Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:72])[C:25]([C:47]3[N:48]=[C:49]([NH:52][C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[S:50][CH:51]=3)=[N:26][O:27][CH:28]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH3:30])[C:21](=[O:73])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:74].[Na+]>CC(C)=O>[I:74][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:72])[C:25]([C:47]3[N:48]=[C:49]([NH:52][C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[S:50][CH:51]=3)=[N:26][O:27][CH:28]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH3:30])[C:21](=[O:73])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10]
Reactant: CCC(ON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(ON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
100 mg (0.1 mmol) of p-methoxybenzyl 3-chloromethyl-7-{2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonylpropyloxyimino)acetamido}-ceph-3-em-4-carboxylate-syn isomer was dissolved in 1 ml of acetone, and 0.5 ml of acetone solution containing 28 mg (0.19 mmol) of sodium iodide was added to the resulting solution at room temperature and reacted for 40 minutes. After the reaction, the solvent was distilled out, methylene chloride was added to the residue, the insoluble materials were filtrated out, and the remaining filtrate was concentrated under reduced pressure, to obtain p-methoxybenzyl 3-iodomethyl-7-{2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-propyloxyimino) acetamido}-ceph-3-em-4-carboxylate-syn isomer. To this was added 18 mg (0.11 mmol) of 1-(2-fluoroethyl)-4-pyridothione, and the resulting mixture was dissolved in 1 ml of chloroform and reacted for 1 hour at room temperature. After the reaction, the chloroform was distilled out under reduced pressure, and the residue was purified by silicagel-chromatography (chloroform/methanol=10/1) and dissolved in 0.4 ml of anisole, and then 1.3 ml of trifluoroacetic acid was added thereto, while cooled with ice, and reacted for 1 hour. After the reaction, isopropylether was added to the reaction solution to form a precipitate therein. After dried, 80 mg of a powder was obtained. To this was added 1 ml of water and the pH value of the resulting solution was adjusted to 7.8 with sodium hydrogencarbonate, and the solution was purified with HP-20 resin (methanol/H2O=1/4) to obtain 45 mg of the above-entitled compound.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20](COCCOC)[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:10]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:51]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CCOCC.CO.ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:17]=[N:18][N:19]([CH3:51])[N:20]=3)[CH2:15][C@@:9]1([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:10]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[C:32]([C:40]([F:42])([F:43])[F:41])[CH:31]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nnc([C@]2(F)C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]-methoxy}-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Example 172; 150 mg, 0.22 mmol), 1M solution of hydrogen chloride in ether (3 ml) and methanol (3 ml) was stirred at reflux for 9 hours. The reaction mixture was concentrated. The residue (170 mg) was treated with dichloromethane (3 ml), methanol (0.5 ml), triphenylphosphine (220 mg, 0.83 mmol) and diethyl azodicarboxylate (0.12 ml, 0.56 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo to give a 1:3.3 mixture of isomers A and B, respectively. Both isomers were separated by chromatography on silica gel (iso-hexane:ethyl acetate 0-20%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[CH:43][CH:42]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)nc23)CC1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.036 g, 0.09 mmol) and EtOH (4.5 ml) was added 4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 ml, 0.38 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.016 g, 32%); 1H-NMR (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 1.45 (m, 2H) and 1.82 (m, 2H) (piperidine CH2), 2.54 (m, 2H), 2.62 (br s, 2H), 2.98 (t, 2H) and 3.70 (m, 3H) (piperazine N—(CH2)2, piperidine CH2 and piperidine CHOH), 3.50 (q, J=6.7 Hz, 1H, CHCH3), 3.67 (br s, 4H, piperazine N(CH2)2), 4.67 (d, J=4.1 Hz, CHOH, exchangeable with D2O), 7.03 (d, J=8.9 Hz, 2H) and 8.00 (d, J=8.8 Hz, 2H) (3,5-C6H4—N and 2,6-C6H4—N), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.16 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.39 min—561, 563 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 561.1975, calculated for C29H34BrN6O (M+H)+: 561.1977.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (175 mg), hydroxylamine hydrochloride (50 mg), potassium carbonate (70 mg), ethanol (1 mL), and water (1.5 mL) is heated under reflux for 2 h. The reaction mixture is concentrated in vacuo and chromatographed on silica gel (dichloromethane/methanol 92:8→60:40) to give the title compound. LC (method 5): tR=0.65 min; Mass spectrum (ESI+): m/z=417 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[CH3:14][C:15]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])[CH3:16].[CH2:32]([O:39][C:40]([O:42]N1C(=O)CCC1=O)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1.O1CCOCC1.O>[CH2:32]([O:39][C:40]([N:3]1[CH2:8][CH2:7][N:6]([C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])[CH2:5][CH:4]1[C:9]([OH:11])=[O:10])=[O:42])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution 0.164 M of 2-piperazinecarboxylic acid dihydrochloride in a 1:1 dioxane-water mixture was made basic (pH 11) with 50% aqueous NaOH. A 0.68 M solution of Boc-ON (1.1 eq) in dioxane was added dropwise at RT to the above mixture and the reaction mixture was stirred at RT overnight. The mixture was extracted with Et2O (×3) and acidified with conc. HCl to pH 2. The aqueous layer was extracted with EtOAc (×3). The aqueous solution was basified to pH 10 with 50% NaOH. A 0.59 M solution N-(benzyloxycarbonyloxy)succinimide (1.1 eq.) in dioxane was added to the mixture at 0° C. The reaction mixture was stirred 3 h at RT. Dioxane was removed under reduced pressure. The basic solution was extracted with Et2O (×2) then acidified to pH 1 with conc. HCl, and extracted with EtOAc (×3). The combined organic layers were dried and evaporated. The residue was used as such in next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[C:5]([Cl:11])=[CH:4][N:3]=1.O=S(Cl)[Cl:14].ClC1C=NC=C(Cl)C=1CCl>>[Cl:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Cl:11])[C:6]=1[CH2:9][Cl:14]
Reactant: Nc1ncc(Cl)c(CO)c1Cl
Reactant: O=S(Cl)Cl
Agent: ClCc1c(Cl)cncc1Cl
Product: Nc1ncc(Cl)c(CCl)c1Cl

