Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[N:43]=[C:42]([O:44][CH3:45])[C:41]([CH2:46][CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[N:43]=[C:42]([O:44][CH3:45])[C:41]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)OC(C)(C)C)c(OC)n2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Anisole (1 mL) was added to a solution of tert-butyl 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoate (293 mg) in trifluoroacetic acid (2 mL), and the mixture was stirred at 65° C. for two hours. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoic acid as a colorless amorphous (172 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]([C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9])[CH3:36]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1C(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), 2-methylamino-benzoic acid methyl ester (119 mg, 0.722 mmol), BOP (137 mg, 0.312 mmol), DIEA (265 μL, 1.08 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-methyl-amino}-benzoic acid methyl ester: MS m/z: (M+H) 562.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=3[S:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].O.C(O)C>O1CCOCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=3[S:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCOCC1

Procedure:
Stir a mixture of 1.77 gm. (5 mmole) of the ester of Example 11, 1.12 gm. (10 mmole) of 85% aqueous potassium hydroxide, 5.5 ml. of water, 27.5 ml. of ethanol and 2.75 ml. of dioxane under argon at room temperature for 21/2 hours. Evaporate to a small volume and dilute with 18 ml. of water. Filter and acidify with acetic acid to pH 4.5. Separate the precipitate by filtration, wash with water and dry in vacuo over calcium chloride. Recrystallize from acetonitrile to obtain the title product, (m.p. 267°-269° C.).
Reaction SMILES: S1C=CN=NC1=[O:7].[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]([CH3:25])[S:23][CH2:22][NH:21][N:20]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.[C:26]12([CH3:38])[C:32]([CH3:34])([CH3:33])[CH:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]2[C:35](Cl)=[O:36]>>[C:26]12([CH3:38])[C:32]([CH3:34])([CH3:33])[CH:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]2[C:35]([N:21]1[N:20]=[C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([CH3:8])[CH2:10][CH2:11][CH2:12]3)[CH:24]([CH3:25])[S:23][C:22]1=[O:7])=[O:36]
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Reactant: O=c1nnccs1
Reactant: CC1SCNN=C1c1ccc2c(c1)CCCN2C
Product: CC1SC(=O)N(C(=O)C2CC3CCC2(C)C3(C)C)N=C1c1ccc2c(c1)CCCN2C

Procedure:
Analogously to Example 1, the racemic mixture of 5-[1-methyl-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2 H-1,3,4-thiadiazin-2-one (m.p. 177°) is reacted with (+)-camphanic acid chloride to give 3- [(+)-camphanoyl]-5-(1-methyl-1,2,3, 4-tetrahydroquinol-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one as a mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]([O:15][CH2:16][CH:17]=[CH2:18])[CH:12]1[O:14][CH2:13]1>>[CH2:11]([O:15][CH2:16][CH2:17][CH2:18][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH:12]1[O:14][CH2:13]1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCOCC1CO1
Product: CCO[Si](CCCOCC1CO1)(OCC)OCC
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
140 g (0.85 mol) of hydridotriethoxysilane were mixed with 100 g (0.88 mol) of allyl glycidyl ether, and 10 g of this mixture were initially introduced into a reaction vessel at 95° C. under normal pressure with 100 mg (9.5×10-5 mol) of tetrakis(1-phenyl-3-n-hexyl-1-triazenido) platinum complex. The remainder of the above mentioned was added dropwise to the mixture in the course of 80 minutes, the temperature rose to 160° C. When the addition was complete, the reaction mixture was stirred at 150° C. for an additional 30 minutes. After distillation, 3-glycidoxypropyltriethoxysilane was obtained as a colorless, liquid product in a 62.6% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.ClC[C:23]1[C:24]([CH3:29])=[N:25][N:26]([CH3:28])[CH:27]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:28][N:26]1[C:27]([CH2:30][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[CH:23][C:24]([CH3:29])=[N:25]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Cc1nn(C)cc1CCl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)n(C)n1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (10a)(200 mg, 0.7 mmol), 4-(chloromethyl)-1,3-dimethyl-1H-pyrazole (144 mg, 1 mmol), and cesium carbonate (325 mg, 1 mmol) were dissolved in 2 mL DMF and irradiated in the microwave reactor at 165° C. for 5 minutes. The reaction was cooled to room temperature, and salt precipitate was removed by filtration. The clear solution containing crude product was obtained and was purified by HPLC (10 to 95% Acetonitrile/water; 25 minutes) to afford 1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (150 mg, 53%) as a light brown solid. 12.09H NMR (DMSO, 400 MHz): δ (s, 3H), 2.14 (s, 3H), 2.20 (s, 3H), 3.70 (s, 3H), 3.99 (s, 2H), 4.55 (s, 2H), 5.19 (s, 2H), 6.06 (s, H), 7.77 (s, H), 8.17 (s, H), MS M+H calculated for 384.2; found 384.2. Melting point: 145-146° C.
