Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:25]1
Reactant: NCC1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 35.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-aminomethylpyrrolidine (80 mg), DBU (110 mg) and anhydorous acetonitrile (3 ml) was refluxed for 2.5 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (90 mg) as white powdery crystals, mp 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([CH2:41][CH2:40]2)[CH2:32][NH:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([CH2:41][CH2:40]2)[CH2:32][N:31]1[C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:21]=1)=[O:28]
Reactant: c1ccc2c(c1)CNCC21CC1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5ccccc5C5(CC5)C4)ncn3)CC1)C(=O)N2

Procedure:
50 mg (0.13 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 20 mg (0.13 mmol) 2′,3′-dihydro-1′H-spiro-[cyclopropane-1,4′-isoquinoline], 37 μL (0.26 mmol) TEA and 44.3 mg (0.14 mmol) TBTU were stirred in 1.5 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.Cl.[CH3:18]O>>[CH3:18][O:15][C:14]([CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1)=[O:16]
Reactant: CO
Reactant: O=C(O)C1NCCc2c1[nH]c1ccccc21
Agent: Cl
Product: COC(=O)C1NCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tetrahydro-beta-carboline-1-carboxylic acid (7.4 g) in MeOH (250 ml) was saturated with HCl gas for 20 min. The reaction mixture was gently stirred at room temperature for 18 h. and ca. 80% conversion was observed. The reaction mixture was re-treated with HCl gas and allowed to stir for another 18 h. Upon completion of the reaction the mixture was concentrated in vacuo to yield 2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid methyl ester (building block C), LCMS purity 95%, m/z 231 [M++H]+. The product was used without further purification.
Reaction SMILES: [SH:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[CH:5]=[CH:4][N:3]=1>CCO>[NH2:8][C:7]1[C:2]([SH:1])=[N:3][CH:4]=[CH:5][C:6]=1[NH:11][C@H:12]([C:14]1[N:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:16](=[O:28])[C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][C:18]=2[C:24]([F:25])([F:27])[F:26])[CH3:13]
Reactant: C[C@H](Nc1ccnc(S)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Solvent: CCO
Product: C[C@H](Nc1ccnc(S)c1N)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of (S)-3-(1-(2-mercapto-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoro methyl)isoquinolin-1(2H)-one III-34 (120 mg, 0.247 mmol, 1.0 eq) and stannous chloride dihydrate (297 mg, 1.32 mmol, 5.3 eq) in EtOH (5 mL) was stirred at refluxed for 2 h. The resulting mixture was cooled to RT and concentrated in vacuo. The residue was suspended in water (5 mL), neutralized with saturated NaHCO3 solution to adjust the pH to 7-8 and then extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product, (S)-3-(1-(3-amino-2-mercaptopyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-35.
Reaction SMILES: [O:1]([C@@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@@H:15]2[CH3:17])[CH2:11][CH2:10]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@H:15]2[CH3:17])[CH2:11][CH2:10]1
Reactant: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a solution of 80G (11 mg, 0.026 mmol) in THF (1 mL) was added TBAF (1.0 M in THF, 0.26 mL). The reaction was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC (Phenomenex Luna 20×100 mm S5 C18, 10 min. grad, 20 mL/min, 20-100% B solvent, A=10% MeOH/water+0.1% TFA, B=90% MeOH/Water+0.1% TFA) to provide the title compound (5.1 mg): HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 2.40 min (100%); Chiral analytical HPLC (ChiralPak AD 4.6×250 mm, 20% IPA/hexane isocratic) retention time 18.6 min (100% ee); MS (ES) m/z 306.1 [M+H]+; HRMS calcd for C15H17ClN3O2 306.1009, Found 306.1010.
Reaction SMILES: [CH2:1]([CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])[CH2:2][CH2:3][CH3:4].[NH2:12][NH2:13]>C(O)C>[CH2:1]([C:5]1[C:9]([CH3:10])=[N:12][NH:13][C:6]=1[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCC(C(C)=O)C(C)=O
Solvent: CCO
Product: CCCCc1c(C)n[nH]c1C
Yield: 102.6 %

