Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9](Br)[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH3:2].[Cu][C:17]#[N:18].CN(C)C=O.Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([C:17]#[N:18])[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OC
Reactant: N#C[Cu]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C#N)c(Cl)cc1OC

Procedure:
14.7 g (0.05 mol) of 5-bromo-4-chloro-2-methoxybenzoic acid ethyl ester, 5.4 g (0.06 mol) of copper(I) cyanide and 8 ml of dimethylformamide are heated at 190° for three hours while stirring under a nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off with suction and the layers are separated in a separating funnel. The methylene chloride solution is washed neutral with water and then concentrated by evaporation. 4-Chloro-5-cyano-2-methoxybenzoic acid ethyl ester is obtained as residue which, after recrystallisation from methylene chloride/hexane, melts at 102°-103°.
Reaction SMILES: [Cl:1][C:2]1(C)[C:14]([CH3:15])=[C:13]2[C:5]([CH2:6][CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]1[OH:16].Cl.[CH3:19][N:20]([CH2:22][C:23](Cl)=[O:24])[CH3:21].Cl[CH2:27]Cl>C(OCC)(=O)C>[CH3:19][N:20]([CH2:22][C:23]([O:16][C:3]1[C:4]([CH3:27])=[C:5]2[C:13](=[C:14]([CH3:15])[C:2]=1[Cl:1])[O:12][C:8]1([CH2:11][CH2:10][CH2:9]1)[CH2:7][CH2:6]2)=[O:24])[CH3:21]
Reactant: CN(C)CC(=O)Cl
Reactant: ClCCl
Reactant: CC1=C2OC3(CCC3)CCC2=CC(O)C1(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c2c(c(C)c(Cl)c1OC(=O)CN(C)C)OC1(CCC1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-chloro-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (300 mg), prepared as described above, and dimethylaminoacetyl chloride hydrochloride (564 mg) in dichloromethane (8 mL) was added N-ethyldiiospropylamine (1.4 mL) dropwise at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed with water and brine, dried and evaporated. Chromatography (silica gel, hexane-ethyl acetate 5% to 25%) gave 276 mg of 7-chloro-5,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl (dimethylamino)acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1)(=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+]>ClCCl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2][NH:1][C:38]([N:35]3[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]3)=[O:39])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)CN(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)NCCN(CC(C)(C)C)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 40.8 %

Procedure:
The mixture 3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (75 mg, 0.179 mmol), 4-Acetyl-piperazine-1-carbonyl chloride (41 mg, 0.215 mmol) and K2CO3 (37 mg, 0.268 mmol) in dichloro-methane (2 mL) was stirred at room temperature for 2 h. Then the solution was concentrated and the crude product was purified by chromatography to give 42 mg rac-4-Acetyl-piperazine-1-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide of as a yellow solid. Then 15 mg rac-4-Acetyl-piperazine-1-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide was separated by chiral column to obtain 4 mg 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:3]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[NH3:4].[Si:25]([O:13][CH2:12][C:11]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([I:1])=[CH:3]1)([CH3:15])[CH3:14])([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)n1cc(I)c2cnccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.5 %

