Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:33]3[CH:32]=[N:31][C:30]([NH2:44])=[C:29]([C:21]4[S:20][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=4)[CH:34]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)s2)CC1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.079 g, 0.229 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.105 g, 0.298 mmol), potassium carbonate (0.101 g, 0.732 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol) in previously degassed DME/H2O (4:1) (4.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on prep-TLC eluting with 3% 7M NH3 in MeOH/DCM yielding 4-[5-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=495.06 [MH+]. To a solution of this compound in DCM (1.0 mL) was added 1M HCl in ether (2.0 mL, 2.0 mmol), and the mixture was stirred at room temperature overnight. The solid that formed was filtered off and purified on the MDP. To a solution of the material thus obtained in DCM (1.0 mL) was added 1M HCl in ether (1.0 mL, 1.0 mmol). The precipitate was filtered off and dried in vacuo, yielding the title compound as yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.95-3.00 (m, 4H), 3.46-3.53 (m, 4H), 7.40 (s, 1H), 7.42-7.48 (m, 1H), 7.53 (dd, J=15.3, 1.1 Hz, 1H), 7.98-8.05 (m, 2H), 8.07 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H). MS (ES+): m/z=395.06 (55) [MH+]. HPLC: tR=2.11 min (ZQ2, polar—5 min).
Reaction SMILES: COS(OC)(=O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N+:10]=1[O-].[C-:19]#[N:20].[K+]>O>[CH3:8][C:9]1[N:10]=[C:11]([C:19]#[N:20])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: [C-]#N
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C#N)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
To 10.2 ml (13.5 g, 104 mmol, 1.1 equiv.) of dimethylsulfate were added 15.0 g (94.4 mmol) of 2-Methyl-4-nitropyridine-N-oxide at 60° C. The reaction mixture was then stirred for 90 min at 70° C., and allowed to cool to room temperature. The solidified residue was triturated with 30 ml of ether. The product was filtered, washed with 20 ml of ether, and dried. The product was then dissolved in 100 ml of water and added dropwise over a period of 30 min. to a at −8° C. cooled solution of 24.6 g (377 mmol, 4.0 equiv.) of potassium cyanide in 100 ml of water. The reaction mixture was stirred for a further 15 min. at −8° C. The product was filtered off, washed twice with 15 ml of water and dried in vaccuo to yield the title compound (11.1 g, 72%) as a light brown solid.
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)=[S:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>CO>[O:4]=[C:3]1[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:19][C:18](=[N:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[N:17]1[C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1
Reactant: O=C(O)C#CC(=O)O
Reactant: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: O=C(O)C=C1SC(=Nc2ccc(Cl)c(Cl)c2)N(c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A mixture of acetylenedicarboxylic acid (6.6 g, 55 mmoles) and N,N'-bis(3,4-dichlorophenyl)thiourea (20.0 g, 55 mmoles) in methanol (400 mls) is stirred at room temperature for 16 hours. The suspended solid is filtered off and rinsed with cold methanol. The solid is then rinsed repeatedly with boiling CH2Cl2 and filtered off. The combined dichloromethane filtrates are concentrated and cooled to afford the crystalline product (7.6 g), mp 221°-222° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:45])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:42][CH3:43])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[C:25]([CH3:41])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:44])=[N:12][CH:13]=1)C.Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:12]=[CH:13][C:8]([CH2:7][C:6]([OH:45])=[O:5])=[CH:9][N:10]=2)=[C:15]([CH3:44])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:38])([F:39])[F:37])[C:32]([F:35])([F:33])[F:34])=[C:25]([CH3:41])[CH:24]=1)[CH2:42][CH3:43])[CH3:22]
Reactant: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ncc(CC(=O)O)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.039 mL) was added to a solution of [2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid ethyl ester (Example 77-(2); 11.8 mg, 0.0194 mmol) in methanol (0.28 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (11.2 mg, 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(c1cccc(Br)c1)N1CCNCC1