Procedure:
At room temperature, to a mixture of 3-butyl-pentane-2,4-dione 7 g and ethanol 70 ml was added hydrazine one hydrate 3.3 g and the resulting mixture was stirred for twelve hours. The reaction mixture was subjected to a silica gel column chromatography to give 4-butyl-3,5-dimethyl-1H-pyrazole 7 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]2=[O:18].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]2=[O:18]
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1CC(F)(F)F
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CC(F)(F)F
Yield: 85.5 %

Procedure:
8-Bromo-2-(tert-butylamino)-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (501d, 505 mg, 86%) as an off-white solid was prepared according to the procedures described for 408 using 8-bromo-2-chloro-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (534 mg, 1.562 mmol, 501c), tert-butylamine (4.9 mL, 46.9 mmol), and NMP (0.5 mL). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87-8.00 (2H, m) 7.06 (1H, t, J=7.73 Hz) 6.44 (1H, s) 5.22 (2H, q, J=9.00 Hz) 1.55 (9H, s). m/z (ESI, +ve) 379.9/381.0 (M+H)+.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Al].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[C:1]([Cl:15])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: [Al]
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1ccccc1
Reaction time: 8 h
Yield: 90 %

Procedure:
1 mmol of the cinnamic acid (4) was solved in anhydrous benzene and stirred in an aluminum foil covered flask. 3 mmol thionyl chloride was added and refluxed under stirring overnight. The solvent was removed under vacuum and the product (5) recrystallized from hexane. The derivatives of cinnamoyl chloride were obtained in a 90% yield.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1([F:13])[CH2:9][CH:8]([C:10]([O-:12])=[O:11])[CH2:7][CH2:6][CH2:5]1>CO.C1COCC1.O>[F:3][C:4]1([F:13])[CH2:9][CH:8]([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5]1
Reactant: O=C([O-])C1CCCC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2 M aqueous solution of lithium hydroxide (26 mL) was added to a solution of methyl (1R,2R)-2-2-bromophenyl)-5,5-difluorocyclohexanecarboxylate (1.81 g, 5.46 mmol) in a mixture of methanol (20 mL) and THF (10 mL) with rapid stirring at room temperature for 15 hours. The reaction mixture was then diluted with water and extracted with ether prior to acidification to pH 2 with 2 M HCl followed by extraction with ethyl acetate (2×). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4), and concentrated to afford (1R,2R)-2-2-bromophenyl)-5,5-difluorocyclohexanecarboxylic acid as a tan foam.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34]1([NH:39][C:40]2([CH2:45]O)[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.[S:47]1C=C[CH:49]=[C:48]1CC(O)=O>C1COCC1>[CH:34]1([NH:39][C:40]2([CH2:45][C:48](=[S:47])[CH3:49])[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: OCC1(NC2CCCC2)CCCC1
Reactant: O=C(O)Cc1cccs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)CC1(NC2CCCC2)CCCC1
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a 0° C. solution of Ph3P (27.9 g, 0.107 mol, 1.3 equiv.) in anh. THF (400 mL) were successively added diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 equiv.) and 1-cyclopentylamino-1-(hydroxymethyl)cyclopentane (Method B4d; 15.0 g, 0.082 mol). The resulting slurry was stirred for 30 min., then was treated with thiolacetic acid (7.6 mL, 0.107 mol, 1.3 equiv.). The resulting yellow solution was stirred for 15 min. and concentrated under reduced pressure to about 100 mL. The residue was dissolved in EtOAc (200 mL) and the resulting solution was extracted with a 1N HCl solution (5×125 mL). The combined aqueous layers were washed with EtOAc (2×200 mL), neutralized with K2CO3 to pH 7.0-7.5, then extracted with EtOAc (5×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The residue was dried in vacuo to afford 1-cyclopentylamino-1-(thioacetylmethyl)cyclopentane as a yellow oil (19.1 g): TLC (10% EtOAc/hexanes) Rf0.16; 1H NMR (CDCl3) δ1.20-1.87 (m, 16H), 2.34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H); 13C NMR (CDCl3) δ23.9, 25.2, 29.3, 36.4, 40.1, 55.8, 73.0, 169.8; CI-LRMS m/z (rel abundance) 242 ((M+H)+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][O:16][CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenethyloxy-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cn1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cn1
Agent: Cl
Product: Cn1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4[nH]cnc34)c2F)cn1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide (19 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:42])[C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=3)[C:36](O)=[O:37])[CH:28]=[CH:29][CH:30]=2)=[C:21]([CH2:45][CH2:46][CH3:47])[C:20]=1[OH:48])(=[O:18])[CH3:17].[CH3:49][C:50]1([CH3:58])[O:55][C:54](=[O:56])[CH2:53][C:52](=[O:57])[O:51]1>ClCCl>[C:16]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:42])[C:33]3[CH:41]=[CH:40][CH:39]=[C:35]([C:36](=[C:53]4[C:54](=[O:56])[O:55][C:50]([CH3:58])([CH3:49])[O:51][C:52]4=[O:57])[OH:37])[CH:34]=3)[CH:28]=[CH:29][CH:30]=2)=[C:21]([CH2:45][CH2:46][CH3:47])[C:20]=1[OH:48])(=[O:18])[CH3:17]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(O)=C4C(=O)OC(C)(C)OC4=O)c3)c2)ccc(C(C)=O)c1O
Yield: 100 %

