Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:12]C(=O)CCl)([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.NC(N)=S.C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Cc1cccc(Br)c1)NC(=O)CCl
Agent: NC(N)=S
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(N)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of N-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide (Preparation 30) (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo and basified using aqueous sodium hydroxide solution (1M, 450 ml). The product was extracted with dichloromethane (2×500 ml) and the combined organics washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to afford the title compound as a black oil (23 g). 1H NMR (400 MHz, CDCl3) δ=7.36-7.32 (2H, m), 7.16-7.08 (2H, m), 2.62 (2H, s), 1.84 (2H, bs), 1.12 (6H, s). LRMS (electrospray) m/z 228 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]2[CH3:34])=[O:16])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC1CCCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCCCN1C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Reaction time: 3 h
Yield: 110.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in dichloromethane (4 ml) was added DMF (0.025 ml) followed by 2M oxalyl chloride solution in dichloromethane (0.091 ml). The resultant solution was stirred at room temperature for 1 h, and then 2-methylpiperidine (0.03 g) followed by DIPEA (0.080 ml) were added. After 3 h, the solution was concentrated under reduced pressure and the residue was subjected to preparative hplc. The title compound (0.080 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])COC)(=[O:13])=[O:12])=[C:7]([C:27]#[N:28])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([C:27]#[N:28])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1C#N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C#N
Temperature: 75 °C
Yield: 79.3 %

Procedure:
To a solution of 37 (340.0 mg; 0.80 mmol) in tetrahydrofuran (16 mL) was added aqueous hydrochloric acid (5 mL; 10 mmol; 2N). The reaction mixture was heated at 75° C. for 4 hours, and then additional aqueous hydrochloric acid (3.0 mL; 6N) was added and the reaction mixture further heated at reflux for 4-5 hours. The reaction mixture was allowed to cool to room temperature and then extracted with ethyl acetate (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an off-white residue which was triturated from diisopropyl ether to yield the title product as a white solid (240 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([S:26](=[O:27])(=[O:28])[NH:25][CH3:24])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CNS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylaminosulfonyl)phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.33 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+].C(O)COCCOCCO>>[C:1]1([C:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CCC(=O)CCCCC(=O)CCC(CC(=O)O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: O=C(O)CC(CCCCCCCCCCC(CC(=O)O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C

Procedure:
0.27 g. 3,3,14,14-Tetraphenyl-6,11-diketohexadecane-1,16-dioic acid, prepared according to Example 23, and 0.23 g. 85% hydrazine hydrate were added to a solution of 0.4 g. KOH in 10 ml. triethylene glycol. The mixture was heated for 24 hours at 120° C., subsequently heated to 195° C. in order to evaporate the water and then boiled under reflux for 7 hours. The mixture was cooled, diluted with water, extracted with ether, acidified and extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][C:34](=[O:36])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][C:34](=[O:36])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: O=C1CNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-oxo-azetidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidin-3-one following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH:8]=[C:7]([CH3:11])[S:6]1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])=[O:4]
Reactant: COC(=O)C1SC(C)=CC1O
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1sc(C)cc1O
Yield: 75 %

Procedure:
17.4 Parts of 3-hydroxy-5-methyldihydrothiophene-2-carboxylic acid methyl ester are dissolved in 100 parts by volume of methylene chloride. 14.9 parts of sulfuryl chloride in 20 parts by volume of methylene chloride are added in the course of 30 minutes at 10° C., whilst passing nitrogen into the mixture. The mixture is then distilled. 12.9 parts (75% of theory) of 3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester of boiling point 67°-70° C./0.3 mbar are obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCCCNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(c2cccc(OC)c2)CCCCNC1

Procedure:
3-Ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described in Step H above) (1.05 g, 4.24 mmol) in anhydrous THF (4.2 mL) was added to a solution of LiAlH4 (0.193 g, 5.09 mmol) in anhydrous THF (4.2 mL) and refluxed for 24 h. The solution was cooled, quenched with H2O (0.18 mL), 15% NaOH (0.18 mL), H2O (0.54 mL), filtered and concentrated. The residue was purified using reverse phase chromatography (95/5-5/95 H2O/CH3CN with 0.1% TFA, flow =65 mL/min) and converted to its free base using saturated NaHCO3 solution, extracted with CH2Cl2 (3×) and dried (MgSO4) to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:36]=[CH:35][C:10]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:17]=[CH:18][C:19]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:16]2[CH:17]=[CH:18][C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:5][CH2:6][C@@H:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:3]4)=[CH:36][CH:35]=3)[CH:15]=2)=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N2CC[C@@H](N)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N2CC[C@@H](NS(C)(=O)=O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
A solution of compound 404 (420 mg, 0.856 mmol) in DCM (2 mL) was cooled down to 0° C. and treated with neat methanesulfonyl chloride (148 mg, 1.29 mmol). The mixture was allowed to warm up to room temperature for 18 h. Cooled down to 0° C., treated with sat. NaHCO3 (1 mL), stirred for 1.5 h, diluted with DCM, washed with sat NaHCO3, dried over MgSO4 and concentrated under vacuum to afford the title compound 405 as a brown solid (430 mg, 88%) which was used without further purification
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:6]2=[O:13].[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]2=[O:13]
Reactant: [H][H]
Reactant: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CC2Cc3c(C)cc(C)c(O)c3C2=O)cc1