Procedure:
Using analogous procedures to those described in the portion of Example 58 which is concerned with the preparation of starting materials, piperazine was reacted with 3-bromophenylsulphonyl chloride to give 1-(3-bromophenylsulphonyl)piperazine which, in turn, was reacted with 3,5-dichlorophenylboronic acid to give 1-(3′,5′-dichlorobiphenyl-3-ylsulphonyl)piperazine in 29% yield;
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:17][C:12]1[CH:11]=[C:10]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(Br)cc1C
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-n2ccc([N+](=O)[O-])n2)cc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
Into a 250-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-nitro-1H-pyrazole (6 g, 53.10 mmol, 1.00 equiv) in DMSO (80 mL), 4-bromo-1,2-dimethylbenzene (11.8 g, 64.13 mmol, 1.21 equiv), CuI (1.6 g, 8.42 mmol, 0.16 equiv), L-proline (1 g, 8.70 mmol, 0.16 equiv), and potassium carbonate (14.6 g, 105.80 mmol, 1.99 equiv). The resulting solution was stirred overnight at 85° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 4×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of water and 1×100 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10) to give 1 g (9%) of 1-(3,4-dimethylphenyl)-3-nitro-1H-pyrazole as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:11][C:10]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:11][C:10]1=[O:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1CCCCCCC(=CC(=O)OC(C)(C)C)C(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCCCC(CC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 4.5 h

Procedure:
Ethyl 3-t-butoxycarbonylmethylidene-2-oxo-1-azacyclodecane-10-carboxylate (2.85 g, 8.4 mmol) is dissolved in ethyl acetate (75 mL). 10% Pd/C (2.0 g) is added, and the reaction is stirred under an atmosphere of hydrogen for 4.5 hours. The reaction is filtered through Celite, and the solvent is removed. The crude product is purified by silica gel chromatography (20% ethyl acetate/hexane) to give separately the two diastereomers of ethyl 3-t-butoxycarbonylmethyl-2-oxo-1-azacyclodecane-10-carboxylate.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:2]1.[F:16][CH:17]([F:35])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[F:35][CH:17]([F:16])[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28]([C:30]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:7]=[CH:8][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:10][CH:11]=4)[CH2:4]3)=[O:31])=[N:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC(F)F)cc2)o1
Reactant: CN(C)Cc1ccc(OC2CNC2)cc1
Product: CN(C)Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccc(OC(F)F)cc4)o3)C2)cc1
Yield: 15.2 %

Procedure:
Using a similar protocol as described in Example 36 employing 33B (0.19 g, 0.92 mmol) and 37A (0.26 g, 0.92 mmol) as starting materials afforded 62 mg (15%) of 37 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 6H), 3.44 (s, 2H), 4.35 (dd, 1H), 4.66 (dd, 1H), 4.77 (dd, 1H), 5.10 (m, 2H), 6.62 (t, 1H), 6.75 (d, 2H), 7.28 (m, 4H), 8.19 (d, 2H), MS (APCI+) m/z 445 [M+H]+, LC purity: 94%.
Reaction SMILES: COC(=O)C1C=CC(N=[N:11][C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:16]=2)=CC=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>[Pt](=O)=O.CO>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:15]1[N:16]=[C:12]([NH2:11])[NH:13][CH:14]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]
Reactant: COC(=O)Cc1c[nH]c(N=Nc2ccc(C(=O)OC)cc2)n1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1c[nH]c(N)n1

Procedure:
A mixture of 4-(4-methoxycarbonylmethyl-1H-imidazol-2-ylazo)-benzoic acid methyl ester (2 mmol, 604 mg) synthesized above, platinum (IV) oxide (60 mg) and methanol (50 mL) was hydrogenated (60 psi) for two days (another portion of PtO2 was added after one day). Trifluoroacetic acid (TFA) (2 mmol, 0.15 mL) was added to the reaction mixture and it was filtered. The filtrate was concentrated and diluted with water, washed with ether (2×50 mL). Evaporation of the water from the aqueous solution gave the (2-Amino-1H-imidazol-4-yl)-acetic acid methyl ester as a TFA salt. (273.8 mg, 51%). LCMS: 156 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc31)C1CCC(C2)N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(N)cc4)ccc31)C1CCC(C2)N1
Yield: 95.9 %

