Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[C:39]([S:58][CH2:59][CH2:60][NH2:61])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O.O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH:61][CH2:60][CH2:59][S:58][C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc([N+](=O)[O-])c2[nH]1
Yield: 95.7 %

Procedure:
A solution of 7-nitro-1H-indole-2-carboxylic acid (4.4 g), 1H-1,2,3-benzotriazol-1-ol (3.8 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (4.8 g), 2-(tritylthio)ethylamine hydrochloride (7.4 g) and triethylamine (3.5 mL) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was crystallized from diethyl ether-hexane to give the title compound (10.1 g, yield 95%) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[CH:20](I)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH:20]([CH3:22])[CH3:21])#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Reactant: CC(C)I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ccc(OC(C)C)c(C#N)c2)c1
Yield: 95.2 %

Procedure:
In 5 ml of DMF were dissolved 82 mg of methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and 66 mg of isopropyl iodide, and the resulting solution was heated at 80° C. for 3 hours in the presence of 72 mg of potassium carbonate and 10 mg of tetra-n-butylammonium bromide. The reaction solution was cooled and then diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent (hexane:ethyl acetate=10:1) to obtain 91 mg of methyl 2-(3-cyano-4-isopropoxyphenyl)isonicotinate. (2) Then, 86 mg of the compound was dissolved in a mixed solution of 3 ml of methanol and 3 ml of THF, and 0.35 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 1 hour. After being cooled to room temperature, the resulting solution was diluted with diisopropyl ether and water and an aqueous layer was separated. The aqueous layer was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. After being washed with water, the organic layer was dried and concentrated under reduced pressure to obtain 55 mg of 2-(3-cyano-4-isopropoxyphenyl)isonicotinic acid.
Reaction SMILES: [CH2:1]([O:8][P:9](=[O:19])([OH:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(#N)C>[O:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[P:9]([O:18][P:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])(=[O:19])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=P(OCc1ccccc1)(OCc1ccccc1)OP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 2 h

Procedure:
A flask fitted with a nitrogen inlet, overhead stirrer, teflon-coated thermocouple probe, and pressure-equalizing addition funnel was charged with 350 milliliters of dry (water content ≤50 μg/mL), peroxide-free tetrahydrofuran, followed by 50.0 grams (174 millimoles) of dibenzylphosphoric acid (DBP), and the resulting mixture was stirred until the solid dissolved (about 10-15 minutes). A solution of 18.9 grams (91.6 millimoles) of dicyclohexylcarbodiimide (DCC) in 215 milliliters of THF was added from the addition funnel to a stirred, cooled (water-bath) solution of DBP at a rate to maintain the temperature at about 20°-25° C. The reaction is slightly exothermic and the addition took about 30 minutes. Within minutes, a precipitate of dicyclohexylurea formed in the mixture. Stirring was continued for about 2 hours at 20°-25° C. The reaction was monitored by HPLC assay using VYDAC C-18 (300A, 4.6×250 mm) column with water (0.02M KH2PO4) acetonitrile as eluent. The reaction was complete in about 1 hour (assay showing <2 percent unreacted DBP). The mixture was then filtered while excluding moisture to remove dicyclohexylurea. The filter cake was washed with two 25 milliliter portions of THF. The solution when assayed by HPLC showed 45.9 grams (98 percent) yield of tetrabenzyl pyrophosphate (TBPP) in 620 milliliters of THF (0.137M). The filtrate was then stored at 0° C. with exclusion of moisture until the next step.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:37])[C@H:7]([CH3:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][C@@H:12]([CH3:26])[CH2:13][CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH2:2][CH2:3][CH3:4].[CH2:38](NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(S(CC)(=O)=O)C1)=O)[CH2:39][CH2:40]C>>[CH2:1]([NH:5][C:6](=[O:37])[C@H:7]([CH3:36])[CH2:8][C@@H:9]1[O:35][C:39]([CH3:40])([CH3:38])[N:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:10]1[CH2:11][C@@H:12]([CH3:26])[CH2:13][CH2:14][O:15][Si:16]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:24])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(S(=O)(=O)CC)Cc2ccccc21)NC(=O)OC(C)(C)C
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
The title compound is prepared in a manner analogous to that described in Example 72e) starting from 800 mg of 5(S)tert-butoxycarbonylamino-4(S)-hydroxy-9-triisopropylsilyloxy-2(R),7(R)-dimethyl-nonanoic acid (N-butyl)amide: Rf (A)=0.69.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Br)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cu][C:14]#[N:15]>CN1CCCC1=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:14]#[N:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1ccc2cccc(C#N)c2n1

