Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4](C(O)=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])=CC=1.C([N:42]([CH2:45]C)CC)C>CC(O)(C)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:42][C:45](=[O:30])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[Cl:22])[C:3]=12
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (100 mg, 0.25 mmol) in t-BuOH (5 mL) was added DPPA (103 mg, 0.37 mmol) followed by triethylamine (76 mg, 0.75 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (90 mg, 90.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.67 (s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 7.50 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH3:60].CCN(CC)CC>C1COCC1.CCOC(C)=O>[CH3:60][O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][N:47]([CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH3:34])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: COCCOCCOCCOCCNCCOCCOCCOCCOC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCN(CCOCCOCCOCCOC)S(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 35.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.258 g, 0.528 mmol) by treatment with bis-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-amine [CAS-no. 123852-08-4] (0.210 g, 0.528 mmol) and Et3N (0.221 mL, 1.58 mmol) in THF (5 mL) at 23° C. for 1 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. +2 M Na2CO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc/EtOH gave the title compound (0.158 g, 63%) as a yellow oil. MS (ISP) 850.5 [(M+H)+].
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:27])[NH:14][CH:15]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:9][CH:10]=2)[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=1.[Cl:34]CCl>>[ClH:34].[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([NH:14][CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[O:27])=[CH:9][CH:10]=2)[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=1
Reactant: ClCCl
Reactant: CSc1nn(-c2ccccc2)c2cc(NC(=O)NC3CCN(C(=O)OC(C)(C)C)C3)ccc12
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)NC3CCNC3)ccc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 3-(3-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)ureido)pyrrolidine-1-carboxylate (120 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (4 mL). The solution was bubbled with HCl (g) at 0° C. in 30 min. The resulting solution was stirred for 30 min at 0° C. The solids were collected by filtration. The solid was washed with ethyl acetate/methanol (2×3.8 mL) to yield 1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)-3-(pyrrolidin-3-yl)urea hydrochloride as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34OCCO4)C(=O)C12
Yield: 42.3 %

Procedure:
A solution of 110 mg (0.5 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 112 mg (0.35 mmol) of rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene in 10 ml of toluene was stirred and heated under reflux for 3 hours under an atmosphere of nitrogen. The solution was evaporated and the resulting yellow gum was crystallised from diethyl either to yield 80 mg (42%) of rac-3,6,11-triacetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,5a,6,11,11a,12-decahydro-5,12-dioxonaphthacene in the form of a pale yellow solid of melting point 133°-143° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:12]=[C:13]([C:17]#[C:18][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C#Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Fc1cnc(Cl)nc1C#Cc1cccc(Br)c1
Yield: 80.2 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloro-5-fluoropyrimidine (1.66 g, 10 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (180 mg, 0.26 mmol), copper(I) iodide (29 mg, 0.15 mmol), and TEA (2.02 g, 20 mmol). After heating the reaction at 60° C. for 30 min, 1-bromo-3-ethynylbenzene (0.9 g, 5.0 mmol) was added dropwise as a solution in THF (25 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (2-10% EtOAc in hexanes) to afford the desired product (1.25 g, 78%) as an off white solid. ESIMS (M+H)+=311.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8](O)/[CH:9]=[CH:10]/[C:11]1[C:21]([CH3:23])([CH3:22])[CH2:20][C:14]2([S:19][CH2:18][CH2:17][CH2:16][S:15]2)[CH2:13][C:12]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[CH:25]=1)[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl.CCOCC>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:12]2[CH2:13][C:14]3([CH2:20][C:21]([CH3:23])([CH3:22])[C:11]=2/[CH:10]=[CH:9]/[C@@H:8]2[O:5][C:4](=[O:6])[CH2:3][C@@H:2]([OH:1])[CH2:7]2)[S:19][CH2:18][CH2:17][CH2:16][S:15]3)=[CH:25][C:26]=1[CH3:31]
Reactant: Cc1cc(C2=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Agent: CCOC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC3(C2)SCCCS3)ccc1F
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a 0°-5° C. solution of 12 (0.90 gm, 1.87 mmol) and triethylamine (315 μL, 2.25 mmol) in 10 mL CH2Cl2 was added dropwise ethyl chloroformate (185 μL 1.87 mmol). The mixture was stirred for 30 min, diluted with ether, washed with H2O saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by SiO2 using 3:2 hexanes:EtOAc as eluent provided 0.61 g of the product. mp 136°-138° C. Anal. C25H31FO3S2 : Theory C: 64.91; H: 6.75. Found C: 65.31; H: 6.82.