Reaction SMILES: [CH2:1]([C:5]1[C:12]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([Cl:28])[CH:19]=3)[O:15][N:14]=2)=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH2:2][CH:3]=C.[O:29]=O.CSC.Cl>C(Cl)Cl.C1COCC1>[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:12]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([Cl:28])[CH:19]=3)[O:15][N:14]=2)[C:5]=1[CH2:1][CH2:2][CH2:3][OH:29]
Reactant: O=O
Reactant: C=CCCc1c(C#N)cccc1-c1noc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc(CN)c3CCCO)no2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.9 %

Procedure:
Through a solution of 2-(3-buten-1-yl)-3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)benzonitrile (Preparation 22) (8.26 g, 20.97 mmol) in DCM (125 ml) under Ar at −78° C. was bubbled Ar then O2 (5 min each). The ozonoliser (model 502; 75 lh−1; 0.3 A) was switched on and the orange solution ozonolised until it had turned an opaque green-grey colour (3 hrs). The ozonoliser was switched off, and O2, then Ar bubbled though the solution (10 min each). The solution was allowed to warm to RT under Ar, then concentrated in vacuo to give an opaque yellow oil. This was redissolved in dry THF (200 ml), BH3.DMS (9.96 ml, 105 mmol) added (CARE: gas evolution), and the solution stirred at RT for 18 hrs and then at 40° C. for 3 hrs. The reaction was cooled to 0° C., then 0.1M aqueous HCl (150 ml) was added cautiously (CARE: gas evolution), then allowed to stir at RT for 18 hrs. The solution was passed directly down an SCX-2 column (50 g), washing with MeOH. The product was eluted with 0.5M NH3 in MeOH; concentration in vacuo gave an orange foam 3-[2-(aminomethyl)-6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)phenyl]-1-propanol (2.73 g, 3.95 mmol, 18.9% yield). 1H NMR (400 MHz, CDCl3) δ (inter alia) 8.23 (1H, d), 8.05 (1H, dd), 7.86 (1H, d), 7.46 (1H, d), 7.34 (1H, t), 7.06 (1H, d), 4.72 (1H, sept), 4.03 (2H, s), 3.47 (2H, t), 3.27 (2H, t), 1.78 (2H, quin), 1.45 (6H, d); MS (ES) C21H2435ClN3O3 requires 401; found 402 [M+H]+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]>C(O)(=O)C.O.C(OCC)(=O)C>[C:16]([C:18](=[C:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C1CCCC1
Temperature: 70 °C

Procedure:
To an ambient solution of hexamethyldisilazane (17.7 mL, 84.0 mmol) in acetic acid (56 mL) was added sequentially cyclopentanone (5.0 mL, 56.3 mmol) and ethyl 2-cyanoacetate (12.0 mL, 113 mmol). The solution was heated to 70° C. for 15 hours. The reaction was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (100 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 100% hexane to 5% ethyl acetate in hexane, to give the title product as a white, solid. MS (ESI) m/z 180 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:24]=[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]=3[Cl:41])[N:22]([CH3:42])[C:9]2=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13]1)=[O:5])C.CCO.OS([O-])(=O)=O.[K+]>O>[Cl:41][C:27]1[C:28]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:23]1[N:22]([CH3:42])[C:9]2=[N:10][C:11]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]([F:19])([F:20])[F:21])[CH2:16][CH2:17]3)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]2[N:24]=1
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2nc1N1CCC(C(F)(F)F)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)nc21
