Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=4)=[O:24])=[CH:18][CH:17]=3)=[O:14])=[N:11][CH:12]=2)[CH2:3]1.Cl.F[CH2:37][C:38](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:39]F>>[C:31]([C:29]1[O:28][N:27]=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH:4]4[CH2:5][N:2]([CH:38]([CH3:39])[CH3:37])[CH2:3]4)=[CH:12][N:11]=3)=[CH:21][CH:20]=2)[CH:30]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CNC4)cn3)cc2)no1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 19 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylazetidin-3-yloxy)picolinamide (25 mg, 19%) was prepared as an off-white powder using a procedure analogous to that described in Example 20, substituting 5-(azetidin-3-yloxy)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 493 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.48 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 8.08 (dd, J=1.32, 8.67 Hz, 1H), 7.81 (d, J=7.35 Hz, 2H), 7.50 (dd, J=2.64, 8.67 Hz, 1H), 7.41 (d, J=7.16 Hz, 2H), 6.50 (d, J=1.88 Hz, 1H), 4.94 (t, J=5.46 Hz, 1H), 3.73 (t, J=6.40 Hz, 2H), 3.00 (t, J=6.03 Hz, 2H), 2.29-2.41 (m, 1H), 1.29 (d, J=1.88 Hz, 9H), 0.77-0.95 (m, 6H).
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:14]1([O:22][CH3:23])[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:16][CH3:17]>O1CCCC1.C1(C)C=CC=CC=1>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:15]([O:16][CH3:17])[C:14]=1[O:22][CH3:23]
Reactant: COc1ccccc1OC
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 2 L flask, 72 g of veratrole was dissolved in 300 g of tetrahydrofuran and 155.3 g of butyllithium in toluene was added at temperatures from −10° C. to over 30° C. The mixture was stirred from 1-4 hours at ambient temperature. Then 40 g of 4-pyridinecarboxaldehyde (9) in 180 mL of toluene was added around ambient temperature. The reaction mixture was stirred from 30 minutes to 5 hours. The solution was then cooled to around 5° C. and quenched with 200 mL of water. The phases were separated and the organic phase was distilled to remove the tetrahydrofuran. The residue was taken up in toluene at −5° C. The 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) was collected by filtration and washed with 60 g of toluene.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][N:6]1[CH2:10][C:9](=[CH2:11])[C@@H:8]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:7]1)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[CH:25][C:24]=1[F:36]>>[F:36][C:24]1[CH:25]=[C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])[CH:27]=[CH:28][C:23]=1[NH:22][C:4]([CH2:5][N:6]1[CH2:10][C:9](=[CH2:11])[C@@H:8]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:7]1)=[O:21]
Reactant: C=C1CN(CC(=O)OCC)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: C=C1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
39.4 Using general procedure F {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methylene-pyrrolidin-1-yl}-acetic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid ((R)-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-4-methylene-pyrrolidin-3-yl)-amide. Yellow solid. MS 487.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25].C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(C)O
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCNc1nc2ccc(C#CC(C)(C)O)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (120 mg, 0.33 mmol), 2-methylbut-3-yn-2-ol (277.2 mg, 3.30 mmol), bis(triphenylphosphine)palladium(II) dichloride (231.67 mg) and triethylamine (2.4 mL) in dimethylsulfoxide (1 mL) was stirred under nitrogen for 1 hr at 70° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with 5 mL of water then extracted with 3×30 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to give 5.0 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol as a white solid: 1H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.16-7.12 (m, 3H), 6.91 (d, 1H), 5.40 (s, 1H), 3.63-3.57 (m, 4H), 3.35 (s, 3H), 1.47 (s, 6H); LC-MS: m/z=+367 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(C)=O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 4.5 g quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (2-a)) is dissolved in a mixture of 50 ml of n-hexhane and 50 ml of acetone, and 7 g of a Lindlar catalyst is added to the solution. Hydrogen gas is introduced into the solution with stirring. The reaction is completed when the solution has absorbed the theoretical amount of the gas. On completion of the reaction, the catalyst is filtered off from the reaction mixture, and the filtrate is concentrated at reduced pressure. The residue is distilled in a vacuum, affording 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (2-b), R1 =CH3, R2 =CH3) in a yield of 99.8%, b.p. 81-85° C./0.005 mm Hg.