Procedure:
A mixture of the product of step A (145 mg, 0.29 mmol), iron powder (82 mg, 1.45 mmol) and ammonium chloride (17 mg, 0.32 mmol) was taken up in ethanol (2.3 mL) and water (1.1 mL). The mixture was refluxed for 3 h then diluted with water and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated in vacuo to give tert-butyl 2-(4-aminophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 96%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.15 (s, 1H), 7.69-7.71 (m, 2H), 7.62 (d, J=9.3 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 6.60-6.65 (m, 2H), 5.24 (br s, 1H), 4.69 (br s, 1H), 4.04 (br s, 2H), 3.58 (s, 3H), 3.48 (br s, 1H), 2.48 (d, J=16.5 Hz, 1H), 2.12-2.32 (m, 2H), 1.89-1.97 (m, 1H), 1.52-1.64 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: Br[CH:2]([C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=2)[N:9]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:20]([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O.C(OCC)(=O)C>CN(C)C=O>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:18])[NH:17][C:8]([CH:2]([NH:31][CH2:30][CH2:29][CH2:28][NH:27][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])=[N:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)[nH]1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of 2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (950 mg, 1 eq.) in N,N-dimethylformamide (10 ml), was added N-Boc-1,3-diaminopropane (2.4 g, 5 eq.). The reaction was stirred at 60° C. for 30 minutes. Water and ethyl acetate was added. Ethyl acetate layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give tert-butyl 3-{[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (1.2 g) as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13]>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C)C(=O)Nc1cccc(F)c1Cl
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1cccc(F)c1Cl

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(2-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoate (5.0 g, 18.27 mmol) in THF (18.3 mL) to give 3-(2-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=245.9 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[CH:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28]>>[C:22]1([CH3:28])[CH:23]=[CH:24][CH:25]=[C:26]([O:27][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=2)[CH:21]=1
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Product: Cc1cccc(Oc2ccc(C(=O)Nc3ccccc3C(=O)O)cc2)c1

Procedure:
In analogy to example 2,2-(4-m-Tolyloxy-benzoylamino)-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and m-cresol. MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C@H:9]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12]C)=[O:11])[CH:2]=1.[OH-].[Li+].O.Cl>CO.C1COCC1.CCOC(C)=O>[C:1]1([CH3:34])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C@H:9]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])[CH:2]=1
Reactant: COC(=O)[C@H](COc1cccc(C)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(OC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask equipped with a stir bar and charged with (S)-methyl 3-(m-tolyloxy)-2-(tritylamino)propanoate (8.28 g, 18.34 mmol) in MeOH (30 mL) and THF (30 mL) was added lithium hydroxide in water (55.0 mmol, 27.5 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with aq. 2N HCl. The mixture was diluted with EtOAc and the organic phase was isolated and washed with brine; dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was purified via silica gel chromatography to afford (S)-3-(m-tolyloxy)-2-(tritylamino)propanoic acid, 1.47 g (18%). 1H-NMR (400 MHz, CDCl3) δ 7.44 (d, J=7.1 Hz, 6H), 7.35-7.24 (m, 8H), 7.09 (t, J=7.8 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.52 (s, 1H), 6.46 (d, J=8.1 Hz, 1H), 4.07 (dd, J=9.2, 2.3 Hz, 1H), 3.71 (t, J=3.2 Hz, 1H), 2.79 (dd, J=9.2, 4.0 Hz, 1H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([CH:21]=O)[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1COCC1.II.Cl.O.[NH3:32]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([C:21]#[N:32])[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: N
Reactant: Cc1cc(C)cc(Nc2nccc(-c3nc(C=O)cs3)n2)c1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(Nc2nccc(-c3nc(C#N)cs3)n2)c1
Reaction time: 1 h

