Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Cl:14])=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].CC([O-])=O.[Na+]>>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[C:3]1[CH:2]=[N:22][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:21]=1
Reactant: Nc1ccccc1N
Reactant: O=C(CBr)c1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cnc3ccccc3n2)c1
Yield: 60 %

Procedure:
Procedure B was performed with 2-bromo-2′chloro-5′-nitroacetophenone (14.16 g, 50 mmol), 1,2-phenylenediamine (13.1 g, 120 mmol) and NaOAc (12.4, 150 mmol) to give the desired 2-(2-chloro-5-nitro-phenyl)-quinoxaline (8.6 g, 30 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=3[CH:9]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[Li+].[OH-]>O1CCOCC1.ClCCl.CO>[Cl:20][C:5]1[C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=3[CH:9]=2)=[N:7][C:2]([NH:36][CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: NC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CC[SiH](CC)CC
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Temperature: 97 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid amide (305 mg, 0.941 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (430 mg, 1.88 mmol) and diisopropylethylamine (0.492 mL, 2.82 mmol) in 1,4-dioxane (6 mL) is heated at 97° C. under a nitrogen atmosphere for 7 hours. At room temperature the mixture is concentrated in vacuo to give a crude solid and it is subjected to a subsequent deprotection reaction. The solid is suspended in dichloromethane (12 mL), followed by the successive addition of triethylsilane (0.9 mL) and TFA (4 mL). The resultant yellow solution is stirred for 2 hours. After concentration and subsequent chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 3-10%, the fractions containing the desired product are collected and concentrated to give a solid. The solid is dissolved in MeOH (20 mL) and dichloromethane (20 mL) with stirring and the solution is treated in portions with 0.5 N LiOH (14 mL) to form a suspension. Methanol and dichloromethane are concentrated at 45° C. to give a yellow suspension. After filtration and drying the title compound is obtained as a yellow solid (0.200 g, 51% yield). ES+(m/z) 416 (35Cl) and 418 (37Cl) [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:20]([O:19][CH3:15])[CH3:21])=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cnc(O)c(Br)c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-hydroxy-nicotinic acid (Preparation 238, 4 g, 18.4 mmol), HATU (13.95 g, 36.71 mmol), O,N-Dimethyl-hydroxylamine hydrochloride (2.15 g, 22.02 mmol) and DIPEA (15.82 mL, 91.75 mmol) were taken in anhydrous DMF (30 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated aq. Na2CO3 (2×50 mL), water (4×30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo. The crude mixture was purified by column chromatography on silica gel (gradient of EtOAc:Hex 4:6 to 6:4) to afford the title compound as light yellow sticky solid in 38%, 1.8 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Si:7]([O:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].CN(C)C.C(=O)(O)[O-].[Na+]>ClCCl.CS(C)=O>[Si:7]([O:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)cc1
Agent: CN(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A solution of oxalyichloride (1.6 ml) in dry dichloromethane (37 ml) was cooled to -70° C. under N2. Dry dimethylsulfoxide (2.5 ml) in dichloromethane (10 ml) and a solution of 4-(tert-butyldimethylsilyloxymethyl)benzylalcohol (24) (3.94 g, 15.6 mmol) in dichloromethane (20 ml) were added carefully. The reaction mixture was stirred at -70° C. for 1 h. trimethylamine (12 ml) was then added. The reaction mixture was allowed to warm up no 0° C. Saturated aqueous sodium bicarbonate (50 ml) was added, the organic layer was separated and the aqueous layer was extracted with dichloromethane (4×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/hexane; 4:1) to yield 4-butyldimethylsilyloxymethyl)benzaldehyde (25) 3.21 g, 82%); νmax /cm-1 2020s, 2850s, 2730w, 1700s, 1090s; δH (CDCl3) 0.11 (6H, s, SiCH3), 0.94 (9 H, s, tert-butyl), 4.80 (2 H, s, CH2O), 7.47 and 7.84 (4 H, AA'BB', PhH) and 9.98 (1 H, s, CHO); (CDCl3) -5.3, 18.4, 25.9, 64.4, 126.2, 129.8, 135.3, 148.6 and 192.0; m/z 251.1467 M+ +H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:68]=[CH:67][C:33]([CH2:34][O:35][C:36]([C:38]2[CH:39]=[C:40]([C:44]([C:46]3[N:47]=[CH:48][N:49]4[CH:53]=[C:52]([Sn](CCCC)(CCCC)CCCC)[S:51][C:50]=34)=[O:45])[CH:41]=[N:42][CH:43]=2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:52]3[S:51][C:50]4=[C:46]([C:44]([C:40]5[CH:41]=[N:42][CH:43]=[C:38]([C:36]([O:35][CH2:34][C:33]6[CH:67]=[CH:68][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH:39]=5)=[O:45])[N:47]=[CH:48][N:49]4[CH:53]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(C(=O)OCc4ccc([N+](=O)[O-])cc4)c3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(C(=O)OCc6ccc([N+](=O)[O-])cc6)c5)c4s3)[C@H](C)[C@H]12
Yield: 47.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzyloxycarbonyl)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (97.2 mg) was prepared in the same manner as in step a) of Example 1, except that 98 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 198 mg of 7-[5-(4-nitrobenzyloxycarbonyl)pyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[N:36]3[C:31]([CH:32]=[N:33][C:34](S(C)=O)=[N:35]3)=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[N:36]3[C:31]([CH:32]=[N:33][C:34]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:35]3)=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: Clc1cccc(-c2ccc3cnc(-n4cnc5cnccc54)nn23)c1