Procedure:
To a suspension of 2-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-methylpropan-1-ol (Preparation 66, 3.86 g, 12.2 mmol) in DCM (50 mL) was added imidazole (2.08 g, 30.5 mmol) followed by TBDMSCl (2.21 g, 14.7 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was partitioned between water (30 mL) and DCM (40 mL). The aqueous layer was washed twice with DCM (40 mL), the organic layers combined, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30% EtOAc in heptanes followed by 80:20:2 EtOAc:MeOH:NH3 to afford the title compound as a colourless oil (3.90 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:55][CH2:56][C:57]([OH:59])=[O:58]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([S:55][CH2:56][C:57]([OH:59])=[O:58])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: O=C(O)CS
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)SCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoic acid (0.25 g, 0.724 mmol) in dry DMF (7.5 ml), HATU (0.275 g, 0.724 mmol) and 4-methylmorpholine (0.080 ml, 0.724 mmol) were added, and the resulting solution was stirred under nitrogen at RT until complete conversion of starting acid into the activated ester intermediate (UPLC-MS check). Then 2-mercaptoacetic acid (0.042 ml, 0.603 mmol) was added drop wise, and the reaction was stirred at RT overnight. Additional 2-mercaptoacetic acid (0.008 ml, 0.120 mmol) was added, and the mixture was stirred at the same temperature for 5 days. The solvent was removed under vacuum and the residue was partitioned between EtOAc and HCl 1N; the organic phase was dried over Na2SO4 and the solvent was evaporated. The crude was purified by chromatography on silica gel column (DCM:MeOH=95:5) to afford 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetic acid (0.206 g, 0.491 mmol, 81% yield, MS/ESI+ 419.9 [MH]+). This intermediate was used as such without any further purification.
Reaction SMILES: C[C:2](C1C=C(Br)C(O)=C(Br)C=1)([C:4]1[CH:5]=[C:6](Br)[C:7]([OH:11])=[C:8](Br)[CH:9]=1)C.CC([C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=1)(C)C.[O:35]1CC1>>[OH:35][C:26]1[CH:27]=[CH:28][C:29]([C:32]([CH2:2][C:4]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][CH:5]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: C1CO1
Reactant: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Synthesis of the diepoxide (diglycidyl ether) of 3,3′,5,5′-tetrabromobisphenol A (ETBBA) (See, Wang et al. J Appl Polym Sci 1991; 43: 1315-1321.) ETBBA was prepared in a similar manner as BEDB, using TBBA (24.9 g) instead of BHDB. This gave ETBBA (25.4 g, 85%). 1H-NMR (CDCl3, ppm): 7.30 (s, 4H, Ar—H), 4.21-4.18 (q, 2H, 2(—O—CH2-oxirane)), 4.09-4.05 (q, 2H, 2(—O—CH2-oxirane)), 3.51-3.46 (m, 2H, 2(oxirane CH2)), 2.92-2.90 (t, 2H, 2(oxirane CH2)), 2.75-2.74 (q, 2H, 2(oxirane CH2)), 1.60 (s, 6H, Ar—C(CH3)2—Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19](O)=[CH:18][C:16]=4[NH:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:28]1[O:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:29]=1)([O-])=O.C(O)(=[O:39])C>CS(C)=O.O>[CH3:36][O:35][C:33]([CH:31]1[CH2:30][CH2:29][CH:28]([O:39][C:12]2[CH:11]=[CH:10][CH:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:14]3[C:13]=2[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=32)[O:32]1)=[O:34]
Reactant: Oc1ccc2c3c([nH]c2c1)CCCC3Cc1ccc(F)cc1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1CCC(OC2=C3N=c4ccccc4=C3C(Cc3ccc(F)cc3)C=C2)O1
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A solution of approximately 7.25 mmol of 5,6,7,8-tetrahydro-9-[(4-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrol-3-ol as a crude oil from Example 100 in 20 ml of dimethyl sulfoxide was added dropwise to a freshly prepared suspention of 0.35 g of sodium hydride (55% dispersion in mineral oil) in 2 ml dimethylsulfoxide at room temperature and under argon. The resulting mixture was stirred an additional 15 minutes and a solution of methyl 5-nitro-2-furoate (1.37 g) in dimethylsulfoxide (10 mL) was added. The black mixture was stirred an additional 2 hours and poured into ice and water containing a few drops of acetic acid. The product was extracted with dichloromethane and the organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by HPLC eluting with ethyl acetate-hexane (1:9) and crystallized from ether-hexane. 2.2 g (72%) of 1,2,3,4-tetrahydro-5-[[9-[(4-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrol-6-yl]oxy] -2-furancarboxylic acid methyl ester was obtained as a colorless crystalline material, mp 85°-86° C.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:14]([N:16]1[CH2:19][CH:18]([F:20])[CH2:17]1)=[O:15])[C@@H:10]([CH3:13])[CH2:11][CH3:12])(C)(C)C>>[NH2:8][C@@H:9]([C@@H:10]([CH3:13])[CH2:11][CH3:12])[C:14]([N:16]1[CH2:17][CH:18]([F:20])[CH2:19]1)=[O:15]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Agent: Cl
Product: CC[C@H](C)[C@H](N)C(=O)N1CC(F)C1