Procedure:
Prepared by reacting 2-methyl-8-bromo-quinoline with copper(I)cyanide in N-methylpyrrolidinone under a protective gas atmosphere at 180° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11]S(C1C=CC(C)=CC=1)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:30][CH2:31][CH2:32]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:34]([N:29]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:30][CH2:31][CH2:32][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Reactant: OCCCN(Cc1ccccc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: c1ccc(COCCOCCCN(Cc2ccccc2)Cc2ccccc2)cc1
Yield: 29.7 %

Procedure:
Dibenzyl-[3-(2-benzyloxy-ethoxy)-propyl]-amine (378 mg) was prepared by following General Procedure W starting from toluene-4-sulfonic acid 2-benzyloxy-ethyl ester (1.0 g), 3-dibenzylamino-propan-1-ol (1.08 g), 50% aqueous sodium hydroxide solution (1.3 g in 1.3 mL of water), and tetrabutylammonium hydrogen sulfate (111 mg).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25](O)(=[O:29])[C:26]([CH3:28])=O>C(O)C>[CH2:1]([CH:3]([O:6][C:7]1[C:8]2[N:24]=[C:26]([CH3:28])[C:25](=[O:29])[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)C(=O)O
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CCO
Product: CCC(CC)Oc1nc(C)nc2c1nc(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
To a solution of 6-(1-ethyl-propoxy)-2-methyl-4-N-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine (100 mg, 0.305 mmol) in 2 ml of ethanol was added pyruvic acid (30 mg, 0.335 mmol) and the resulting mixture was heated at reflux for 1 hour. An additional 60 mg of pyruvic acid was added and the resulting mixture was heated at reflux overnight. The mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give an oil residue. The residue was purified through silica gel column chromatography using hexane to 15% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. 1H NMR (CDCl3) δ 6.99 (s,2H), 5.39(m,1H), 2.61(s,3H), 2.40(s,3H), 2.35(s,3H), 1.88(s,6H), 1.7-1.9(m,4H), 0.99(t,6H)ppm.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[N:17][OH:18])[CH:2]1O[CH2:3]1.[CH2:19]([O:21][C:22]([CH2:24][CH2:25]CCCOC1C=CC2C(=CC=CC=2)C=1C=O)=[O:23])[CH3:20].[OH-].[Na+].Cl.NO>C(O)C.O>[CH2:19]([O:21][C:22]([CH2:24][CH2:25][CH2:3][CH2:2][CH2:1][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[N:17][OH:18])=[O:23])[CH3:20]
Reactant: CCOC(=O)CCCCCOc1ccc2ccccc2c1C=O
Reactant: ON=Cc1c(OCC2CO2)ccc2ccccc12
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1C=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
As shown in Chemical Formula 4, a mixed solution in which 0.206 g (0.654 mmol) of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthoaldehyde (6) was dissolved in a solvent mixture of 2 mL of ethanol and 1 mL of water was prepared. Separately, an aqueous solution in which 25.1 mg (0.628 mmol) of sodium hydroxide and 68.7 mg (0.994 mmol) of hydroxylamine hydrochloride were dissolved in 1 mL of water in an ice bath was prepared. This aqueous solution was added to the mixed solution and the resultant reaction mixture was stirred at room temperature for 30 minutes to effect the reaction. However, by the sampling of the reaction mixture, remaining of the raw material was confirmed, so 27.3 mg (0.683 mmol) of sodium hydroxide and 55.8 mg (0.803 mmol) of hydroxylamine hydrochloride were added to the reaction mixture, and the resultant reaction mixture was stirred at room temperature for 1 hour to effect the reaction. The resultant solid was recovered by filtration and the crude product was recrystallized in hexane-EtOH (hexane-ethanol) to obtain 127 mg (yield: 59%) of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthoaldehyde oxime (7) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([NH2:25])[S:17][C:18]=1[CH2:19][CH2:20][O:21][N+:22]([O-:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:25][C:16]1[S:17][C:18]([CH2:19][CH2:20][O:21][N+:22]([O-:24])=[O:23])=[C:14]([CH3:13])[N:15]=1)=[O:12]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: Cc1nc(NC(=O)Cc2ccc(Cl)cc2Cl)sc1CCO[N+](=O)[O-]
Yield: 69 %

