Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OC(OCC)C[Mg]Br)C.[BH4-].[Na+].[CH2:30]([OH:32])[CH3:31]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:2])[CH2:31][CH2:30][OH:32])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CCO
Agent: CCOC(C[Mg]Br)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
A solution of 2.76 g. of 3 hydroxy-3-(2',4'-difluoro-4-biphenylyl)-butanol, obtained by reacting 4-acetyl-2',4'-difluorobiphenyl with 2,2-diethoxyethyl magnesium bromide and subsequently hydrolyzing the reaction product, in 12 ml. of ethanol is added dropwise to a solution of 0.6 g. of NaBH4 in 15 ml. of ethanol. The mixture is stirred for 2 hours at 20° and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:31]([Cl:32])=[CH:30][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3(OCC[O:26]3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[O:8])=[C:5]([O:33][CH3:34])[CH:4]=1>CO>[ClH:32].[NH2:2][C:3]1[C:31]([Cl:32])=[CH:30][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16]2)=[O:8])=[C:5]([O:33][CH3:34])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCC2(c3ccccc3)OCCO2)CC1
Agent: Cl
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCC(=O)c2ccccc2)CC1
Yield: 154.8 %

Procedure:
Methanol (40 ml) and 1N hydrochloric acid (100 ml) were added to 4-amino-5-chloro-N-((1-(3,3-ethylenedioxy-3-phenylpropyl)piperidin-4-yl)methyl)-2-methoxybenzamide (8.8 g), and the mixture was stirred at refluxing temperature for 1.5 hr. The reaction mixture was further stirred under ice-cooling for 1 hr, and the precipitated crystals were collected by filtration to give 6.7 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-oxo-3-phenylpropyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:34]#[N:35].O>CN1CCCC1=O>[C:34]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(C#N)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 3 %