Procedure:
Add dicyclohexylcarbodiimide (0.231 g, 1.12 mmol, Aldrich Chemical Co.) to a solution of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-isophthalamic acid (0.500 g, 1.12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (0.161 g, 1.12 mmol), and 4-N,N-dimethylaminopyridine (0.273 g, 2.23 mmol, Chem-Impex) in dichloromethane (50 mL, 0.2 M). Filter precipitate, wash filter cake with dichloromethane, and concentrate filtrate. Dilute residue with dichloromethane and wash with 1N hydrochloric acid. Dry the organic layer with sodium sulfate and concentrate to afford the title compound (0.641 g, 1.12 mmol): MS (m/z): 572 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO.CC(O)=O.[Br:19]Br>>[Br:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:12])[NH:7][CH:8]=[N:9]2
Reactant: BrBr
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(Br)c2c(=O)[nH]cnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a solution of 7-methylquinazolin-4(3H)-one (900 mg, 5.63 mmol) in MeOH (180 mg, 5.63 mmol) and AcOH (5.07 g, 84.45 mmol) was added bromine (300 μL, 5.63 mmol) and the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with an aq. solution of sodium thiosulphate. The precipitate obtained was filtered and dried to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:9]([C@@H:10]([N:11]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:32][N:33]=[N:34][N:35]=2)=[CH:23][CH:24]=1)[CH:36]([CH3:37])[CH3:38])([OH:39])=[O:8]
Reactant: [H][H]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
A solution of 21.1 g (40 mmol) of N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester in 210 ml of methanol is hydrogenated at room temperature with the addition of 4 g of Pd/C (10% ) until the calculated amount of hydrogen has been absorbed (24 hours). The crude acid is obtained by filtration and evaporation of the solution. It is partitioned between 80 ml of 2N potassium hydroxide solution and 50 ml of ether. The aqueous phase is separated off and rendered acidic, and the title compound is isolated by extraction with ethyl acetate. It is obtained from ethyl acetate in crystalline form and has a melting interval of 105°-1150° and an optical rotation [α]D20 of -69.95°±0.05° (c=1% in methanol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (3.0 g, 19.7 mmol) in N,N-dimethylformamide (50 mL), potassium carbonate (3.27 g, 23.6 mmol) was added and furthermore benzyl bromide (2.6 mL, 21.7 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (4.8 g, 100%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:6]=1)(=O)=O.C([Li])CCC.[F:33][C:34]1[CH:35]=[C:36]([OH:41])[CH:37]=[CH:38][C:39]=1[F:40].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[F:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][C:39]=1[F:40])[O:41][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:6]=1
Reactant: COc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reactant: Oc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
2-Methylsulfonyl-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (93 mg, 0.19 mmol), prepared as described in Reference Example 16, was suspended in THF (500 μL) in a vial fitted with a magnetic stir bar and rubber septum. The reaction mixture was cooled to −78° and 3,4-difluorolithium phenoxide, prepared by adding n-butyl lithium (100 μL, 2M solution) to 3,4-difluorophenol (26 mg, 0.19 mmol) in 500 μL THF at 0° C., was added by syringe. The mixture was brought to room temperature, stirred for 1 h and worked up by adding 2 mL DCM and 1 mL saturated ammonium chloride. The organic layer was separated, dried over MgSO4, filtered and the solvent removed under reduced pressure. HPLC analysis showed the product to be 95% pure and it was used in the next step without further purification. Rt=4.51 min. 1H-NMR 500 MHz (CDCl3): δ 4.12 (s, 3H), 7.02 (m, 1H), 7.15 (m, 1H), 7.20-7.45 (m, 3H), 7.54 (d, J=2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH2:5]2.[Li]CCCC.CN([CH:23]=[O:24])C>>[CH3:13][C:7]1([CH3:14])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=2)[O:8]1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cc2c1OC(C)(C)CC2
Agent: [Li]CCCC
Product: Cc1cc(C=O)cc2c1OC(C)(C)CC2