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 90.14 mg of 1-[7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=347.6. 1H NMR (400 MHz, DMSO, d6) δ 9.42 (s, 1H), 9.21 (s, 1H), 8.61 (m, 1H), 8.53 (m, 1H), 8.35 (m, 1H), 8.15 (m, 1H), 7.63 (m, 4H), 7.36 (d, 1H, J=4.89 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[CH2:24](Br)[C:25]#[CH:26].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH2:26][C:25]#[CH:24])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: C#CCBr
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl) -4-trifluoromethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 2-ethoxy-1-[4-chloro-2-fluoro-5 -(2-propynyloxy)-phenyl]-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.34 ppm (d,1H), 6.97 ppm (d,1H), 6.60 ppm (s,1H), 4.76 ppm (m,2H), 4.50 ppm (m,2H), 2.57 ppm (t,1H), 1.29 ppm (t,3H);
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]1=[O:18].[ClH:28]>C(OCC)(=O)C>[ClH:28].[Br:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2Br)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(Br)c(CN2CCNCC2=O)c1
Reaction time: 0.5 h

Procedure:
Through a solution of the product from Step D (7.71 g, 16.6 mmol) in 100 mL of ethyl acetate at 0° C. was bubbled anhydrous HCl gas for 10 minutes. After 30 minutes, the solution was concentrated in vacuo to provide the titled salt as a white foam which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12](NCC2C=CN=C(C3C=CC(OC(F)(F)F)=CC=3)C=2)=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:47]1([C:52]2[CH:57]=[C:56]([CH2:58][NH2:59])[CH:55]=[C:54]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=3)[N:53]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12]([NH:59][CH2:58][C:56]2[CH:55]=[C:54]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:67])[F:68])=[CH:62][CH:61]=3)[N:53]=[C:52]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:57]=2)=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Acid 7 (295.76 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (1.1 equiv., 353.47 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 150 mg of a pale yellow solid. Yield=25% 1HNMR (DMSO, 200 MHz) δ 1.07 (3H, t), 1.94 (4H, m), 3.41 (6H, m), 4.37 (2H, d), 5.39 (1H, s), 6.21 (1H, s), 6.31 (1H, s), 7.20 (1H, s), 7.34 (1H, d, J=4.2 Hz), 7.57 (1H, d, J=4 Hz), 7.91 (2H, d), 8.48 (2H, d), 8.75 (1H, bt) [M+1] 599.9 (C26H26ClF3N4O3S2 requires 599.09).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[CH:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)c2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
To 5-[4-methyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-thiophene-2-sulfonic acid tert-butylamide (example 320) (0.240 g, 0.45 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.215 g, 100%). MS (ISP) 476.1 [(M+H)+]; mp 228° C. (dec.).
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[CH2:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11]S1.C(O)C>O>[CH2:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:1]1(=[O:6])=[O:2]
Reactant: c1ccc2c(c1)CSC2
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=S1(=O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Potassium peroxymonosulphate (110 g) was added portionwise to a mixture of 1,3-dihydrobenzo[c]thiophene (23 g; J. Amer. Chem. Soc., 81, 4266), ethanol (400 ml) and water (300 ml) and the mixture was stirred at ambient temperature for 18 hours. Water (400 ml) was added and the mixture was extracted with chloroform (3×100 ml). The combined organic extracts were washed with water, dried (MgSO4) and evaporated. The residue was recrystallised from ethyl acetate to give 1,3-dihydrobenzo[c]thiophene-2,2-dioxide (17 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40].Cl>C(Cl)Cl.CCOC(C)=O.O>[C:29]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=2)[C:20]([OH:21])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C@@H:2]([NH:1][C:39]([O:41][CH3:42])=[O:40])[C:3]([OH:5])=[O:4])=[O:10])[N:12]=1)#[N:30]
Reactant: N#Cc1nc(C(=O)NCC[C@@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(R)-2-Amino-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (15 mg, 0.03 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. To the solution were added triethylamine (0.03 mL, 0.21 mmol) and methyl chloroformate (4 μL, 0.05 mmol). After stirring for 5 minutes at 0° C., H2O (10 mL) and EtOAc (10 mL) were added. To the stirred mixture was added 1 N hydrochloric acid (1 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 5 mg. MS: (−) m/z 463.21 (M−1).
Reaction SMILES: I(O)(=O)(=O)=[O:2].[C:6]([O:10][C:11]([N:13]1[C@@H:17]([CH2:18][OH:19])[CH2:16][C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:14]1=[O:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[C:6]([O:10][C:11]([N:13]1[C:14](=[O:28])[C@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16][C@@H:17]1[C:18]([OH:2])=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc([C@@H]2C[C@H](CO)N(C(=O)OC(C)(C)C)C2=O)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: COc1ccc([C@@H]2C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stock solution containing 12.0 grams of periodic acid and chromium trioxide (24 mg) in wet acetonitrile (0.75 volume % water) was prepared. A portion of this solution (9.6 mL) was added to a solution of (3S, 5R)-5-hydroxymethyl-3-(4-methoxyphenyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, 1.58 mmol) in wet acetonitrile (0.75 volume % water) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then quenched by addition of a solution of dibasic sodium phosphate (1.2 grams) in water (20 mL). The mixture was extracted with ethyl acetate and the organic extract was washed with aqueous sodium bisulfite solution and brine. After drying over magnesium sulfate, the solvent was evaporated to provide the title compound as a white solid, 518 mg (98%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:31]([C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: CCn1nc(C)cc1C(=O)O
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=464.4.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][S:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)([CH3:3])[CH3:2].OO.C(=O)([O-])[O-:24].[Na+].[Na+]>ClCCl.CO.C(O)(=O)C.[NH4+].[O-][V](=O)=O>[CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][S:11]([C:12]1[NH:16][CH:15]=[CH:14][N:13]=1)=[O:24])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OCCNc1ccccc1CSc1ncc[nH]1
Agent: O=[V](=O)[O-]
Agent: OO
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)OCCNc1ccccc1CS(=O)c1ncc[nH]1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
1.50 g (5.2 mmol) of 2-[2-(2-isopropoxyethylamino)benzylthio]imidazole was dissolved in a mixture of 15 ml of dichloromethane, 15 ml of methanol and 1.5 ml of acetic acid. To the resulting mixture were added 2.3 ml of 35 % aqueous hydrogen peroxide and 48 mg of ammonium metavanadate under chilling with ice. Then the mixture was stirred for 2 hrs. under chilling with ice. After the reaction was completed, 5 % aqueous sodium carbonate was added to the stirred mixture. The organic portion was collected and was subjected to extraction with 20 ml of 0.2 N aqueous sodium hydroxide. To the collected aqueous portion was little by little added 60 ml of 1 N aqueous ammonium chloride. The deposited oily product was extracted with chloroform. The chloroform extractant was dried over anhydrous sodium sulfate and then chloroform was distilled off. The residue was crystallized from ether to give 1.20 g of the desired compound as a white crystalline powder. (Yield: 75.8 %)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[N:18]1([C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CC=C(N2CCCC2)CC1

