Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:49](=[O:50])C1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[C:49]3=[O:50])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCCNc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc([N+](=O)[O-])cc3)Cc3ccccc3)c2c1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN(CCCCc4ccc([N+](=O)[O-])cc4)Cc4ccccc4)c3c2)C1=O
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a solution of N-[3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N′-ethyl-ethane-1,2-diamine (20 mg in 3 mL dry methylene chloride) at 0° C. was added 9.6 mg N,N′-disuccinimidyl carbonate followed by triethylamine (0.110 mL of a 10% solution in methylene chloride) and the mixture stirred at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to provide the crude title compound (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(Cl)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 2,5-dichlorophenol (10 g, 61.3 mmol) in CCl4 (400 mL) at 0° C. was dropwise added 4.7 mL (73.6 mmol) of 70% HNO3 in 30 mL of CCl4 during 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The yellow precipitate was collected by filtration and dried to give the desired product (8.4 g) at 62% yield. MS (DCI/NH3) m/z 224.91 (M+NH4)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 7.17 (s, 1 H) 8.25 (s, 1 H) 12.12 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@:8]2([CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:10]2)[CH2:7][N:6]1[C:22](=[O:36])[C@@H:23]([NH:28]C(OC(C)(C)C)=O)[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:28][C@@H:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]([N:6]1[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:9][C@@:8]2([CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:10]2)[CH2:7]1)=[O:36]
Reactant: COC(=O)[C@@H]1C[C@@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)[C@@H](N)C(C)(C)C

Procedure:
The compound (3S,5R)-methyl-2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (C7a) (36.9 mg, 70.6 pimp was dissolved in CH2Cl2 (1.0 ml) and treated with trifluoroacetic acid (0.3 ml) for 6 hrs at room temperature. The reaction was concentrated to dryness to give (3S,5R)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (D7a) (70.6 μmol). The minor diastereomer (3S,5S)-methyl-2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-7-(3-chloro phenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (C7b) (9.4 mg, 18 μmol) was treated similarly to give (3S,5S)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (D7b) (18 μmol, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:25][NH:26][O:27][CH3:28]>O1CCCC1>[CH3:28][O:27][N:26]([CH3:25])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)acetic acid (8.75 g, 0.05 mol) in tetrahydrofuran (150 mL) was added CDI (11.34 g, 0.07 mmol) at 0° C. The formed mixture was stirred for 1 h. Then N,O-dimethylhydroxylamine (6.8 g, 0.07 mol) and TEA (8 mL) were added to the above mixture. The mixture was stirred at rt overnight. When the reaction was over, the mixture was concentrated. The residue was washed with 1 N aq HCl and aq. NaHCO3 (3×). The combined organic phase was concentrated to give crude product, which was used for next step without purification. 1H NMR (400 MHz, CDCl3): δ=1.42 (s, 9H), 3.16 (s, 3H), 3.66 (s, 3H), 4.04 (s, 2H), 5.22 (s, 1H).
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.O.[NH2:21][NH2:22]>C(O)C>[C:8]1([C:6]2[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:2]([SH:1])[NH:22][N:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C(=C1SCS1)c1ccccc1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Sc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a suspension of 2-(1,3-dithietan-2-ylidene)-1,2-diphenylethanone (1.88 g, 6.61 mmol) in ethanol (50 mL) was added hydrazine hydrate (0.496 g, 9.92 mmol). The reaction was refluxed for 16 h, cooled to room temperature and concentrated. The residue was neutralized with HCl (1.0 M) to pH 6-7 and extracted with EtOAc/H2O. The organic extract was dried over MgSO4 and concentrated to give the title compound (1.5 g). LCMS m/z=253.4 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 4.01-4.19 (m, 1H), 6.92-7.58 (m, 10H).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O>>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH2:2][CH3:3])=[O:11]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(F)c(F)c1
Yield: 56 %

