Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[N:44]=[C:43](O)[C:42]3[N:46]([CH3:49])[CH:47]=[N:48][C:41]=3[CH:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.CCOC(C)=O.O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[N:44]=[C:43]([O:1][C@@H:2]([C@H:4]3[CH2:8][NH:7][C:6](=[O:9])[CH2:5]3)[CH3:3])[C:42]3[N:46]([CH3:49])[CH:47]=[N:48][C:41]=3[CH:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: C[C@H](O)[C@H]1CNC(=O)C1
Reactant: COc1ccc(-c2cc3ncn(C)c3c(O)n2)cc1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ncn(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reaction time: 8 h

Procedure:
To a mixture of (R)-4-((R)-1-hydroxyethyl)pyrrolidin-2-one 1.18 (350 mg, 2.73 mmol), PPh3 (720 mg, 2.73 mmol), and 6-(3,4-dimethoxyphenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-ol 2.27 (130 mg, 0.60 mmol) in CH2Cl2 (6 mL) was added DEAD (475 mg, 2.73 mmol) and the reaction was stirred overnight. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The organic layer was washed with brine (1×10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (CH2Cl2→10% MeOH in CH2Cl2) to afford (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.01.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.Cl[CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=O.Cl.[NH2:51][C@H:52]([C:56]1[CH:61]=[C:60]([F:62])[C:59]([F:63])=[C:58]([F:64])[CH:57]=1)[C@H:53]([OH:55])[CH3:54].C(=O)([O-])O.[Na+].[H-].[Na+]>O.C(OCC)(=O)C.CN(C=O)C.C(Cl)CCl>[OH:55][C@H:53]([CH3:54])[C@H:52]([N:51]1[CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]3)=[C:38]([O:48][CH3:49])[CH:37]=2)/[C:32]1=[O:34])[C:56]1[CH:57]=[C:58]([F:64])[C:59]([F:63])=[C:60]([F:62])[CH:61]=1
Reactant: C[C@@H](O)[C@H](N)c1cc(F)c(F)c(F)c1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cc(/C=C2\CCCN([C@H](c3cc(F)c(F)c(F)c3)[C@@H](C)O)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
IPEA (4 mL), HOBT (1.11 g), and EDC (1.57 g) were added to a DMF solution (40 mL) of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid trifluoroacetate (CAS Registry No. 870850-40-1, 3.69 g) and (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propan-2-ol hydrochloride (1.98 g). This reaction solution was stirred at room temperature for 3.5 hr, and ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added thereto. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was suspended in diisopropyl ether and collected by filtration to give 3.16 g of a condensed substance. To a DMF solution (50 mL) of this condensed substance (3.16 g), sodium hydride (containing 40% mineral oil, 278 mg) was added at 0° C. The resulting reaction solution was stirred at room temperature for 15 min, and ethyl acetate and water were added thereto. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH, eluting solvent: heptane to ethyl acetate) to give 2.3 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH:31][C:19]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:21])[O:27][N:26]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)nn1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)nn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridazine-3-carboxylic acid (example P) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 454.0888 (M+H)+.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[Si]([O:46][CH2:47][CH2:48][N:49]([CH2:83][CH:84]1[CH2:86][CH2:85]1)[C:50]([C:52]1[C:57]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:56]([OH:66])[N:55]=[C:54]([CH2:67][C:68]2([C:73]3[C:82]4[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:76]=[CH:75][CH:74]=3)[CH2:72][CH2:71][CH2:70][CH2:69]2)[N:53]=1)=[O:51])(C(C)(C)C)(C)C>>[CH:84]1([CH2:83][N:49]([CH2:48][CH2:47][OH:46])[C:50]([C:52]2[C:57]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[C:56]([OH:66])[N:55]=[C:54]([CH2:67][C:68]3([C:73]4[C:82]5[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=5)[CH:76]=[CH:75][CH:74]=4)[CH2:69][CH2:70][CH2:71][CH2:72]3)[N:53]=2)=[O:51])[CH2:86][CH2:85]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (358) (350 mg, 0.53 mmol). The yield was 225 mg, 78% of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][N:25]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[N:13]([CH2:31][CH2:30][C:27]4[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][CH:28]=4)[C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: COc1ccc(N2CCc3[nH]c4ccc(C)cc4c3C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCc3c(c4cc(C)ccc4n3CCc3ccc(C)nc3)C2)cc1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:20])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.Br.O.C(=O)([O-])[OH:24].[Na+]>CS(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:20])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:24])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: O=C([O-])O
Reactant: Cc1cccc(CC(=O)c2ccc3nnn(C)c3c2)n1
Agent: Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(C(=O)C(=O)c2ccc3nnn(C)c3c2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone (280 mg, 1.05 mmol) in 16 ml dimethyl sulfoxide was heated to 60° C. 48% hydrobromic acid solution in water (7.4 ml, 65.1 mmol) was slowly added over several minutes. Once the addition was complete, the reaction was stirred at 60° C. for 3 hours. The reaction was cooled to room temperature and poured into 75 ml water. The pH was adjusted to 8 with the addition of saturated sodium hydrogen carbonate solution. The aqueous layer was then extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to afford 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione (146 mg, 50%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH3:11])[C:4]=1N.N([O-])=O.[Na+].CCO.[BrH:19]>[Cu]Br>[Br:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH3:11])[C:4]=1[Br:19]
Reactant: Br
Reactant: Cc1cc(F)cc(Br)c1N
Agent: [Cu]Br
Agent: Cl
Agent: O=N[O-]
Solvent: CCO
Product: Cc1cc(F)cc(Br)c1Br
Reaction time: 0.42 h