Procedure:
A mixture of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl ]1-[5-(4-fluorophenyl)2-methylthiazol-4-yl]methanone, E66 (216 mg, 0.42 mmol) and copper(I)cyanide (76 mg, 0.84 mmol) in N-methylpyrrolidinone (15 ml) was heated at reflux for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (2×). Solid sodium chloride was added to the aqueous layer which was further extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was Chromatograped (silica gel, 10-100% ethyl acetate-hexane then 1-20% methanol-ethyl acetate). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown amorphous solid (5.3 mg, 3%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: COc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 460 was prepared from 4-morpholinoaniline and 4-(5-methoxy-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C25H24N4O3: 429.18; found: 428.97.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[C:5]([O:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=2[NH:15][C:14](=S)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O1CCOCC1>[C:5]([O:9][C:10]([N:12]1[CH2:13][C:14]2[N:15]([CH:1]=[N:3][N:4]=2)[C:16]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:17]=2[CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(=S)Nc2ccc(Cl)cc2C1
Reactant: NNC=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2cnnc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Formylhydrazine (10.7 g, 160 mmol) was added over a period of 4 hours to a solution of 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (10.0 g, 32.0 mmol) in dioxane (200 ml) at 90° C. The reaction mixture was stirred at 90° C. overnight, then evaporated. The residue was purified by chromatography (300 g silica gel, heptane: ethyl acetate, 8:2 to 0:1) to yield 7.71 g (75%) 8-chloro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester as white solid. MS m/e: 379 ([M+CH3COO−])
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[N:36][C:35]([NH2:38])=[CH:34][N:33]=1)=[O:31].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH3:28][O:29][C:30]([C:32]1[CH:37]=[N:36][C:35]([NH:38][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][N:33]=1)=[O:31]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: COC(=O)c1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 196.4 mg, 0.59 mmol) in methylene chloride (3 mL) was cooled to 0° C. The reaction mixture was then treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (109 μL, 1.25 mmol). The reaction mixture was stirred at 0° C. for 15 min and then at 25° C. for 2 h. The solution was then concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (1 mL) and cooled to 0° C. To this solution was added a suspension of 5-amino-pyrazine-2-carboxylic acid methyl ester (100.0 mg, 0.65 mmol) and pyridine (53 μL, 0.6529 mmol) in warm methylene chloride (2 mL). The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction mixture was then concentrated in vacuo. The reaction material was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (100 mL), a saturated aqueous sodium chloride solution (100 mL), a 1N aqueous hydrochloric acid solution (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 ethyl acetate/hexanes) afforded 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid methyl ester (225.9 mg, 82%) as a white foam: mp 94–97° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H24ClN3O5S (M+H)+466.1198, found 466.1204.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:13]1([CH:19]([C:25]#[N:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[NH2:26][C:25]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C#N)C1(Cc2ccccc2)CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1=C(N)c2ccccc2CC12CCCCC2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Concentrated H2SO4 (4.59 ml) was added dropwise to ethyl 2-(1-benzylcyclohexyl)-2-cyanoacetate (2.46 g, 8.62 mmol) at 0° C. The mixture was stirred at room temperature for 7 h. Ice water was added to the mixture resulting in a precipitate. The precipitate was taken up in Et2O and washed with 28% NH3 solution. The organics were washed with water, dried over Na2SO4, filtered, and concentrated to an orange oil.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH2:10][C:11]([OH:13])=[O:12])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH3:14]C1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-(methylenedioxy)phenylacetic acid (28.0 g, 155 mmol), catalytic TsOH, and MeOH (125 mL) was stirred over 60 h. Saturated aqueous NaHCO3 was added and the product was extracted into CH2 Cl2. The organic solution was dried (MgSO4), filtered, and concentrated. Distillation (120 -1° C., 1 mmHg) provided the title compound as a clear and colorless oil (27.6 g). 1H NMR (250 MHz, CDCl3): δ6.74 (m, 3H), 5.94 (s, 2H), 3.69 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 69 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:33]([O:35][CH2:36]C)=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:44]=[C:43](I)[C:42]([CH3:46])=[CH:41][N:40]=1.[F-].[Cs+]>C(COC)OC.CO.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:38][C:39]1[CH:44]=[C:43]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[NH:17][C:16]([C:33]([O:35][CH3:36])=[O:34])=[C:15]3[CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:42]([CH3:46])=[CH:41][N:40]=1
Reactant: CCOC(=O)c1[nH]c2c(B3OC(C)(C)C(C)(C)O3)cccc2c1CCCOc1cccc2ccccc12
Reactant: Cc1cnc(F)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1[nH]c2c(-c3cc(F)ncc3C)cccc2c1CCCOc1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 43A (0.40 g), 2-fluoro-4-iodo-5-methylpyridine (0.209 g), tetrakis(triphenylphosphine)palladium (46 mg) and cesium fluoride (0.365 g) in dimethoxyethane (3 mL) and methanol (1.5 mL) was heated at 120° C. for 20 minutes under microwave conditions (CEM Discovery). After cooling to room temperature, the reaction mixture was loaded onto a silica gel cartridge. The cartridge was dried in vacuum oven for 1 hour and eluted with 1:4 ethyl acetate/hexanes to give the desired product. 1H NMR (500 MHz, DMSO-d6): 11.33 (s, 1H), 8.23-8.25 (m, 1H), 8.17 (s, 1H), 7.86-7.88 (m, 1H), 7.79-7.81 (m, 1H), 7.45-7.56 (m, 3H), 7.39 (t, J=7.93 Hz, 1H), 7.12-7.14 (m, 2H), 7.04 (d, J=2.14 Hz, 1H), 6.91 (d, J=7.32 Hz, 1H), 4.20 (t, J=5.95 Hz, 2H), 3.78 (s, 3H), 3.37 (t, J=7.48 Hz, 2H), 2.20-2.26 (m, 2H), 2.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH:9]([CH2:19][O:20]CC2C=CC=CC=2)[CH2:10][O:11]CC2C=CC=CC=2)[C:5]2[C:28]([Cl:35])=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:4]=2[N:3]=1.B(Cl)(Cl)Cl.C(Cl)Cl>CO>[Cl:1][C:2]1[N:6]([CH2:7][O:8][CH:9]([CH2:19][OH:20])[CH2:10][OH:11])[C:5]2[C:28]([Cl:35])=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:4]=2[N:3]=1
Reactant: Clc1c(Cl)c(Cl)c2c(nc(Cl)n2COC(COCc2ccccc2)COCc2ccccc2)c1Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: OCC(CO)OCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 50.7 %

Procedure:
Compound 155 (0.52 g, 51%) was prepared from 154 (1.5 g, 2.6 mmole), BCl3 (5M solution in CH2Cl2, 14 mL), CH2Cl2 (30 mL) and MeOH (20 mL) by the method described for 166 which on recrystallization from EtOAC gave 155: m.p. 155°; 1H NMR (DMSO-d6): d 5.76 (s, 2H, C-1'), 4.63 (t, 2H, exchanges with D2 O, 2×OH), 3.54-3.48 (m, 1H, C-3'), 3.43-3.25 (m, 4H, C-4' and 5'H). Anal. Calcd. for C11H9N2Cl5O3 : C, 33.46; H, 2.28; N, 7.09. Found: C, 33.60; H, 2.15; N, 6.91.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:22]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH3:23])=[N:17][C:16]=13)=[CH:5]2.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][C:19]1[C:18]([CH:22]([NH:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH3:23])=[N:17][C:16]2[N:15]([N:14]=[CH:13][C:12]=2[C:6]2[CH:7]=[N:8][C:9]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[C:20]=1[NH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Solvent: CN(C)C=O
Product: CC(NC1CCOCC1)c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N)c1Br
Reaction time: 0.17 h

Procedure:
To a solution of 3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine (Crude, ˜0.13 mmol) in DMF (2 ml) at room temperature was added NBS (25 mg, 0.14 mmol) and stirring continued for 10 minutes. LC/MS showed no starting material (M.W=406) remaining. This crude compound was submitted to the analytical group for purification to afford the desired 6-bromo-3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](B(O)O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3]1[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[F:16])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=1
Reactant: Fc1ccccc1Br
Reactant: COc1cc2ccccc2cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2ccccc2cc1-c1ccccc1F
Temperature: 25 °C
Yield: 75 %

