Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:28](O)(=[O:33])[CH2:29][C:30](O)=[O:31].P(Cl)(Cl)(Cl)=O>>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:33][C:28]1[C:27]2[C:19](=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[CH:26]=2)[NH:18][C:30](=[O:31])[CH:29]=1
Reactant: O=C(O)CC(=O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: c1ccc(Oc2ccnc3ccccc23)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1ccc2[nH]c(=O)cc(O)c2c1

Procedure:
The 4-phenoxyquinoline core structure was synthesized according to a published procedure (42). The synthesis of compound 3 is described in FIG. 13. The synthesis began with stirring p-aminobenzoic acid with malonic acid and phosphorus oxychloride to yield 4-hydroxy-6-carboxy-2-(1H)-quinolinone. Reacting the quinolinone with dichloroiodobenzene is followed by refluxing with butanol produced 3-Iodo-4-phenoxyl-6-carboxyl-2-(1H)-quinolinone. Diodination of the 3-iodo quinolinone yielded compound 3.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[Mn]([O-])(=O)(=O)=O.[K+].C[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH2:5]([O:4][C:2]([NH:1][C:18]1[CH:17]=[C:16]([NH:1][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:15]=[CH:14][C:19]=1[CH3:20])=[O:3])[CH3:6]
Reactant: Cc1ccccc1C
Reactant: CCOC(N)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
10 g of the urethane which had previously been treated in this way were dissolved in 60 g o-xylene. The solution is heated to 80° C. and mixed with 2 g of a 2%, by weight, aqueous potassium permanganate solution. The mixture was stirred intensely for 30 minutes at 80° C. The hot organic phase was then separated from the solid and aqueous constituents. The organic phase was concentrated by distilling off a proportion of the xylene to half of its original volume, and the purified 2,4-bis-(ethoxycarbonylamino)-toluene was obtained in a virtually quantitative yield from the concentrated solution by crystallization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(=O)NC2=O
Reaction time: 17 h
Yield: 59.3 %

Procedure:
To a solution of 5-nitro-1H-isoindole-1,3(2H)-dione (1.0 g, 5.2 mmol) in dry THF (15 mL) was added 10% Pd/C (0.2 g). The mixture was hydrogenated at 30-40 psi for 17 h. The catalyst was filtered, and the filtrate was evaporated under vacuo to give 0.5 g (59.3%) of 5-amino-1H-isoindole-1,3(2H)-dione as a yellow colour solid.
Reaction SMILES: C(CNC([C@@H](NC1C=CC(C2C=CC(N3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=CC=1)CC(C)C)=O)#N.[C:38]([CH2:40][NH:41][C:42](=[O:75])[CH:43]([S:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([N:62]3[CH2:67][CH2:66][N:65](C(OC(C)(C)C)=O)[CH2:64][CH2:63]3)=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)[CH2:44][C:45]1([CH3:48])[CH2:47][CH2:46]1)#[N:39]>>[C:38]([CH2:40][NH:41][C:42](=[O:75])[CH:43]([S:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([N:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)[CH2:44][C:45]1([CH3:48])[CH2:47][CH2:46]1)#[N:39]
Reactant: CC1(CC(Sc2ccc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2)C(=O)NCC#N)CC1
Agent: CC(C)C[C@H](Nc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Product: CC1(CC(Sc2ccc(-c3ccc(N4CCNCC4)cc3)cc2)C(=O)NCC#N)CC1

Procedure:
Using the procedure described in Example 1 where tert-butyl 4-{4′-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate is substituted for tert-butyl 4-[4′-({2-[(cyanomethyl)amino]-1-[(1-methylcyclopropyl)methyl]-2-oxoethyl}thio)-1,1′-biphenyl-4-yl]piperazine-1-carboxylate, N-(cyanomethyl)-3-(1-methylcyclopropyl)-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)thio]propanamide was obtained after crystallization in EtOAc and hexane (1:2) as a beige solid. MS (+ESI): 435.2 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:10])[CH:5]([CH3:9])[CH2:6][C:7]=1[CH3:8].Cl>>[OH:10][C:4]1[C:3](=[O:2])[CH:7]([CH3:8])[CH2:6][C:5]=1[CH3:9]
Reactant: COC1=C(C)CC(C)C1=O
Agent: Cl
Product: CC1=C(O)C(=O)C(C)C1
Yield: 54.2 %