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-5-[4-trifluoromethyl-piperidinyl]-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester (3.85 g, 6.1 mmol) 2 N NaOH (12 mL, 24 mmol) and 60 mL EtOH is stirred for 4.5 h at 55° C. and overnight at rt. Then the mixture is poured into 150 mL water, the mixture is acidified to pH ˜5.5 with aq. KHSO4 and the mixture is concentrated. The resulting precipitate is collected by filtration and dried. Yield: 1.44 g. HPLC Rt=1.47 min (method D). MS m/z: 599 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 36.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (53 mg, 0.18 mmol), and p-toluenesulfonicacid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (50 mg, 0.066 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) d ppm 9.78 (s, 1H), 9.38 (d, J=6.97 Hz, 1H), 8.49 (s, 1H), 8.24 (d, J=5.13 Hz, 1H), 8.10 (d, J=2.20 Hz, 1H), 7.78 (dd, J=8.80, 2.20 Hz, 1H), 7.70 (d, J=8.80 Hz, 1H), 7.54 (s, 1H), 7.42-7.48 (m, 1H), 7.34-7.42 (m, 1H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.92-7.01 (m, 1H), 6.83 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 3.24-3.30 (m, 4H), 2.95-2.99 (m, 4H), 2.94 (s, 3H), 2.17 (s, 3H); MS (ESI): 755 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].O1CCCC1>O>[C:26]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:28])[CH3:27]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3ccccc32)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3ccccc32)cc1C(=O)O
Reaction time: 48 h

Procedure:
A mixture of 8.25 g. (0.025 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenylindole and 76.5 g. (0.75 mole) of acetic anhydride was heated under reflux for 1 hour, diluted with 75 ml. of tetrahydrofuran and poured into 1 l. of water. An oil separated, and during 2 days solidified. The solid was collected and recrystallized from acetonitrile to provide 4.8 g. (52%) of colorless crystals, m.p. 178°-180°.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:21]=2)[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:51]([C:55]#[CH:56])([CH3:54])([CH3:53])[CH3:52]>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[CH3:52][C:51]([CH3:54])([CH3:53])[C:55]#[C:56]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:21]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: CCN(C/C=C/Cl)Cc1cccc(OCc2cc(-c3ccsc3)cs2)c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cc(-c3ccsc3)cs2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
To 10 ml of tetrahydrofuran were added 1.01 g (2.5 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethyoxy]benzylamine, 23.8 mg (0.125 mmol) of copper (I) iodide, 8.9 mg (0.05 mmol) of palladium chloride and 26.2 mg (0.1 mmol) of triphenylphosphine, and further, 0.50 ml (5.0 mmol) of n-butylamine and 0.37 ml (3.0 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 17 hours at room temperature, and extracted with a mixture of 70 ml of ethyl acetate and 30 ml of water. The organic layer was separated, washed with a mixture of 40 ml of water and 4 ml of 2N hydrochloric acid, a mixture of 40 ml of water and 6 ml of saturated sodium bicarbonate aqueous solution and 20 ml of saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After ethyl acetate was evaporated under reduced pressure, the residue was treated with 3 ml of methanol, and stirred for 17 hours under ice cooling. The resulting crystals were collected by filtration, washed with 2 ml of methanol and dried under reduced pressure to obtain 0.81 g (yield: 72%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[CH2:3]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[CH2:22](N(CC)CC)C.