Procedure:
16.09 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one was dissolved in a mixed solvent of 150 ml of ethyl acetate with 100 ml of acetic acid, this solution was let subjected to catalytic reduction at room temperature under 3 atmospheric hydrogen gas pressure in the presence of 1.5 g of palladium black as the hydrogenation catalyst. After the catalytic reduction, the catalyst was removed by filtration, and the filtrate was concentrated by removing the solvent under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane: ethyl acetate=9 : 1) to obtain 8.5 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzyl)-1H-inden-1-one as in the form of colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]=[O:17]>[OH-]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: C=O
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Agent: [OH-]
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-7-trifluoromethylquinoline (30.0 g.), 40% aqueous formaldehyde solution (36 ml.) and 1 M aqueous solution hydroxide solution (250 ml.) was stirred at 40°-50° for 8 hours. The solid product was collected and dried to give the novel 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline, m.p. 302-304°.
Reaction SMILES: [NH2:1][C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:9]=1[N+:10]([O-:12])=[O:11].C1C(=O)N([O:30][C:31]([O:33][CH2:34][CH:35]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]3[C:36]2=[CH:37][CH:38]=[CH:39][CH:40]=3)=O)C(=O)C1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:30])[C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: N[C@@H](CCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(N[C@@H](CCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Fmoc-Lys(Dnp) was prepared from Lys(Dnp) as follows. Fmoc N-hydroxysuccinimide ester (1.89 g; 5.60 mmol) was dissolved in 30 mL of dimethoxyethane and stored at 4° C. Lys(Dnp) (1.63 g; 4.67 mmol) was dissolved in 10 mL of 10% aqueous Na2CO3 and added slowly to the dimethoxyethane solution. The reaction proceeded for 2 hours at 4° C. and overnight at room temperature. The solution was filtered, and the filtrate acidified to a pH of about 3 with concentrated HCl. Dimethoxyethane was removed by heating the solution under reduced pressure. The solution was extracted with ethyl acetate, and the ethyl acetate layer reduced by heating under reduced pressure to an oil. The oil [Fmoc-Lys(Dnp)] was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[C:27]([F:29])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH2:24])[C:21]([O:25][CH3:26])=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:30])[CH:5]=1)[CH3:2].Cl[C:32]1[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=[CH:34][CH:33]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:30])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:21]([O:25][CH3:26])=[CH:20][N:19]=3)=[N:10]2)=[C:27]([F:29])[CH:28]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)c(F)c1
Reactant: CCOC(=O)c1cnccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(=O)c1cnccc1Nc1nc(-c2nn(Cc3c(F)cc(OCC)cc3F)c3ccccc23)ncc1OC
Temperature: 105 °C
Reaction time: 3 h

Procedure:
150 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine (1-4-3, 0.365 mmol, 1.0 eq.), 89 mg of commercial ethyl 4-chloronicotinate (0.401 mmol, 1.1 eq.), 31.6 mg of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.055 mmol, 0.15 eq.), 356 mg of caesium carbonate (1.09 mmol, 3.0 eq.) and 8.2 mg of palladium diacetate (0.036 mmol, 0.1 eq.) were suspended in 4.7 mL of dry dioxane and stirred under nitrogen atmosphere at 105° C. bath temperature for 3 h. Solids were filtered off, washed with dioxane and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography yielding 77 mg from which only 15.7 mg were further purified by crystallization from THF to yield 3.1 mg (0.01 mmol, 1.44%) of analytically pure target compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[C:32][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1ccc(C=O)cc1
Yield: 86 %

