Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].CN(C1C=CC=CN=1)C.[C:30]([NH:40][C@H:41]([C:45](O)=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[C:30]([NH:40][C@H:41]([C:45]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:10])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(COC(=O)Cc2ccccc2OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Yield: 93.5 %

Procedure:
4-Methoxybenzyl 2-hydroxyphenylacetate 3 g, 11 mmol), N,N-dicyclohexyl-carbodiimide (2.7 g, 13.2 mmol), dimethylaminopyridine (0.134 g, 1.1 mmol) and CBz-L-valine (3.3 g, 13.2 mmol) were dissolved in dichloromethane (50 ml). After the weekend the solid was filtered off, the solvent removed under reduced pressure and the crude product purified by chromatography (ethyl acetate, hexane, 1:2) to give the title compound (5.2 g, 93%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]([CH3:16])(OCC)(OCC)[O:7][CH2:8][CH3:9]>CC(O)=O>[CH2:6]([O:7][C:8](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:9])[CH3:16]
Reactant: N#CCC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: CCOC(C)=C(C#N)C#N
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A mixture of malononitrile (5.0 g, 76 mmol), (EtO)3CCH3 (14.8 g, 91 mmol) and CH3COOH (1 mL) was stirred at 80° C. for 45 min. Then the mixture was cooled to room temperature and filtered to give 2-(1-ethoxy-ethylidene)-malononitrile (8.9 g, yield 86%) as a yellow solid.
Reaction SMILES: [N+]([O-])(O)=O.[Mn]([O-])(=O)(=O)=O.[K+].[O-2:11].[Mg+2].[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:28])[C:19]=2[CH:29]=1)[CH3:14]>O>[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:28])[C:19]=2[CH:29]=1)(=[O:11])[CH3:14]
Reactant: [O-2]
Reactant: CCc1ccc2oc3ncccc3c(=O)c2c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 60 °C
Yield: 67 %

Procedure:
7.6 ml of nitric acid (specific gravity 1.38) and 7.9 g of potassium permanganate are added to a suspension of 2 g of magnesium oxide in 50 ml of water, and the mixture is heated to 60°C. To the mixture is added 4.5 g of 7-ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine over a period of 30 minutes with stirring, keeping the temperature at 60°-70°C. After the addition the mixture is stirred at 60°-70°C for 4.5 hours. After cooling, the reaction mixture is filtered under reduced pressure, and the residue containing manganese dioxide is extracted several times with chloroform. The chloroform layer is washed with water, dried, and the chloroform is distilled off. The residue is recrystallized from toluene to give 3.2 g of 7-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 195°-196°C.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C#C)C=CC=CC=1.[C:28]([O:36][CH:37]([CH2:41][CH:42]=[CH2:43])[CH2:38]C=C)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:28]([O:36][CH:37]1[CH2:38][CH:43]=[CH:42][CH2:41]1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=CCC(CC=C)OC(=O)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C#Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OC1CC=CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 22 h
Yield: 69.4 %

Procedure:
A 100 ml flask was charged with 0.53 g (1.9 mmol) of tricyclohexylphosphine, 0.62 g (1.0 mmol) of di-μ-chlorobis((p-cymene)chlororuthenium), 50 ml of toluene, 0.22 ml (2 mmol) of phenylacetylene and 8.28 g (38.3 mmol) of 1,6-heptadiene-4-yl benzoate and the mixture was stirred at 80° C. for 22 hours in a nitrogen stream. The reaction solution was washed with an aqueous 1% sodium hydroxide solution and saturated brine in this order, followed by drying using magnesium sulfate anhydride. A solvent was distilled and the residue was subjected to vacuum distillation (73-74° C./5 mmHg) to obtain 5.00 g of an object material in a yield of 69.4%.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].[OH-].[Na+]>ClCCl>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:14][CH2:13][CH:11]2[O:12][CH2:10]2)[N:1]=1
Reactant: OCC1CO1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1nc(Cl)nc(OCC2CO2)n1
Reaction time: 3 h

