Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:17](=O)([O-])[O-:18].[K+].[K+].O.C1N=CN(C(N2C=NC=C2)=O)C=1>C(#N)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]2[C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][S:1][C:17]2=[O:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(CNC(CS)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)O)cc1
Temperature: 40 °C

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 3-mercapto-2-(4-methoxybenzylamino)-propionic acid (400.0 g, 1.66 mol), potassium carbonate (480.0 g, 3.47 mol) and 2.80 L of water. The mixture was heated at 40° C. with stirring until it became homogeneous and was then cooled to 20-25° C. A solution of N,N-carbonyldiimidazole (400.0 g, 222.47 mol) in 2.8 L of acetonitrile was added while maintaining an internal reaction temperature of less than 30° C. The reaction was monitored by HPLC and was complete upon the disappearance of starting material. The acetonitrile was removed by distillation at 40° C. and 80-100 torr. Iso-propyl acetate (200 mL) was added and the pH of the mixture was adjusted to 2 with 150 mL of 3M H2SO4. The biphasic mixture was filtered, separated and the organic layer azeotropically dried by distillation at atmospheric pressure. The final measured water content was less than 0.5%. The resulting solution was further diluted with 1.8 L of iso-propyl acetate and used in the next example. 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.3 Hz, 2H), 6.88 (d, 8.3 Hz, 2H), 4.52 (AB, JAB=15.5 Hz, ΔvAB=238.4 Hz, 2H), 4.31-4.24 (m, 1H), 3.71 (s, 3H), 3.67-3.59 (m, 1H), 3.36-3.28 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13]
Reactant: Cc1cc(=O)oc2ccc(O)cc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4oc(=O)cc(C)c4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 14.8 %

Procedure:
6-Hydroxy-4-methyl-chromen-2-one (238 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (165 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 3.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (24 mg, yield 5%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([OH:11])=O.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([Cl:15])=[O:11]
Reactant: O=C(O)[C@H]1C[C@@H]1c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (1.08 g, 6.45 mmol) in dichloromethane (50 ml) in an ice-bath was added oxalyl chloride (6.50 ml, 64.4 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 250 ml round-bottom flask was charged with {(R)-2-hydroxy-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide HCl (6.47 mmol), dichloromethane (60 ml) and triethylamine (4.30 ml, 32.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×30 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (1.42 g, 58% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (d, J=8.6 Hz, 2H), 7.09 (m, 1H), 6.91 (m, 3H), 6.82 (d, J=3.5 Hz, 1H), 6.23 (d, J=6.1 Hz, 1H), 5.06 (td, J=6.3, 4.3 Hz, 1H), 3.91 (m, 2H), 3.78 (m, 2H), 2.75 (m, 2H), 1.88 (m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C21H28NO3S 374.5].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CCN(CCO)CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(CCO)CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 19.3 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 2-[(3-chloro-propyl)-ethyl-amino]-ethanol (353 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM:MeOH:NH3) to give the title compound as a white solid (150 mg, 19%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.60-3.49 (m, 4H), 2.68 (t, 2H), 2.62 (t, 2H), 2.59 (q, 2H), 2.40 (s, 2H), 2.14-1.82 (m, 6H), 1.97 (s, 6H), 1.62 (br s, 1H), 1.03 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=C(CC(N[C@@H](C2C=CC=CC=2)C(N[C@H]2[C@@H](C3C=CC=CC=3)SCCNC2=O)=O)=O)C=C(F)C=1.[Br:59]C1C=C(C=O)SC=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([Br:59])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)NCCS[C@@H]1c1ccccc1)c1ccccc1
Product: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that the reaction product was passed through a Dowex ion exchange resin 50×2-200 and 4-bromo-2-thiphenecarboxaldehyde (955 mg) was used as the aldehyde component to afford the desired product (1.52 g ). 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 3H), 5.24 (s, 2H), 5.99 (br., 1H), 7.20-7.37 (m, 7H), 7.67 (s, 1H). LC/MS: 2.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([N:13]([CH:29]2[CH2:31][CH2:30]2)[C:14]([C@@H:16]2[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:15])[CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:37])=[N:5][N:6]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36].Cl.O1CCOCC1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C@H:11]([N:13]([CH:29]2[CH2:31][CH2:30]2)[C:14]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])[CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:37])=[N:5][N:6]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36].[Cl:1][C:2]1[CH:10]=[C:9]([C@@H:11]([N:13]([CH:29]2[CH2:31][CH2:30]2)[C:14]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])[CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:37])=[N:5][N:6]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36]
Reactant: COCCCn1nc(C)c2c(Cl)cc(C(C)N(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COCCCn1nc(C)c2c(Cl)cc([C@@H](C)N(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Product: COCCCn1nc(C)c2c(Cl)cc([C@H](C)N(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2R)-2-{[{1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}(cyclopropyl)amino]carbonyl}morpholine-4-carboxylate (146 mg) in chloroform (2.0 mL) was added 4-normal hydrogen chloride-dioxane solution (2.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then thereto was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol/ammonia water=500/10/1) to give (2R)-N-{(1R)-1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(4-1)] (50.2 mg) and (2R)-N-{(1S)-1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(4-2)] (18.4 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1([O:24][CH3:25])[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]2[N:7]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:6][CH2:5][C:4]=2[CH2:3]1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:21]1[CH:22]=[C:17]([NH:16][C:15]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([O:24][CH3:25])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=3)[CH2:5][CH2:6]2)=[O:23])[CH:18]=[N:19][CH:20]=1
Reactant: Cc1ccncc1B(O)O
Reactant: COC1(Br)CC2=C(C=C1C(F)(F)F)N(C(=O)Nc1cccnc1)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(-c3cnccc3C)c1)CC2
Yield: 66.7 %