Procedure:
A mixture of 4-bromobenzaldehyde (3.7 g), triphenylphosphine (0.32 g), palladium(II) acetate (135 mg), and 3,3-dimethyl-1-butyne (4 ml) in triethylamine (20 ml) is thoroughly purged with nitrogen, then heated to 100° in a sealed tube under nitrogen for 2 hr. The mixture is cooled, and the precipitated triethylamine hydrobromide is removed by filtration. The filtrate is concentrated, and the residue dissolved in 3:1 dichloromethane-hexane and filtered through a 2-cm pad of silica gel. The filtrate is concentrated and vacuum-distilled to provide 4-(3,3-dimethyl-1-butynyl)benzaldehyde as a pale yellow solid (3.25 g, 86%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([Cl:22])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([Cl:22])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14]
Reactant: O=C(O)c1c(Cl)cc(CO)cc1Cl
Reactant: c1cc2[nH]ccc2cn1
Product: O=C(c1c(Cl)cc(CO)cc1Cl)n1ccc2cnccc21

Procedure:
[2,6-Dichloro-4-(hydroxymethyl)phenyl](1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (Compound No. 90) was synthesized from N-(1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-(hydroxymethyl)benzoic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@@H:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[N:24]1[N:25]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](O)=[O:32])[N:26]=[CH:27][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[N:25]1[N:26]=[CH:27][CH:28]=[N:24]1)=[O:32]
Reactant: Ic1cccc(C[C@@H]2COCCN2)c1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccccc1-n1nccn1)N1CCOC[C@H]1Cc1cccc(I)c1
Reaction time: 22 h

Procedure:
A solution of (R)-3-(3-iodo-benzyl)-morpholine B-5 (100 mg, 0.33 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (1.5 mL) was added to a RT solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid E-2 (62 mg, 0.33 mmol), TBTU (111 mg, 0.35 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (1.5 ml) under argon and the resulting mixture was stirred for 22 h. The reaction mixture was quenched with sat. aq. NaHCO3 and stirred for 10 min before being diluted with water and extracted with DCM (3×). The combined organic extracts were washed with 2M aq. NaOH (1×), 2M aq. HCl (1×) and brine (1×), dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method F) to give the title compound as a white solid. LC-MS D: tR=0.93 min; [M+H]+=474.91.
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OCC3C=CC=CC=3)=O)=C(OS(C(F)(F)F)(=O)=O)CC[C@H]12.C(N(CC)CC)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)C[NH:44][C:45]2[S:46][CH:47]=[C:48]([C:50](=[N:81][O:82][CH3:83])[C:51]([NH:53][C@@H:54]3[C:79](=[O:80])[N:56]4[C:57]([C:69]([O:71]CC5C=CC=CC=5)=[O:70])=[C:58]([O:61][S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH2:59][CH2:60][C@H:55]34)=[O:52])[N:49]=2)C=CC=CC=1.C(O)=O>C(#N)C>[NH2:44][C:45]1[S:46][CH:47]=[C:48]([C:50](=[N:81][O:82][CH3:83])[C:51]([NH:53][C@@H:54]2[C:79](=[O:80])[N:56]3[C:57]([C:69]([OH:71])=[O:70])=[C:58]([O:61][S:62]([C:65]([F:67])([F:66])[F:68])(=[O:63])=[O:64])[CH2:59][CH2:60][C@H:55]23)=[O:52])[N:49]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(NCC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(N)n1

Procedure:
syn-2-(2-Triphenylmethylthiazol-4-yl)-2-methoxyiminoacetyl chloride is reacted in acetonitrile with benzyl 7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate in the presence of triethylamine and the acylation product, benzyl 7β-[2-(2-triphenylethylaminothiazol-4-yl)-2-methoxyiminoacetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate is treated with formic acid to remove the triphenylmethyl group and with aluminum chloride ih anisole to remove the benzyl ester group to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](C(O)=O)[C:15]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[N:24]=2)=[CH:14]3)[N:8]([CH3:10])[N:9]=1)=[O:4].[Li+].[OH-]>O1CCCC1.CO.O>[CH3:10][N:8]1[C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[N:24]=2)=[CH:14]3)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[N:9]1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)cc(-c2nc(C)no2)n3C(=O)O)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(-c2cc3cc(-c4cc(C(=O)O)nn4C)ccc3[nH]2)n1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 5-(5-Methoxycarbonyl-2-methyl-2H-pyrazol-3-yl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-indole-1-carboxylic acid (2.7 g) in tetrahydrofuran (40 ml) and methanol (40 ml) at room temperature is added a solution of LiOH (3M, 103.3 mmol) in water over 5 minutes. The reaction is stirred for 30 minutes and the organic solvents are evaporated in vacuo. The reaction mixture is diluted 3x with water and washed with dichloromethane (100 ml). The aqueous layer is acidified with HCl (12 N) and the product extracted 3× with 200 ml of ethyl acetate. The combined ethyl acetate washings are dried (Na2SO4), filtered, and evaporated in vacuo to give the title compound 1.9 g, 57%, LC/MS ESI m/z (M+H)+=324.5.