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4]1=[O:21])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][C:35]1[CH:36]=[C:37]([NH:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)=[O:44])[CH:38]=[CH:39][C:40]=1[F:41]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:35]1[CH:36]=[C:37]([NH:42][C:43](=[O:44])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[C:4](=[O:21])[C@@:3]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:1][CH3:2])[CH2:12][CH2:11]4)=[CH:50][CH:51]=2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccc(F)c(F)c3)cc2)OC1(C)C
Reactant: CCOC(=O)C[C@]1(CC)CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@@]1(CC(=O)OC)CCc2cc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)ccc2C1=O
Yield: 40 %

Procedure:
Pd(PPh3)4 (0.018 g, 0.015 mmol) was added to a solution of (S)-ethyl 2-(2-ethyl-1-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)acetate (129C, 0.3 g, 0.761 mmol) in 10 mL 1,4 dioxane-H2O (4:1) mixture under argon atmosphere, followed by cesium carbonate (0.74 g, 2.28 mmol) and Example 217B (0.313 g, 0.837 mmol). The reaction mixture was degassed for 30 min. The reaction mixture was refluxed for 12 h, and solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography using 20% ethyl acetate in hexane to afford title compound (0.15 g, 40%) as solid. 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 8.03 (s, 1H), 7.44-7.37 (m, 3H), 7.35-7.31 (m, 4H), 7.18 (m, 1H), 7.08-6.97 (m, 2H), 3.67 (s, 3H), 3.14 (m, 1H), 3.04 (d, J=16 Hz, 1H), 2.90 (m, 1H), 2.5 (d, J=16 Hz, 1H), 2.45 (m, 1H), 2.05 (m, 1H), 1.79-1.6 (m, 2H), 0.94 (t, J=7.6 Hz, 3H); ESI-MS m/z=493 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]C)=[O:22])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([O:5][C:6](=[O:28])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22])(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(NS(=O)(=O)c1cccc(C(=O)O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a stirring solution of methyl 3-[(2-tert-butoxy-2-oxo-1-phenylethyl)-sulfamoyl]benzoate (2.2 g, 5.4 mmol) in tetrahydrofuran (33.7 mL) and methanol (33.7 mL) was added 1.0 N aqueous lithium hydroxide (13.5 mL, 13.5 mmol) in one portion. The reaction mixture was stirred for 18 hours at ambient temperature, after which time the mixture was concentrated under reduced pressure. The resulting crude was partitioned between ethyl acetate (20 mL) and water (40 mL); the resulting aqueous was acidified with concentrated sulphuric acid (c. 1.0 mL) and washed with ethyl acetate (2×20 mL). The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a white solid (1.21 g, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccncc1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 62.1 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (207 mg, 0.3 mmol) and pyridin-4-ylboronic acid (123 mg, 1.0 mmol) to obtain 4-{2-(2-ethoxycarbony-ethyl)-3-[6-(3-pyridin-4-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (120 mg, 62%) as an yellow oil: ES(+)-HRMS m/e calculated for C38H45NO6S (M+H)+ 644.3041, found 644.3041.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]4[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:34][CH:35]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(OCc5ccccc5)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 6.9 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(benzyloxy)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated under 120° C. at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 2′-amino-6-(4-(benzyloxy)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.75 mg, 7%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.59 (m, 1H), 3.29 (s, 3H), 5.12 (s, 2H), 5.83 (m, 1H), 7.04 (m, 2H), 7.09 (m, 1H), 7.31 (m, 1H), 7.38 (m, 4H), 7.45 (m, 4H), 7.50 (m, 4H), 7.56 (m, 1H).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([C:16]3[S:17][C:18]4[C:24]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=5)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35]CC)=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=4[N:20]=3)[CH:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>C1COCC1.CO>[N:1]1([C:10]2[CH:15]=[C:14]([C:16]3[S:17][C:18]4[C:24]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=5)=[C:23]([C@H:32]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[C:33]([OH:35])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=4[N:20]=3)[CH:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-(2-(2-(1H-indazol-1-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (6.8 mg, 0.011 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H28ClN4O3S: 583.2; found: 583.3. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J=8.8 Hz, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.81-7.77 (m, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.58-7.50 (m, 4H), 7.30 (t, J=7.2 Hz, 1H), 5.35 (s, 1H), 2.61 (s, 3H), 1.