Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[NH:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>COCCO>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[N:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: COCCO
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Temperature: 127 °C

Procedure:
The compound of Example 1 was prepared on a still larger scale as follows: A mixture of 970 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, 1600 ml of N-methylpiperazine and 8 liters of 2-methoxyethanol was heated to reflux (about 127° C.) over a period of three hours. After 20 hours at reflux, the reaction mixture was cooled to 10° C. and filtered. The filter cake was washed with cold methoxyethanol, followed by methanol. The product was dried at 40° C., affording 925 g of 6-fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid which was purified in the form of its methanesulfonate salt.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([F:24])=[CH:19][CH:18]=3)=[O:14])[C@H:8]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:7]1)=O)C.[ClH:38].[CH3:39][NH2:40]>>[ClH:38].[F:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:3])[NH:40][CH3:39])[CH2:7][C@H:8]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:14])=[CH:23]2
Reactant: CN
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Product: CNC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4S)-4-Ethoxycarbonyl-N1-[(5-fluoroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was hydrolyzed and then subjected to a condensation reaction with monomethylamine hydrochloride in a similar manner to Example 157 to obtain the title compound.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C([O-])=O.[OH:30][CH2:31][CH2:32][CH2:33][NH2+:34][NH2:35].CO>C(Cl)Cl>[NH2:2][C:1]1[N:34]([CH2:33][CH2:32][CH2:31][OH:30])[N:35]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N[NH2+]CCCO
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2nn(CCCO)c(N)c2C(N)=O)cc1
Yield: 43.7 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol), sodium carbonate (424 mg, 4.0 mmol) and 1-(3-hydroxypropyl)hydrazinium trifluoroacetate (449 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 8% methanol in CH2Cl2) and was recrystallised from ethyl acetate to give the title compound as white crystals (240 mg) m.p. 164-165°. δH (CDCl3) 7.43 (2H, d, J 8.1 Hz), 7.26 (2H, d, J 7.8 Hz), 5.73 (2H, br s), 5.18 (2H, br s), 4.12 (2H, t, J 6.1 Hz), 3.66 (2H, t, J 5.5 Hz), 2.40 (3H, s), 2.04 (2H, quintet, J 6.1 Hz) and 1.59 (1H, br s).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]C)=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:40]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25](=[O:27])[NH2:40])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[C:8]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Solvent: CO
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(N)=O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A solution of 3-butyl-4-[[4-[1-(carbomethoxy)-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 1, Step F) in methanol is saturated with gaseous ammonia at 0° and then stirred at that temperature in a stoppered vessel for about 6 hours or until TLC indicates complete reaction. The mixture is then concentrated to dryness to yield the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCN3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCc2cc(C(=O)CCC3CCN(C(C)=O)CC3)ccc21
Yield: 97.2 %

Procedure:
In 10 ml of ethanol were dissolved 0.8 g of 5-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydro-1H-indole, 2.1 g of ethyl iodide and 0.5 g of potassium carbonate and the solution was refluxed for 24 hours. The solid matter and the solvent were removed and the residue was purified by column chromatography (eluent: ethyl acetate: methanol=20:1) to give 0.85 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[OH:10].[Br:21][CH2:22][C:23](Cl)=[O:24]>>[Br:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:10])([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)=[O:24]
Reactant: Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1
Reactant: O=C(Cl)CBr
Product: O=C(CBr)Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1