Procedure:
A solution of 2-bromo-4-fluoro-6-methylaniline HCl (5.0 g, 17.6 mmol) in 25% aq. HBr (38.1 mL, 175 mmol) was cooled to 0° C. and an aq. solution of sodium nitrite (0.59 mL, 18.4 mmol) added, followed by a small amount of EtOH to aid solubility. The reaction was stirred at this temperature for 25 min before transferring by pipette to a solution of copper(I) bromide (2.64 g, 18.4 mmol) in 25% aq. HBr (20 ml) at 70° C. The reaction was stirred at this temperature for 3 h. The reaction was quenched with NaHCO3 and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-10% Hexene/EtOAC) to yield 1,2-dibromo-5-fluoro-3-methylbenzene as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)=[CH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)/[C:3]([OH:19])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(=CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C(=C/C1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 26.3 %

Procedure:
A solution of the isomeric mixture of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-acrylic acid methyl ester [821.1 mg, 2.74 mmol, (E):(Z)=4.5:1] in tetrahydrofuran (3.4 mL) was treated with a 0.8M aqueous lithium hydroxide solution (3.4 mL, 2.74 mmol). The reaction mixture was stirred at 25° C. for 17 h and then heated under reflux for 4 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded pure (E)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-acrylic acid (205.4 mg, 26%) as a white solid: mp 119-120° C.; EI-HRMS m/e calcd for C14H14Cl2O2 (M+) 284.0371, found 284.0370.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:14]2[CH2:15][O:16][N:17]=[C:13]2[CH2:12][CH:11]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:10]1[OH:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[C:34]([O:26][CH:10]1[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:14]2[CH2:15][O:16][N:17]=[C:13]2[CH2:12][CH:11]1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC1C(O[Si](C)(C)C(C)(C)C)CC2=NOCC2C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
4,6-Bis(tert-butyldimethylsilyloxy)-5-hydroxy-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (401 mg) was dissolved in 20 ml of methylene chloride. Five milliliters of triethylamine and 0.5 g of 4-dimethylaminopyridine were added, and 100 mg of acetyl chloride was then added, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, and washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 355 mg of 5-acetoxy-4,6-bis(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[CH2:13][CH2:12]1)(=[O:10])=[O:9].CC[N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])=O.[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([NH2:28])=[O:20])[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccccc1N1CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: O=C[O-]
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1N1CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
2-(4-(2-Chlorophenylsulfonyl)piperazin-1-yl)benzoic acid (76 mg, 0.02 mmole), EDCI (39 mg, 0.02 mmole), HOBt (31 mg, 0.02 mmole) and ammonium formate (13 mg, 0.02 mmole) were combined in 1 ml of dry DMF. The mixture was treated with 1 equivalent of TEA and stirred at room temperature overnight. The title compound was obtained in yield of 37% after purification on preparative HPLC. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.21 (s, 4 H), 3.31 (s, 4 H), 5.87 (br, s, 2 H), 6.68 (s, 1 H), 6.75 (s, 1 H), 6.90 (s, 1 H), 7.26 (s, 1 H), 7.59 (s, 1 H), 7.72 (s, 2 H), 8.02 (s, 1 H); ESI-MS: m/z 380.1 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[ClH:21]>[Pd].CO>[ClH:21].[OH:20][C@@H:18]1[CH2:19][NH:11][C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17]1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)CN1
Reaction time: 4 h
Yield: 103.1 %

Procedure:
Into a 1 liter Parr hydrogenation bottle was placed 29.90 g (107.12 mmol) of (cis)-1-benzyloxycarbonyl-4-hydroxy-L-proline, methyl ester (reference: J. Am. Chem. Soc., 79, 185, (1957)), 400 ml of methanol, 9.83 ml (117.90 mmol) of concentrated HCl, and 3.00 g of 10% palladium on activated carbon. The mixture was shaken under a hydrogen atmosphere at 50 psi for 4 hours, then filtered through a Millipore filter; the palladium was washed with 100 ml of methanol. The filtrate was concentrated under vacuum to a minimal volume, then treated with 250 ml of ethyl acetate, which caused a white precipitate to form. The solids were filtered, washed twice with ethyl acetate and once with hexane, and dried under vacuum to yield 20.05 g (93.1%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])[CH2:7][CH3:8])=[N:2]1.[H-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1>[CH3:30][S:31]([N:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])[CH2:7][CH3:8])=[N:2]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccn(S(C)(=O)=O)n1
Reaction time: 0.33 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(1H-pyrazol-3-yl)-propyl]-amide (0.040 g, 0.11 mmol) in THF was added 60% sodium hydride (9 mg, 0.2 mmol) in mineral oil. After 20 minutes, methansulfonyl chloride (25 mg, 0.22 mmol) was added. After 3 hours, the reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (the column was equilibrated with dichloromethane-Et3N) eluting with 5% methanol in dichloromethane. Material from the column was crystallized in ether to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC=CC=2)=[C:4]([C:17](=[O:27])[C:18]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[F:26])[CH:3]=1.[OH-].[K+]>CO.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:17]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[F:26])=[O:27]
Reactant: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C

