Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[N:8]=[C:7]2[N:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][C:28]2[N:31]([CH2:44][C@@H:45]3[CH2:47][O:46]3)[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[C:27]=2[CH2:26]1)(=[O:24])=[O:23]>CCO.ClC(Cl)C>[CH3:1][N:2]([CH3:20])[C:3]1[N:8]=[C:7]2[N:9]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:47][C@H:45]([OH:46])[CH2:44][N:31]4[C:28]5[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][C:27]=5[C:33]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=5)=[N:32]4)[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2C[C@@H]2CO2)C1
Reactant: CN(C)c1ccc2c(n1)n(C1CCNCC1)c(=O)n2C
Solvent: CC(Cl)Cl
Solvent: CCO
Product: CN(C)c1ccc2c(n1)n(C1CCN(C[C@H](O)Cn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(C)(=O)=O)C4)CC1)c(=O)n2C
Temperature: 80 °C
Reaction time: 16 h
Yield: 112.3 %

Procedure:
To a stirring solution of 0.24 g (0.0009 mol) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in EtOH/Dichloroethane (1.5 mL/1.5 mL) was added 0.23 g (0.0005 mol) of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was heated to 80° C. and stirred for 16 h and concentrated. The crude product was then dissolved in CH2Cl2 (40 mL) and purified using flash chromatography (0-6% MeOH/CH2Cl2) affording 0.38 g (97%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C31H39F3N8O4S, 676.28; m/z found, 677.28 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 and 7.67 (A and B of AA′BB′ quartet, Jab=8.3 Hz, 4H), 7.03 (d, J=8.6 Hz, 1H), 6.16 (d, J=8.6 Hz, 1H), 4.58 and 4.56 (A and B of AB quartet, Jab=14.5 Hz, 2H), 4.36 (ft, J=12.1 Hz, 4.04 Hz, 1H), 4.25-4.01 (m, 4H), 3.77-3.60 (m, 2H), 3.33 (s, 3H), 3.16-3.04 (m, 2H), 3.03 (s, 6H), 2.99-2.90 (m, 2H), 2.88 (s, 3H), 2.77 (qd, J=12.1 Hz, 3.54 Hz, 2H), 2.56-2.42 (m, 3H), 2.21 (t, J=11.6 Hz, 1H), 1.75 (d, J=11.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=2[N:40]([CH2:43][C@H:44]2[CH2:49][CH2:48][C@H:47]([CH2:50][C:51]([OH:53])=[O:52])[CH2:46][CH2:45]2)[CH2:41][CH3:42])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:18][N:17]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:56](O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.CCN=C=NCCCN(C)C.Cl.O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:56]([O:52][C:51](=[O:53])[CH2:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([CH2:43][N:40]([C:31]2[CH:32]=[CH:33][C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:30]=2[CH2:29][N:15]([CH:13]([C:5]2[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:54])[F:55])[CH:4]=2)[CH3:14])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:18][N:17]=2)[CH2:41][CH3:42])[CH2:45][CH2:46]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: OCc1ccccc1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (racemate compound (I), 20 g, 24.61 mmol) synthesized by the method described in Patent document 2 (International Patent Publication WO2008/129951), Example 45 in anhydrous dichloromethane (200 mL) was added with benzyl alcohol (2.93 g, 27.07 mmol), DMAP (300 mg, 2.46 mmol) and WSC.HCl (5.19 g, 27.07 mmol) under ice cooling, and the mixture was warmed to room temperature, and stirred for 16 hours. The reaction mixture was added with water (100 mL), and the mixture was extracted with chloroform (500 mL). The organic layer was washed with 2 M aqueous hydrochloric acid (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 350 g, developing solvent: N-hexane/ethyl acetate=3/1→1/1) to obtain trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (21.15 g, yield: 95.2%) as white amorphous.
Reaction SMILES: C(=O)=O.CC(C)=O.[CH3:8][C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:21](Cl)([Cl:23])=[O:22].Cl.CC1C=CC=CC=1NCCC(O)=O>C(Cl)Cl>[Cl:23][C:21]([N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[CH3:8])=[O:22]
Reactant: Cc1ccccc1NCCC(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccccc1N(CCC(=O)O)C(=O)Cl
Temperature: 40 °C
Reaction time: 0.42 h
Yield: 97.9 %

