Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:32][C:25]4[C:26]5[S:31][CH:30]=[CH:29][C:27]=5[S:28][C:24]=4[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][C:48](Cl)=[O:49])=[CH:43][CH:42]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:33]([O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][C:48]([NH:21][C:18]2[C:17]([C:22]3[S:32][C:25]4[C:26]5[S:31][CH:30]=[CH:29][C:27]=5[S:28][C:24]=4[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:49])=[CH:45][CH:46]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4sc5ccsc5c4s3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3sc4ccsc4c3s2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thieno[3,2-b:2′,3′-d]thiophen-2-yl)pyrazin-2-amine (7l) (370 mg, 746 μmol) and 4-(dimethylamino)pyridine (14.8 mg, 121 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethyl acetate) to give Compound 11l (116 mg, 156 μmol, 20.9%) as a brown solid. Rf=0.19 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.21 (s, 6H), 0.93 (s, 9H), 0.94 (s, 9H), 3.68 (s, 2H), 6.78-6.88 (AA′BB′, 2H), 6.94-7.06 (AA′BB′, 2H), 7.20-7.30 (AA′BB′, 2H), 7.47 (d, 1H, J=5.2 Hz), 7.65 (s, 1H), 7.75 (d, 1H, J=5.2 Hz), 8.06-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.72 (s, 1H); IR (KBr, cm−1) 530, 602, 644, 700, 779, 837, 922, 1072, 1171, 1265, 1361, 1447, 1504, 1603, 1657, 2857, 2928, 2955, 3208.
Reaction SMILES: C(OC([C:6]1[C:7]([CH:13]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:14]2[C:26]([O:28]C(C)(C)C)=O)=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=O)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]2[C:26](=[O:28])[N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:13]3[C:7]=2[N:8]=1
Reactant: CCOC(=O)c1ccc(C)nc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(n1)C1CNCCN1C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of bis(1,1-dimethylethyl) 2-{3-[(ethyloxy)carbonyl]-6-methyl-2-pyridinyl}-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 5; 4.96 g) in dichloromethane (200 mL) was cooled to 0° C. and then TFA (20 mL, 260 mmol) was added. This was allowed to warm to room temperature then stirred for 4 hours. The reaction mixture was redissolved in DCM (100 ml), then TFA (10 ml) added and the whole stirred at room temperature for 1.5 hours. The reaction mixture was fully evaporated and azeotroped with toluene. This was dissolved in methanol (200 mL) and then potassium carbonate (3.05 g) was added and the mixture heated to reflux for 8 hours. The methanol was evaporated and then the residue was partitioned between EtOAc and water. The organic layer was then washed with water and then brine, dried through a hydrophobic frit and then evaporated to an orange oil (87 mg), which was found to be impurities.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[N+:25]([O-])=O)[C@H:13]([C:28]([OH:30])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O>C(O)(=O)C.[Fe]>[Cl:24][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][C:21]=1[Cl:23])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]1[C:28](=[O:30])[NH:25]2
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNC[C@@H]12
Temperature: 60 °C
Yield: 120.2 %

Procedure:
To a solution of 1.5 g (S)-4-carbobenzyloxy-1-(4,5-dichloro-2-nitrophenyl)-piperazine-2-carboxylic acid in 40 mL of acetic acid is added 1.2 g of iron powder. With good stirring, the mixture is heated at 60° C. for 2 hours, then concentrated under reduced pressure (1-2 mm, <40° C.) to a gray-black residue. This material was slurried with 100 mL of ethyl acetate (2×). The combined ethyl acetate filtrates are washed with 100 mL of 1 N HCl, 200 mL of water (2×), 100 mL of brine and dried over MgSO4. Filtration and concentration of the solvent gave a semi-solid material that is crystallized from hexane to afford 1.08 g (80.6%) of title compound as a white solid, mp 174-6° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([Cl:16])[CH:9]=2)=[CH:6][N:5]=[CH:4][C:3]=1[CH:17]([CH:24]1[CH2:26][CH2:25]1)[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:16][C:10]1[CH:9]=[C:8]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]3[C:2]=2[CH2:22][S:19](=[O:21])(=[O:20])[N:18]([CH3:23])[CH:17]3[CH:24]2[CH2:26][CH2:25]2)[CH:13]=[CH:12][C:11]=1[C:14]#[N:15]
Reactant: CN(C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1Cl)C1CC1)S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN1C(C2CC2)c2cncc(-c3ccc(C#N)c(Cl)c3)c2CS1(=O)=O
Temperature: 65 °C