Procedure:
(2-Amino-3,5-dichloro-pyridin-4-yl)-methanol (7 mg, 0.036 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 211.0 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:20][CH2:19][C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:11]=[CH:10]3)=[CH:24][CH:23]=1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Nc1ccc(F)cc1
Product: Cc1ccc(CNc2ccc3cc(Nc4ccc(F)cc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=348.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 4-fluoroaniline.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[N:9]=1)([CH3:7])([CH3:6])[CH3:5].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[C:4]([C:8]1[C:12]([CH2:13][NH:3][CH2:1][CH3:2])=[CH:11][N:10]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[N:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCN
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCNCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(C)(C)C
Reaction time: 17 h
Yield: 8 %

Procedure:
Ethylamine (175 mg, 0.205 mL, 3.89 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (151 mg, 0.389 mmol) and acetic acid (0.5 mL) in DMF (2.5 mL). Sodium triacetoxyborohydride (824 mg, 3.89 mmol) was added and the mixture stirred for 17 h. Water (300 μL) was added and the reaction stirred for 30 min. The reaction was filtered and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and the product eluted with 2M NH3 in MeOH. Volatiles were blown down to give 2-(2-(3-tert-butyl-4-((ethylamino)methyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (13 mg, 0.031 mmol, 8%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])=[CH:5][CH:6]=1.[F:18][C:19]([F:24])([F:23])C([O-])=O.[Na+].Cl.C(Cl)Cl>CN(C)C(=O)C.[Cu]I>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([C:19]([F:24])([F:23])[F:18])=[CH:6][CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc(Br)s1
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc(C(F)(F)F)s1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A stirred solution of 8.0 g (0.026 mole) of 2-bromo-5-(2-methoxy-4-nitrophenyl)thiophene, 13.9 g (0.1 mole) of sodium trifluoroacetate and 9.7 g (0.05 mole) of copper(I)iodide in 160 ml of dry N,N-dimethylacetamide was heated at 175° C. for four hours. The reaction mixture was cooled to room temperature then poured into 400 ml of 2N hydrochloric acid and ice (approximately 1:1). Methylene chloride was added and the resultant mixture filtered. The filtrate separated into two phases. The organic phase was separated then washed with three portions of 2N hydrochloric acid and one portion of water. The washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to leave a residue. The residue was subjected to column chromatography on silica gel, eluting with toluene, to yield 1.8 g of a mixture of 2-(2-methoxy-4-nitrophenyl)-5-trifluoromethylthiophene and 2-(2-methoxy-4-nitrophenyl)thiophene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20](=O)[CH2:21][CH3:22]>>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[CH2:20][CH2:21][CH2:22][CH2:8][CH2:5][CH2:6][CH2:7][CH2:2][CH:3]=[CH2:4]
Reactant: CCC(C)=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCCCCCCCCOc1ccc(CC(=O)OC)cc1

Procedure:
A solution of methyl (4-hydroxyphenyl)ethanoate (7.50 g, 45 mmol)1-bromoudec-10-ene (10 g, 43 mmol) and potassium carbonate (7.50 g, 54 mmol) in butanone (250 ml) was heated under reflux (12 h). The solvent was removed in vacuo to yield a pale yellow oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[N:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:28]([C:18]1[CH:17]=[C:16]([NH2:15])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[CH:22]=2)[N:19]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
DIAD (847 μL, 4.32 mmol) was added slowly to a solution of 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenol (for reference procedure see US 2006/35922, which is incorporated herein by reference in its entirety; 500 mg, 2.16 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (439 μL, 3.25 mmol), and triphenylphosphine (1.13 g, 4.32 mmol) in THF (10.0 mL) and stirred for 72 h. The reaction mixture was partitioned between EtOAc (75 mL) and H2O (75 mL), and the aqueous layer extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo. Purification by FCC, using 5-60% EtOAc in cyclohexane, gave semi-pure title compound (1.26 g). This was used in the next reaction without further purification. LCMS (Method 4): Rt 2.77, m/z 360 [MH+].
Reaction SMILES: Cl[C:2]1[C:11]([I:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=[O:15])C>O>[I:12][C:11]1[C:2](=[O:15])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)O
Reactant: Clc1nc2ccccc2cc1I
Solvent: O
Product: O=c1[nH]c2ccccc2cc1I
Temperature: 25 °C

