Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([Br:19])[CH:13]=1.C(OCC)C>CN(C=O)C.O>[CH2:1]([O:8][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([Br:19])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a solution of benzyl alcohol (10.8 g, 100 mmol) in dry DMF (40 mL), 60% NaH (4.4 g, 110 mmol) was added portionwise and the mixture was stirred at 55° C. for 10 min. Then, 1,3,5-tribromobenzene (22.0 g, 70 mmol) was added slowly to the reaction mixture and the resulting solution was heated at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was poured into a mixture of diethyl ether (500 mL) and water (200 mL) along with intense stirring. The organic layer was separated and washed with water (2×100 mL), 5% HCl (100 mL), saturated NaHCO3 aqueous solution (100 mL) and brine (100 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica using hexanes-acetone (10:0.5) as eluent to afford 18.5 g (77%) of title compound as an yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.45-7.32 (m, 5H); 7.25 (s, 1H); 7.07 (s, 2H); 5.05 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([C:50]([N:52]6[CH2:53][CH2:54][O:55][CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][C:47]=5[O:48][CH3:49])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: COc1ccc(C(=O)N2CCOCC2)cc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)N4CCOCC4)ccc3OC)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (3-bromo-4-methoxy-phenyl)-morpholin-4-yl-methanone (59 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methoxy-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-300) as a pale brown powder (67 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[Si:9]([O:16][CH2:17][CH2:18]Br)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(Cl)Cl.O>[Si:9]([O:16][CH2:17][CH2:18][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Temperature: 70 °C
Yield: 85 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 3-nitro-1H-pyrazole (500 mg, 4.42 mmol), 2-(tert-butyldimethylsilyloxy)-1-bromoethane (2.12 g, 8.85 mmol), cesium carbonate (5.76 g, 17.7 mmol) and anhydrous DMF (5 mL). After heating at 70° C. for 1 h, the mixture was cooled to room temperature and diluted with methylene chloride (50 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 85% yield (1.02 g) of 119a as a white solid: mp 76-77° C.; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, 1H, J=2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 4.29 (t, 2H, J=5.0 Hz), 3.98 (t, 2H, J=5.0 Hz), 0.84 (s, 9H), −0.44 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=3)[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>C(Cl)(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[O:26])=[CH:23][CH:22]=3)[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 73.9 %

Procedure:
In a solution of 0.29 g of 2,2,2-trifluoroethylamine and 0.37 g of triethylamine in 20 ml of chloroform, 1.81 g of the crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid chloride dissolved in 10 ml of chloroform was added dropwise with cooling with ice and with stirring. After the completion of addition dropwise, the mixture was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of water, and extracted with chloroform (20 ml×3), the organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and passed through a glass filter packed with silica gel, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 1.05 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][N:4]=1.[F-].[K+].C(OCC)C>CN(C=O)C.O>[C:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1)#[CH:10]
Reactant: COc1ncc(C#C[Si](C)(C)C)cn1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cnc(OC)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-5-((trimethylsilyl)ethynyl)pyrimidine (520 mg, 2.5 mmol) in DMF (10 mL) and water (1 mL) was added potassium fluoride (290 mg, 5 mmol) and the mixture was stirred at 0° C. for 1 h. Diethyl ether (100 mL) was added and the solution was washed with water (2×10 mL) and brine (10 mL), dried over MgSO4 and concentrated. The title compound was isolated by silica gel:chromatography (9:1 CH2Cl2/hexane) as a clear oil (120 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 2H), 4.05 (s, 3H), 3.28 (s, 1H).
Reaction SMILES: CC(O)(C)C.CC[Mg+].[Br-].[NH2:10][C:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:13]([O:15][CH3:16])=[O:14].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH:30]=[C:31]([C:36](=O)[CH2:37][CH2:38][C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C:32]([O:34][CH3:35])=[O:33].C(O)(=O)C>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH:30]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:36]([CH2:37][CH2:38][C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[NH:10][C:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1nccs1
Reactant: COC(=O)C=C(N)CC(=O)OC
Agent: CC[Mg+]
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2nccs2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a stirred solution of 2-methyl-2-propanol (92.8g, 1252 mmol; 2.1 eq.) in anhydrous THF (1100 ml) was added a 1.0M solution of EtMgBr in THF (1192 ml, 1192 mmol; 2.0 eq.) dropwise slowly at 0° C. under nitrogen atmosphere for 2 h period. The resulting solution was stirred at room temperature for 1 h. Then to the mixture was added a solution of dimethyl 3-amino-2-pentenedioate (113.5 g, 655 mmol; 1.1 eq.) in anhydrous THF (550 ml) dropwise slowly at 0° C. for 20 min. The resulting pale yellow solution was stirred at the same temperature for 1 h, then a solution of methyl 3-(2,6-dichlorophenyl)-2-[(1,3-thiazol-2-yl)propanoyl]-2-propenoate (219.9 g, 594 mmol; 1.0 eq.) in anhydrous THF (550 ml) was added at 0° C. for 30 min. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere, then acetic acid (170 ml; 5.0 eq.) was added at 0° C. The resulting mixture was stirred at room temperature for 6 h. The mixture was poured into 2N NaOHaq. (1000 ml), the organic phase was separated and the aqueous phase was extracted with EtOAc (2000 ml). The combined organic phase was washed with H2O (1000 ml) and brine (1000 ml), dried (Na2SO4) and concentrated to give a crude mixture. Purification on silica gel column chromatography (3 times 1700 g) eluted with hexane/EtOAc (2/1 to 1/2) to afford 246.0 g (85%) of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate as a brown oil
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4])[NH2:2].[Si:17]([O:34][CH2:35][C:36](O)=[O:37])([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>O.C(Cl)(Cl)Cl>[Si:17]([O:34][CH2:35][C:36]([NH:2][NH:1][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4])=[O:37])([C:30]([CH3:32])([CH3:33])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NN
Reactant: CC(C)(C)[Si](OCC(=O)O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 61.1 %

