Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)(=[O:28])[CH3:27]>>[C:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:31][CH:30]=1)(=[O:28])[CH3:27]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(=O)c1ccc(CBr)cc1
Product: CC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 81.8 %

Procedure:
Use a method similar to the General Procedure 7 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.521 mmol) with 4-acetylbenzyl bromide (555 mg, 2.605 mmol). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1, 4:1) to obtain 6-(4-acetyl-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27](=NO)(N)[CH2:28][CH2:29]C.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH2:27][CH2:28][CH3:29])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: CCCC(N)=NO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1

Procedure:
41.20 g (112.1 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole and 12.6 g (123.4 mmol) of butyramidoxime are stirred at 60° for 2.5 hours in 200 ml of N,N-dimethylformamide. The cooled suspension is then filtered; the filter residue is rinsed with ether and dried. The product obtained is stirred at 1120° for 3 hours with 350 ml of glacial acetic acid. The reaction mixture is evaporated and the residue is dissolved in methylene chloride. The solution is washed with a saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-propyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one of melting point 176°-178°.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH:2]1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1.O.N1CCNCC1>[N:1]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:4][CH2:3][CH:2]1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)C1CCN1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)C1CCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Benzyl azetidine-2-carboxylate (4.0 g, 21 mmol) and potassium carbonate (5 g, 36 mmol) in a mixture of 1,4-dioxane (25 ml) and water (30 ml) was treated with benzyl chloroformate (3 ml, 21 mmol) at room temperature for 6 hours. Piperazine (5 drops) was added and the mixture was stirred for additional 0.5 hour. The organic volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and 2 N HCl solution. The upper layer was washed with brine and dried over MgSO4. Removal of solvents afforded the desired compound (6.8 g, Yield: 96%). MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH2:19][C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[F:36])([CH3:26])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:57])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH:19]([F:57])[C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[F:36])([CH3:26])[N:17]=1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)C(F)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A solution of tert-butyl N-tert-butoxycarbonyl-N-[(3R)-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (bis-boc intermediate) (2.03 g, 3.83 mmol)) in THF (24 mL) was cooled to −78° C. LHMDS (1.0 M in THF; 4.02 ml, 4.02 mmol) was added dropwise and the reaction was stirred at −78° C. for 1 hour. To this was added N-fluorobenzenesulfonimide (1.813 g, 5.75 mmol) as a solution in THF (4 mL). The reaction was stirred at −78° C. for 30 minutes. The reaction was treated with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic portion was e dried over Na2SO4, filtered, concentrated and purified by column chromatography, eluting with 0-40% tert-butyl methyl ether in Heptanes to afford the title compound (1.1 g, 2.01 mmol, 52.4% yield) as a mixture of diastereomers. MS m/z=570.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:13]([C:17]1[S:21][C:20](=[NH:22])[N:19]([CH2:23][CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N>>[C:13]([C:17]1[S:21]/[C:20](=[N:22]\[C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])/[N:19]([CH2:23][CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)sc2=N)C1
Agent: N
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to the procedure described in Example 54A by substituting 5-chloro-2-methoxybenzoic acid for Example 26B and the product of Example 63A for Example 16A. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.34 (s, 9H) 1.44 (s, 9H) 3.10-3.30 (m, 1H) 3.77 (dd, J=9.12, 5.16 Hz, 2H) 3.90 (s, 3H) 4.05 (t, J=8.53 Hz, 2H) 4.37 (s, 2H) 6.63 (s, 1H) 6.91 (d, J=8.73 Hz, 1H) 7.33 (dd, J=8.72, 2.78 Hz, 1H) 7.89 (d, J=2.78 Hz, 1H). MS (DCI/NH3) m/z 494.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.O.[NH2:10][NH2:11]>CO>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:7])[NH:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: N#CCC(=O)C1CC1
Solvent: CO
Solvent: O
Product: Nc1cc(C2CC2)n[nH]1
Temperature: 75 °C
Yield: 46 %

