Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:34]([O:36]C)=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.CNC.[NH:58]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:59]([C:75]([OH:77])=O)[CH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.C(Cl)(Cl)Cl.CO>[NH:58]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:59]([C:75]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:34]([OH:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:8][CH:9]=1)=[O:77])[CH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:65]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:66]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
To a solution of Fmoc-Tyr(tBu)-Lys(Z)-OMe (7.72 g, 10.49 mmol) in THF (105 mL), was added dimethyl amine (52.5 mL, 2 M, 104.9 mmol). This reaction was allowed to reach room temperature and stirred for 1.5 h. At this time, the reaction mixture was concentrated in vacuo. To the yellowish solid, was added DCM (225 mL) and DMF (45 mL). To this solution, was added Boc-Lys(Z)—OH (4.19 g, 11.01 mmol), then HOBt (1.488 g, 11.01 mmol), then EDC.HCl (2.112 g, 11.01 mmol). This solution was allowed to stir for 8 h at which time the organic solution was washed with 1 N HCl (3×100 mL), then saturated NaHCO3 (3×100 mL), and finally H2O (3×100 mL). The organic layer became jelly like and MeOH was added to break the gel. The organic layer was dried over MgSO4 and concentrated in vacuo to yield a white solid. Column chromatography (0-1% MeOH, CHCl3) afforded the product (5.51 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[K]>>[Cl:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[C:4]2[C:3]=1[N:14]([CH:15]1[CH2:17][CH2:16]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1ccc(F)c(Cl)c1F
Agent: [K]
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O

Procedure:
Reaction of 3-chloro-2,4-difluoro-benzoyl chloride with diethyl malonate gives diethyl (3-chloro-2,4-difluoro-benzoyl)-malonate, and partial hydrolysis and decarboxylation lead to ethyl (3-chloro-2,4-difluoro-benzoyl)-acetate, which is reacted with ethyl orthoformate/acetic anhydride to give ethyl 2-(3-chloro-2,4-difluorobenzoyl)-3-ethoxy-acrylate; further reaction with cyclopropylamine leads to ethyl 2-(3-chloro-2,4-difluoro-benzoyl)-3-cyclopropylaminoacrylate, which is cyclized with potassium carbonateldimethylformamide to give ethyl 8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate; hydrolysis then finally leads to the corresponding carboxylic acid. The reaction sequence described can be represented by the following equation: ##STR4## The quinolonecarboxylic acid obtained in the 6th stage can be converted by reaction with compounds Z--H of the formulae ##STR5## wherein R1 represents hydrogen, straight-chain or branched C1 -C3 -alkyl or cyclopropyl,
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:22]([C:26]1[N:27]=[CH:28][C:29]([C:32]([NH:34][C:35]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][C:36]=2[F:50])=[O:33])=[N:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:22]([C:26]1[N:27]=[CH:28][C:29]([C:32]([NH:34][C:35]2[CH:40]=[C:39]([C:2]3[CH:3]=[C:4]([NH:9][C:10]4[N:11]=[N:12][C:13]([C:16]5[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=5)=[CH:14][CH:15]=4)[C:5](=[O:8])[NH:6][N:7]=3)[CH:38]=[CH:37][C:36]=2[F:50])=[O:33])=[N:30][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cnc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cn1
Reactant: O=c1[nH]nc(Cl)cc1Nc1ccc(-c2ccncc2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cnc(C(=O)Nc2cc(-c3cc(Nc4ccc(-c5ccncc5)nn4)c(=O)[nH]n3)ccc2F)cn1
Temperature: 120 °C
Yield: 49 %