Reaction SMILES: [C:1]([C:3](=[C:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][C:13]=2[F:29])[CH2:8][CH2:7]1)[C:4]#[N:5])#[N:2].[I-].[CH3:31][S+](C)(C)=O.CC(C)([O-])C.[K+]>CS(C)=O>[C:1]([C:3]1([C:4]#[N:5])[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:14][C:13]=3[F:29])[CH2:8][CH2:7]2)[CH2:31]1)#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)C(=O)O1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CC4(C#N)C#N)c(F)c2)C(=O)O1
Yield: 57 %

Procedure:
The title compound was prepared by reacting (S)—N-[3-{4-[4-dicyanomethylidene piperidin-1-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]-acetamide (1.0 mmol, Example C), trimethyloxosulphonium iodide (1.3 mmol), potassium tert-butoxide (1.3 mmol) in dimethylsulfoxide (10 ml) at a temperature 25° C. for 14 hours in 57% yield.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:21][C:22]1[C:27]([N:18]2[CH2:19][CH2:20][C@@H:16]([NH:15][C@@H:13]([C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH3:14])[CH2:17]2)=[N:26][CH:25]=[CH:24][N:23]=1
Reactant: C[C@@H](N[C@@H]1CCNC1)c1cccc2ccccc12
Reactant: Clc1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H](N[C@@H]1CCN(c2nccnc2Cl)C1)c1cccc2ccccc12
Yield: 35.1 %

Procedure:
To a solution of 162 mg of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 79.0 mg of 2,3-dichloro-pyrazine in 5 ml of ethanol was added 345 mg of potassium carbonate, and the mixture was stirred under reflux for 16 hours. The reaction mixture was filtered, and the solvent was evaporated, and to the residue was added a saturated aqueous sodium bicarbonate solution and chloroform, and the liquids were separated. The organic layer was dried, and the solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=97:3→80:20) and by silica gel chromatography (hexane:ethyl acetate=90:10→0:100) to obtain 64.0 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine. (2) In 2 ml of chloroform was dissolved 64.0 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine, and 3 ml of a solution of 4M hydrochloric acid in dioxane was added to the mixture, and the resulting mixture was stirred. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitates were collected by filtration, washed with diethyl ether, and dried to obtain 63.9 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine dihydrochloride (the following Table A2, Example 2.001).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.C1(C)C=CC(S([Cl:53])(=O)=O)=CC=1.[Cl-].[Li+]>C(#N)C.O.C(N(CC)CC)C>[Cl:53][CH2:30][CH2:29][S:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:32])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:34])[C:9]=2[CH3:33])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:35])[CH:17]=[CH:16][N:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCO)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCCl)c1=O
Temperature: 0 °C
Yield: 94.2 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide (Example 320g, 0.15 g) dissolved in acetonitrile (2 mL) was treated with triethylamine (0.048 mL) and triethylamine hydrochloride (4.16 mg) under nitrogen. The resulting solution was stirred at 0° C. before adding p-toluenesulfonyl chloride (0.055 g) over 5 min. Lithium chloride (0.064 g) was then added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (200 mL), and extracted with DCM (200 mL). The organic layer was separated, dried (MgSO4) and evaporated to afford the subtitle compound (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[C:19]2[C:14](=[C:15]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[O:13][C:12](=[O:28])[CH:11]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[C:19]2[C:14](=[C:15]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[O:13][C:12](=[O:28])[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: Nc1ccccc1Cl
Product: COc1ccc2c(Nc3ccccc3Cl)cc(=O)oc2c1OC1CCCC1

Procedure:
The title compound was prepared from 2-chloroaniline and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16. 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 7.93 (d, 1H), 7.66 (d, 1H), 7.51-7.40 (m, 3H), 7.15 (d, 1H), 4.83 (m, 1H), 4.50 (s, 1H), 3.90 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 385.9.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2].F[C:14](F)(F)C(OC(=O)C(F)(F)F)=O.O1[CH2:30][CH2:29][CH2:28]C1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:29]([CH3:28])([CH3:30])[CH3:14])=[O:11])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C1CCOC1