Procedure:
In a 100 cc round-bottomed flask equipped with magnetic stirring, a thermometer, a dry ice/acetone reflux condenser, a device for introducing gas and a dropping funnel, there is introduced 3-(2-methylanilino)propionic acid (5.29 g; 29.6 mmol) and methylene chloride (30 cc). The mixture maintained under an atmosphere of argon is heated to a temperature in the region of 40° C., and phosgene (5.20 g; 52.6 mmol) is then added with stirring in the course of 25 minutes, while maintaining the temperature between 36° C. and 40° C. During the introduction of phosgene, a white precipitate of 3-(2-methylanilino)propionic acid hydrochloride forms. The reaction mixture is heated to a temperature in the region of 40° C. for a further hour. The white precipitate is then almost completely dissolved. After cooling to 20° C. and the removal of the phosgene which has not reacted, the light precipitate which remains is separated by filtration. The filtrate is concentrated to dryness. N-Chloroformyl-3-(2-methylanilino)propionic acid (7 g) is thus obtained almost pure, m.p. 112° C., the structure of which is confirmed by the infrared spectrum, mass spectrum and proton nuclear magnetic resonance spectrum. The product, after recrystallisation in a toluene/hexane mixture (70:30 by volume), melts at 113° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[N:4]=[CH:3]1.[NH2:10][C:11]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[CH:29][N:28]([S:39]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[C:25]3=[N:26][CH:27]=2)=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].N1C=CC=CC=1.[Cl-].[NH4+]>ClCCl>[CH3:17][N:15]([CH3:16])[C:13]([C:12]1[CH:18]=[C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[CH:29][N:28]([S:39]([C:42]4[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=4)(=[O:41])=[O:40])[C:25]3=[N:26][CH:27]=2)[CH:20]=[CH:21][C:11]=1[NH:10][C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])=[O:14]
Reactant: Cn1cnc(C(=O)Cl)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 24 h

Procedure:
1-Methyl-1H-imidazole-4-carbonyl chloride (0.092 mmol) was suspended in dichloromethane (1 mL) and a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (50 mg, 0.092 mmol) in 20% v/v pyridine in dichloromethane (0.5 mL) was added. After 24 h, saturated ammonium chloride solution was added and the layers were separated. The organic layers were dried over sodium sulfate and taken to the next step. MS: m/z 649 (M+H+).
Reaction SMILES: O.[OH-].[Li+].O.[C:5]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=[CH:9][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)[CH3:12])=[CH:7][CH:6]=1>O1CCOCC1>[C:5]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:7][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH3:12])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccc3)cc2)cc1)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=NOCCOc1ccc(CC(Nc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of 72 mg of lithium hydroxide monohydrate and 3 ml of water was added to a solution of 282 mg of ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-(phenylamino)propionate obtained in Example 9 in 3 ml of dioxane. The mixture was stirred at 60° C. for one hour. After the reaction, the reaction mixture was concentrated and diluted with water. Then, 1.71 ml of 1N hydrochloric acid was added to the resulting mixture, and the product thus obtained was extracted with a large amount of hot ethyl acetate. The extract was concentrated to about 5 ml, and 229 mg of the desired compound was obtained by filtration.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:23])=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 72 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 72%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]=[C:17]([NH2:27])[S:18][C:19]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[NH:39]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:16]=[C:17]([NH2:27])[S:18][C:19]=5[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH:41]=[N:40]1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(-c2ccccc2Cl)s1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Nc1nc(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)c(-c2ccccc2Cl)s1

Procedure:
Following the procedure of Example 44, 4-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-5-(2-chlorophenyl)thiazol-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 262. MS: (ESI+) 477.1
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH2:26]>O1CCOCC1.CC#N>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:26][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:21][C:18]1[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)(=[O:11])=[O:10]
Reactant: NCc1c(F)cccc1Cl
Reactant: COc1ccc(N)cn1
Reactant: O=S(=O)(Cl)c1cccc(F)c1F
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ccc(NS(=O)(=O)c2cccc(F)c2NCc2c(F)cccc2Cl)cn1
Yield: 9.4 %

Procedure:
The title compound (139 mg, 0.32 mmol) was prepared in two steps from 2,3-difluorobenzenesulfonyl chloride (1.0 g, 4.7 mmol) and 6-methoxypyridin-3-amine (642 mg, 5.2 mmol) in 1,4-dioxane at 100° C.; followed by 2-chloro-6-fluorobenzyl amine (547 mg, 3.4 mmol) in MeCN (3 mL) at 180° C. in a Biotage Initiator microwave reactor using the methods of (IntB1).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:30])([CH3:3])[CH3:2]>Cl.CO>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:30])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Yield: 75 %

Procedure:
A solution of tert-butyl 4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidine-1-carboxylate (3.992 g, 9.58 mmol) in 50 ml 10% hydrochloric acid in methanol and 10 ml concentrated hydrochloric acid was stirred at room temperature for 18 hours. The mixture was then concentrated and basified with aqueous Na2CO3, extracted with CHCl3 100 ml for 3 times. The combined extract was dried and concentrated. Flash chromatography of the residue (NH-silica gel, elutent: CH2Cl2/methanol=100/1) afforded a colorless oil 2.272 g (75%) as the titled compound.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](Cl)=[O:38])=[CH:28][CH:27]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:37]([C:33]1[N:34]=[CH:35][O:36][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)=[O:38])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Reactant: O=C(Cl)c1ncoc1-c1ccc(F)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccc(F)cc2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-(4-fluoro-phenyl)-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.21. LC-MS-conditions 02: tR=1.07 min, [M+H]+=472.48.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCN(C)C(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (7.0 g, 0.032 mol) and K2CO3 (13.3 g, 0.096 mol) in DMF (100 mL) was added MeI (9.0 g, 0.064 mol) at rt. The resultant solution was stirred at rt for 3 hrs. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2×). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 0%˜10% EtOAc/petroleum ether) to afford methyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (6.9 g, 92%) as a white solid. ESI-MS (EI+, m/z): 118 [M−100+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].[CH2:13]=[O:14]>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:13][OH:14])=[C:5]2[OH:12]
Reactant: C=O
Reactant: Oc1ccnc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2ccc(F)cc2c1O