Procedure:
A 15-mL pressure tube equipped with a magnetic stirrer and screw cap with a septum was charged with 6e (90 rug, 0.30 mmol), 6f (156 mg, 0.39 mmol), sodium carbonate (95 mg, 0.90 mmol), water (0.5 mL), 1,4-dioxane (1.8 mL), and DMF (0.9 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) was added; the tube was sealed, and the reaction mixture was heated for 16 h in a 120° C. bath. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and water (5 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 49% yield (79 mg) of 6g as an off-white solid: mp>300° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.45 (s, 1H), 9.93 (s, 1H), 9.25 (s, 1H), 9.04 (s, 1H), 8.95 (s, 1H), 8.74 (d, 2H, J=3.3 Hz), 8.54 (d, 1H, J=4.2 Hz), 8.33 (d, 1H, J=5.7 Hz), 8.10 (d, 2H, J=3.0 Hz), 8.02 (d, 1H, J=5.4 Hz), 7.69 (m, 1H), 7.53 (m, 1H), 1.43 (s, 9H); MS (ESI+) m/z 538.2 (M+H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:12]=[C:11]([CH2:13][CH:14]=O)[CH:10]=[CH:9][C:6]=2[C:7]#[N:8])[CH2:3][CH2:2]1.[N:16]1([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([O:4][C:5]2[CH:12]=[C:11]([CH2:13][CH2:14][N:19]3[CH2:20][CH2:21][N:16]([CH2:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]5[C:28](=[O:31])[O:29][CH2:30][C:26]=5[CH:25]=4)[CH2:17][CH2:18]3)[CH:10]=[CH:9][C:6]=2[C:7]#[N:8])[CH2:2][CH2:3]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: N#Cc1ccc(CC=O)cc1OC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1OC1CC1

Procedure:
A solution of crude 2-(cyclopropyloxy)-4-(2-oxoethyl)benzonitrile (80 mg, 0.4 mmol), 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (150 mg, 0.6 mmol) and NaBH(OAc)3 (400 mg, 2 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(cyclopropyloxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.11 (s, 1H), 6.78˜6.80 (m, 1H), 5.22 (s, 2H), 2.42˜2.93 (m, 17H), 0.77˜0.80 (m, 4H). (0.28 μM)
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[OH:24][CH2:23][C@@H:22]1[CH2:26][C@@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2CO)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To 2 1 of tetrahydrofuran (THF) was added 57.6 g (1523 mmol) of sodium borohydride and the mixture was cooled to 10° C. before 250 ml (1980 mmol) of borontrifluoride etherate was added dropwise over a period of 1 hour. Then 215.3 g (755.4 mmol) of 1-(4-toluenesulfonyl)-4-hydroxy-L-proline was added carefully in 100 ml of THF and the mixture was allowed to stir for 16 hours. The reaction was quenched with methanol and 10% aqueous hydrogen chloride solution was added and the mixture was gently heated to 60° C. for 1 hour. The reaction mixture was filtered and the pH was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 164 g of the product as a white solid in 85 % yield. M.P. 132°-133° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (214 mg, 0.921 mmol), 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (556 mg, 2.76 mmol) and triphenylphosphine (483 mg, 1.841 mmol) in Tetrahydrofuran (THF) (10 mL) was added by drop wise DEAD (0.291 mL, 1.841 mmol). The solution was let stir at room temp. After 2 hr the reaction was concentrated and purified by silica gel chromatography to afford 1,1-dimethylethyl 4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (330 mg, 86% yield) as a white solid
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][N:17]=1.Cl>C1COCC1>[F:15][C:16]1[N:17]=[CH:18][C:19]([CH:20]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[OH:21])=[CH:22][CH:23]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)nc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Magnesium turnings (0.214 g, 8.79 mmol) in a minimal amount of THF were treated with 1,2-dibromoethane (50 μL, cat.) and the mixture was allowed to stand until effervescence was observed (1 min). A solution of 4-bromothioanisole (Aldrich) (1.705 g, 8.39 mmol) in THF (20 mL) was added dropwise and the mixture stirred for 2 h, occasionally heating to gentle reflux with a heat gun, to give a cloudy pale yellow solution. The resulting Grignard solution was added dropwise over 10 min to a solution of 6-fluoronicotinaldehyde (Frontier Scientific) (1.000 g, 7.99 mmol) in THF (10 mL) cooled in a dry ice/acetone bath. The mixture was stirred at −78° C. for 30 min, and then quenched by dropwise addition of 2N aqueous HCl (9.0 mL, 2 equiv.). The cooling bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was extracted into EtOAc from water, dried (MgSO4) and concentrated to give (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (1.856 g, 7.44 mmol, 93% yield) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H); 7.87 (t, J=8.22 Hz, 1H); 7.32 (d, J=8.02 Hz, 2H); 7.22 (d, J=7.82 Hz, 2H); 7.11 (d, J=8.41 Hz, 1H); 6.11 (br. s., 1H); 5.78 (s, 1H); 2.44 (s, 3H). m/z (ESI, +ve) 250.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])(=[O:4])=[O:3].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][S:2]([NH:5][CH2:6][C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[C:15]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[S:14][C:13]=12)=[O:8])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NCC(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CNS(C)(=O)=O)c2s1
Reaction time: 1.5 h