Procedure:
2.15 g (15.36 mmol) of crude 2-methoxy-3,5-dimethyl-2-cyclopenten-1-one are held at reflux temperature for 2 hours with 21.50 g (=10 fold amount by weight) of 5N hydrochloric acid. The reaction mixture is extracted 3 times with 50 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. After recrystallization from ether/hexane 1:1 there are obtained 1.05 g (54.2%) 2-hydroxy-3,5-dimethyl-2-cyclopenten-1-one; m.p. 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1nccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine is dissolved in dimethyl formamide. Potassium carbonate and 2-chloro-4-trifluoromethyl-pyrimidine are added and the reaction mixture is stirred at about 80° C. overnight. It is obtained 2-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-trifluoromethyl-pyrimidine.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][P:31](=[O:47])([O:35][C:36]([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH2:37])[O:32][CH2:33][CH3:34])=[CH:25][CH:24]=1>[Au].ClC(Cl)C>[CH2:33]([O:32][P:31]1(=[O:47])[CH:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=2)[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:35]1)[CH3:34]
Reactant: C=C(CCCc1ccccc1)OP(=O)(C#Cc1ccc(Cl)cc1)OCC
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(Cl)cc2)C=C(CCCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
Method 1—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl 5-phenylpent-1-en-2-yl 2-(4-chlorophenyl)ethynylphosphonate (Example 23, 116 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-chlorophenyl-6-3-phenylpropyl-1,2-oxaphosphorin 2-oxide (83.3 mg, 72%) which is a title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.N([O-])=O.[Na+].[CH3:18][S:19]SC>O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[S:19][CH3:18]
Reactant: Nc1cc(S(=O)(=O)O)ccc1Cl
Reactant: CSSC
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(S(=O)(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 291.5 %

Procedure:
To a solution of 3-amino-4-chloro-benzenesulfonic acid (5.00 g, 24 mmol) in distilled water (38 mL) and concentrated HCl (6 mL, 72 mmol) at 0° C. was added sodium nitrite (1.99 g, 28.9 mmol) in H2O (10 mL). After 1.5 h, the mixture was allowed to warm to 25° C. and stirred for 1.5 h. Methyl disulfide (10.7 mL, 120 mmol) was added and the mixture heated to 70° C. for 18 h. The solvent was removed, in vacuo, to give an orange solid (16.7 g) that was used as is in the next reaction.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[CH:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:1]([N:8]([CH3:23])[CH:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][NH:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C1C2CCC1CN(C(=O)C(F)(F)F)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccccc1)C1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 1-{8-[benzyl(methyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}-2,2,2-trifluoro-1-ethanone (see step (vi) above; 2.1 g, 6.4 mmol) and K2CO3 (3 g, 21.7 mmol) in MeOH/water (110 mL of 10:1) was stirred at rt overnight and then evaporated. DCM and water were added and the layers separated. The water layer was extracted with DCM (3×). The combined organic layers were dried and evaporated to give 1.2 g (81%) of the sub-title compound.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: OB(O)c1ccccn1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccnc2)cc1
Temperature: 90 °C
Yield: 72 %

