Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48]>CN(C)C=O>[C:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:5][C:4]([OH:28])=[O:3])[CH2:22][C:23]([OH:25])=[O:24])([OH:21])=[O:20]
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Reactant: NCCCCCCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxy-carbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0331 616) is suspended in dimethylformamide (DMF) and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 7.65 g (38 mmol) of 11-aminoundecanoic acid. The temperature-is allowed to increase to room temperature and the reaction solution is stirred overnight. After completion of the reaction, the possibly still slightly cloudy solution is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is absorptively precipitated with ether and then recrystallized from water (17.8 g). The ethyl ester is dissolved in 2 N NaOH and is adjusted to pH 7 after 3 hours by adding Amberlite® IR 120 (H+). The ion exchange material is suctioned off, the filtrate is freeze-dried (20.1 g) and then added to H2O/methanol (2:1) on 100 ml of Amberlite® IR 120 (H+) and the acid eluate is concentrated by evaporation and recrystallized from water.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1I.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.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>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1cc(I)c(Cl)s1
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: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Temperature: 80 °C
Yield: 23.5 %

Procedure:
To a solution of methyl 5-chloro-4-iodo-2-thiophenecarboxylate (1.75 g, 5.8 mmol) in dioxane/H2O (50:5 mL) was added K2CO3 (3.4 g, 24.9 mmol), tetrakistriphenylphosphine Pd(0) (0.96 g, 0.83 mmol), and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (3.4 g, 16.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 15 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 4:1) to give the title compound (0.35 g, 24%) as a yellow oil: LC-MS (ES) m/z=257 (M+H)+.
Reaction SMILES: [Cl-].[NH4+].C(O)C.[CH3:6][C:7]1[C:8]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])=[CH:24][C:23]=3[N+:34]([O-])=O)=[O:21])[CH2:16][CH2:15]2)=[N:9][CH:10]=[C:11]([CH3:13])[CH:12]=1>O>[NH2:34][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:26]=[CH:27][C:22]=1[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:8]2[C:7]([CH3:6])=[CH:12][C:11]([CH3:13])=[CH:10][N:9]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3[N+](=O)[O-])CC2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N)CC2)c(C)c1
Temperature: 65 °C
Yield: 17.2 %

Procedure:
A mixture of ammonium chloride (0.779 g), reduced iron (0.56 g), ethanol (16 mL) and water (4.3 mL) was stirred with heating at 60-70° C., and 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-nitrophenyl}oxazolidin-2-one (1.105 g) described in Example 129 was added. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (0.177 g).
Reaction SMILES: [CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 2-Benzyl-4-(4-bromo-benzyl)-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture could be filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C(N(C(C)C)C(C)C)C.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.40 mmole) of ethyldiisopropyl amine and 0.0074 g (0.11 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 0.020 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-285) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:40]=[CH:39][C:31]([O:32][CH2:33][C:34]([O:36]CC)=O)=[CH:30][CH:29]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH3:42].CO>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([NH2:42])=[O:36])=[CH:39][CH:40]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: N
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(=O)OCC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Solvent: CO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(N)=O)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 70 °C
Reaction time: 43 h
Yield: 35 %

Procedure:
Ethyl (4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate (300 mg) was added to a 7N ammonia-methanol solution (15 ml) and then stirred at 70° C. for 43 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:19:1→ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane, giving a pale yellow powder of 2-(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetamide (100 mg, yield: 35%)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(OC)(O[CH3:19])(=O)=O>>[CH3:19][O:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)c1csc(C)n1
Reactant: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Yield: 84.5 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.3 g.) and dimethyl sulfate (0.18 g.) were reacted according to a similar manner to that of Preparation (8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CS(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}methanesulfonamide was prepared from 3-(2-aminoethyl]-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 49) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 4-fluoro-benzenesulfonyl chloride (0.054 g) as a light yellow gum (0.08 g). MS (ESI−): 389.1 ([M−H]−)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([C:28]5([OH:27])[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, colorless semi-solid (73 mg, 69%), MS (ISP) m/z=427.4 [(M+H)+], was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 1-hydroxy-cyclobutane-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([OH:29])=[O:28].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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:27]([OH:29])=[O:28])[CH:35]=2)=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
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
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol), 3-carboxyphenylboronic acid (0.092 g, 0.55 mmol), and potassium carbonate (0.190 g, 1.37 mmol) were combined in 2:1 DME:water (5 mL), and the solution was purged with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.05 mmol) was added, and the reaction was purged with N2 for an additional 10 minutes, and then sealed and stirred at 80° C. overnight. The mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][N:16]([C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH2:17][C:18]([N:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH:2]([N:35]1[CH2:36][CH2:37][C@@H:33]([N:16]([CH3:15])[CH2:17][C:18]([N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:34]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)N(c1ccccc1)c1ccccc1)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(CC(=O)N(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of bromodiphenylmethane (0.33 g, 1.34 mmol) in butanone (10 ml) was added (R)-2-(methyl-pyrrolidin-3-yl-amino)-N,N-diphenyl acetamide(0.5 g, 1.61 mmol), K2CO3 (0.18 g, 1.34 mmol) and KI (0.22 g, 1.34 mmol). The mixture was, heated under reflux for 18 hours, then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (1:1) gave the desired product.
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1B(O)O>>[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate but substituting 2,4-dichloro phenyl boronic acid and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.40–7.25, 5.20–5.13, 4.76, 4.11, 3.98, 3.73–3.60, 3.51–3.31, 2.70, 2.47, 1.31–1.24, 1.15; IR (liq.) 2972, 2342 (w), 1948 (w), 1709 (s), 1567, 1552, 1498 (s), 1470 (s), 1449 (s), 1420 (s), 1397 (s), 1350, 1126, 1100 (s), 1080, cm−1
Reaction SMILES: [C:1](=[O:11])([S:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:11])([S:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:2][CH:3]([O:17][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH3:4]
Reactant: CC(C)C(=O)O
Reactant: CC(Cl)OC(=O)SC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(OC(=O)SC(C)(C)C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 90.6 %

