 33.37 g (Y=84%) of 6,7-difluoro-3H-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[Cl:28][C:29]1[CH:36]=[CH:35]C(CO)=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccc(Cl)cc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 9.90 g of 4-chlorobenzyl alcohol is heated at 130° for 48 hours, the mixture is diluted with about 20 ml of methylene chloride and chromatographed on about 300 g of silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained p-chlorobenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 183°-184°.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[N:29]1[C:38]2[C:33](=[C:34]([NH:39][NH2:40])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[N:23]1([S:20]([C:16]2[CH:15]=[C:14]([N:9]3[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]4[N:39]([C:34]5[CH:35]=[CH:36][CH:37]=[C:38]6[C:33]=5[CH:32]=[CH:31][CH:30]=[N:29]6)[N:40]=[CH:3][CH:4]=4)=[N:8]3)[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NNc1cccc2ncccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=499.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH:12]([N:16]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[N:17]2)[CH2:13][C:14]#[N:15])[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=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>[Cl:1][C:2]1[N:7]=[C:6]([C:19]2[CH:18]=[N:17][N:16]([CH:12]([CH:9]3[CH2:11][CH2:10]3)[CH2:13][C:14]#[N:15])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#CCC(C1CC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloropyrimidine (2.8 g, 0.019 mol), 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (4.50 g, 0.0157 mol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.9 mmol), and potassium phosphate (0.1 g, 0.047 mol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to give the desired product as racemic mixture (3.08 g, 71.81%). LCMS (M+H) 274.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[OH:17])[C@H:9]3[CH2:10][C@@H:11]([CH3:24])[C:12]([O:22]C)=[CH:13]4.[NH4+].[OH-]>Cl.CC(C)=O>[CH3:24][C@H:11]1[CH2:10][C@@H:9]2[C@:14]3([CH2:18][CH2:19][N:20]([CH3:21])[C@@H:8]2[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:16]([OH:17])[C:15]3=2)[CH2:13][C:12]1=[O:22]
Reactant: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(O)c42)[C@@H]3C[C@H]1C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3

Procedure:
A solution of (6) (2.54 g, 7.7 mmole) in 1 N HCl (30 ml) was heated on the steam bath for 30 minutes. The cooled solution was made basic with concentrated NH4OH and extracted with three portions of chloroform. The chloroform extracts were evaporated to give a crystalline residue. The residue was dissolved in hot acetone and cooled. Crystals (1.29 g) of the hemi-acetone solvate of (4a) were collected after cooling. Recrystallization from acetone gave analytically pure (4a) as hemi-acetone solvate, mp 166°-167°, identical with material prepared previously.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br[CH2:19][C:20]1[CH:21]=[C:22]([S:26]([CH2:34][CH3:35])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:32]([O:31][C:29]([N:28]=[S:26]([CH2:34][CH3:35])([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH:21]=1)=[O:27])=[O:30])[CH3:33]
Reactant: COc1cc2c(NC(C)C)ncnc2cc1O
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1
Yield: 62 %

Procedure:
4-(Isopropylamino)-6-methoxyquinazolin-7-ol (50 mg, 0.21 mmol) and (RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (108 mg, 0.32 mmol) are suspended in 5.0 mL of acetone. After addition of potassium carbonate (55 mg, 0.4 mmol), the reaction mixture is refluxed for 6 hours. The batch is diluted with ethyl acetate and the organic phase is washed with water and dried over sodium sulphate to leave, after removal of the solvent and also after chromatographic purification (silica gel, hexane/ethyl acetate: 0→100% ethyl acetate, followed by ethyl acetate/methanol: 9/1) the desired product in 62% yield (65 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:17][CH2:16]2)[CH:3]=1.[CH:30]1(Br)[CH2:33][CH2:32][CH2:31]1.[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)cc(N)c2cc1O
Reactant: BrC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)cc(N)c2cc1OC1CCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
4-Amino-6-hydroxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline (200 mg, 0.0005 mol) and cyclobutyl bromide (75 mg, 0.00055 mol) were added to a suspension of sodium hydride (20 mg, 0.0005 mol) in dimethylformamide (5 ml), and the reaction stirred under a nitrogen atmosphere at 50° C. for 18 hours. On cooling, the mixture was partitioned between ethyl acetate (15 ml) and water (15 ml), and the aqueous layer further extracted with ethyl acetate (30 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of 0.880 aqueous ammonia: methanol:dichloromethane (0:0:100 to 1:10:90 v/v) to give the title compound as a foam (80 mg, 35%). Rf 0.65 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 456 (MH)+. Found: C, 56.54; H, 6.60; N, 13.83; C24H33N5O4 0.6 CH2Cl2 0.8 H2O, requires C, 56.72; H, 6.93; N, 13.44%.