Procedure:
Scheme VI, Step A′: [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.52 mmol, prepared in example 1), pyridyl boronic acid (93 mg, 0.76 mmol), potassium carbonate (104 mg, 0.76 mmol), tetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036 mmol), and dioxane/water (20 mL, 3:1) were mixed together in a 100 mL single neck flask and stirred at 90° C. over night. In the morning, the reaction was cooled to room temperature and poured into H2O, and the desired product was extracted with ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, filtered, and concentrated under reduced pressure to yield 235 mg. of a viscous oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (126 mg, 72%) as a semi-solid. Ion spray M.S. 337.2 (M*+1).
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:21]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:2]([NH:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[CH:21]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a 25 ml flask was added (S)-tert-butyl 1-oxo-3-phenyl-1-(3-(pyridin-4-yl)isoxazol-5-ylamino)propan-2-ylcarbamate 3.3B (160 mg, 0.40 mmoles), 10 ml of CH2Cl2, and 5 ml of TFA. The reaction was stirred at room temperature for 3 hour at which time the solvent was removed with a stream of nitrogen. The crude material was then partitioned between 200 ml of DCM and 100 ml of saturated sodium bicarbonate. The organic solvent was removed by rotary evaporation to give (S)-2-amino-3-phenyl-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide 3.3.C as a light yellow solid (100 mg, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:6]=1.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(Cl)nn2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(-n2cc(Cl)nn2)cc1
Temperature: 85 °C

Procedure:
To a solution of 4-chloro-1-(4-nitrophenyl)-1H-1,2,3-triazole (0.1 g, 0.45 mmol) in ethanol (3 mL) was added SnCl2 (0.4 g, 1.8 mmol) portionwise. The slurry was warmed up to 85° C. for 2.5 h, then quenched with NaOH (2M), filtered and concentrated. The residue was redissolved in EtOAc and washed with brine. The organic layer was separated, dried (MgSO4), and concentrated to afford 4-(4-chloro-1H-1,2,3-triazol-1-yl)aniline.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[NH2:7][CH:8]([CH2:9][CH3:10])[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)C(=O)c1nc2ccccc2o1
Reaction time: 1 h

Procedure:
[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butyl ester (275 mg, 0.89 mmol) and MeCl2 (5 ml) were mixed and TFA (1 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 260 mg of 2-amino-1-benzooxazol-2-yl-butan-1-one TFA salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH:17]([CH2:20][C:21]([CH3:26])([N+:23]([O-:25])=[O:24])[CH3:22])[CH:18]=O>C(O)C>[CH3:22][C:21]([N+:23]([O-:25])=[O:24])([CH3:26])[CH2:20][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[N:1][CH:18]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(Cc1cnc2c(OCc3ccccc3)cccn12)[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.4 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.7 g, 13.5 mmol) and 2-bromo-4-methyl-4-nitropentanal (3.0 g, 13.5 mmol) in ethanol (20 ml) is heated at 100° C. overnight. The solvent is removed under reduced pressure and the residue is treated with saturated aqueous NaHCO3 solution. The aqueous mixture is extracted two times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed (silica gel, dichloromethane/ethanol 9:1) to give 2.83 g of 3-(2-methyl-2-nitropropyl)-8-(phenylmethoxy)imidazo[1,2-a]pyridine (64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1)=[O:25].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)=[O:25])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(CO)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3.29 g (16.4 mmol) 4-benzyloxy-1H-pyridin-2-one in 16 mL DMF is added 13.3 g (40.9 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 3.75 g (16.4 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a) is added and is stirred 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:3]1>CCO.[Pd]>[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Agent: [Pd]
Solvent: CCO
Product: CC1CN(c2ccc(N)cc2)CC(C)N1
Yield: 80.2 %

