Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[CH2:9][N:10]([C:11]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:12])[C:4]=2[CH:3]=1.C(OC(Cl)=O)C(C)C.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[CH2:9][N:10]([C:11]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([NH:36][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[O:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NCc1ccncc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(NCc1ccncc1)c1ccccc1C(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the title product of Example 11 (0.55 g) in CH2Cl2 (10 mL) at 0° C. was added 1-methyl morpholine (0.168 mL) and isobutylchloroformate (0.199 mL) successively. After 30 minutes, 4-(aminomethyl)pyridine (0.156 mL) was added. The mixture was allowed to warm to ambient temperature for hours. The mixture was extracted with ethyl acetate and water. The organic extract was dried over MgSO4 and concentrated. The residue was purified by chromatography over silica gel using ethyl acetate as eluant to give the free base of the title compound as a white solid. The hydrochloride salt of the free base was made in the manner described in Example 3 to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.ClC(Cl)Cl.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])=[O:13]>O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:12](=[O:13])[CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)c1ccc(F)cc1F
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Cn1ccnc1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a refluxing and stirred solution of 457.6 parts of 1H-imidazole in 2400 parts of trichloromethane was added dropwise a solution of 320 parts of 2-chloro-1-(2,4-difluorophenyl)ethanone in 1440 parts of trichloromethane. After stirring for 1/2 hour at reflux temperature, the reaction mixture was poured into water. The organic layer was washed with water (2x), dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 244 parts (69%) of 1-(2,4-difluorophenyl)-2-(1H-imidazol-1-yl)ethanone; mp. 125° C. (interm. 1).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].Cl>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCc1ccccn1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Agent: Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccccn3)s2)c(C)[nH]c1=O
Yield: 38 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (pyridin-2-yl)methylamine as described in Step 5, Example 24 and the resulting sulfonamide is converted to hydrochloride following the procedures as set forth in Step 6, Example 24 to give the title compound as a solid (38% yield). LC/MS: RT 2.28 min; me 390 (M+H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([NH:21][S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])(=[O:24])=[O:23])[CH:15]=1.[CH3:35][C:36]([CH3:38])=O>>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:1][CH:2]=[CH2:3])=[C:16]([N:21]([CH2:38][CH:36]=[CH2:35])[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])(=[O:23])=[O:24])[CH:15]=1
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: C=CCBr
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(C(=O)OC)cc1N(CC=C)S(=O)(=O)c1cc(Cl)ccc1OC
Temperature: 60 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Allyl bromide (195 mg, 1.63 mmol) and potassium carbonate (372 mg, 2.69 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 200 mg, 0.538 mmol) in acetone, and the reaction mixture was stirred at 60° C. for 16 h. After cooling, insoluble material was filtered off and the filtrate evaporated to produce 3-[allyl-(5-chloro-2-methoxy-benzenesulfonyl)-amino]-4-allyloxy-benzoic acid methyl ester (243 mg, 100%). Orange solid, MS (ISP)=452.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]1[C:22]([C:18]#[N:17])=[C:21]([CH:4]2[CH2:1][CH2:2]2)[NH:17][C:18]2=[N:19][NH:20][CH:21]=[C:22]12
Reactant: COC(=O)C1CC1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1Cl
Product: N#CC1=C(C2CC2)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[C@@H:12]2[CH2:14][C@@H:13]2[F:15])=[CH:4][C:3]=1[F:20].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][N:28]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]4[C@@H:12]4[CH2:14][C@@H:13]4[F:15])=[CH:4][C:3]=3[F:20])[CH2:27]2)[CH2:23][CH2:22]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2nc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 35.9 %

Procedure:
Using 7-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (200 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (116 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as pale yellow crystals (101 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:15](Cl)(Cl)=[O:16].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:15](=[O:16])[NH:1][CH2:2]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C(O)CN)cc1OC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2CNC(=O)O2)cc1OC
Reaction time: 1 h
Yield: 75 %

Procedure:
100 mmol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol is dissolved in 100 ml. of chloroform. After cooling to 0°, a solution of 100 mmol of phosgene in 100 ml. of chloroform is added dropwise so slowly that the internal temperature does not rise above 5°. After one hour of agitation at 5°-10°, 200 mmol of pyridine in 100 ml. of chloroform is added dropwise to the reaction mixture, and the latter is stirred for 3 hours. After washing the organic phase in semisaturated NaCl solution, the mixture is concentrated by evaporation and recrystallized from methanol, thus obtaining in a 75% yield 5-(3,4-dimethoxyphenyl)-2-oxazolidinone, m.p. 114°-117°.