Procedure:
To a solution of N-((4-chloro-5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)-N-methylmethanesulfonamide (51 mg, 0.124 mmol) in THF (10 mL) and DMSO (0.1 mL) was added 1M KOtBu in THF (0.37 mL, 0.37 mmol), and the mixture was heated to 65° C. for 10 min under microwave irradiation. The mixture was quenched with MeOH (2 mL) and concentrated. The residue was purified by Xbridge C18 eluting with 20-100% ACN-water to give 2-chloro-4-(4-cyclopropyl-3-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thia-3,6-diaza-naphthalen-8-yl)-benzonitrile
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([OH:27])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:52]3[CH2:56][C:55](=[O:57])[NH:54][CH2:53]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([N:52]3[CH2:56][C:55](=[O:57])[NH:54][CH2:53]3)=[O:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(C(F)(F)F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 96A in analogy to the synthesis of the compound of Example 23. 17 mg (27% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c(=O)c(CCC#N)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(CCc2nnn[nH]2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A mixture of 700 mg of 4-(3-chlorophenyl)-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthyridin-2-(1H)-one, 388 mg of sodium azide, 411 mg of triethylamine hydrochloride and 10 ml of 1-methylpyrrolidin-2-one were stirred at 130° C. for 20 hours. The reaction mixture was cooled to room temperature, acidified by adding 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and the solvent was evaporated. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 130 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthyridin-2(1H)-one as pale yellow crystals.
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ncnc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)[nH]c1ncnc(Cl)c12
Temperature: 90 °C
Yield: 30.6 %

Procedure:
In a 100 mL round-bottom flask a mixture of methyl 4-hydroxy-9H-pyrimido[4,5-b]indole-7-carboxylate (1.1 g, 4.5 mmol) and phosphorous oxychloride (15 mL, 161 mmol) was heated to 90° C. for 16 hours, cooled down to room temperature and evaporated under reduced pressure. The residue was suspended in dichloromethane (20 mL) and filtered through Celite. Evaporation afforded the title compound as an orange solid (360 mg). LCMS m/z 262.0 (M+H)+, retention time (on analytical HPLC)=2.02 minutes.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH2:23].C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CNCc1ccc(Cl)cc1Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (10.0 g, 41.15 mmol, 1.00 equiv) in THF (150 mL), (2,4-dichlorophenyl)methanamine (7.16 g, 40.91 mmol, 1.00 equiv) and triethylamine (5.96 g, 59.01 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The filtrate was concentrated to dryness and used for next step, assuming theoretical yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[C:14]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>ClCCl>[C:14]([O:18][C:19](=[O:28])[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:24][CH:25]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and 4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and dichloromethane. The organic layer was dried (magnesium sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of 4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as an off-white solid. 1H-NMR (CDCl3); δ 8.00 (dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H), 4.36 (d, 2H), and 1.57 (s, 9H). MS: M+=392.1 Da Step (2): Synthesis of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC1C=CC(S(O)(=O)=O)=CC=1.O.O.CC(C)=O>[O:14]=[C:11]1[NH:10][C:8]2[N:9]=[C:4]([CH:3]=[O:2])[N:5]=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: COC(OC)c1ncc2c(n1)NC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1ncc2c(n1)NC(=O)CC2
Yield: 147.7 %

Procedure:
To a solution of 2-[bis(methyloxy)methyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.873 g, 3.91 mmol) in 1:1 H2O/acetone (10 mL) was added p-TsOH.H2O (0.074 g, 0.391 mmol) and the reaction was heated to 80° C. for 3 days with additional p-TsOH.H2O (0.20 g). After the disappearance of starting material, the solution was concentrated under vacuum to yield the desired product (1.023 g).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:12]4[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1NC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Yield: 97 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound (175 mg, 97%) as a white powder.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14]([NH:16][CH2:17][C:18]([O:20]C1C(F)=C(F)C(F)=C(F)C=1F)=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[N:33](C)C=O>O>[NH:16]([C:14]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([NH2:33])=[O:20]
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The amine trifluoroacetate from Example 4 (215 mg, 0.180 mmol) is dissolved in N,N-dimethylformamide (2 ml). To this solution 1M sodium bicarbonate (200 μl, 0.200 mmol) and pentafluorophenyl N-benzyloxycarbonylglycinate (106 mg, 0.270 mmol) is added. After 1 h, the reaction mixture is diluted with water (2×). Isolation by reverse-phase (C18) flash column chromatography eluting with acetonitrile/water gives, after lyophilization of the product-containing fractions, the N-CBZ glyamide: C61H92N10O19, formula weight=1269.47.
Reaction SMILES: B.C1COCC1.[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[O:11])[CH3:8]>C1COCC1>[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cccc(O)c1CCCC(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(O)c1CCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane THF complex (56 ml of 1M in THF, 56 mmol) was slowly added to a solution of 4-[2-ethoxycarbonyl-6-hydroxyphenyl]butanoic acid in THF at 0° C. The solution was stirred for 2 hr and allowed to warm to room temperature. The reaction was quenched slowly with aqueous acetic acid (5 ml of 50%) and stirred until the bubbling subsided. The mixture was concentrated in vacuo to a slurry, which was dissolved in cold 10% potassium carbonate. The solution was extracted with ethyl acetate twice. The organic extracts were dried with brine and concentrated in vacuo to a tan oil that solidified upon standing (5.14 g, 84.9%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19]Br)=[CH:4][CH:3]=1.[NH3:21].CO>O1CCCC1>[NH2:21][CH2:19][C:5]1[C:6]([F:18])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reaction time: 16 h
Yield: 21 %