Procedure:
(2S,3S)-2-amino-1-(3-fluoro-azetidin-1-yl)-3-methyl-pentan-1-one was prepared by HCl treatment of [(1S,2S)-1-(3-fluoro-azetidine-1-carbonyl)-2-methyl-butyl]-carbamic acid tert-butyl ester as analogously described in Step 2 of Example 1. (mp 208-210° C.).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(-c2ccccn2)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccn2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Yield: 58.5 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl]acetate (9h) (58 mg, 0.13 mmol) and potassium hydroxide (65 mg, 0.53 mmol) in a mixture of ethanol (1.0 mL) and water (1.0 mL) was refluxed overnight. The mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with ethyl acetate (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl]acetic acid (example 9) (32 mg, 0.076 mmol, 57%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C2CCCO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3CCCO3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of 4-(tetrahydrofuran-2-yl)benzoic acid (95 mg, 0.5 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) and triethylamine (202 mg, 2 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (120 mg, 0.8 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was washed with water (50 mL). The organic phase was separated and concentrated to give a residue. The residue was purified through column chromatography (silica gel, dichloromethane/methanol=20:1) and to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(tetrahydrofuran-2-yl)benzamide (35 mg, 21%) as a white solid. LRMS (M+H+) m/z: calcd 326.16. found 326.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.CN(C=O)C.[C:36]([O:42][CH2:43]Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>>[O:27]=[C:4]1[N:3]([CH2:28][CH2:29][CH3:30])[CH:2]=[N:10][C:9]2[N:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)[N:6]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:5]1=2
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)n(COC(=O)C(C)(C)C)c2c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.35 gm, 0.87 mmol) in DMF (5 ml) K2CO3 (0.360 gm, 2.59 mmol) was added under nitrogen atmosphere. To this reaction mixture Chloromethyl pivalate (0.395 gm, 2.62 mmol) was added at room temperature. It was stirred at 50° C. for 24 hrs. Reaction mixture was filtered and DMF was evaporated. Residue obtained was purified by LCMS to obtain above two isomers, Example 5 and Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10]C)=[CH:4][CH:3]=1.[N+:12]([C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:20][C:18]2[S:19][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: COC=Cc1ccc(Cl)cc1
Product: O=CC(=Cc1ccc([N+](=O)[O-])s1)c1ccc(Cl)cc1

Procedure:
1-(4-chlorophenyl)-2-methoxyethylene is reacted in analogous manner with 5-nitrothiophene-2-aldehyde, and the title compound is obtained in the form of brown crystals having a M.P. of 135°-136°, after purification by column chromatography over silica gel with toluene.
Reaction SMILES: [C:1](=[O:21])([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1.BrC1C=C(CO)C=CC=1.[CH3:31][C:32]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:33]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]1[C:49]2[C:44](=[C:45](C3C=CC(CO)=CC=3)[CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39]>>[C:1](=[O:21])([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:44]=2[CH2:43][CH2:42][CH2:41][N:40]3[C:38](=[O:39])[CH2:37][CH2:36][CH2:35][O:34][C:33]2[CH:58]=[CH:59][CH:60]=[C:61]([CH3:62])[C:32]=2[CH3:31])=[CH:6][CH:5]=1
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Agent: OCc1cccc(Br)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(COC(=O)Oc5ccc([N+](=O)[O-])cc5)cc4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 3-bromobenzyl 4-nitrophenyl carbonate except that (3-bromophenyl)methanol was replaced with 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one. LCMS, [M+H]+=595.2. 1H NMR (400 MHz, CDCl3) δ 8.32-8.16 (m, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.37 (d, J=9.1 Hz, 2H), 7.28-7.13 (m, 4H), 7.09 (s, 1H), 6.98 (t, J=7.8 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.31 (s, 2H), 3.92 (br. s, 2H), 3.76 (t, J=6.7 Hz, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.44 (br. s, 2H), 2.29-2.08 (m, 5H), 1.92 (s, 3H), 1.84-1.71 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>B(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
In a 200 ml flask, there were charged (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid (30.0 g) and toluene (70 g), and thionyl chloride (24.0 g) was added thereto from a dropping funnel at 70° to 80° C. over a period of 30 minutes with stirring. After completion of the addition, stirring was continued for an additional 2.5 hours at the same temperature. Thereafter, the reaction mixture was cooled to 0° C., and boron trichloride (0.94 g) was added thereto, followed by stirring for 30 minutes. Then, the catalyst was removed from the reaction mixture, the solvent was recovered by distillation, and the residue was distilled to obtain racemized 2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride (28.6 g) having a boiling point of 55°-62° C./0.3 mmHg. The proportion of the optical isomers in the resulting product was determined by gas chromatography. The result was as follows: (+)-trans, 46.8%; (-)-trans, 46.8%; (+)-cis, 3.2%; (-)-cis, 3.2%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]#[C:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(O)(=O)C>[Fe].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([C:18]#[C:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 90.5 %