Procedure:
To a stirring solution of the crude aldehyde 9a (35 mg, 0.11 mmol) in 1 mL of ammonia water 28% solution and 0.1 mL of THF at rt was added iodine (32 mg, 0.12 mmol). The dark solution became colorless after 1 h of stirring. The reaction mixture was neutralized with 0.5 mL of a 1M aqueous solution of HCl and extracted with ether. Concentrated in vacuo and passed through a short pad of silica gel (30% ethyl acetate/70% hexanes) to give 20 mg (59%) of pure 10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCO.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(CBr)c1
Reactant: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CCOc1cccc2c1ccn2Cc1cccc(F)c1)C(=O)OC(C)(C)C

Procedure:
[2-(1H-Indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was treated NaOH/EtOH followed by addition of 3-fluorobenzylbromide as described above in Step 1 of Example 5 to afford {2-[1-(3-fluoro-benzyl)-1H-indol-4-yloxy]-ethyl}-methyl-carbamic acid tert-butyl ester. MS: 299 (M−Boc+H)+.
Reaction SMILES: [O:1]1[CH:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]1[C:3]([O:5][CH3:6])=[O:4]>C1(C)C=CC=CC=1>[O:1]1[C@H:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C@H:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C1OC1C1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1O[C@@H]1C1CCCCC1
Reaction time: 48 h

Procedure:
500 ml of toluene containing 100 g of methyl 2,3-epoxy-3-cyclohexylpropionate, was added to 500 ml of a 1M tris-HCl buffer solution (pH 8.0) containing lipase (derived from hog pancreas, manufactured by Wako Pure Chemical Industries, Ltd.) in a concentration of 5 g/l, and asymmetric hydrolysis reaction was carried out at 30° C. for 48 hours at a stirring speed of 600 rpm. After the reaction, the toluene phase was separated and concentrated under reduced pressure to obtain 25.2 g of a crude product of methyl (2S,3R)-2,3-epoxy-3-cyclohexylpropionate as a colorless oil substance. By purification by silica gel chromatography (hexane/ethyl acetate=9/1 (v/v)), 23.0 g of methyl (2S,3R)-2,3-epoxy-3-cyclohexylpropionate was obtained (98.6% ee [α]D20=+32.6 (c 1.18, CHCl3)).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=N)[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]=[C:5]1[O:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH3:3].CI.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27](C=O)C>>[CH2:1]([N:4]1[C:9](=[CH:26][NH2:27])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]=[C:5]1[O:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCOc1nc2sccc2c(=N)n1CCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCCOC1=Nc2sccc2C(=CN)N1CCC

Procedure:
In a sulfonation flask 4.5 g (0.018 mol) 3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylidene amine, 5.1 g (0.036 mol) CH3I, 5.0 g (0.036 mol) powdered potassium carbonate and 80 ml of absolute DMF are stirred for 4 hours at an internal temperature of 90-100° C. Then the solvent is distilled off in vacuum, the residue taken up in ethylacetate and the organic phase twice washed with water. After drying the organic phase over Na2SO4 the ethylacetate is distilled off in a water jet vacuum and the residue purified by column chromatography over silica gel (eluant: hexane/ethylacetate 1:6). Yield: 4.4 g of (3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylidene)methylamine in the form of a brown oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]=[C:57]=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:57]([NH:56][CH3:55])=[O:58])[CH2:49][CH2:48]1
Reactant: CN=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and methyl isocyanate as starting materials in 43% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.33 (m, 2H), 8.20 (s, 1H), 7.63 (m, 1H), 7.30 (m, 1H), 7.09 (m, 1H), 6.38 (m, 1H), 3.92 (m, 2H), 2.97 (s, 4H), 2.68 (m, 2H), 2.55 (s, 3H), 2.28 (m, 2H), 1.91 (m, 1H), 1.64 (m, 2H), 1.09 (m, 2H). LCMS for C26H30ClN8O2 (M+H)+: m/z=521.2.