Procedure:
6-Fluoro-4-hydroxyquinoline was reacted with 40% aqueous formaldehyde in aqueous sodium hydroxide solution to give the novel 6-fluoro-4-hydroxy-3-hydroxymethylquinoline m.p. 310°-315°. The product was methylated with dimethyl sulphate to give the novel 6-fluoro-1-methyl-3-hydroxymethyl-4-quinolone, m.p. 209°-212°. Reaction of this product with thionyl chloride, then sodium methanethiolate gave the novel 6-fluoro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 114°-116° (from industrial methylated spirit).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17]1([S:23]([C:26]2[CH:31]=[CH:30][C:29](F)=[C:28]([Cl:33])[CH:27]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:33][C:28]1[CH:27]=[C:26]([S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][C:29]=1[O:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(Cl)c1
Product: CC(C(=O)O)c1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 50 step (iii) and the product from example 29 step (i).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.N1CCC[C@H:28]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]([CH3:50])[C:43]([CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=[O:44]>[Cu]I>[CH3:50][N:42]([CH3:41])[C:43]([CH:45]1[CH2:49][CH2:28][CH2:48][N:47]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]3=[N:6][CH:7]=2)[CH2:46]1)=[O:44]
Reactant: CN(C)C(=O)C1CCNC1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(N3CCCC(C(=O)N(C)C)C3)cc12
Yield: 228.3 %

Procedure:
To a microwave reaction vial were added 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.5 mmol), copper (I)-iodide (26 mg, 0.067 mmol), proline (0.13 mmol), potassium cabonate (280 mg, 1.5 mmol) and pyrrolidine-3-carboxylic acid dimethylamide (260 mg, 1.67 mmol). The vial was purged with nitrogen and DMSO (2.0 ml) was added. The mixture was sealed and irradiated in the microwave to 140° C. for 1 hour. The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (10 mL). The combined organic layers were dried over Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 151 mg (˜60% with minor impurity) of 1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-piperidine-3-carboxylic acid dimethylamide as a yellowish oil. MS: m/z 509.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:8])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH:9]([CH3:13])[C:10]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]4[NH:28][N:29]=[N:30][N:31]=4)[CH3:25])[CH2:22][S:23][C@H:18]23)=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: CC(C(=O)O)S(=O)Cc1ccc(O)cc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)S(=O)Cc3ccc(O)cc3)[C@H]2SC1

Procedure:
456 mg. of 2-(p-hydroxybenzylsulfinyl)propionic acid and 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 291 mg. of 7-[2-(p-hydroxybenzylsulfinyl)propionamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][O-:14].[Na+].CO>CN(C)C=O.O>[Cl:12][C:8]1[C:5]2=[N:6][CH:7]=[C:2]([O:14][CH3:13])[N:3]=[C:4]2[CH:11]=[CH:10][N:9]=1
Reactant: C[O-]
Reactant: Clc1cnc2c(Cl)nccc2n1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(Cl)nccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,5-dichloropyrido[3,4-b]pyrazine (580 mg, 2.90 mmol) in N,N-dimethylformamide (10 mL) was added a 0.5-M solution of sodium methoxide in methanol (6.09 mL, 3.04 mmol), and the reaction was stirred at room temperature for 5 minutes. The solution was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (550 mg, 2.81 mmol). MS m/z=196 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:11][CH:12]([N:14]1[C:18]([C:19]2[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:16]=[N:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[CH:12]([N:14]1[C:18]([C:19]2[C:24]([O:25][CH2:2][C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[CH:5]=[O:6])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:16]=[N:15]1)([CH3:13])[CH3:11]
Reactant: CC(C)n1nccc1-c1ncccc1O
Reactant: O=Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)n1nccc1-c1ncccc1OCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-(bromomethyl)benzaldehyde (150 mg, 0.75 mmol, 1.00 equiv) in CH3CN (25 mL). 2-[1-(Propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1.52 mmol, 2.00 equiv), and KI (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt. The resulting solution was diluted with 20 mL of H2O, and then it was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×30 mL of brine and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase, water with 0.05% TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm. This provided 98.6 mg (41%) of 2-[([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; 1HNMR (300 MHz, CDCl3, ppm): 10.01 (s, 1H), 8.43 (m, 1H), 7.88 (m, 1H), 7.86 (m, 1H), 7.61-7.79 (m, 6H), 6.61 (d, J=2.1 Hz, 1H), 5.60 (s, 2H), 4.69-4.78 (m, 1H), 1.46 (d, J=6.6 Hz, 6H); (ES, m/z): 322 [M+1]+.