Procedure:
A solution of 73.76 g (0.4 moles) cyanuric chloride in 360 ml of dichloromethane was chilled in an ice-water bath to about 0-5° C. and 31.85 g (0.43 moles) glycidol was added. A solution of 34.4 g 50% aqueous sodium hydroxide was added over about 30-45 minutes with stirring keeping the temperature between about 0° C. and about 10° C. Stirring was continued for an additional 3 hours after which time the layers were separated and the organic layer washed two times with water, and once with brine and the solution was dried over magnesium sulfate. Filtration and evaporation of the solution afforded a white solid, a sample of which was further purified by trituration with hexane-ethyl acetate. The proton and carbon nuclear magnetic resonance (NMR) spectra were consistent with the desired product, 2,4-dichloro-6-glycidoxy-1,3,5-triazine.
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[S:60]1[C:68]2[CH:67]=[CH:66][N:65]=[CH:64][C:63]=2[N:62]=[CH:61]1>CS(C)=O.C(OCC)(=O)C>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:29](=[N:55]/[O:56][CH3:57])/[C:28]([NH:27][CH:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][N+:65]4[CH:66]=[CH:67][C:68]5[S:60][CH:61]=[N:62][C:63]=5[CH:64]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1cc2scnc2cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4scnc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate [VIIa] (1.50 g, 1.61 mmoles) and thiazolo[4,5-c]-pyridine (300 mg, 2.20 mmoles) in dry dimethylsulfoxide (DMSO) (7.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (5 mL), dried and evaporated to dryness. To a solution of the residue in CHCl3 (5 mL) was added ether (50 mL) to give the quaternized blocked cephalosporin [XIIIa] (1.7 g), which was collected by filtration and treated with 90% trifluoroacetic acid [TFA] (17 mL) at room temperature for 1 hour. After evaporation of the solvent, the residue was triturated with ether, filtered and dissolved in CH3OH (2 mL). The solution was treated with 1M sodium 2-ethylhexanoate [SEH] in ethyl acetate (3.2 mL) at room temperature for 30 minutes to afford 774 mg of the crude title compound (Ia), which was purified by HPLC (Column, Lichrosorb RP-18, 8×300 mm; eluted with 0.01M ammonium phosphate buffer, pH 7.2--15% CH3OH) and HP-20 column chromatography (3×30 cm, washed with 1 L of water and eluted with 700 mL of 30% CH3OH). The fractions containing the desired product were collected, concentrated and lyophilized to afford 180 mg (22%) of the title compound (Ia) as a colorless powder, mp 165° C. (dec.).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl:20]CCl.S(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([Cl:20])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)O
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)Cl

Procedure:
A solution of 2-isobutoxycarbonylamino-3-phenyl-propionic acid (5 gm), dichloromethane (25 mL) and dimethylformamide (0.5 mL) was cooled to 0-5° C. To the resulting solution, thionyl chloride (1.5 mL) was added at same temperature. The solvent was distilled out completely to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[C:9]2=[O:36])=[CH:4][C:3]=1[CH3:37].[CH:38]([N:42]=[C:43]=[O:44])([CH2:40][CH3:41])[CH3:39].O>ClCCCl>[CH3:14][C:11]1([CH3:15])[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:43]([NH:42][CH:38]([CH3:39])[CH2:40][CH3:41])=[O:44])=[C:3]([CH3:37])[CH:4]=2)[C:9](=[O:36])[N:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:31])[F:32]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Reactant: CCC(C)N=C=O
Solvent: ClCCCl
Solvent: O
Product: CCC(C)NC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C
Yield: 36 %