Procedure:
1-[5-Bromo-(3-pyridylcarbamoyl]-5-methoxy-6-trifluoromethylindoline (D26) (0.3 g, 0.7 mmoles) and 4-methyl-3-pyridylboronic acid (0.12 g, 0.9 mmoles) was heated under reflux in dimethoxyethane (80 ml) and water (10 ml) with sodium carbonate (0.15 g, 1.4 moles) and palladium tetrakis triphenylphosphine (0.1 g, 12 mole %) under an inert atmosphere for 18 hours. After cooling the mixture was partitioned between ethyl acetate (250 ml) and water (200 ml). The organic layer was separated and washed with saturated sodium chloride solution then dried (Na2SO4). Evaporation of the solvent followed by flash chromatography on silica gel eluting with 3-7% MeOH/CH2Cl2 and recrystallisation from ethyl acetate/60-80 petrol gave the title compound (E35) (0.2 g, 65%) mp. 125-8° C.
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:7][CH:8]([C:13]([O:15]C)=O)[C:9]([O:11]C)=O)C.[O:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[NH:34])[CH2:28][CH2:27]1.CC[O-].[Na+].Cl.O1CCOCC1>CCO>[CH2:20]([O:19][C:17](=[O:18])[C@@H:5]([OH:4])[CH2:6][CH2:7][C:8]1[C:9]([OH:11])=[N:34][C:33]([NH:32][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[N:35][C:13]=1[OH:15])[CH3:21]
Reactant: N=C(N)NC1CCOCC1
Reactant: CCOC(=O)[C@H](CCC(C(=O)OC)C(=O)OC)O[Si](CC)(CC)CC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)[C@@H](O)CCc1c(O)nc(NC2CCOCC2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A solution of 398 (3.75 g, 9.46 mmol), 24 (1.63 g, 11.4 mmol), EtOH (30 mL) and NaOEt (3.86 g, 11.4 mmol) was heated to 85° C. and stirred overnight. The reaction was cooled to RT and quenched reaction by addition of 4N HCl in dioxane (2.37 mL, 9.46 mmol) and the solution concentrated. The crude product was purified by reverse phase chromatography (Biotage 40 M C18 using a C18 samplet loaded using water) eluting with a MeCH/H2O chromatography (0-60% MeCN) over 30 column volumes to afford 1.25 g (37%) of (S)-ethyl-4-(4,6-dihydroxy-2-(tetrahydro-2H-pyran-4-ylamino) pyrimidin-5-yl)-2-hydroxybutanoate (400): MS m/z (APCI-pos) M+1=342.1.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH:8](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2/[CH:19]=[CH:18]/[CH:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)Cc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(C#N)cc1