Reactant: C=Cc1ccc(CC(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-Vinylphenylacetic acid 34 (8.15 g, 50.3 mmol) was placed in a three-neck round bottom flask attached with a thermometer, and an addition funnel with a drying tube. Tetrahydrofuran (80 mL, distilled over Na/K alloy) was added to the reaction flask, and the solution was cooled with an ice bath. Trifluoroacetic anhydride (15 mL, 106.2 mmol) was slowly added using an addition funnel so that the reaction temperature was kept below 10° C. The solution was allowed to stir at 5° C. for 2 h. A solution of 2-Methylpropanol (freshly distilled over CaH2, 36 mL, 376 mmol) in THF (50 mL) was added dropwise keeping the reaction temperature below 10° C. The solution was stirred for an additional 2 hours at 5° C., and then overnight at room temperature. Ethyl ether (200 mL) was added to the solution, and 170 mL of 1.25 N aqueous NaOH was slowly added while cooling with an ice bath. The solution was then allowed to stir at room temperature for 2 h. The organic layer was separated, washed with water until neutral, washed with brine, and then dried over anhydrous MgSO4. The solvents were removed in vacuo, and 9.85 g of clear liquid was obtained in 90% yield.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9]/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:14][CH:13]=1>CN(C)C=O.O>[Cl:1]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:16][CH:17]=1)=[N:10]\[OH:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C=N/O)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C(Cl)=N/O)cc2)C1
Temperature: 55 °C
Yield: 100 %

Procedure:
N-chlorosuccinimide (239.0 mg, 1.790 mmol) was added to a stirred suspension of (E)-di-tert-butyl 2-(4-((hydroxyimino)methyl)phenyl)piperazine-1,4-dicarboxylate (725.8 mg, 1.790 mmol) in N,N-dimethyl formamide (10 mL). The reaction was then heated at 55° C. for 1 hour. The reaction was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with ethyl acetate (×3). Organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The sub-titled compound was used directly in the next step without further purification. (787.5 mg, assume 100% yield).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14]>I.[PH2](O)=O>[CH3:7][C:8]1[NH:9][C:10]([CH2:3][C:2]([OH:6])=[O:5])=[C:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(CC(=O)O)c1C
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Glyoxalic acid monohydrate (500mg) was added to a solution of 548 mg of 2,4-dimethyl-3-acetyl-pyrrole in 10 ml of aqueous hydriodic acid and 2 ml of hypophosphorous acid. The solution was stirred for one hour at 15° C. The yellow crystalline solid was filtered off, washed with ether, dried, then slurried with 5 ml of water. The solid was again separated, washed with 5 ml of water, dried, and extracted into 40 ml of ether (thimble). When the ether solution was concentrated the produce separated as yellow prisms (550 mg), m.p. 195°-205° C. For analysis, it was recrystallized by dissolving it in 40 parts of cold 50% aqueous acetone, boiling off the acetone, and cooling. It separated as nearly colourless prismatic rods, m.p. 206°-210° C. after changing to prisms at 155° and evolving gas at 175°; presumably it decarboxylated to the 5-methyl derivative before melting. Anal. Calc. for C10H13NO3 : C, 61.52; H, 6.71; N, 7.18; eq. wt. 195. Found: C, 61.35: H, 6.90; N, 7.10; eq. wt. 197.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CC(C)C.[C:12]([O:17]C)(=[O:16])[C:13]([CH3:15])=C.C(OC)(=[O:22])C=C.C(OCCN(C)C)(=O)C(C)=C.N(C(C(C)C)C#N)=NC(C(C)C)C#N.CC(N=NC(C#N)(C)C)(C#N)C>>[CH3:1][C:2](/[CH:3]=[CH:4]/[CH:5]=[C:6]=[CH:7]/[CH:15]=[CH:13]/[C:12]([OH:17])=[O:16])=[O:22]
Reactant: CCCCCCCCC(C)C
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)C(C#N)N=NC(C#N)C(C)C
Product: CC(=O)/C=C/C=C=C/C=C/C(=O)O
Temperature: 70 °C

Procedure:
A mixed solution of 10 g of Resin for Dispersion Stabilization (P-1) shown below and 280 g of Isopar G was heated to temperature of 70° C. with stirring under a nitrogen gas stream. To the solution was dropwise added a mixture of 30 g of methyl methacrylate, 61 g of methyl acrylate, 9 g of 2-(N,N-dimethylamino)ethyl methacrylate and 1.5 g of 2,2′-azobis(isovaleronitrile) (abbreviated as AIVN) over a period of one hour, followed by stirring for 2 hours. Then, 1.0 g of AIVN was added to the reaction mixture and the mixture was heated to temperature of 75° C., followed by stirring for 3 hours. Then, 0.8 g of 2,2′-azc)bis(isobutyronitrile) (abbreviated as AIBN) was added to the mixture and the mixture was heated to temperature of 80° C., followed by stirring for 3 hours. The temperature of the reaction mixture was raised to 100° C., followed by stirring under a reduced pressure of 200 mmHg for 2 hours, thereby distilling off the unreacted monomers. After cooling the reaction mixture, it was passed through a nylon cloth of 200 mesh. The resulting white dispersion was a latex having a polymerization rate of 99% and an average particle size of 0.35 μm. The particle size was measured by CAPA-500 manufactured by Horiba Ltd. (hereinafter the same).