Procedure:
7-Methanesulfonylaminoacetylimidazo[5,1-b]thiazole (46.2 mg) was dissolved in 2 ml of THF and 0.4 ml of HMPA. Tri-n-butylstannyl chloride (0.076 ml) and 0.713 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order to the solution in an argon atmosphere at −70° C. The mixture was stirred at the same temperature for 1.5 hr. A 1.59 Nn-butyllithium/n-hexane solution (0.146 ml) was added dropwise thereto. The mixture was stirred at the same temperature for one hr. A 1.59 N n-butyllithium/n-hexane solution (0.146 ml) and 0.076 ml of tri-n-butylstannyl chloride were added dropwise thereto. The mixture was stirred at the same temperature for 45 min. An ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 37.5 mg of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][S:13](=S)(OC)=O>O.C(O)C.CCOCC>[CH3:12][S:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1S
Reactant: COS(C)(=O)=S
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CSSc1ccccc1CC(=O)O
Reaction time: 20 h
Yield: 100.7 %

Procedure:
To a solution of (2-mercaptophenyl)acetic acid (449 mg) in H2O (15 mL) and ethanol (7 mL) was added methyl methanethiosulfonate (372 mg, 2.93 mmol). After stirring for 20 hours, the reaction mixture was diluted with ether and washed with 1 N KOH twice. The water layers were combined and acidified to pH 2 with 5 N hydrochloric acid. This solution was extracted with CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford 576 mg (100% yield) of the (2-methyl disulfanylphenyl)acetic acid product in the form of a yellow oil: 1H NMR (400 MHz, CDCl3) δ (ppm): 2.42 (s, 3H), 3.92 (s, 2H), 7.10-7.40 (m, 3H), 7.80 (d, J=7.6 Hz, 1H), 10.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 22.7, 38.9, 127.8, 128.1, 128.3, 128.8, 130.4, 130.8, 130.9, 177.1. HRMS (EI): m/e calcd. for C9H10O2S2: 214.012223, Found: 214.012637 (Δ=−1.9 ppm).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]#[N:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(C#N)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 92.7 %

Procedure:
To a solution of 1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (500 mg, 1.91 mmol) in DMF (4 mL) was added cyanuric chloride (0.267 mL, 1.91 mmol) at 0° C., and the mixture was stirred at 0° C. for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give 1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (430 mg, 1.77 mmol, 92%) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:27].Cl.CC(O)=O>C(Cl)Cl.CO>[CH2:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:11]2([CH2:10][C:9](=[O:27])[C:8]3[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=3)[O:23]2)[CH2:12][CH2:13]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2

