Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[N:28]=[C:27](Cl)[N:26]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:26]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1cc(Oc2ccc(C(C)(C)C)cc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(C(C)(C)C)cc3)n2)ccc1-n1cnc(C)c1
Yield: 39 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-(4-tert-butyl-phenoxy)-2-chloro-6-methyl-pyrimidine in a yield of 39%. MS ISP (m/e): 444.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 d, 1H), 7.55 (d, 1H, 7.42 (d, 2H), 7.18 (s, 1H), 7.08 (d, 2H), 7.03 (d, 1H), 6.91 (dxd, 1H), 6.82 (s, 1H), 6.21 (s, 1H), 3.59 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([C:6]2[CH:13]=[CH:12][C:9](C#N)=[CH:8][CH:7]=2)[CH2:3]1.[Cl:14]C1C=CC(B(O)O)=CC=1>>[ClH:14].[Cl:1][C:9]1[CH:12]=[CH:13][C:6]([CH:4]2[CH2:5][NH:2][CH2:3]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl
Product: Clc1ccc(C2CNC2)cc1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.2, except (4-chlorophenyl)boronic acid was used in place of (4-cyanophenyl)boronic acid. The title compound was obtained in 20% yield over two steps.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[C:3]([C:1](=[N:17][OH:18])[NH2:2])[N:4]=1
Reactant: NO
Reactant: N#Cc1cc2c(cn1)[nH]c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 22 h
Yield: 85.4 %

Procedure:
A mixture of 2.4 g of 3-cyano-beta-carboline, 1.1 g of hydroxylamine-hydrochloride, 200 ml of 99% ethanol and 5.2 ml of a potassium carbonate solution (2.2 g of potassium carbonate in 10 ml of water) is boiled in an oil bath at 90° C. outside temperature for 22 h at the reflux. The reaction mixture is filtered hot. The filtrate is concentrated. The residue is treated with 100 ml of water. The precipitate is filtered off, washed with water and dried in air. 2.4 g of beta-carboline-3-carboxylic-acid-amide-oxime with a m.p. of 159°-163° C. is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]2[C:24]([C:25]3[N:30]=[C:29](S(C)=O)[C:28]([F:34])=[CH:27][N:26]=3)=[CH:23][N:22]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]2=[N:20][CH:21]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:34][C:28]1[C:29]([NH:1][CH:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:30][C:25]([C:24]2[C:18]3[C:19](=[N:20][CH:21]=[C:16]([F:15])[CH:17]=3)[N:22]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:23]=2)=[N:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Temperature: 80 °C