Procedure:
In the atmosphere of argon, 14.3 g of 3-methoxynaphthalene-2-boronic acid, 12.4 g of 2-fluorobromobenzene, 1.64 g of tetrakistriphenylphosphine palladium (0), 220 mL of 1,2-dimethoxyethane, 110 mL of a 2M aqueous solution of sodium carbonate were placed in a flask, and the resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and then an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate and then concentrated. Residues were purified by silica gel column chromatography, whereby 13.4 g (yield: 75%) of 2-methoxy-3-(2-fluorophenyl)naphthalene was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:34][NH:35][O:36][CH3:37]>C(N(CC)CC)C>[CH3:37][O:36][N:35]([CH3:34])[C:8](=[O:10])[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.8 %

Procedure:
To a suspension of pyridin-3-yl-acetic acid (856 mg in 20 mL dry methylene chloride) was added in sequence 0.35 mL triethylamine, 1-hydroxybenzotriazole (862 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.08 g) and the reagents allowed to mix for 1 hour. At this time, N,O-dimethylhydroxylamine hydrochloride (1.22 g) was added followed by 2.0 mL triethylamine and the reaction stirred at room temperature. After 20 hours, the mixture applied to a silica gel column and purified by flash chromatography (methylene chloride:methanol, 94:6) to give the title compound (796 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:37])[N:17]([CH2:31][CH:32](OC)OC)[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:32]=[CH:31][N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)[C:16]2=[O:37])=[CH:11][CH:10]=1
Reactant: COC(CN(C(=O)Nc1ccc(OCc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1n(-c2ccc(O)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Reaction time: 72 h

Procedure:
A solution of 3-(4-benzyloxyphenyl)-1-(2,2-dimethoxyethyl)-1-(4-phenoxy-phenyl)urea (498 mg) in trifluoroacetic acid (5 ml) was left to stand for 3 days and then neutralized with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 9:1). The product with the molecular weight of 434.50 (C28H22N2O3); MS (ESI): 435 ([M+H]+), was obtained in this way. 1-(4-Hydroxyphenyl)-3-(4-phenoxy-phenyl)-1,3-dihydroimidazol-2-one was obtained as a further product.
Reaction SMILES: [BrH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:16])[C:11](=[O:15])[NH:12]2)=[C:7]([CH2:17][NH:18][CH:19](C2C=CC=CC=2)CC(O)=O)[CH:6]=1)([O-:4])=[O:3].CO.[C:32]([OH:35])(=O)[CH3:33]>>[BrH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:16])[C:11](=[O:15])[NH:12]2)=[C:7]([CH2:17][N:18]([CH3:19])[CH2:33][CH2:32][OH:35])[CH:6]=1)([O-:4])=[O:3]
Reactant: O=C(O)CC(NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)c1ccccc1
Reactant: CC(=O)O
Agent: Br
Solvent: CO
Product: CN(CCO)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
3-[N-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)amino]-3-phenyl-propionic acid hydrobromide, ESCl+ -MS: (M+H)+ =385; TLC: methanol/acetic acid (9:1) Rf =0.34;
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([N:15]([CH3:14])[C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:4]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Product: CN(C(=O)C(C)(C)Cc1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 2,2-dimethyl-3-phenylpropanoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 419.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:15]=[CH:16][C:17]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:38]2[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=3[N:34]=[CH:35][N:36]=2)[CH:3]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(NCc1ccccc1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 55 %

Procedure:
The product of Example 35A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 35A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (39 mg, 55%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.45 (d, J=5.88 Hz, 2 H) 6.83 (d, J=8.82 Hz, 2 H) 6.82-6.93 (m, 1 H) 7.16-7.44 (m, 7 H) 7.56-7.81 (m, 2 H) 7.90 (br s, 1 H) 8.61 (br s, 1 H) 8.79-9.22 (br m, 3 H) 9.94 (br s, 1 H) 10.28 (br s, 1 H); MS (ESI+) m/z 480 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH3:23])[C:16]([CH3:24])=[CH:15][CH:14]=3)=[O:11])[C:7]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[I-].[Li+]>N1C=CC=CC=1>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:23])[C:16]([CH3:24])=[CH:15][CH:14]=3)=[O:11])[C:7]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)ccc(C)c1C
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c(C(=O)O)c1C

Procedure:
To a solution of methyl 6-(6-cyclopropyl-3-(pyrimidin-5-ylamino)pyrazine-2-carboxamido)-2,3-dimethylbenzoate (0.05 g, 119 μmol) in pyridine (1 ml) at r.t under an argon atmosphere was added lithium iodide (125 mg, 932 μmol). The mixture was heated at 100° for 16 hr. The solvent was evaporated. The crude product was used directly in the next step.