Procedure:
The compound of Example 25 (395 mg, 0.72 mmole) is dissolved in anhydrous 1,2-dichloroethane (10 ml) under an argon atmosphere, before the dropwise addition of sec-butylisocyanate (0.35 ml, 3 mmoles) at 23° C. The mixture is then heated under reflux for 24 hours. The reaction medium is then poured onto cold water and extracted using CH2Cl2. After decantation, the organic phase is washed with water and salt water. The organic solution is then dried over MgSO4, filtered, concentrated to dryness under vacuum and the evaporation residue is purified on a silica column (eluent: heptane/AcOEt: 1/0 to 4/6). The expected compound is obtained in the form of a colourless oil with a yield of 36%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 482 (M++1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.CN(C=O)C.CC(C)([O-])C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
In a 250 ml round bottom flask, under a nitrogen atmosphere, was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (5.0 g, 18.6 mmol) from Example I(1), step 1b, tert-butyl 4-aminobenzoate (3.95 g, 20.5 mmol), and DMF (30 ml). The solution was cooled to 0° C. and 1.0 M potassium tert-butoxide in THF (46 ml) was added dropwise via syringe over 30 minutes. The reaction was allowed to stir at room temperature for 30 minutes and then warmed to 50° C. for 2 hrs and then concentrated in vacuo to remove THF. The resulting solution was taken up in ethyl acetate, washed with H2O (3×300 ml) and then brine (1×50 ml). The organic layers were combined, dried over Na2SO4 and filtered. Following solvent evaporation, 6.0 g of crude product was obtained. Further purification was done via triteration with 3:1 diethyl ether/heptane to give 2.2 g of tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate as a brown solid after filtration.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1.[OH-].[K+]>C1(C)C=CC=CC=1>[OH:5][CH:6]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:1]2=[O:2])[CH2:10][CH2:9]1
Reactant: COc1ccccc1OCC(O)CN1CCC(NCCNc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1OCC(O)CN1CCC(N2CCN(c3ccc(Cl)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
With vigorous stirring, 630 ml of a 20% solution of phosgene in toluene are added dropwise at a reaction temperature of 5° to 10° C. in the course of 13/4 hours to an emulsion of 56 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-ethylamino]-piperidine in 340 ml of toluene and 200 ml of a 3 N potassium hydroxide solution. Thereafter 193 ml of a 6 N aqueous potassium hydroxide solution are added dropwise at the same reaction temperature in the course of half an hour. The reaction mixture is further stirred for 1 hour at 5° to 10° C. and for 20 hours at room temperature and then concentrated. The residue is made alkaline with a 2 N aqueous sodium hydroxide solution and extracted with five 100 ml portions of methylene chloride. The extracts are dried over sodium sulphate and concentrated under reduced pressure. The residue is dissolved in methanol and boiled for 30 minutes with the addition of activated charcoal. The batch is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from isopropanol to yield 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-chlorophenyl)-imidazolidin-2-one with a melting point of 136°-137° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:26]=[C:23]([CH:24]=[O:25])[C:22]([OH:27])=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:26][C:23]=1[CH:24]=[O:25]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(OC(F)(F)F)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-trifluoromethoxysalicylaldehyde (412 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:28]3[S:27][C:26](=[O:29])[NH:25][C:24]=3[CH:23]=[C:22]([Br:30])[CH:21]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-].Cl>O1CCOCC1.O>[Br:30][C:22]1[CH:21]=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C@@H:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]2=[O:31])[C:28]2[S:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=1
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3[nH]c(=O)sc23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3[nH]c(=O)sc23)c2ccccc21
Reaction time: 1 h
Yield: 34 %

Procedure:
(S)-3-[3-(5-Bromo-2-oxo-2,3-dihydro-benzothiazol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (33 mg, 0.06 mmol) is dissolved in dioxane (3 mL) and then LiOH (8 mg, 0.3 mmol) in water (3 mL) is added to the reaction. The reaction is stirred for 1 hour then acidified with 4N HCl and the solvents evaporated in vacuo. The resulting crude solid is purified on reverse phase LC/MS to give 10 mg (32%) of the title compound as a white solid. LCMS (ESMS): m/z 491.8 (M+H+).
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[F:18])(O)=[O:2].S(Cl)([Cl:21])=O.CN(C=O)C>ClCCl>[F:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[N:8]1[CH2:7][CH2:6][O:5][CH2:4][C:1]1=[O:2])[C:13]([Cl:21])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COCCNc1ccc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(N2CCOCC2=O)c(F)c1