Procedure:
An amount of 3,5-dimethyl-1-(4-nitrophenyl)piperazine (1.86 g, 7.90 mmol) in EtOH is hydrogenated with Pd/C catalyst for 4 h. The solid is removed by filtration, and solvent is evaporated under vacuum to give pinkish residue. Recrystallization of this residue from MeOH/ether gives 1.30 g (80.2% yield) of pinkish crystal: mp 124-125° C.; MS (ESI) m/z 206.1 (M+H)+1
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:34]=[CH:33][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:23])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH3-]C#N.[Na+].CCOC(C)=O>C(O)(C(F)(F)F)=O.O>[CH:1]1([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:23])=[CH:33][CH:34]=3)(=[O:16])=[O:17])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(C3CCCC3)c3ccccc32)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
Add 4-(3-cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (0.152 g, 0.319 mmol) portionwise to a stirring mixture of NaCNBH3 (0.096 g, 1.52 mmol) in TFA at 0 to 5° C. under N2. Stir the mixture for 15 minutes at 0-5° C., allow to warm to ambient temperature and add an additional 0.096 g NaCNBH3. Stir the resulting yellow solution for 2 h at ambient temperature, dilute with H2O (13.0 mL) and stir overnight. Pour the reaction mixture is into EtOAc (100 mL). Separate the EtOAc, extract with H2O, 5% NaHCO3 and wash with brine. Separate the EtOAc, dry (MgSO4), filter and evaporate giving a glass. Chromatograph on the chromatotron eluting with EtOAc-hexane 3:7 to give 0.060 g of the title compound: Mass spectrum (m/e) (M+H) 479.1805; found 479.1788.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.O.OP([O-])(O)=O.[Na+].[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OC(C)C)(=O)C.O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COC(=O)c1cc(O)cc(OC(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (1.0 eq), sodium phosphate mono-basic monohydrate (0.46 eq) and water (10.5 vols) under a nitrogen atmosphere. The temperature was adjusted to 20° C.±3° C. 10% w/w Sodium hydroxide was added to adjust the pH to pH 7.8±0.2. Benzoyl chloride (1.0 eq) was added drop-wise in small portions over 1-2 hours, and sodium hydroxide was added concurrently drop-wise in small portions over the same time period to maintain the reaction in a pH range of pH 7.8±0.2 and at a reaction temperature of 20° C.±3° C. The crude reaction mixture was agitated for a further 30 minutes, filtered, and then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH7.5 with 10% w/w sodium hydroxide. The crude solid was then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH6.5 with 10% w/w sodium hydroxide. The crude solid was then dissolved in iso-propyl acetate (8 vols) and water (2 vols) and the mixture agitated for at least 30 minutes to ensure the solid had dissolved. The mixture was filtered through a CUNO™ filter to remove a small amount of brown solid. The aqueous layer was separated off. Water (2 vols) was added to the organic layer and the batch agitated for at least 30 minutes. The aqueous layer was separated off and the organic layer was vacuum distilled, keeping the batch temperature below 40° C. to reduce the volume to 5-6 vols. Toluene was added then added (5 vols) and the mixture was vacuum distilled keeping the batch temperature below 40° C., reducing the volume to approximately 3.5 vols. The mixture was cooled to 15° C.±3° C. and agitated at this temperature for at least 30 minutes, then filtered, and the solid washed with toluene (1 vol). The product was dried at 20° C.-40° C. to give the desired product as a solid (corrected yield 40%-70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](=O)[CH3:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:27])[CH3:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: CC(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 84.7 %

Procedure:
A mixture of 1-[4-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.13 g, 0.45 mmol) and ammonium acetate (0.348 g, 4.52 mmol) in methanol (2.0 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, to the resultant mixture was added sodium cyanoborohydride (57 mg, 0.91 mmol). The reaction was heated at 65° C. for another 4 hours. After cooling to room temperature, the reaction was quenched with aqueous saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.11 g), which was used directly in the next step. LCMS calculated for C16H12ClFN(M-NH2)+: m/z=272.1. Found: 272.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[CH:21]([C:23]4[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=4)[O:26][CH2:27][C:28]([O:30]C)=[O:29])[OH:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:21]([C:23]4[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=4)[O:26][CH2:27][C:28]([OH:30])=[O:29])[OH:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCSC(c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)C(O)c1cccc(OCC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCSC(c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)C(O)c1cccc(OCC(=O)O)c1

Procedure:
To an ethanolic solution (100 mL) of the diester from Step F (0.01 mol) is added 1N sodium hydroxide solution (30 mL). This mixture is stirred at ambient temperature until all of the diester is converted to the diacid. The product is isolated and purified by first removing the solvent then resuspending the solidified residue in water. This basic suspension is then made acid (pH 4 to 5) with dilute hydrogen chloride solution and the resulting solid isolated by filtration and air dried. This is then purified further by recrystallization to obtain pure 3-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-1-hydroxy-2-((2-carboxyethyl)thio)ethyl]phenoxyacetic acid.