Procedure:
Compound (3) (392 mg, 2 mmol) was dissolved in isobutyric acid (264 mg, 3 mmol) and the solution was slowly added to a pre-mixed solution of isobutyric acid (264 mg, 3 mmol) and diisopropylethylamine (387 mg, 3 mmol). The reaction mixture was heated to 55° C. for 16 h, then diluted with ether (50 mL), washed with water (2×10 mL), saturated bicarbonate solution (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (8) as a colorless liquid (450 mg, 90%). The product was further purified by vacuum distillation (170° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=7.2 Hz, 6H), 1.47 (s, 9H), 1.48 (d, J=5.6 Hz, 3H), 2.53 (m, 1H), 6.90 (q, J=5.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5])[O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2.87 g (15 mmol) A1, 2.76 g (16.5 mmol) ethyl bromoacetate and 2.90 g (21 mmol) potassium carbonate in 50 ml dry acetone were stirred for 3 h at 60° C. After filtration and removal of the solvent the residue was purified by column chromatography on Silica (ethyl acetate/methanol 100:2). Yield: 3.5.5 g (86 %) A2, colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:4][CH2:3]1.[C:20]([N:28]=[C:29]=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:28][C:29]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]1)=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC1(C)CCN(c2ccccc2N)c2ccccc21
Solvent: ClCCl
Product: CC1(C)CCN(c2ccccc2NC(=S)NC(=O)c2ccccc2)c2ccccc21
Reaction time: 0.07 h

Procedure:
1d (65.4 mg, mmol) and benzoyl isothiocyanate (60 mg) were heated at refluxing CH2Cl2 for 2 h. After cooling, the solvent was evaporated. The resulting crude 1e was dried over vacuum and used directly in the next step: LC-MS ESI, 416.3 (M+H) (10-90% MeOH in H2O with 0.1% TFA in a 4 min run, tR=4.49 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=[O:12])=[O:11])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)OCC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1S(=O)(=O)OCC(F)(F)F
Yield: 91.4 %

Procedure:
In a pressure vessel, 107 g of 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate and 8 g of 5% palladium-on-carbon in 300 ml of ethyl acetate was heated to 110° and shaken under 500 psi hydrogen pressure until hydrogen was no longer absorbed. The reaction mixture was cooled and the catalyst filtered off. The filtrate was stripped in vacuo to give 87.5 g of 2,2,2-trifluoroethyl 2-aminobenzenesulfonate as a dark oil.
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH:21]3[NH:24][C:25]3[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=3)[O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH:21]3[NH:24][C:25]3[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=3)[O:28][CH2:29][C:30]([O:32][CH3:3])=[O:31])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A 2 M solution of (diazomethyl)trimethylsilane in THF (0.20 mL, 0.40 mmol) was added to a solution of 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetic acid (159 mg, 0.421 mmol) in THF (5 mL) at 0° C. in a 50 mL round bottom flask. The mixture was allowed to stir for 2 hours at room temperature. The resulting mixture was concentrated in vacuo and the resulting crude residue was purified on a Teledyne-Isco combiflash machine (12 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 135 mg (82%) of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].CC([O-])=O.[K+].[NH2:21]O.Cl.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:21])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1cc(C=O)ccc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc(C#N)ccc1OC
Temperature: 130 °C
Yield: 89.3 %

Procedure:
To a solution of 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (10 g) in AcOH (80 mL) was added KOAc (9.5 g) and NH2OH.HCl (6.7 g). The resulting mixture was heated at 130° C. for 18 h under N2 atmospheres. After reaction finished, the mixture was poured into water (400 mL). The solid was collected, washed with water (100 mL) and air-dried to give 4-methoxy-3-(2-methoxyethoxy)benzonitrile (8.8 g) as a light yellow solid.