Reaction SMILES: C(O)C.[NH2:4][C:5]1[C:6]([N+:28]([O-])=O)=[CH:7][C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17](=[O:19])[CH3:18])[CH:10]=1.[H][H].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O>[Ni].CN1CCCC1=O.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:8]2[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17](=[O:19])[CH3:18])=[CH:10][C:5]3[NH:4][C:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[N:28][C:6]=3[CH:7]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccccn1
Reactant: [H][H]
Reactant: CC(=O)N1CCCCC1c1cc(N)c([N+](=O)[O-])cc1Oc1ccc(F)cc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
50 mg of developed Raney nickel catalyst was added to an ethanol (10 ml) solution of 180 mg of 1-(2-(5-amino-2-(4-fluoro-phenoxy)-4-nitro-phenyl)-piperidin-1-yl)-ethanone, and the reaction liquid was stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration through Celite, and the filtrate was distilled under reduced pressure to obtain 171 mg of a crude product. 50 mg of the resulting crude product was dissolved in 1 ml of N-methylpyrrolidone, and 16 mg of pyridine-2-carboxaldehyde was added to it, and the reaction liquid was stirred at room temperature for 3 days. Water was added to the reaction liquid, and extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[C:4]([OH:6])=[O:5].OO.C1CCCCCCC=1.[C:22]([O-])([OH:24])=[O:23].[Na+]>CC(=O)CC.CCOCC.O>[C:22]([OH:24])(=[O:23])[CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: C1=CCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: O=C(O)CCCCCCC(=O)O
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a mixture of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (16.2 mg, 20 μmol, 0.2 mol %) and 2,6-dichlorobenzoic acid (57.3 mg, 0.30 mmol, 3.0 mol %) in 2-butanone (7 ml) was added H2O2 (30 μl of a 50% aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently cyclooctene (1.149 g, 9.90 mmol) was added together with 2-butanone (2 ml) and water (1 ml). H2O2 (5.67 ml of a 50% aq. solution, 100 mmol, 10.0 equiv.) was then added at 40° C. using a syringe pump (0.7 ml/h). New batches of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (16.2 mg, 20 μmol, 0.2 mol % per batch) were added to the reaction mixture 1.5, 3, 4.5, 6 and 7.5 hours after the addition of H2O2 had commenced. When the addition of H2O2 was completed, the mixture was stirred for additional 15 hours. Water (10 ml) and Et2O (10 ml) were added and the pH of the aqueous layer was set to pH >9 by adding some saturated NaHCO3 (aq.). The organic layer was separated and the aqueous layer was washed with Et2O (3×15 ml). The pH of the aqueous layer was subsequently set to pH <2 with some 10% HCl (aq.) and was extracted with Et2O (3×20 ml). The combined organic extracts were dried over anhydrous Na2SO4. The solvents were removed in vacuo yielding 926 mg of a solid with a purity of circa 74% (determined by 1H NMR), 40% yield of suberic acid. N.B. NMR showed other compounds as well, including 2,6-dichlorobenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O=[C:12]1[CH2:16][S:15][CH2:14][CH:13]1[C:17](OC)=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:18]=[C:17]1[N:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]2=[N:1][C:12]2[CH2:16][S:15][CH2:14][C:13]1=2
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: COC(=O)C1CSCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Temperature: 170 °C
Yield: 63.2 %

Procedure:
6-Aminonicotinic acid (10 g., 0.072 mol) [Berichte, 26, 2187,(1893)], methyl 4-oxotetrahydro-thiophene-3-carboxylate (28 g., 0.175 mol) [Monats, Chem., 104, 1520(1973)]and p-toluenesulfonic acid monohydrate (1.0 g) are thoroughly mixed and heated at 170° C. under nitrogen for 75 minutes. The distillate is collected in a Dean-Stark trap. The residue is cooled, tritrated with boiling chloroform and filtered to give the product as a yellow powder (11.3 g.). Recrystallization from dimethylformamide gives an analytical sample mp 314°-315° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:27][C:28]1([CH2:32][O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:31][O:30][CH2:29]1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC2(C)COC2)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (500 mg), (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (915 mg), and potassium carbonate (850 mg) in N,N-dimethylformamide (3 mL) is stirred at 50° C. for 5 h. The reaction mixture is diluted with water and the precipitate is filtered off, washed with water, and dried to give the title compound. LC (method 7): tR=0.97 min; Mass spectrum (ESI+): m/z=295 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C.O>[C:1]1([C:7]2[C:15]([CH:16]=[C:24]3[S:18][C:19](=[S:20])[NH:21][C:22]3=[O:23])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 86.9 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (15.0 g), rhodanine (9.44 g), sodium acetate (16.6 g) and glacial acetic acid (90 ml) was refluxed for 10 hours. Water (200 ml) and ethyl acetate (90 ml) were added to the reaction mixture and the resulting precipitates were collected by filtration to give 5-(2-phenylpyrazolo[1,5-a]pyridine-3-yl)methylenerhodanine (cis and trans mixture) (19.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:43](=[O:44])[NH:42][C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=C=Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CN(c1ccc2c(c1)CCN2C(=O)Nc1cccnc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