Procedure:
A suspension of ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.20 g, 1.00 mmol), 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 25a (0.54 g, 1.20 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.50 mmol) in THF (14.4 mL) was refluxed at 80° C. overnight. After removing the solvent in vacuo, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 300 mg of the desired product as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=9.0, 2.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.99 (d, J=3.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 5.23 (d, J=8.9 Hz, 1H), 4.80 (td, J=9.7, 3.6 Hz, 1H), 4.04 (q, J=7.1 Hz, 1H), 3.91 (q, J=7.1 Hz, 2H), 2.73-2.58 (m, 1H), 2.44 (dd, J=14.7, 9.6 Hz, 1H), 2.33-2.21 (m, 3H), 1.72-1.46 (m, 7H), 1.42-1.31 (m, 1H), 1.28 (t, J=6.1 Hz, 1H), 1.17 (dd, J=13.4, 6.2 Hz, 2H), 0.98 (t, J=7.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.25 minutes (M+H) 584.29.
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]C)=O)=[CH:15][N:14]=2)[CH2:8][CH2:7]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH2:40])[NH:38][N:39]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH:40][C:19]([C:16]3[CH:17]=[N:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][N:6]([CH3:5])[CH2:7][CH2:8]4)=[N:14][CH:15]=3)=[O:21])[NH:38][N:39]=2)[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCCN(C)CC2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
Trimethylaluminium (1.35 ml, 2.70 mmol) was added dropwise to a stirred suspension of methyl 2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (270 mg, 1.08 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (267 mg, 1.08 mmol) in toluene (5.39 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing pure desired compound were evaporated to dryness to afford the title compound (136 mg, 27%) as a cream solid. The fractions containing impure product were concentrated and purified by crystallisation from MeCN to afford the title compound (56.0 mg, 11%) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:14]2[N:13]=[N:12][NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:15].[CH3:20][N:21](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:17]1[CH:18]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:14]3[N:13]=[N:12][NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[Cl:15])[CH:16]=1)[C:20]#[N:21]
Reactant: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-1,2,3-benzotriazole (5.0 g, 14 mmol), tetrakis triphenylphosphine palladium (0) (4.83 g, 4.83 mmol) and zinc cyanide (1.96 g, 16.7 mmol) were suspended in dry DMF (50 mL) under N2 and placed in an oil bath at 90° C. After 2.5 hours, the reaction was allowed to cool to room temperature. The mixture was diluted with EtOAc (300 mL) and washed with water (4×100 mL), dried (MgSO4), filtered and concentrated with silica gel (20 g). This was purified by automated column chromatography on silica gel (120 g), eluting with 0-30% EtOAc/hexanes to deliver the title compound. LRMS (M+1)=304.8.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>>[CH3:20][O:21][C:22](=[O:25])[CH2:23][N:11]1[C:10](=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=2)[C:12]1=[O:16]
Reactant: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)cc3)cc2C1=O
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 5-(4-fluoro-phenoxy)-isoindole-1,3-dione (42.9 g, 167 mmol), Bromo-acetic acid methyl ester (21.1 ml, 223 mmol), K2CO3 (62.3 g, 446 mmol) and Et2CO (700 ml) was refluxed with stirring for 16 h before the mixture was concentrated in vacuo. To the residue was added water (150 ml) and the resulting slurry was extracted with EtOAc (1×750 ml, 1×250 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (49.7 g); 1H NMR (CDCl3) δ=7.80 (d, 1H), 7.01 to 7.30 (m, 6H), 4.41 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.Cl.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52].C([O-])(=O)C.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:15]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])=[NH:47])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NCC(F)(F)F
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)NCC(F)(F)F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a slurry of 2,2,2-trifluoroethylamine hydrochloride (406 mg., 3.0 mmoles) and anhydrous sodium acetate (246 mg., 3.0 mmoles) in chloroform (10 ml.) and glacial acetic acid (0.3 ml., 5.3 mmoles). The mixture was held for 12 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (2 × 50 ml.), washed with saturated aqueous sodium chloride solution (2 × 50 ml.), dried (Na2SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5 ml.) and then evaporated in vacuo to a foam. The foam was recrystallized from 1,2-dimethoxyethane [974 mg., 86% yield, Rf 0.39 (4:1, benzene:ethanol on silicic acid), m.p.-forms a gel at 125°-127° C⟧
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+].I[CH3:32]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][N:11]([CH3:32])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: O=C(NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of N-[2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]benzamide (3.3 g) in dimethyl sulfoxide (20 mL) was added powdered potassium hydroxide (1.6 g), followed by iodomethane (1.0 mL) after 15 minutes. After 1 hour, the mixture was diluted with water (330 mL) and extracted with dichloromethane. The combined organic extracts were dried and evaporated to give the N-methylbenzamide (3.1 g) as an oil; MS: m/z=352[(M+1)-tetrahydropyranyl].
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Br[CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)OCc2ccccc2)cc(OC)c1C
Temperature: 80 °C
Yield: 47.5 %

Procedure:
A suspension of compound 1g (382 mg, 1.0 mmol), benzyl 2-bromoacetate (0.224 mL, 1.4 mmol), and potassium carbonate (276 mg, 2.0 mmol) in DMF (3 mL) was sealed in a pressure tube and heated at 80° C. for 5 h and at rt for two days. The reaction mixture was diluted with water, and the resulting solid precipitate was recovered by filtration and washed with MeOH and hexane to give compound 14a (252 mg, 48%) as a yellow solid. ESI-MS m/e 531.3 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:12]([NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N=C=NCCCN(C)C)C.CCN(CC)CC>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:25](=[O:26])[CH2:24][CH2:23][NH:22][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: COC(=O)CCCCCN
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Yield: 91.3 %

Procedure:
The compound 35 was prepared using General Procedure B with 6-aminohexanoic acid methyl ester hydrochloride salt (3.0 g, 16.5 mmol), N-Cbz-β-alanine (3.68 g, 16.5 mmol), 1-hydrobenzotriazole (HOBt) (2.68 g, 19.8 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC) (3.80 g, 19.8 mmol) and Et3N (5.52 mL, 39.6 mmol) in CH2Cl2, (100 mL). Recrystallization of the crude product from a mixture of MeOH and H2O (10:1 ratio) afforded 5.28 g (91%) of the desired product (35) as a white solid. 1H NMR (CDCl3): 7.32 (m, 5H, ArH), 5.82 (s, 1H, NH), 5.54 (s, 1H, NH), 5.07 (s, 2H, OCH2Ar), 3.64 (s, 3H, OCH3), 3.45 (dt, J=6.1, 12.0 Hz, 2H, CH2NHCO), 3.21 (dt, J=6.4, 12.8 Hz, 2H, CH2NHCO), 2.38 (dt, J=6.1, 6.8 Hz, 2H, CH2CO), 2.29 (t, J=7.2 Hz, 2H, CH2CO), 1.61 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.33 (m, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])=[CH:17][C:10]=3[C:9](=[O:23])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([OH:26])C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:26])=[O:20])=[CH:17][C:10]=3[C:9](=[O:23])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1cccc2c1Sc1ccc(C(C)C(N)=O)cc1C(=O)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1Sc1ccc(C(C)C(=O)O)cc1C(=O)C2
Reaction time: 6 h
Yield: 60 %