Procedure:
A mixture of CHCl3 (100 mL) with (S)-t-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (4.791 g), 2-((t-butyldiphenylsilyl)oxy)acetic acid (6.28 g), WSC.HCl (4.371 g) and HOBt.H2O (3.081 g) was stirred at room temperature for 15 hours. To the reaction mixture, a saturated aqueous solution of NH4Cl (500 mL) was added, followed by extraction with AcOEt (500 mL). The organic layer was washed successively with saturated aqueous sodium bicarbonate (500 mL) and brine (500 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (6.42 g, colorless amorphous.)
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[C:12]([S@:16]([NH2:18])=[O:17])([CH3:15])([CH3:14])[CH3:13]>>[F:1][CH2:2]/[C:3](=[N:18]\[S@@:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:17])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11]
Reactant: O=C(CF)c1ccccc1F
Reactant: CC(C)(C)[S@](N)=O
Product: CC(C)(C)[S@@](=O)/N=C(\CF)c1ccccc1F
Yield: 52 %

Procedure:
In a manner analogous to that described for the preparation of sulfinyl imine A2.1 the reaction of 2-fluoro-1-(2-fluoro-phenyl)-ethanone with (R)-tert-butylsulfinamide yielded the (R)-2-methyl-propane-2-sulfinic acid [2-fluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-amide (52% of theory) as an orange oil. MS (ISP): m/z=260.2 [M+H]+.
Reaction SMILES: [Mg].[C:2]([CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])(=[O:4])[CH3:3].[N+:11]([C:14]1C=[CH:21][CH:20]=[CH:19][C:15]=1C(Cl)=O)([O-:13])=[O:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(O)C>[N+:11]([C:14]1[CH:15]=[CH:19][CH:20]=[CH:21][C:3]=1[C:2]([CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])=[O:4])([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)C1CCOC1=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: O=C1OCCC1C(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 16.2 g of magnesium turnings, 67.5 g of anhydrous ethanol and 5 ml of carbon tetrachloride was allowed to react on standing for several minutes. After the exothermic reaction had subsided, 500 ml of anhydrous toluene was slowly added under stirring, and the resulting mixture was stirred at 35°-40° C for an additional 2 hours. To the resulting mixture, a solution of α-acetyl-γ-butyro lactone (170.8 g) in anhydrous toluene (200 ml) was added thereto dropwise under cooling below 10° C, and the resultant mixture was stirred at room temperature for 1 hour. A solution of o-nitrobenzoyl chloride, prepared from 100 g of the corresponding acid, in anhydrous toluene (200 ml) was added thereto dropwise at 20°-25° C, and stirring was carried out for an additional 2 hours. Under cooling, 1.4 liters of 5% sulfuric acid was slowly added to the resulting mixture, and the whole was extracted with ethyl acetate (900 ml). The aqueous layer was extracted with two portions of toluene-ethyl acetate (1:1), and the combined extracts were washed with water and aqueous saturated sodium chloride solution and extracted with three portions of cold 5% aqueous ammonium hydroxide solution (840 g × 3). The combined aqueous layer was washed with toluene and acidified with 25% sulfuric acid under cooling. The precipitated crystals were collected by filtration, washed with water and dried to give 120 g (85%) of α-(2-nitrobenzoyl)-γ-butyrolactone. M.P. 75°-76° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:71])[NH:10][CH:11]([C:37](=[O:70])[N:38]([CH:40]([C:56](=[O:69])[NH:57][CH2:58][C:59]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:62][CH2:61][CH2:60]1)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)[CH3:39])[CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:71])[NH:10][CH:11]([C:37](=[O:70])[N:38]([CH:40]([C:56](=[O:69])[NH:57][CH2:58][C:59]1([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:62][CH2:61][CH2:60]1)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[CH:44][CH:43]=1)[CH3:39])[CH2:12][C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)C(Cc1cnc[nH]1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [S-[R*,R*)]-[1-({2-(4-Benzyloxy-phenyl)-1-[(1-phenyl-cyclobutymethyl)-carbamoyl}-ethyl}-methyl-carbamoyl)-2-(1-trityl-1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (from Step 3, 1.28 g, 1.36 mmol) in methylene chloride (10 mL) was added TFA (10 mL). The solution was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and the solution was washed with saturated NaHCO3, dried over MgSO4, filtered, and concentrated. The residue was purified twice by chromatography (first: CH2Cl2:CH3OH 10:1; second: CH2Cl2:CH3OH 15:1) (0.23 g, 0.33 mmol; 24% yield); MS-APCI 700 (m+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][C@H:21]2[CH2:54][N:24]3[C:25](=[O:53])[C@@H:26]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:44])([F:43])[CH2:33][C@@H:34]4[CH2:39][C@@:35]4([C:40](O)=[O:41])[NH:36][C:37](=[O:38])[C@@H:23]3[CH2:22]2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:67]1([S:70]([NH2:73])(=[O:72])=[O:71])[CH2:69][CH2:68]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl.ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][C@H:21]2[CH2:54][N:24]3[C:25](=[O:53])[C@@H:26]([NH:45][C:46](=[O:47])[O:48][C:49]([CH3:51])([CH3:52])[CH3:50])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:44])([F:43])[CH2:33][C@@H:34]4[CH2:39][C@@:35]4([C:40](=[O:41])[NH:73][S:70]([CH:67]4[CH2:69][CH2:68]4)(=[O:72])=[O:71])[NH:36][C:37](=[O:38])[C@@H:23]3[CH2:22]2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 13d, 6.22 mg, 8.13 μmol) was added molecular sieves and DCE (81 μl). CDI (2.91 mg, 0.018 mmol) was added, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was cooled to rt and cyclopropanesulfonamide (2.4 mg, 0.020 mmol) was added followed by DBU (3 μl, 0.020 mmol). The mixture was stirred at rt for 2.5 h, diluted with dichloromethane and cooled to 0° C. The mixture was neutralized with HCl (14 μl, 4 N in dioxane, diluted with EA) and stirred for 5 min at 0° C., and evaporated under reduced pressure. The residue was purified by silica gel prep-TLC (dichloromethane/EA =1/1) to provide the title compound as a yellow solid, (5.2 mg, 74% yield). MS (ESI): m/z=868.3 [M+H], 866.3 [M−H].
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C(O)(=O)C.[BH4-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(OC)OC)c2c1
Reactant: CN(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(OC)OC)c2c1