Procedure:
The 2-chloro-3-iodoquinoline (30.0 g) was weighed into a 250 mL flask and suspended in of 50% aqueous acetic acid (125 mL). The mixture was heated to 100 C and allowed to reflux for 16 h to completion by TLC analysis of the crude reaction mixture. The mixture was allowed to cool to ambient temperature followed by dilution with 200 mL of water. The resulting a suspension of the desired product was isolated by vacuum filtration follows by washing with water (50 mL). The water and traces of acetic acid were removed under vacuum for 5 h to afford the desired quinolinone as a tan powder (5-5, 26.5 g, 94%); 1H NMR (500 MHz, CDCl3) δ 12.13 (br s, 1H), 8.71 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.54 (m, 1H), 7.31 (d, 1H, J=8.0 Hz), 7.20 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CCN(CC)CC.Cl.CN>CN(C)C=O>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a stirred solution of 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (600.0 mg, 1.36 mmol) in dimethylformamide (10 mL) were added HBTU (O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (772.74 mg, 2.04 mmol) and triethylamine Et3N (0.942 mL, 6.78 mmol). The mixture was stirred for 30 min., then methylamine hydrochloride salt (274.88 mg, 4.07 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and then extracted with ethyl acetate. Then combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-02) (140.0 mg, 22.64%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: COCC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 33 %

Procedure:
According to the procedure for compound 398 using methoxyacetyl chloride (50 mg, 0.46 mmol) afforded 8.6 mg (33% yield) of 481, as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.B.O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1CO
Yield: 95 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (10.75 g) in tetrahydrofuran (50 ml) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 150 ml) by syringe under nitrogen atmosphere at 5° C. and the mixture was heated under reflux for 18 hours. After cooling, water (50 ml) and potassium carbonate (20 g) were added to the solution at 5° C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-bromo-2-methylbenzyl alcohol (9.55 g). This compound was used to the next reaction without further purification.
Reaction SMILES: [N+](C1N(CCOC(=O)C)C(C2N3N=C([Cl:24])C=CC3=NN=2)=NC=1)([O-])=O.O1CCOCC1.CNC.[N+:34]([C:37]1[N:41]([CH2:42][CH2:43][O:44]C(=O)C)[C:40]([C:48]2[N:52]3[N:53]=[C:54]([N:57]([CH3:59])[CH3:58])[CH:55]=[CH:56][C:51]3=[N:50][N:49]=2)=[N:39][CH:38]=1)([O-:36])=[O:35]>CO>[ClH:24].[N+:34]([C:37]1[N:41]([CH2:42][CH2:43][OH:44])[C:40]([C:48]2[N:52]3[N:53]=[C:54]([N:57]([CH3:59])[CH3:58])[CH:55]=[CH:56][C:51]3=[N:50][N:49]=2)=[N:39][CH:38]=1)([O-:36])=[O:35]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N(C)C)nn12
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Agent: CNC
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3CCO)n2n1
Product: Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5 g. crude 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-chloro-s-triazolo[4,5-b]pyridazine were dissolved in 50 ml. of a mixture of dioxan and methanol (1:1), 5.4 ml. 40% aqueous dimethylamine were added thereto, the reaction mixture was stirred for 1 hour at 60° C., evaporated almost completely, the residue triturated with 20 ml. isopropanol, 1.6 g. of solid substance being obtained which has a melting point of 164° - 167° C. After recrystallization thereof from 55 ml. isopropanol, with the addition of charcoal, there was obtained 1 g. 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-dimethylamino-s-triazolo[4,3-b]-pyridazine in the form of green-yellow crystals with a melting point of 172° - 174° C. After hydrolysis of 0.4 g. of this substance with 8 ml. 2N hydrochloric acid (90 minutes at 50° C.), the desired compound can be obtained by evaporating the hydrochloric acid solution in a vacuum at 50° C., taking up the residue with 5 ml. water, adjusting to pH 8 - 9 with concentrated aqueous ammonia, filtering off with suction the crystals obtained, washing with water and drying for 2 hours at 120° C. There was thus obtained 0.32 g. 3-(5-nitro-1-β-hydroxyethyl-2-imidazolyl)-6-dimethylamino-s-triazolo[4,3-b]pyridazine, which has a melting point of 220° - 222° C.