Procedure:
Into the reaction flask was added tert-butyl [3-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)phenyl]carbamate (2.7 g, 6.0 mmol), methanol (70 mL), acetic acid (10 mL), and water (7 mL). Then iron powder (1.8 g, 30 mmol) was added. The reaction mixture was heated at 60° C. for 3 h. After filtration, the cake was rinsed with EtOAc. The filtrate was concentrated and the residue was diluted with NaHCO3 (aq) and EtOAc. After the layers were separated, the organic layer was dried, filtered and concentrated to give the desired product (2.3 g, 91%). LCMS for C24H30N3O4 (M+H)+: m/z=424.2.
Reaction SMILES: N1C[CH2:4][CH2:3][C:2]1=[O:6].BrC1C=CC(C2CCN(C3COC3)CC2)=CC=1.[CH:24]12[CH2:30][CH:28]([NH:29]1)[CH2:27][N:26]([C:31]1[CH:36]=[CH:35][C:34]([C:37]3[N:42]=[C:41]([O:43][C@@H:44]([C@H:46]4[CH2:50][NH:49][C:48](=[O:51])[CH2:47]4)[CH3:45])[C:40]4[N:52]([CH:55]5[CH2:57][CH2:56]5)[CH:53]=[N:54][C:39]=4[CH:38]=3)=[CH:33][CH:32]=1)[CH2:25]2>>[CH:55]1([N:52]2[C:40]3[C:41]([O:43][C@@H:44]([C@H:46]4[CH2:50][NH:49][C:48](=[O:51])[CH2:47]4)[CH3:45])=[N:42][C:37]([C:34]4[CH:33]=[CH:32][C:31]([N:26]5[CH2:25][CH:24]6[CH2:30][CH:28]([N:29]6[CH:3]6[CH2:4][O:6][CH2:2]6)[CH2:27]5)=[CH:36][CH:35]=4)=[CH:38][C:39]=3[N:54]=[CH:53]2)[CH2:57][CH2:56]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: O=C1CCCN1
Agent: Brc1ccc(C2CCN(C3COC3)CC2)cc1
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4C3COC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 11 %

Procedure:
Preparation of (4R)-4-0R)-1-((3-cyclopropyl-6-(4-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: Prepared by the procedure, previously described for the synthesis of 4-(4-bromophenyl)-1-(oxetan-3-yl)piperidine, using instead (4R)-4-((1R)-1-((6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)- 3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: as a starting material to afford 10.1 mg (11%) of (4R)-4-((1R)-1-((3-cyclopropyl-6-(4-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.57 (s, 1H), 6.78 (d, J=8.8 Hz, 2H), 5.57 (m, 1H), 4.57 (m, 2H), 4.27 (m, 2H), 3.78 (m, 4H), 3.42 (m, 1H), 3.22 (m, 2H), 2.84 (m, 1H), 2.34 (m, 3H), 1.53 (m, 1H), 1.41 (d, J=6.3 Hz, 3H), 1.18 (m, 7H). MS (ESI+) m/z 515.1 (M+H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[CH:5]([OH:8])[CH2:6][NH2:7].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([NH:7][CH2:6][CH:5]([OH:8])[C:4]([OH:3])=[O:9])=[O:21])=[CH:14]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(O)CN
Agent: Cl
Product: O=C(NCC(O)C(=O)O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(RS)-3-amino-2-hydroxypropionic acid methyl ester hydrochloride (6.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (6.6 mmol) were coupled according to Procedure A (except that acid, then base extraction was performed, and during the first acid wash a precipitate appeared so the mixture was filtered and the filtrate carried on in the usual manner of Procedure A). The crude product (920 mg) was dissolved in methanol and treated with 1 N NaOH (6.6 mL) for 2 hours at 25° C. 1N NaOH was added (6.6 mL) and the mixture was concentrated, the residue dissolved in ethyl acetate, and the resulting solution washed with 2N HCl, brine, dried, and concentrated. The resulting colorless solid was stirred in chloroform and filtered giving the title substance: Yield 763 mg, 40%; HPLC (60/40) 2.86 minutes (89%); mp 214-215° C.; PBMS 283/285 (MH+, 100%);