Procedure:
Using ethylamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids (Scheme C), the title compound was obtained (56% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.24, 5.56 Hz, 2 H) 7.55 (dt, J=10.48, 8.40 Hz, 1 H) 7.73 (m, J=7.33, 4.74, 2.08, 1.14, 1.14 Hz, 1 H) 7.88 (ddd, J=11.75, 7.83, 2.15 Hz, 1 H) 8.58 (t, J=4.93 Hz, 1 H). ESI-MS: m/z 186.1 (M+H)+. mp=94.1-96.2° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:55][C:56]1[CH:57]=[C:58]([C:63]([CH3:68])([CH3:67])[C:64](=[O:66])[CH3:65])[CH:59]=[CH:60][C:61]=1[Cl:62]>CO.C(Cl)Cl>[Br:1][CH2:65][C:64](=[O:66])[C:63]([C:58]1[CH:59]=[CH:60][C:61]([Cl:62])=[C:56]([Cl:55])[CH:57]=1)([CH3:68])[CH3:67]
Reactant: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 91.7 %

Procedure:
Tetrabutylammonium tribromide (20.4 g, 41.5 mmol) was added to a solution of 3-(3,4-dichlorophenyl)-3-methylbutan-2-one (9.60 g, 41.5 mmol) in MeOH-DCM (160 mL, 1:2, v/v). After stirring 24 h, the reaction mixture was concentrated under reduced pressure and then combined with EtOAc (80 mL). The organic layer was washed with H2O (50 mL), 1N HCl (50 mL), and H2O (20 mL) successively. The organic layer was washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography afforded 1-bromo-3-(3,4-dichlorophenyl)-3-methylbutan-2-one (11.8 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.38 (d, 1H), 7.08 (d, 1H), 3.86 (s, 2H), 1.56 (s, 6H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[CH:2]=[CH2:3].[OH-].[Na+].[CH2:15](Cl)[CH:16]=[CH2:17]>C(O)CC>[CH2:17]([C:8]1[CH:9]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[OH:10])[CH:16]=[CH2:15]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: C=CCc1cc(CC=C)c(O)c(OC)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To the solution of 162.4 g (1 mol) of 4-allyl-2-methoxyphenol (Eugenol) in 500 ml of 1-propanol heated to 70° C., 40 g (1 mol) of NaOH pellets are added and the mixture is stirred at 90° C. until NaOH is dissolved. The solution is cooled to 70° C. and 95.6 g (1.25 mol) of allyl chloride are added dropwise. After that, the reaction mixture is refluxed at 90° C. for 3 hours, then filtered, and propanol distilled off. 500 ml of toluene are added to the residue and the obtained solution is washed with 10% NaOH in water. The toluene-water mixture is distilled off and 6.5 g of LiCl and 1.6 g of Na2CO3 are added. The reaction mixture is heated to 130° C. under vacuum and kept at this temperature for 1 hour, then filtered and distilled under vacuum. The product 2,4-diallyl-6-methoxyphenol is off-white, low viscosity liquid (viscosity is 7 cPs at 25° C.) having a boiling point of 109°-112° C. (2-3 mm Hg), the structure is confirmed by IR and NMR Data. Yield is 163 g (80%).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][CH:18]([CH3:21])[C:19]#[CH:20]>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:17][CH:18]([CH3:21])[C:19]#[C:20][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)C
Reactant: OCc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C#Cc1ccc(CO)cc1
Reaction time: 0.17 h

Procedure:
4-Iodobenzyl alcohol (1.00 g) was dissolved in DMF (17 mL), added with copper (1) iodide (97.7 mg), triethylamine (0.89 mL), and 3-methyl-1-butyne (1.27 mL), and stirred for 10 minutes in argon atmosphere. Subsequently, it was added with bis(triphenylphosphine)palladium (II) chloride (300 mg) and stirred for 4.3 hours at room temperature in argon atmosphere. After filtration through Celite, it was washed with ethyl acetate and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (6 to 40% ethyl acetate/hexane) to obtain the title compound as a yellow oil.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH:12]([NH:20]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])([O-:3])=[O:2].N1CCCCC1>CC#N>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH:12]([NH2:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[O:9])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)C(COC(=O)CCCO[N+](=O)[O-])NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(N)COC(=O)CCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69.8 %