Procedure:
A solution of 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (2.5 g, 5.96 mmol) in tetrahydrofuran (THF) (50 mL) was added dropwise to a 7M solution of ammonia in MeOH (42.6 mL, 298 mmol) at RT under nitrogen. The reaction was stirred for 16 h then the reaction mixture was evaporated to dryness. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue and the mixture was shaken in a separatory funnel. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography with hexane:ethyl acetate to give the title compound (0.453 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (s, 1H), 7.56 (d, 1H), 7.39-7.46 (m, 2H), 7.37 (m, 1H), 3.70 (s, 2H), 1.85 (br. s., 2H).
Reaction SMILES: C(N[C:6](=O)[N:7]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(C)(C)C.[CH:22]1[CH:23]=[CH:24][NH+]=[CH:26][CH:27]=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:15]1([N:7]([CH:6]2[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: c1cc[nH+]cc1
Reactant: CC(C)(C)NC(=O)N(CCCCCCO)C1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: O=CCCCCCN(C1CCCCC1)C1CCCCC1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a stirred suspension of silica gel (432 mg) in methylene chloride (10 mL) at room temperature was added 3-(tert-butyl)-1-cyclohexyl-1-(6-hydroxyhexyl)urea (400 mg, 1.34 mmol) and PCC (432 mg, 2.0 mmol). The mixture was stirred at this temperature for 2 hours, and then filtered through a pad of celite. The filtrate was concentrated and purified on silica gel column with a gradient of ethyl acetate in hexanes from 0:1 to 2:8 provided the product as a clear oil (190 mg, 48%). 1H NMR (300 MHz, CDCl3): δ 9.78 (t, J=1.8 Hz, 1H), 4.16 (s, 1H), 3.86-3.50 (m, 1H), 3.00 (t, J=7.9 Hz, 2H), 2.46 (td, J=7.3, 1.8 Hz, 2H), 1.87-1.46 (m, 9H), 1.46-1.20 (m, 15H), 1.20-0.95 (s, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[C:7]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49].C(OCC)(=O)C>CN(C=O)C>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][Br:49])=[CH:8][C:7]=2[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])=[N:21]1
Reactant: Cc1ccsc1C(=O)Nc1cc(CO)ccc1/C=C/c1n[nH]c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)Nc1cc(CBr)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 108 (0.30 g, 0.77 mmol) was dissolved in DMF (12 mL) and the solution was added with triphenylphosphine (0.45 g, 1.5 mmol) and carbon tetrabromide (0.51 g, 1.5 mmol), followed by stirring at room temperature for 1 hour. After the reaction, the mixture was added with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was concentrated under reduced pressure to obtain (E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(bromomethyl)phenyl}-3-methylthiophene-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][N:46]=2)[C:41](O)=[O:42])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][N:46]=2)[C:41]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:42])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (160 mg) and 2-(3,4,5-trimethoxyphenyl)-isonicotinic acid (113 mg) were reacted in the same manner as in Example 56 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]2[CH2:11][CH:10]2[N:12]([C:20]([C:22]2[C:23]([CH:28]([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=2)=[O:21])C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH:9]2[CH2:11][CH:10]2[NH:12][C:20]([C:22]2[C:23]([CH:28]([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=2)=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1cc(C(=O)N(C(=O)OC(C)(C)C)C2CC2c2ncc(Cl)cc2Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)NC2CC2c2ncc(Cl)cc2Cl)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
0.200 g of tert-butyl [2-(3,5-dichloropyridin-2-yl)cyclopropyl]{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]carbonyl}carbamate (0.00039 mol) are dissolved in 5 ml of dichloromethane. 0.50 ml of trifluoroacetic acid are added to the reaction mixture which is left stirring at room temperature overnight. The reaction mixture is quenched with 15 ml of an aqueous solution of saturated sodium bicarbonate. After separation, the aqueous phase is extracted with dichloromethane (10 ml). The combined organic phases are dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 120 mg of N-[2-(3,5-dichloropyridin-2-yl)cyclopropyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (76%).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:12]1[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18]1)=[O:15]>C1COCC1.O>[Cl:31][C:29]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]([F:24])([F:25])[F:26])[CH2:21][CH2:22]2)=[O:15])=[C:12]([O:4][CH2:3][CH2:2][F:1])[N:30]=1
Reactant: O=C(NC1CCC(C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Reactant: OCCF
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCCF
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Fluoroethanol (380 μL, 6.45 mmol) is added to potassium tert-butoxide (730 mg, 6.16 mmol) in THF (60 mL) and stirred for 5 min at rt. After the addition of 2,6-dichloro-N-(4-trifluoromethyl-cyclohexyl)-nicotinamide (2.00 g, 5.86 mmol) the reaction mixture is stirred for 1 h hour at rt, then diluted with water and concentrated. The residue is stirred in ice water, the precipitate is filtered off and dried.