Procedure:
Prepared analogously to Example 41c from 4-(2-carboxymethoxy-ethylamino)-3-fluoro-benzoic acid and thionylchloride in dichloromethane with DMF.
Reaction SMILES: C(N1CCOCC1)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.C(Cl)(=O)C(Cl)=O.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4-Formylmorpholine (50 μL) was added to a stirred solution of 4-bromophenylacetic acid (5.00 g, 23.3 mmol) and oxalyl chloride (5.89 g, 4.05 mL, 46.6 mmol) in dichloromethane (30 mL) under nitrogen at room temperature. When gas evolution ceased the volatiles were evaporated and the residue was taken up in dichloromethane (30 mL). Benzyl alcohol (2.52 g, 2.41 mL, 23.3 mmol) was added in one portion and stirring was continued under nitrogen for 2 h. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and saturated sodium hydrogen carbonate solution (50 mL). The phases were separated and the aqueous phase was washed with dichloromethane (2×50 mL). The organic layers were combined, dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (20% diethyl ether: cyclohexane) to give the title compound as a white solid (6.76 g, 95%). LC/MS: 3.57 min; z/e 322 and 324, calcd (M+18) 322 and 324. 1H NMR (400 MHz: CDCl3): 7.45 (2H), 7.30 (5H), 7.15 (2H), 5.15 (2H), 3.60 (2H).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]=[CH2:13])[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)(=[O:4])=[O:5]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C=CCN(C)S(=O)(=O)CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of methyl 2-({methyl[allyl]amino}sulfonyl)acetate (300 mg, 1.4 mmol) and 4-bromobiphenyl (370 mg, 1.54 mmol) in acetonitrile (4 ml) was added triethylamine (0.3 ml, 2.1 mmol), palladium(II) acetate (17 mg, 0.07 mmol) and tri-ortho-tolyl phosphine (52 mg, 0.14 mmol) and the solution was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to ambient temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (dichloromethane as eluent) to give the title compound as a pale yellow solid (300 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14]C)=[O:13])=[CH:8][NH:9]2)=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)=[C:18]([O:29][CH3:30])[CH:17]=1.O1CCCC1.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)=[C:18]([O:29][CH3:30])[CH:17]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1OC[C@@H]1CCCN1
Temperature: 65 °C
Reaction time: 41 h

Procedure:
To a solution of (S)-methyl 6-chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylate hydrochloride (22.6 mg, 0.050 mmol) in methanol (0.26 mL) was added tetrahydrofuran (0.26 mL) and sodium hydroxide (1N in water, 0.26 mL, 0.26 mmol). The mixture was then sealed and heated to 65° C. After 41 h, the mixture was allowed to cool to 23° C., concentrated in vacuo, diluted with water (1 mL), then acidified to pH 7.5 with hydrochloric acid (1N in water). The solid was filtered and purified by reverse phase HPLC to provide the title compound. MS (ES+) 401.2 (M+H)+. HPLC retention time: 1.44 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min.
Reaction SMILES: C(OC([NH:8][C:9]1([C:22](=[O:36])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[CH:25]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.Cl.O1CCOCC1>CO>[CH3:33][N:32]([CH3:34])[C:31](=[O:35])[O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][C:22]([C:9]2([NH2:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:36])[CH:25]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(N)CCNCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)piperidine-1-carboxylate from step A (0.141 g, 0.28 mmol) in MeOH (2 mL) was added HCl (4 N in dioxane, 0.21 mL, 0.84 mmol). The mixture was stirred at room temperature for 14 hours. Further eqivalents of HCl/dioxane were added at this time, and the mixture stirred for a further 24 hours at room temperature. The solvent was removed under vacuum to afford the title compound (0.084 g, 98%), which was carried on crude. MS (ES+) [M+H]+=307.