Procedure:
To a mixture of 273 mg of 2-(10,11-dihydro-6-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 8 ml of ethanol was added 800 mg of potassium hydroxide in 2 ml of water, and the resulting mixture was refluxed with stirring for 6 hours. The solvent or ethanol was distilled off to obtain a residue, to which was added water, and the mixture was washed with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellowish-brown oil, which was chromatographed over 9 g silica gel and eluted with chloroform to obtain light yellow crystals. The crystals were recrystallized from benzene-n-hexane to obtain 165 mg (yield: 60%) of 2-(10,11-dihydro-6-methoxy-11-oxodibenzo-[b,f]thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 176°-178° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1>ClCCl.N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:17][CH:14]2[CH2:15][CH2:16][CH:12]([OH:18])[CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC(O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
A solution of 9.00 g p-toluenesulphonic acid chloride in 30 ml dichloromethane is added dropwise to an ice-cooled solution of 4.97 g cyclopentan-1,3-diol (cis/trans mixture) in 15 ml of pyridine and 10 ml dichloromethane. The solution is stirred for 45 min at 15° C. The solution is diluted with 100 ml dichloromethane, washed twice with 2 N hydrochloric acid and once with water. After drying through sodium sulphate and elimination of the solvent the product is obtained as a brown oil.
Reaction SMILES: [CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][N:7]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C=CCC1(C(=O)OC)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
A mixture of methyl 4-allylpiperidine-4-carboxylate from Step A (5.30 g, 24.2 mmol), N-(benzyloxycarbonyloxy)succinimide (7.25 g, 29.1 mmol), and N,N-diisopropylethylamine (12.7 mL, 72.7 mmol) in CH3CN (61 mL) was stirred for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and saturated NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×100 mL).The combined organic extracts were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 40:60, to give the title compound. MS: m/z=318 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([OH:24])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Fc1ccccc1CBr
Product: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccc2F)c1

Procedure:
The title compound was prepared from ethyl 4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinoline-3-carboxylate and 2-fluorobenzyl bromide according to the procedure of Example 41. MS (ES) m/z 439.9.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccccc1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide (compound B). After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 360 mg of the title compound (77%) as a yellow powder in 99.4% purity by HPLC (Rt: 4.68, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccccc12
Temperature: -16 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
3-Iodo-1-methyl-1H-indazole (0.15 g, 0.58 mmol) was dissolved in THF (3 ml) and the solution was cooled to −16° C. using a NaCl/ice bath. Isopropylmagnesium chloride (2.0M in THF, 0.32 ml, 0.64 mmol) was added dropwise and the reaction mixture was stirred at −16° C. for 15 min. Tributylchlorostannane (0.18 ml, 0.66 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (0.5% triethylamine, gradient 0-5% EtOAc) to give 224 mg (92%) of 1-methyl-3-tributylstannanyl-1H-indazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.70 (d, J=8.3 Hz, 1H), 7.32-7.45 (m, 2H), 7.11 (ddd, J=8.0, 6.3, 1.5 Hz, 1H), 1.52-1.69 (m, 6H), 1.19-1.44 (m, 12H), 0.83-0.95 (m, 9H).
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1)=[O:4].COCCN(S(F)(F)[F:37])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:37][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:2]([OH:1])([CH3:26])[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=2)=[O:4])=[CH:19][CH:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1cc(NC(=O)C(C)(O)COc2ccc(CO)cc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(CF)cc2)ccc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A solution of 2-hydroxy-3-(4-hydroxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (prepared in Example 70, 950 mg, 0.002636 mol) in dry CH2Cl2 (6.5 ml) was treated with Deoxo-Fluor® (875 mg, 0.003954 mol) in CH2Cl2 (3 ml) at −76° C. The solution was stirred at −10° C. for 3 hours. The saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-5:5). Crystallization from dichloromethane/heptane gave the desired compound. 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.00 (1H, d, 2Jgem=9.7 Hz), 4.24 (1H, d, 2Jgem=9.6 Hz), 5.30 (2H, d, 2JHF=48.6 Hz), 6.21 (1H, s, —OH), 6.95 (2H, d, 3J=8.4 Hz), 7.34 (2H, d, 3J=8.6 Hz), 7.84 (1H, dd, 3J=9.0 Hz, 4J=2.0 Hz), 7.93 (1H, broad s), 8.03 (1H, d, 3J=9.0 Hz), 10.14 (1H, s, —NHCO—).