Procedure:
To a solution of 126a (477 mg, 4.38 mmol) in methanol (5 mL) was added hydrazine hydrate (5 mL, 80%). The reaction mixture was heated at 75° C. for 15 h. The methanol was removed under reduced pressure and the residue was extracted with dichloromethane (2×8 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was purified by flash column eluting with 100:1 dichloromethane/methanol to afford 126b as a yellow oil (250 mg, 46%, over two steps). MS: [M+H]+ 124.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1([F:32])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:28]([CH3:29])=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=3[CH3:30])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O.CO>C1COCC1>[F:32][C:4]1([F:3])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][C:28]=3[CH3:29])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(F)(F)CC3)ccc2C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CCC(F)(F)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Lithium hydroxide (LiOH.H2O, 0.048 g, 0.00115 mol) is added to a stirred solution of methyl 4-[[6-(4,4-difluoro-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.24 g, 0.575 mmol) in THF:H2O:MeOH (1.5 ml:0.7 ml:1.5 ml). After 3 hours at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with aqueous 1N HCl, and extracted with ethyl acetate (3×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a white solid (0.166 g, 71%). Mass spectrum (m/z): 404.2 (M+1).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC(C#N)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(C#N)cc2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: N#Cc1ccc(Br)cc1
Product: N#Cc1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Yield: 79 %

Procedure:
4-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzonitrile. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (53 mg, 0.080 mmol) and 4-bromobenzonitrile following General Procedure A. Flash chromatography (5-10% EtOAc/hexanes) yielded the title compound as a clear oil (30 mg, 79%): 1H NMR (CDCl3, 500 MHz) δ 7.82-7.78 (m, 4H), 7.50 (s, 1H), 7.36-7.33 (m, 2H), 7.26-7.23 (m, 3H), 4.93 (t, 1H, J=5.5 Hz), 2.67 (t, 2H, J=7.5 Hz), 2.06-1.95 (m, 2H), 1.75-1.67 (m, 2H), 1.47-1.40 (m, 6H), 0.98 (s, 9H), 0.19 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.7, 149.7, 143.2, 133.2, 132.4, 128.8, 128.7, 126.0, 124.8, 124.8, 119.0, 112.0, 69.1, 36.8, 36.3, 31.8, 29.6, 28.3, 26.1, 25.5, 18.6, −4.5, −4.7.
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([C:10]([O:19][CH2:20][O:21][CH3:22])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1.O>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[C:10]([C:8]1[CH:9]=[C:4](/[CH:1]=[CH:2]/[CH3:3])[C:5]([O:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([O:27][CH3:26])=[O:36])=[N:6][CH:7]=1)([O:19][CH2:20][O:21][CH3:22])[C:15]([F:18])([F:17])[F:16]
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=CCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 3-allyl-2-chloro-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)pyridine (80 mg, 0.220 mmol) in N,N-dimethylformamide (2 mL), sodium hydride (14.4 mg, 0.330 mmol) and 3-hydroxybenzoic acid methyl ester (50 mg, 0.330 mmol) were added under ice-cold conditions, and the resultant mixture was stirred at 80° C. for 18 hours and further stirred at 100° C. for 3 hours. The reaction solution was added with water under room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (81 mg, yield 76.5%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[NH:17][C:16](=[O:18])[C:15]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26]C)=[CH:24][CH:25]=2)=[CH:14][N:13]=1.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[ClH:28].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[NH:17][C:16](=[O:18])[C:15]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:14][N:13]=1
Reactant: COc1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cn1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(O)nc2)c(=O)[nH]1
Yield: 71 %