Procedure:
To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate 1.26 g, 2.45 mmol) in CH3CN (15 ml), piperidine (1.21 ml, 12.2 mmol) was added in the dark, the reaction was stirred at room temperature for 25 min. Then the mixture was concentrated to a small volume and diluted with EtOAc (80 ml) and washed with 5% aqueous NaHPO4. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH 98:2 as eluent) yielding the title compound (0.500 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[NH:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19]CC)=O)=[C:4]([F:24])[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>CN(C)C=O.C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:17](=[O:19])[CH:16]=[C:15]([CH3:22])[N:14]([CH3:31])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)/C=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C
Reaction time: 1 h

Procedure:
A solution of 9.00 g of ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-crotonate in 100 ml of anhydrous dimethylformamide is added dropwise at room temperature while stirring to a solution of 1.10 g of a 55% sodium hydride dispersion in 100 ml of isopropanol/dimethylformamide (1:1) and stirred for 1 hour. The reaction mixture is subsequently treated with 4.70 g of dimethYl sulphate and stirred at room temperature for 2 hours. The solvent is largely distilled off under reduced pressure and the residue is poured into 500 ml of water and extracted twice with 200 ml of ethyl acetate each time. The organic phases are washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6 -dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][N:4]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(C)cc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ncc(CBr)cc1[N+](=O)[O-]
Yield: 67.2 %

Procedure:
To a well stirred solution of 2-methoxy-5-methyl-3-nitro-pyridine (8.4 g, 0.05 mol) in carbon tetrachloride (100 mL), benzoyl peroxide (3.5 g, 0.015 mol) and N-bromosuccinimide (17.8 g, 0.1 mol) were added. The reaction mixture was heated at reflux for 48 h under N2 atmosphere. After cooling, the mixture was evaporated. The residue was diluted with saturated aq. Na2CO3 (200 mL) and extracted (3×50 mL CH2Cl2). The combined extracts were washed with brine, dried on MgSO4, and filtered to yield an orange oil-like solid (8.3 g). Purification by chromatography over silica gel eluting with EtOAc/Petroleum ether (0:1 to 1:99 v/v) afforded product as a pale yellow solid. (4.1 g, 43%). 1H-NMR (CDCl3): δ 4.15 (s, 3H, OCH3), 4.51 (s, 2H, CH2), 8.34 (d, 1H, J=2.4 Hz, Py-H), 8.43 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (CDCl3): δ 27.72, 55, 17, 127.18, 133.66, 135.67, 151.40, 156.30.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C@@H:7]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nc(N[C@@H](C)C3CCCCC3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1nc2ccc(O)cc2s1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To the solution of (S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine (3.39 g, 10 mmol) in 30 ml of DCM was added 1 M boron tribromide in DCM (20 ml, 20 mmol) slowly at 0° C. The reaction solution was stirred at 0° C. then at RT for 2 hr. The reaction mixture was concentrated to a solid. To the residual solids add 400 ml of ethyl acetate and 90 ml of water and stir at RT. for 10 minutes. With stirring, carefully add excess solid NaHCO3 until basic. Stir at RT about 1 hour to dissolve the solids. Remove the aqueous layer and extract with 100 ml of ethyl acetate. Combine organic layers and wash with 1×50 ml water, 1×50 ml saturated NaCl solution, dry with sodium sulfate, filter and concentrate under reduced pressure. The resulting solid was purified by silica gel column chromatography, eluted with (30% EtOAc: 70% Hexanes) and concentrated in vacuo to give (S)-2-(1-cyclohexylethylamino)benzo[d]thiazol-6-ol as solid (2.0 grams). ES/MS m/z 277.1 (MH+).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>C(#N)C>[CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][Cl:13]
Reactant: O=c1cc(CO)occ1O
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=c1cc(CCl)occ1O
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A 2-liter 3-neck round bottom flask was equipped with a mechanical stirrer. The flask was charged with kojic acid (0.25 kg, 1.759 mol) and 750 ml acetonitrile at 0° C. The kojic acid was insoluble in acetonitrile and stayed as a suspension. Thionyl chloride (140 ml, 1.919 mol) was added dropwise via a dropping funnel at ice bath temperature. The solid slowly dissolved to give a red clear solution. After 15 minutes, a white solid appeared. After 3 hrs at 0° C., the insoluble solid was filtered. The solid was filtered by suction filtration. The solid was mixed with water (0.5 L) and then filtered. The acetonitrile mother liquor was reduced to 15% of the original volume and filtered. The solid was washed with water (200 ml) and then acetonitrile (50 ml). The combined solid was dried to constant weight. (269 g, 95.2% yield). M.p. 166-168° C. [lit value 166-167° C.]. 1H-NMR (DMSO-d6) δ: 4.66 (s, 2H, CH2Cl), 6.57 (s,1H, CH), 8.12 (s, 1H, CH), 9.3 (br. s, 1H, OH).
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=O)[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[NH:11][C:10](=[S:39])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=S
Temperature: 110 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
2-Cyclohexyl-8-(2-o-tolyl-ethanesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (24.2 mg, 0.058 mmol), Lawesson's reagent (48.3 mg, 0.116 mmol) and toluene (1.16 ml) were added to a sealed test tube and stirred at 110° C. overnight. The reaction mixture was cooled to ambient temperature, and the solvent was then distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2-MeOH) to give 2-cyclohexyl-8-(2-o-tolyl-ethanesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-4-thione (11.2 mg, 45%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:15]O>N1C=CC=CC=1.C(O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:12]#[N:15])[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1csc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCc1csc(C#N)c1
Yield: 84.5 %