Procedure:
To a stirred solution of methyl 3-cyclohexyl-1-(2,2-dimethoxyethyl)-2-(2-formylphenyl)-1H-indole-6-carboxylate (0.16 M, 1 eq, from Step 2) and 2-dimethylaminoethylamine (2 eq) in THF was added glacial acetic acid to adjust the pH of the reaction to ca. pH 4. The reaction was stirred for 1 h after which the THF was removed under reduced pressure and the residue redissolved in MeOH. NaBH4 (8 eq) was added portionwise until complete conversion was observed by LC-MS analysis. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc (×3). The combined organics were washed with H2O and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a pale yellow oil and taken on without further purification (quantitative); MS (ES+) m/z 522 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]3[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=3[CH3:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (2.5 g, 9.1 mmol), 4-bromoaniline (1.6 g, 9.3 mmol), tetrahydrofuran (60 ml), and diisopropylethylamine (1.6 ml, 9.2 mmol) was stirred for 1 hour. The solution was treated with dichloromethane (200 ml), washed with saturated aqueous sodium chloride solution (50 ml), and concentrated under reduced pressure. The residual solid was treated with hydrochloric acid (1 M, 25 ml) and stirred vigorously for 30 minutes. Filtration and drying under reduced pressure provided the title compound (3.2 g, 86% yield). 1H NMR (DMSO-d6) 10.75-10.80 (m, 1H), 7.85-7.92 (m, 1H), 7.50-7.65 (m, 4H), 7.40 (m, 1H), 2.58 (s, 3H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)([O-:3])=O.C[O-].[Li+].C(=O)([O-])O.[Na+].[C:27]([C:29]1[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.CO>[O:12]([C:10]1[CH:11]=[C:6]([CH2:5][C:4]2[CH:28]=[C:27]([C:29]3[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=3)[O:3][N:1]=2)[CH:7]=[N:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])CCc1cncc(Oc2ccccc2)c1
Reactant: C#Cc1ccc(N)nc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cncc(Oc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 14.2 %

Procedure:
To a methanol (5 mL) solution of 3-(2-nitro-ethyl)-5-phenoxy-pyridine (210 mg, 0.860 mmol) described in Manufacturing Example 145-1-4 was added lithium methoxide (65 mg, 1.72 mmol), which was stirred for 25 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (5 mL) ad methylene chloride (5 mL) was added titanium (IV) tetrachloride (236 μL, 2.15 mmol) under nitrogen atmosphere, which was stirred for 50 minutes at 0° C. Sodium hydrogencarbonate was added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a tetrahydrofuran (4 mL) solution of this residue were added 3-ethynyl-pyridin-2,6-diamine (15 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and triethylamine (240 μL, 1.72 mmol), which was stirred for 1 hour and 15 minutes at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.6 mg, 1.1%) as a ditrifluoroacetic acid salt.