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone (0.55 g) in 2N hydrogen chloride in ethanol was boiled under reflux for 24 hours. The mixture was evaporated to dryness and the residue was recrystallised from 2-propanol/ethanol containing hydrogen chloride to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 205-209° in 71% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.[F:20][C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[F:26][C:22]([F:27])([C:21]([F:29])([F:28])[F:20])[C:23]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:24]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
2-aminopyridine (300 mg, 3.19 mmol) was dissolved in 15 mL of anhydrous dichloromethane, following which 919 mg (4.78 mmol) of EDC-HCl, 583 mg (4.78 mmol) of DMAP and 397 μL (628 mg, 3.83 mmol) of pentafluoropropionic acid were added in this order and the mixture was stirred overnight at room temperature. Following reaction completion, the reaction mixture was diluted with dichloromethane, washed once with water and twice with 1% hydrochloric acid, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure, affording 85 mg of 2,2,3,3,3-pentafluoro-N-(pyridin-2(1H)-ylidene)propanamide (yield, 11%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:5]([C:13]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1Br.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:4][C:5]([C:13]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh3)4 (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])=[CH:17][CH:18]=2)[N:13]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O1CCCC1>[C:25]([O:24][C:22](=[O:23])[N:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:3][OH:2])=[CH:12][N:13]2[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[CH:18][CH:17]=1)[CH3:21])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccccc1Sc1cn(Cc2cc(F)cc(F)c2)c2cc(N(C)C(=O)OC(C)(C)C)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3CO)cn(Cc3cc(F)cc(F)c3)c2c1
Reaction time: 1 h
Yield: 95.3 %

Procedure:
i)—A solution of 2-[6-(tert-butoxycarbonyl-methyl-amino)-1-(3,5-difluoro-benzyl)-1H-indol-3-ylsulfanyl]-benzoic acid methyl ester (Example 6, method 1, step ii; 0.163 g, 0.30 mmol) in a mixture of diethyl ether and tetrahydrofuran was treated with lithium aluminium hydride (1 M solution in tetrahydrofuran; 0.3 ml, 0.3 mmol). After 1 h stirring, the reaction mixture was quenched with a saturated aqueous solution of sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→2:8) afforded [1-(3,5-difluoro-benzyl)-3-(2-hydroxymethyl-phenylsulfanyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (0.146 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 63.4 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 70%, 0.53 g, 2.1 mmol) in chloroform (10 ml) was added dropwise to a solution of 2-{6-[(4-methylphenyl)sulfinyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one (0.35 g, 1.0 mmol) in chloroform (50 ml) with stirring. The reaction mixture was stirred at room temperature for 5 hrs and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethanol to give the titled compound (0.25 g, 64%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:3]2[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc(Cl)c1
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Yield: 55.9 %

Procedure:
Using a procedure analogous to Example A1, 2-fluoro-4-aminophenol (2.6 g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined to provide 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.2 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90 (m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H); MS (ESI) m/z: 239.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:30])[C:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH:28]=O)([CH2:18][CH3:19])[CH2:16][CH3:17].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:30])[C:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1/[CH:28]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH2:16][CH3:17])[CH2:18][CH3:19]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21)C(=O)OC
Temperature: 70 °C
Yield: 77.9 %

Procedure:
To the mixture of 6-chlorooxindole (8.3 g, 49.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-ethyl-butyric acid methyl ester (13 g, 45.8 mmol) in methanol (200 mL) was added pyrrolidine (4.1 mL, 49.7 mmol) dropwise. The mixture was then heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (15.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN4CCCC4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (86 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([O:15]C)=[O:14])[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.1 %

Procedure:
Methyl N-(tert-butoxycarbonyl)-O-methyl-D-serinate (2.0 g, 85.7 mmol) was dissolved in tetrahydrofuran (40 ml) and water (20 ml) and lithium hydroxide mono hydrate (1.8 g, 42.9 mmol) added. The mixture was stirred for 4 hours at room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran and then acidified by the addition of concentrated hydrochloric acid. The solution was extracted with ethyl acetate (three times). The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-O-methyl-D-serine (1.9 g, 100%) as a colourless oil; 1H NMR spectrum: (DMSO d6) 1.37 (s, 9H), 3.23 (s, 3H), 3.53 (m, 2H), 4.18 (m, 1H), 6.87 (d, 1H), 12.60 (brs, 1H).