Procedure:
Prepared from (2-amino-5-bromophenyl)(dithien-2-yl)methanol and bromoacetyl chloride using the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 8.42 (s, 1H), 8.05 (d, J=9.0 Hz, 1H) 7.59 (m, 3H), 7.05 (m, 2H), 6.87 (m, 2H), 6.78 (d, J=3 Hz, 1H), 3.92 (s, 2H); MS (ES) m/z 484 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]([CH3:27])[C@H:18]([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([N:17]([CH3:27])[C@H:18]([CH3:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-amino-6-{methyl[(1R)-1-methyl-2-phenylethyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (200 mg, 0.55 mmol) in ethanol (2 mL) was added hydrazine hydrate (2.0 mL, 99%), and the reaction mixture was heated at 120° C. under microwave conditions with stirring for 1 hour. The mixture was cooled to room temperature and concentrated. The resulting residue was washed with Et2O (30 mL) and dried in vacuo to afford the title compound (156 mg) as a yellow solid. LC-MS (ES) m/z=374 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.0 Hz, 3H), 2.77-2.89 (m, 6H), 5.36 (s, 2H), 5.99 (s, 2H), 6.35 (s, 1H), 7.12-7.16 (m, 1H), 7.23-7.27 (m, 4H), 7.49-7.52 (m, 1H), 7.68-7.70 (m, 1H), 7.88 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8]O)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:8][CH2:7][N:6]1[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2ccccc2n1CCO
Solvent: ClCCl
Product: Cc1nc2ccccc2n1CCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(2-methyl-1H-benzoimidazol-1-yl)ethanol (4.00 g, 22.70 mmol) in DCM (80 mL) at 0° C., thionylchloride (3.5 mL, 48.25 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 5 h at this temperature, then the reaction mixture was quenched with aq. sat. NaHCO3-solution (gas evolution) and extracted with DCM (3×). The org. layers was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(2-chloroethyl)-2-methyl-1H-benzoimidazole which was used without further prufication in the next step. LC-MS conditions B: tR=0.37 min, [M+H]+=195.09.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[C:7]([C:23]([F:25])([F:26])[F:24])=[N:6][C:5]=1[C:3]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4]
Reactant: COC(=O)c1nc(C(F)(F)F)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(C(F)(F)F)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-trifluoromethyl-isoquinoline-3-carboxylic acid methyl ester (41 mg, 0.11 mmol), β-alanine (503 mg, 5.65 mmol) and NaOMe (8.5 mL, 4.24 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound as a white solid. MS: (+) m/z 421.06 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([NH:17][C:18]3[CH:19]=[C:20]([C:21](=[O:22])[NH:23][CH:24]4[CH2:26][CH2:25]4)[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)furan-2-carboxylic acid (45 mg, 0.20 mmol) and 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) (50 mg, 0.22 mmol) in DMF (0.5 mL) DIPEA (0.105 mL, 0.6 mmol) and the resulting mixture was stirred at rt for 1 h then at 80° C. for 1 h. The reaction was cooled to rt and water (3 mL) was added and the crude product was collected by vacuum filtration and dried under vacuum to afford 78 mg of a tan solid. The crude product was recrystallized from CH2Cl2 to afford 48 mg of a light tan solid as the title compound (Example 127). HPLC Ret. Time=3.52 min, LCMS [M+H]+ 395.23.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[CH2:9]1)C1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[CH2:9]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a stirred solution of N-[(4-benzyl-2-morpholinyl)methyl]phthalimide (30.0 g) in toluene (200 ml), ethyl chloroformate (19.4 g) is added dropwise at 60° C., and the mixture is refluxed with stirring for 1 hour. The reaction mixture is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from isopropyl alcohol-diethyl ether to give N-[(4-ethoxycarbonyl-2-morpholinyl)methyl]phthalimide (27.8 g), mp 113°-115° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:3]=1
Reactant: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc(CN2CCNCC2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate (800 mg, 2.40 mmol, 1.00 equiv), dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added dropwise. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to provide 590 mg (crude) of 1-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 282 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C([O-])(=O)C>CN(C)C=O>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1S
Reactant: O=C(O)CCCc1ccc(I)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCc1ccc(Sc2ccccc2O)cc1