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:14][C:10]#[C:9][C@H:8]([OH:11])[CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: C#C[C@H](O)COc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: O[C@@H](C#CBr)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (2.5 g, 14 mmol), N-bromosuccinimide (NBS) (2.74 g, 15.4 mmol) and AgNO3 (0.12 g, 0.7 mmol) in acetone (70 mL) was stirred at ambient temperature. The pale solution became cloudy over 30 minutes. The mixture was concentrated under vacuum and the resulting residue was filtered through a plug of silica gel (1×5 cm) eluted with 1:4 ethyl acetate:hexane to obtain (3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butyne, a compound of formula (CC), as a pale yellow oil containing some ethyl acetate, 4.75 g (quant.); 1H NMR (CDCl3) δ 3.95–4.15 (m, 2H),4.75 (m, 1H), 6.86 (m, 2H), 6.97 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH3:29])[CH:22]=[O:23]>>[CH2:28]([NH:27][C:26]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17])[CH3:29]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: CCNc1ccc(C=O)cc1Br
Product: CCNc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CC(=O)N2CC
Yield: 53 %

Procedure:
The intermediate 4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 3-bromo-4-ethylamino benzaldehyde. 53% yield. 1H NMR (300 MHz; CDCl3): 1.21 (t, J=6.9 Hz, 3 H), 1.31 (s, 3 H), 1.35 (s, 3 H), 2.08 (s, 3 H), 2.53 (s, 2 H), 3.27 (m, 2 H), 4.02 (q, J=7.5 Hz, 1 H), 6.75 (d, J=8.7 Hz, 1 H), 6.83 (s, 1 H), 7.21 (s, 1 H), 7.52 (s, 1 H), 7.81 (d, J=8.4 Hz, 1 H), 9.76 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)C>[N:21]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(-c2cccc(F)c2)c2ccc(CBr)cc2o1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Reaction time: 8 h

Procedure:
To a solution of 7-(bromomethyl)-4-(3-fluorophenyl)-2H-chromen-2-one (1.16 g, 3.5 mmol) in ethanol (35 mL), sodium azide (248 mg, 3.8 mmol) was added. The reaction mixture was then stirred overnight at reflux. After cooling, the reaction mixture was concentrated under reduced pressure and the crude residue was dissolved with CH2Cl2. Salts were removed by filtration and the filtrate was concentrated under reduced pressure to afford the tittle compound. 1H NMR (400 MHz, acetone-d6): 7.72-7.6 (m, 1H), 7.65 (d, 1H), 7.47-7.32 (m, 5H), 6.42 (s, 1H), 4.67 (s, 2H).
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[S:25]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=3[O:35][CH3:36])(=[O:27])=[O:26])=[CH:18][CH:17]=2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C>Cl>[CH3:36][O:35][C:29]1[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=1[S:25]([N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:37])=[O:5])=[CH:12][CH:11]=3)=[O:15])[CH:24]=2)[CH:20]=[CH:21]1)(=[O:26])=[O:27]
Reactant: COc1ccc(C)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: Cl
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A suspension of 4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid tert-butyl ester (305 mg, 0.585 mmol) in hydrogen chloride solution (4 M in 1,4-dioxane, 5 mL) was stirred at room temperature for 16 h, then the precipitate was collected by filtration and washed with ethyl acetate, to afford 4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid (211 mg, 78%). Pink solid, MS (ISP): m/e 463.1 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:6]=[CH:5]2.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[CH:25][N:24]=[C:23]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:6]=[CH:5]2
Reactant: O=C(Cc1ccccc1)Nc1ccc2cc(O)ccc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4cc(NC(=O)Cc5ccccc5)ccc4c3)c2cc1OC

Procedure:
N-(6-Hydroxy-2-naphthyl)-2-phenylacetamide from step (b) above (260 mg, 0.9 mmol) reacted with 4-chloro-6,7-dimethoxy-quinazoline (210 mg, 0.9 mmol, Oakwood) under the conditions of Example 4b to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 466.2 (M+1). Mass Calc'd for C28H23N3O4: 465.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Li]CCCC.[B:18](OC)([O:21]C)[O:19]C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][OH:7])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[B:18]([OH:21])[OH:19]
Reactant: COc1cc(CO)cc(OC)c1
Reactant: COB(OC)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1B(O)O
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxybenzyl alcohol (80 g) in THF (1900 ml) was added n-BuLi (1.6 M in n-hexane, 750 ml) portionwise at −50° C. for 0.5 hour under argon. The mixture was warmed up to room temperature for 2 hours and cooled again to −60° C. To the mixture was added (MeO)3B (200 ml). The resulting mixture was warmed to room temperature and stirred over night. To the reaction mixture was added a solution of citric acid (300 g) in H2O (1200 ml) portionwise at 0° C. The aqueous layer was separated, saturated with NaCl and extracted with AcOEt. The combined AcOEt extract was dried (Na2SO4) and evaporated. The crystalline residue was triturated with AcOEt and collected by filtration to yield the title compound (75.1 g). mp. 92-98° C.; IR (Nujol) 3460, 3408, 3218, 1613, 1578, 1288, 1231, 1123, 1055, 960, 779 cm−1; MS (APCI) m/z 230 (M+NH4).