Procedure:
A solution of 1.75 g (4.64 mmol) of ethyl E-6-(4-cyanobenzyl)-8-(2-hydroxyphenyl)oct-7-enoate in 50 ml of dry acetonitrile is mixed with 1579 mg (6.95 mmol) of 4-(tert-butyl)benzyl bromide and 961 mg (6.95 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→4:1). 2.24 g (4.28 mmol, 92% of theory) of a solid are obtained.
Reaction SMILES: [OH:1][C:2](C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20](CC[Si](C)(C)C)[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31]CC2C=CC=CC=2)[CH:12]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[OH:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][N:8]=[C:2]=[O:1])[CH:16]=[CH:15][C:14]=1[N:17]1[S:21](=[O:22])(=[O:23])[NH:20][C:19](=[O:30])[CH2:18]1
Reactant: O=C(O)C(F)(F)F
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C=NCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.266 g, 0.46 mmol) (Example 67, step A) and diisopropylethylamine (0.177 mL, 1.02 mmol) in a minimum amount of CH2Cl2 is added dropwise over a period of 30 min to triphosgene (0.051 g, 0.17 mmol) dissolved in CH2Cl2 (10 mL). This solution is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH2:18][OH:19])=[C:16]3[C:11]([NH:12][C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[NH:15]3)=[CH:10][CH:9]=2)=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1.C(OCC)(=O)C>[OH:19][CH2:18][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])=[CH:3][C:4]=2[O:23][CH3:24])=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:20])[C:13]([CH3:21])([CH3:22])[NH:12]2
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC(=O)c2ccccc2C)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Reaction time: 1.33 h
Yield: 62 %

Procedure:
7-(4-Hydroxy-2-methoxyphenyl)-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-5, 430 mg 1.31 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine (365 μL, 2.62 mmol) and 2-methylbenzoyl chloride (222 μL, 1.70 mmol) were added thereto successively. After the reaction mixture was stirred at the same temperature for 80 minutes, the reaction mixture was diluted with ethyl acetate (200 mL). The mixture was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound mg) as a colorless solid. (Yield 62%)
Reaction SMILES: O[C:2]1([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:2]1([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: Oc1ccc(C2(O)CCCCC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(C2=CCCCC2)nc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a suspension of 6-(1-hydroxy-cyclohexyl)-pyridin-3-ol (2.5 g, 12.9 mmol) in toluene (130 mL) was added p-toluenesulfonic acid monohydrate (8.12 g, 42.7 mmol). The mixture was refluxed with azeotropic removal of water for 2 hours. The reaction mixture was cooled to room temperature, neutralized with aqueous NaHCO3 and extracted three times with EtOAc. The organic phase was washed with brine, dried (Na2SO4), passed through a silica gel pad and concentrated to provide the title compound as a solid (2.2 g).
Reaction SMILES: N[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].C([N:23](C(C)C)CC)(C)C.O>C1COCC1>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:23][C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])=[C:9]([N+:10]([O-:12])=[O:11])[CH:2]=1)#[N:5]
Reactant: N#Cc1cccc([N+](=O)[O-])c1N
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-3-nitrobenzonitrile (2 g) in THF (30 ml) were added 4-pentenoyl chloride (2.90 g) and diisopropylethylamine (4.27 ml), followed by stirring at 80° C. for 12 hours. The reaction solution was poured into water, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH) to obtain N-(4-cyano-2-nitrophenyl)pent-4-enamide (174 mg) as a colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)=[O:2].[BH4-].[Na+].Cl>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[O:9][CH:8]([C:14]([F:16])([F:17])[F:15])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2cc(C=O)cc(C)c2OC1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(CO)cc(C)c2OC1C(F)(F)F
Temperature: 0 °C
Yield: 99.3 %