Procedure:
In stage 1, the compound 1-acetyl-4-piperidinone is reacted in a reaction medium, preferably selected from the group consisting of toluene and benzene, with pyrrolidine in the presence of a catalytic quantity of an acid, preferably in the presence of p-toluenesulfonic acid, with refluxing on a water separator to yield the compound 1-(4-pyrrolidin-1-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (A).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=1)=O.[F:13][C:14]([F:27])([F:26])[C:15]1[NH:25][C:18]2=[N:19][CH:20]=[C:21]([CH2:23][NH2:24])[CH:22]=[C:17]2[CH:16]=1>C(O)(C)C.C(#N)C.CS(C)=O>[F:27][C:14]([F:13])([F:26])[C:15]1[NH:25][C:18]2=[N:19][CH:20]=[C:21]([CH2:23][NH:24][C:4]3[N:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=3)[CH:22]=[C:17]2[CH:16]=1
Reactant: CS(=O)c1cc(CC#N)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CC(C)O
Product: N#CCc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 80 °C
Yield: 8.4 %

Procedure:
A mixture of [6-(methylsulfinyl)-4-pyrimidinyl]acetonitrile (Intermediate 16, 150 mg, 0.828 mmol) and 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 178 mg, 0.828 mmol) in isopropanol (7 mL) was stirred and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and condensed. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (2.7 mL) and purified by MDAP (3 injections). Fractions containing the suspected product were combined and concentrated under reduced pressure. The solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (1.8 mL) and purified again by MDAP (2 injections). Fractions containing the suspected product were combined and concentrated under reduced pressure to give the title compound as a solid (23 mg);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:29])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[Cl:28])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:29]
Reactant: CC(=O)C(Cc1ccc(F)cc1Cl)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(F)cc1Cl)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(2-chloro-4-fluorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)OC[C@H]1COc2c(O)cccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)OC[C@H]1COc2c(OCc3ccccc3)cccc2O1
Yield: 1.5 %

Procedure:
A mixture of methanesulfonic acid (R)-5-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (0.6 g, 1.69 mmol), benzyl bromide (0.4 g, 2.30 mmol) and potassium carbonate (1.14 g, 8.30 mmol) in acetone (30 ml) was refluxed under nitrogen atmosphere for 5 h. The crude product was crystallized from 2-propanol to yield 8.8 mg of the pure title compound.