Procedure:
(±)-(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester was obtained starting from the hydrochloride salt of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (500 mg, 1.43 mmol, Intermediate 3) and ethyl chloro formate (0.163 ml, 1.70 mmol), according to the procedure described in Example 24, Step A, giving a yellow solid (540 mg, 97%). (±)-(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (530 mg, 1.37 mmol) was hydrolyzed using HCl and AcOH following the procedure described in Example 22, Step A. (±)-(E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid was obtained after column chromatography (eluent DCM/MeOH 9:1) as a white solid (101 mg, 21%). Hydrolysis of the carbamate function was not observed. The acrylic acid (100 mg, 0.26 mmol) was then treated with NH2OTHP according to the procedure described in Example 22, Step C, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (82 mg, 65%). Finally, removal of THP protecting group following the procedure described in Example 22, Step D gave (±)-(E)-3-[1′ethyloxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide (12.8 mg) as a light yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[C:13]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:24][CH2:25][O:26][C:27]([C:29]([CH2:31]Br)=O)=[O:28]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:19][CH:31]=[C:29]([C:27]([O:26][CH2:25][CH3:24])=[O:28])[N:18]=4)=[C:13]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Temperature: 100 °C

Procedure:
6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide (20) (30 mg, 0.08 mmol) and ethyl bromo pyruvate (0.17 mmol, 2 equiv.) were taken in DMF (5 mL) and heated at 100° C. for 3 h. The reaction mixture was then concentrated under reduced pressure to remove excess of DMF. The residue was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc twice. The organic layers were collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH:CHCl3 as eluent to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=20.00 Hz, 6H), 1.43 (t, J=7.20 Hz, 3H), 3.75-3.77 (m, 1H), 4.41 (q, J=7.20 Hz, 2H), 6.16 (s, 1H), 7.54 (dd, J=2.00, 8.8 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.21 (s, 1H), 8.43 (s, 1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 2.131 min; LCMS (ES-API), m/z 440.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.409 min; Purity: 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=[O:19])[C:11](=[N:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1.O.[C:21](O)(=[O:23])[CH3:22]>C(OC(=O)C)(=O)C.[Zn]>[C:21]([NH:17][CH:11]([C:10](=[O:19])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=NO)C(=O)CCc1cccc(Cl)c1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from step (ii) in acetic acid (125 ml) and acetic anhydride (40 ml) was added zinc dust (45 g) portionwise at a rate to maintain the internal temperature <40° C. The mixture was stirred for 30 min and water (125 ml) was added at such a rate as to maintain the temperature at around 40° C. The mixture was stirred at room temperature for 2 hours and filtered. The mother liquor was extracted with dichloromethane and further washed with water. The organic layer was collected, dried (MgSO4) and solvent evaporated under reduced pressure to give the subtitle product.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[O:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:16][S:13]([C:10]1[O:9][C:8]([CH2:6][OH:5])=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)o1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(CO)o1
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-methanesulfonyl-furan-2-carboxylic acid ethyl ester (1.26 g) in THF (57.0 mL) was treated at −78° C. with DiBAL-H (19.50 mL of a 1M solution in THF, 19.50 mmol) and the reaction mixture was stirred at this temperature for 2 h. The reaction mixture was poured on Rochelle's salt (100 mL) and stirred at rt for 12 h. The aq. layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (30:70 hept-EA) gave the title compound as a yellow oil: TLC:rf (30:70 hept-EA)=0.28. LC-MS-conditions 02: tR=0.50 min.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH:24]=[O:25])=[C:16]([F:21])[CH:15]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cc(Br)cc1F
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of diisopropylamine (194.4 mmol) in tetrahydrofuran (350 mL) was cooled in an ice/water bath as n-BuLi (69.5 mL of a 2.5 M solution in hexanes) was added slowly via syringe. After 30 minutes, the solution was cooled in a dry ice/acetone bath as 1-bromo-3,5-difluorobenzene (173.7 mmol in 50 mL of tetrahydrofuran) was added gradually over the course of 25 minutes. After stirring for 30 minutes, dimethylformamide (208.4 mmol) was added gradually to the reaction mixture over the course of 30 minutes. After stirring for 2 hours more in the cooling bath, acetic acid (35 mL) was added, the cooling bath removed, and water (500 mL) was added. The reaction mixture was then extracted with ether (1 L), and the organic phase was washed with 1 N HCl (250 mL), brine, dried over magnesium sulfate and filtered. After condensing the organic phase with a rotary evaporator, the resulting brown solid was tritrated with hexanes before filtration to afford the title compound (I-1a) as a colorless solid (37.8 g).