Reaction SMILES: [C:1](NCC(O)=O)([CH3:4])([CH3:3])[CH3:2].[C:10](=[O:25])(ON1C(=O)CCC1=O)[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C(=O)(O)[O-].[Na+].CC(C)=O>[CH:12]1([O:11][C:10]([NH:26][C@@H:27]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:28]([OH:30])=[O:29])=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: NCC(=O)O
Reactant: O=C(OC1CCCC1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 5 L RB flask dissolved t-butyl glycine (74 g, 0.56 mol, 1.02 eq.) in saturated sodium bicarbonate (11 vol). Cyclopentyl 2,5-dioxopyrrolidin-1-yl carbonate (126 g, 0.55 mol, 1 eq.) was dissolved in acetone (5.5 vol) and the solution slowly added via addition funnel at room temperature to the solution of the glycine. The reaction mixture was stirred at room temperature until complete (approximately 4 hours). The acetone was removed under reduced pressure and the remaining aqueous solution was extracted with 30% ethyl acetate in hexanes (thrice, 5.5 vol each). The organic layers were discarded. The pH of the aqueous layer was adjusted to 2 with 2 N HCl and then extracted with ethyl acetate (thrice, 5.5 vol). The combined organic layers were dried (Na2SO4), filtered, and the solvent removed under reduced pressure to provide a clear oil the slowly crystallized. The crude product was crystallized from hexanes/ethyl acetate to provide (S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid as a white solid (82 g). The mother liquid was stripped and a second crop of crystals obtained (combined yield 105.54 g).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[C:8]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14]O)([CH3:11])([CH3:10])[CH3:9].Cl[CH2:20]Cl.[OH-].[Na+]>>[C:8]([N:12]([CH2:13][CH2:14][O:6][CH3:7])[CH2:16][CH2:17][O:18][CH3:20])([CH3:11])([CH3:10])[CH3:9]
Reactant: ClCCl
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)N(CCO)CCO
Agent: [Na+]
Agent: [OH-]
Product: COCCN(CCOC)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl sulfate (50.45 g, 0.4 mol) was added dropwise to a vigorously stirred mixture of N-tert-butyldiethanolamine (16.13 g, 0.1 mol), dichloromethane (100 ml) tetrabutylammonium bromide (3.22 g, 10 mmol) and 50% aqueous sodium hydroxide (80 g, 1 mol at 30-40° C. The stirring was continued for 1 h after the addition was completed. The organic solution was separated and the aqueous layer was extracted with dichltromethane (25 ml). The organic solutions were combined. GC analysis showed a mixture of mono- and diethylated product. The methylation was repeated using the same amounts of reagents as described above. The dichloromethane solution after the second workup was stirred with concentrated aqueous ammonia (50 ml) for 1 h at room temperature, separated, dried over anhydrous magnesium sulfate and the product was isolated by distillation to yield 17.00 g, (90%), bp 42-44° C./0.1 mm/Hg; 1H NMR (CDCl3) δ1.60 (s, 9H, CH3), 2.70 (t, J=6.0 Hz, 4H, CH2), 3.35 (s, 6H, CH3), 3.37 (t, J=6.0 Hz, 4H, CH2)