Procedure:
The solution of ethyl 6-formyl-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.9 g, 6.05 mmole) dissolved in a mixture of THF (10 mL) and ethanol (10 mL) was cooled to 0° C. (ice bath). Sodium borohydride (0.11 g, 3.00 mmole) was added to above solution portionwise over 30 minutes. The mixture was poured into 1.2 N HCl (10 ml) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil (1.9 g, 98%). No further purification was performed. GCMS m/z 316.0 (M+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:73][C@H:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>C(#N)C.C(Cl)Cl>[C:1]([NH:8][C@H:9]([C:24]([NH:81][C@@H:74]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:73])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](N)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.0 g; 13 mmol), BOP reagent (6.0 g; 13 mmol), HOBT (1.8 g; 13 mmol) and DiPEA (7.1 mL; 40 mmol) 100 mL of acetonitrile:CH2Cl2 (1:1), followed by (S)-α-methylbenzylamine (1.8 mL; 13 mmol), then stirred overnight. After work up, the crude product was purified by passing it through a plug of silica gel with EtOAc to give 5.9 g (92%) of the sub-title as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH3:23])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([S:18][CH2:19][CH3:20])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CNC
Reactant: CCSc1nsc(NC(=O)Oc2ccccc2)c1C#N
Product: CCSc1nsc(NC(=O)N(C)C)c1C#N
Yield: 160 %

Procedure:
Two samples (30.9 g each) of phenyl (4-cyano-3-(ethylthio)-5-isothiazolyl)carbamate were reacted with dimethylamine (9.13 g per batch) in the manner described in Example IV B. The reaction mixtures from the two runs were combined and processed as in IV B to give 41.5 g of 1,1-dimethyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea, m.p. 198° after recrystallization from ethanol. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [S:1]([N:17](S(C1C2C=CC=C(N(C)C)C=2C=CC=1)(=O)=O)[CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(C(O)=O)CP(CCC(O)=O)CCC(O)=O.Br[C:58]1[C:59]([NH:61][C:62](=[O:64])[CH:63]=1)=[O:60]>CO>[S:1]([NH:17][CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:2])=[O:3].[C:59]1(=[O:60])[NH:61][C:62](=[O:64])[CH:63]=[CH:58]1
Reactant: O=C1C=C(Br)C(=O)N1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N(CCSSCCN)S(=O)(=O)c3cccc4c(N(C)C)cccc34)cccc12
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: CO
Product: CN(C)c1cccc2c(S(=O)(=O)NCCSSCCN)cccc12
Product: O=C1C=CC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A round bottomed flask was charged with di-dansyl cystamine (100 mg, 0.16 mmol), TCEP (46 mg, 1 eq), and MeOH (10 ml). The reaction mixture was stirred at ambient temperature under argon for 3 hrs. Bromomaleimide (56 mg, 2 eq) in MeOH (5 ml), was added to the reaction mixture. After 16 hrs, the reaction mixture was concentrated in vacuo. The residue was worked up with DCM and brine. The organic layers were combined, dried (MgSO4) and purified by flash chromatography (silica gel, 0-30% EtOAC-CHCl3) to yield the desired compound (73 mg, 55%). 1HNMR (CDCl3, 600 MHz), δ8.5 (1H, d J 8.5 Hz aromatic H's), δ8.2 (2H, m aromatic H's), δ8.1 (1H, s CONH), δ7.5 (2H, m, aromatic H's), δ7.15 (1H, d, J=7.5 Hz aromatic H's), δ6.0 (1H, s, CO2CH) δ5.89 (1H, t, J 6.4 SO2NH), δ3.20 (2H, q, J 6.7 NHCH2), δ3.99 (2H, t, J 6.9 SCH2), δ2.86 (6H, s NCH3); 13CNMR (CDCl3, 150 MHz), 6169.6, 168.0, 152.0, 150.7, 134.4, 131.0, 129.9, 129.7, 129.5, 128.8, 123.4, 119.3, 118.7, 115.6, 45.5, 41.0, 31.8; IR (cm−1) 3277 (br) 1720 (s) MS (ES−) m/z relative intensity: 404 (M, 100); Exact mass calculated for [C18H18N3O4S2] requires m/z 404.0739. Found 404.0733.