Procedure:
A solution of 4-(4-iodophenyl)butyric acid (0.86M) and dimethylformamide was treated with 2 eq of potassium carbonate, 1.5 eq of 2-hydroxythiophenol and a catalytic amount of cuperic acetate (0.01 eq). The reaction mixture was refluxed for 18 hr, cooled to 25 C, acidified with aqueous acid and extracted with ethyl acetate. The organic phase was concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane as eluant to give 4-(4-(2-hydroxyphenyl)thiophenyl)butyric acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:40][CH3:41])=[C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:29][CH:28]5[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:27]5[CH2:26]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:40][CH3:41])=[C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH:27]5[CH:28]([CH2:30][NH:31][CH2:32]5)[CH2:29]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CC5CN(C(=O)OC(C)(C)C)CC5C4)cc23)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CC5CNCC5C4)cc23)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.03 g) in DCM (30 mL) was added a solution of HCl in EtOAc at room temperature. The reaction mixture was stirred for 6 h at room temperature and filtered to give crude product. The crude product was recrystallized from a mixture of MeOH and EA to give the title compound as a white solid (0.78 g, 92.60%), HPLC: 95.04%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 462.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.83-1.88 (m, 4H), 2.32-2.45 (m, 6H), 2.66-2.76 (m, 4H), 4.03 (s, 3H), 4.06 (s, 1H), 4.15 (t, J=7.2 Hz, 2H), 7.15 (s, 1H), 7.23 (s, 1H), 7.40 (s, 1H), 7.53-7.60 (m, 1H), 7.90-7.93 (m, 1H), 8.66 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32].CCN=C=NCCCN(C)C>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4cccs4)c3)c2c1
Yield: 27.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-thiophenecarboxylic acid (0.92 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 56 mg (26% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.4 (br s, 1H), 8.1 (br s, 1H), 8.0 (d, 1H), 7.94–7.86 (m, 2H), 7.8 (d, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.3 (br s, 1H), 7.2 (t, 1H); ES-MS (m/z) 363 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>C(#N)CC.CCOC(C)=O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 86.6 %

Procedure:
To a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90° C. for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 95:5-85:15) to obtain the title compound as yellow solid (17.5 g, 68%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1C(F)(F)F
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1C(F)(F)F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-trifluoromethylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and phenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 26.1, 29.5, 42.8, 60.2, 125.1, 126.6, 127.2, 127.4, 129.2, 130.8, 132.5, 137.1, 138.3 and 144.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:21])[OH:19])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)cc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-n2cccn2)cc1
Reaction time: 1 h
Yield: 37.5 %

Procedure:
Under a nitrogen stream, to a solution of 1-(4-bromophenyl)-1H-pyrazole (995 mg, 4.46 mmol) in anhydrous THF (12 ml), a hexane solution of n-butyllithium (1.6 M, 2.79 ml, 4.46 mmol) was added dropwise at −78° C. After stirring at the same temperature for 1 hour, this solution was added dropwise at −78° C. to a solution of trimethyl borate (1.07 ml, 9.37 mmol) in anhydrous THF (8 ml). After stirring at the same temperature for 1 hour, the reaction mixture was stirred at room temperature for one day and a night. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (developing solution=methylene chloride:methanol (50:1)) to give the titled compound (314 mg, 37%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:11]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To a solution of 4-methylbenzenecarboximidamide hydrochloride (1.70 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1.5 hours. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.05 g (50.0%) of the desired product as a solid.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: NC(CCC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC(N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
680 mg (2.49 mmol) 4-Amino-4-(3-nitro-phenyl)-butyric acid were suspended in 5 ml methanol and 635 μl (8.75 mmol) thionyl chloride were added. The mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, methanol was added and again evaporated to dryness.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A heterogeneous mixture of 4-nitrophenol (5 g), methyl 2-bromoisobutyrate (5.6 mL) and K2CO3 (7.5 g) in acetone (60 mL) was refluxed overnight. The reaction mixture was then diluted with water (150 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were evaporated to give methyl 2-(4-nitrophenoxy)isobutyrate (49).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:21][OH:22])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[O:14]([C:10]1[CH:9]=[C:8]([C:5]2([CH2:21][OH:22])[CH2:4][CH2:3][C:2]3([O:31][CH2:1]3)[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CCC(CO)(c2cccc(Oc3ccccc3)c2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCC1(c2cccc(Oc3ccccc3)c2)CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (4-methylene-1-(3-phenoxyphenyl)cyclohexyl)methanol (53 mg, 0.180 mmol) in CH2Cl2 (0.9 mL) at 0° C. was added m-chloroperbenzoic acid (43.5 mg, 0.252 mmol). The solution was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc, washed successively with 1 N aqueous NaOH, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (56 mg, 100% yield) as a colorless oil. LCMS, [M+H]+=311.1.