220 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 166 mg potassium carbonate and 121 mg 3-pyridylisocyanate are added and the mixture is stirred overnight at ambient temperature. The reaction mixture is divided between water and dichloromethane. The aqueous phase is extracted twice with dichloromethane and the combined organic phases are dried on sodium sulphate. The solvent is eliminated in vacuo and the residue is taken up in 8 ml dichloromethane. 4 ml trifluoroacetic acid are added and the mixture is stirred for 2 hours at ambient temperature. The solvents are eliminated in vacuo and the residue is extracted from diisopropylether and petroleum ether. The solid is suction filtered and dried in vacuo.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][N:12]=[N+]=[N-])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:1][NH:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH2:12])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(CN=[N+]=[N-])c(Br)cc1C(=O)NC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(CN)c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 96 h
Yield: 104.7 %

Procedure:
After dissolving the N1-methyl-4-(azidomethyl)-5-bromo-2-ethoxybenzamide (5.32 g) in tetrahydrofuran (50 ml) and water (3 ml), triphenylphosphine (5.4 g) was added and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (5.11 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([C:22](=C)[C:23](O)=O)[CH:19]=[CH:20][CH:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(NC2CCCCC2)CCCCC1.S(Cl)(Cl)=[O:41].Cl[CH2:45][Cl:46]>>[CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:45]([Cl:46])=[O:41])[CH:19]=[CH:20][CH:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(C(=O)O)c1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Agent: C1CCC(NC2CCCCC2)CC1
Product: Cc1cc2c(cc1-c1cccc(C=CC(=O)Cl)c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.5 g (10 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylic acid and 50 ml of dichloromethane are introduced into a round-bottomed flask and 2 ml (10 mmol) of dicylcohexylamine are added. The mixture is stirred at room temperature for 10 minutes and 729 μl (10 mmol) of thionyl chloride are then introduced with stirring for 15 minutes. The reaction medium is evaporated to dryness, the residue is taken up in ethyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 3.7 g (100%) of the crude acid chloride are collected, which will be used in its current state for the rest of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37]B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:37])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: CB(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (375 mg, 0.70 mmol), methyl boronic acid (417 mg, 6.96 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), tricyclohexyl phosphine (PCy3) (39 mg, 0.14 mmol) and K3PO43H2O (556 mg, 2.09 mmol) in toluene (10.0 mL) was sealed in microwave tube. The reaction was purged with N2 before heated at 120° C. by microwave for 30 min. Another portion of methyl boronic acid (417 mg, 6.96 mmol) was introduced and the reaction was continued for additional 30 min. After cooled down to r. t., the reaction mixture was partitioned between DCM and water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatographic (silica gel, 50% ethyl acetate in a mixture of petroleum ether and DCM (1:1)) to afford (R)-tert-butyl 3-(4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (10) (286 mg, 70% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 486.3.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH3:6][C@H:7]1[CH2:12][C@@H:11](O)[C@H:10]([CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8]1.S(=O)(=O)(O)O>C1CCCCC1.O>[C:1]([O:5][CH:9]1[CH:10]([CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:12][CH:7]([CH3:6])[CH2:8]1)(=[O:4])[CH:2]=[O:3]
Reactant: O=CC(=O)O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)C=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of aqueous glyoxalic acid (200 g; 50% w/v), L-menthol (632.4 g) and concentrated sulfuric acid (3.5 g) in cyclohexane (600 mL) was refluxed at 80° C. to 85° C. for 3 to 4 hours. Water (115 mL) was removed by azeotropic distillation using a Dean Stark trap. The resulting solution was allowed to cool to room temperature and diluted with de-ionized water (500 mL). The organic layer was separated and diluted with de-ionized water (800 mL). The pH of the resultant mixture was adjusted to 5 using aqueous sodium carbonate (10%; 15 ml). The organic layer was separated and washed twice with aqueous sodium bisulfite (2×70 g in 2×800 mL of de-ionized water). The pH of the organic layer was again adjusted to 5 using aqueous sodium carbonate (10%; 20 ml) and aqueous solution of formaldehyde (130 mL) was added to it in one hour at room temperature. The pH of the resultant mixture was again adjusted to 7.5 using aqueous sodium carbonate (10%; 15 ml) and stirred for about 6 hours at room temperature. The suspension obtained was filtered and washed with de-ionized water (2×200 mL) at room temperature. The wet mass obtained was suspended in de-ionized water (1000 mL) and stirred for 2 hours at 40° C. to 45° C. The resultant mixture was cooled to 20° C. to 25° C. and stirred at the same temperature for one hour. The suspension was filtered and washed with de-ionized water (200 mL) at room temperature to give menthyl glyoxalate as wet mass.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.[ClH:32].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:32].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4R)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-fluoroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.