Procedure:
Using essentially the same procedure as Example 5-20, Step 3, 6-bromo-2,2,8-trimethyl-3,4-dihydro-2H-chromene (684 mg, 2.68 mmol), n-BuLi (1.30 mL, 3.22 mmol) and DMF (830 μL, 10.7 mmol) afforded the desired product as a pale-yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:7]1([C:3]([NH:2][S:14]([CH3:13])(=[O:16])=[O:15])([CH3:6])[C:4]#[N:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)(C#N)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C#N)(NS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a mixture of 2 g (0.0109 mole) 2-amino-2-phenyl-propionitrile hydrochloride (the product of Example 11) in methylene chloride (about 50 ml), 2.6 g (0.0218 mole) 4-dimethylaminopyridine was added, followed by 1.3 g (0.0109 mole) methanesulfonyl chloride in 10 ml methylene chloride in an exothermic addition. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into 100 ml ice water. The layers were separated using a separatory funnel. The organic (methylene chloride) phase was washed twice with water, dried over magnesium sulfate, filtered and stripped to give 2 g of the above-identified product as an orange slush.
Reaction SMILES: Cl.NO.C([N:6]([CH2:9][CH3:10])CC)C.[Br:11][C:12]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16]C=1C=O.CS(Cl)(=O)=O>C(#N)C>[Br:11][C:12]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:10]=1[C:9]#[N:6]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C=O)c(Br)c1OC
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: NO
Solvent: CC#N
Product: COc1ccc(C#N)c(Br)c1OC
Reaction time: 8 h
Yield: 18.2 %

Procedure:
A mixture of hydroxylamine hydrochloride (1.42 g, 20. 4 mmol) and triethylamine (5.7 ml, 40.8 mmol) in acetonitrile (10 ml) was stirred at room temperature for 15 minutes before a solution of 2-bromo-3,4-dimethoxybenzaldehyde (5.0 g, 20.4 mmol) in acetonitrile (40 ml) was added over 40 minutes. The resulting mixture was stirred overnight before a fifth of the resulting solution was charged with methanesulfonyl chloride (0.74 ml, 10 mmol total) and triethylamine (0.6 ml, 4.3 mmol total) portionwise over 6 hours. The mixture was stirred overnight, quenched with water, extracted with ethyl acetate, dried over MgSO4 and concentrated in-vacuo to give 0.90 g of the subtitle product (93%).