Procedure:
A mixture solution of 4-hexylthiophene-2-carbaldehyde (11.8 g, 60.0 mmol) and hydroxylamine hydrochloride salt (6.3 g, 90 mmol) in pyridine/ethanol (60 mL, 1/1 v/v) was stirred at 80° C. overnight. Then the solvent was removed and the residue was dissolved in chloroform (100 mL). The solution was washed with distilled water (2×50 mL) and dried over anhydrous magnesium sulphate. The solvent was removed and the viscous liquid residue was refluxed in acetic anhydride (30 mL) containing potassium acetate (0.2 g) for 3 h. Then the mixture was poured into distilled water (100 mL) and extracted with hexanes (3×50 mL). The combined organic phase was washed three times with water (50 mL), dried over anhydrous magnesium sulfate before the solvent was removed by rotary evaporation. The yellow liquid residue was purified by silica-gel column chromatography (EtOAc/hexane=7/93, v/v, Rf=0.4) to yield a clear light yellow liquid product. (9.8 g, 84.5% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.43 (d, 1H, J=1.4 Hz); 7.17 (d, 1H, J=1.4 Hz); 2.60 (t, 2H, J=8.0 Hz); 1.59 (m, 2H); 1.22-1.36 (m, 6H); 0.87 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 144.04, 138.22, 127.41, 114.48, 109.28, 31.45, 30.18, 29.86, 28.67, 22.46, 13.96. HRMS EI calcd for C11H15S 193.0925, found 193.0915.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([C:20]#[CH:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:27]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:27])[CH:16]([C:20]#[CH:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Reactant: C=O
Solvent: O=CO
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1C

Procedure:
A mixture of 200 mg of 1-cyclopropyl-7-(3-ethynyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.3 ml of 90% formic acid and 0.24 ml of 37% formalin is heated for 2 hours, then evaporated. The residue is diluted with water, nuetralized to pH 7 with 1N sodium hydroxide, the solid collected, and washed with water, ether and dried in vacuo, giving 156 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:66])[CH3:65])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:48][C:49]3[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:65])[CH3:66])[CH:59]=4)[CH:52]=[CH:53][C:54]=3[CH3:55])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (350 mg, 1.631 mmol), HATU (744 mg, 1.957 mmol) and DIPEA (0.809 mL, 4.89 mmol) in DMF (8 mL) was stirred for 15 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (538 mg, 1.631 mmol) was added and stirred overnight at rt. Quenched in citric acid solution (3%) and the resulting precipitate was collected. Triturating in acetonitrile gave the title compound 2-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 24 (450 mg, 56%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=1.9, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.49 (s, 1H), 8.89 (s, 1H), 10.38 (s, 1H), 10.59 (s, 1H). (m/z)=490 and 492 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:22])=[O:23]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Yield: 90.4 %

Procedure:
5 g (35.5 mmol) of 3-aminobenzoic acid and 8.3 g (36.5 mmol) of 2-naphthylsulfonyl chloride were reacted by the method of procedure 4b, affording 10.5 g (89%) of the product.