Procedure:
To a solution of 1-fluoro-3-methoxy-benzene (19.6 g, 155 mmol) in THF (180 mL), at −78° C., was added dropwise 2.5 M n-butyllithium in hexanes (62 mL, 155 mmol). The solution was stirred at −78° C. for 3 h and then added to a suspension of 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (38.8 g, 150 mmol) in THF (280 mL) at −20° C. The mixture was allowed to gradually warm until the solution became homogenous. 1N HCl (150 mL) followed by EtOAc (250 mL) were then added and the solution allowed to warm to room temperature. The organic portion was collected and washed with H2O (250 mL), saturated NaHCO3 (2×250 mL) and H2O (250 mL). The organic portion was then dried over Na2SO4 and evaporated to dryness, in vacuo, to provide the N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide as an orange solid (42.7 g). To a solution of N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide (42.7 g, 110 mmol) in MeOH (540 mL) was added KOH (56.4 g, 1 mole) in H2O (100 mL). The solution was allowed to reflux for 16 h. The solution was then allowed to cool to room temperature and the resulting precipitate removed by filtration. The filtrate was concentrated in vacuo, diluted with EtOAc (250 mL) and washed with H2O (3×100 mL). The organic portion was then dried over Na2SO4, concentrated in vacuo and then purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to provide 1ac (19.6 g, 47%) MS m/z=280 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]([CH3:29])[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[CH2:23][CH:22]([C:26](O)=[O:27])[CH2:21]1.C1C(NN)=NN=C(N(CCO)CCO)C=1.Cl.Cl.C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:26]([CH:22]3[CH2:23][C:24](=[O:25])[N:20]([CH2:19][CH2:18][N:17]([CH3:29])[CH3:16])[CH2:21]3)=[O:27])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)CCN1CC(C(=O)O)CC1=O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: NNc1ccc(N(CCO)CCO)nn1
Product: CN(C)CCN1CC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CC1=O
Yield: 70 %

Procedure:
Prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 1-(2-dimethylamino-ethyl)-5-oxo-pyrrolidine-3-carboxylic acid in 70-80% yield as the di-HCl salt. 1H-NMR (300 MHz, D2O): δ 2.97 (dd, 1H), 3.03 (s, 6H), 3.08 (dd, 1H), 3.51 (t, 2H), 3.76-3.89 (m, 3H), 3.95 (dd, 1H), 4.01 (dd, 1H), 7.75 (d, 1H), 8.24 (d, 1H), 8.45 (dd, 1H), 8.52 (dd, 1H), 9.10 (bs, 1H). Retention Time (LC, method: ammonium acetate standard): 0.99 min. MS (M+H+): 400.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=4)[NH:21][C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Li+].Cl>O1CCOCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=4)[NH:21][C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C(=O)O)c2[nH]1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylate (30 mg, 0.069 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (2 mL) containing a magnetic star bar and lithium hydroxide (30 mg, 0.71 mmol). The resulting solution was stirred at 70° C. for 45 minutes. The crude product was then acidified with 2.6 M hydrochloric acid and extracted three times with an equivalent volume of dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in a minimum of N,N-dimethylformamide and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylic acid. ESI-MS m/z calc. 434.2, found 435.5. Retention time of 1.85 minutes. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.96 (d, J=1.6 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.22 (d, J=2.3 Hz, 1H), 6.02 (s, 2H), 1.43-1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:9]2[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[OH:4].Cl.[CH3:37][N:38]([CH2:40][CH2:41][SH:42])[CH3:39].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([S:42][CH2:41][CH2:40][N:38]([CH3:39])[CH3:37])=[C:9]2[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[OH:4]
Reactant: CN(C)CCS
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)CCSC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (51 mg), 2-(N,N-dimethylamino)ethylmercaptan hydrochloride (14.2 mg), and triethylamine (14 ml) in anhydrous DMF (2 ml) is stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate (20 ml), washed with 5% sodium bicarbonate (2×5 ml), water (4×10 ml), and brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography on silica gel to yield benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-(2-dimethylaminoethylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[C@@H:20]([NH:19][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (αS)-α-amino-benzeneacetamide hydrochloride (1:1) (CAN 60079-51-8) as starting materials, LC-MS (UV peak area/ESI) 98%, 366.1814 (M+H)+.