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:22])=[O:9])[CH2:3]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1=CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C1=CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A solution of 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid, hydrochloride salt (1.8 g, 10 mmol) in methylene chloride (60 ml) was cooled to 0° C. Benzyl chloroformate (2.74 ml, 19.2 mmol) was added, followed by addition of triethylamine (7.2 ml, 51.2 mmol), and stirring at room temperature for 12 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. Evaporation in vacuo afforded a yellow oil. This was purified by chromatography on silica gel (eluant: 20%, then 30% ethyl acetate/hexane) to give the product as a slightly yellow oil (2.14 g, 7.7 mmol, 77% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH2:27][CH2:28][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])[CH2:30][CH:31]=4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:46])[CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH2:27][CH2:28][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])[CH2:30][CH:31]=4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:46])[CH:10]=1
Reactant: C[C@H](c1ccc(Cl)cc1F)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1F)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of the crude (R)-t-butyl 2-(4-(1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-carboxylate (0.092 g, 0.17 mmol) in dichloromethane (1.5 mL) and stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to give the title compound as a white solid (0.024 g, 0.053 mmol, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.78-9.70 (m, 1 H), 9.32-9.22 (m, 1 H), 8.44-8.38 (m, 1 H), 7.68 (d, J=8.4 Hz, 1 H), 7.58 (s, 1 H), 7.51-7.41 (m, 3 H), 7.27 (d, J=8.4 Hz, 1 H), 6.17-6.13 (m, 2H), 4.61-4.54 (m, 1 H), 4.19-4.05 (m, 3 H), 3.89-3.85 (m, 1 H), 3.69-3.50 (m, 3 H), 2.52-2.34 (m, 1 H), 1.95 (d, J=6.8 Hz, 3 H), 1.90-1.70 (m, 3 H); MS: (ES) m/z calculated for C25H27ClFN4O [M+H]+453.2, found 453.1.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23](Cl)=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.O>[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
To a flame-dried flask under nitrogen is added allylamine (0.60 mL, 8.05 mmol). The flask is cooled in an ice bath, and a solution of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarbonyl chloride (EXAMPLE 1, Step 2, 0.805 mmol theory) in anhydrous tetrahydrofuran (8.0 mL) is added. The resulting mixture is stirred under nitrogen for 2 h, allowing the cooling bath to slowly expire, and is then diluted with water (10 mL) and extracted with methylene chloride (20 mL). The organic phase is washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (0.5/99.5-2/98). Pooling and concentration of those fractions with an Rf=0.44 by TLC (methanol/chloroform, 5/95) provides the title compound, mp 167-169° C.; MS (ESI+) for C17H20FN3O4 m/z 350 (M+H)+; [α]25D=−44° (c 0.94, DMSO).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].O=S(Cl)Cl.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[Cl:18])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccccc1Cl
Yield: 27.4 %

Procedure:
Prepared according to Procedure A using 4-nitroanthranilic acid (5.0 g, 27.5 mmol) and SOCl2 (5.0 mL, 68.6 mmol) in benzene (150 mL), followed by 2-chloroaniline (5.8 mL, 55.0 mmol) and CHCl3 (150 mL). The product was purified by chromatography in CH2Cl2 followed by recrystallization from MeOH to provide 2.20 g of an orange-brown solid (31%). 1H NMR (CDCl3) δ: 8.41 (dd, J=1.3, 8.3 Hz, 1H); 8.31 (br s, 1H); 7.67 (d, J=8.6 Hz, 1H); 7.57 (d, J=2.1 Hz, 1H); 7.52 (dd, J=2.2, 8.5 Hz, 1H); 7.44 (dd, J=1.3, 8.1 Hz, 1H); 7.35 (dt, J=1.3, 7.9 Hz, 1H); 7.13 (dt, J=1.4, 7.8 Hz, 1H); 5.88 (br s, 2H). MS (ES): m/z 292.0 (M+).