Procedure:
Pet-162 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using (2,4-dichloro-phenyl)-acetic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 69%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@:22]([CH2:27][C:28]#[N:29])([OH:26])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Li+].[OH-]>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@:22]([CH2:27][C:28]#[N:29])([OH:26])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC#N)C(=O)O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC#N)C(=O)O)C(=O)O)cc1
Temperature: 25 °C
Yield: 13.9 %

Procedure:
No. 5250270, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-cyanomethyl-2-hydroxy-12-oxo-nonadec-4-enoic acid (81 mg, 0.127 mmol) was dissolved in methanol (4.0 mL), and 2 M LiOH (0.40 mL) was added. The mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (11 mg, 14% yield, yellow oil).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN1CCCC1=O>[C:16]1([C@H:22]([NH:24][C:2]2[N:7]=[N:6][C:5]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[C:4]3[S:13][CH:14]=[CH:15][C:3]=23)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nnc(-c2cccs2)c2sccc12
Reactant: C[C@@H](N)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2cccs2)c2sccc12)c1ccccc1
Temperature: 150 °C
Reaction time: 10 h
Yield: 65.2 %

Procedure:
0.31 g of 4-chloro-7-(2-thienyl)thieno[2,3-d]pyridazine and 0.48 g of (R)-1-phenylethylamine was dissolved in 2 ml of N-methylpyrrolidone, and the solution was stirred at 150° C. for 10 hours. After cooling the solution, an aqueous 5% KOH solution was added thereto, and the solution was extracted with chloroform and dried. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 0.27 g of (R)-4-(1-phenylethylamino)-7-(2-thienyl)-thieno[2,3-d]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:7](=[O:16])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1>C1COCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:7](=[O:16])[CH:8]([CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)[N:9]=[C:10]([C:11]3[CH:15]=[N:14][NH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)CN=C(c3cn[nH]c3)c3cc(Cl)ccc32)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(c3cn[nH]c3)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
7-Chloro-1-(4-methoxybenzyl)-5-(1H-pyrazol-4-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (163 mg) was dissolved in THF (3 mL) and the solution was cooled to −78° C. A solution of KOtBu in THF (1 M, 1.1 mL, 2.6 eq) was then added dropwise and the anion was stirred for 10 minutes. 2-Bromomethyl naphthalene (123 mg, 1.3 eq) was then added and the reaction was allowed to warm to room temperature where it was held for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride and the crude product was partitioned between water and EtOAc. The organic fraction was washed with brine, then dried over sodium sulfate, and concentrated onto silica gel then purified by flash chromatography (gradient: 3:1 hexanes:EtOAc to EtOAc) delivering the product as a solid (106 mg, 48% yield). MS (ES+) m/z 521.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1([CH3:22])[CH2:21][N:8]2[CH2:9][CH:10](C)[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=O)[CH:7]2[CH2:6]1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:29]1COCC1>>[OH:4][CH2:3][C:5]1([CH3:22])[CH2:21][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:29]=3)[CH2:12][CH:7]2[CH2:6]1
Reactant: COC(=O)C1(C)CC2C(=O)N(c3ccccc3)C(C)CN2C1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(CO)CC2CN(Cc3ccccc3)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 3.33 g (11 mmol) of (7RS,8aSR)-7-methoxycarbonyl-7-methyl-2-phenyl-methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Jones, R. C. F., Howard, K. J., J. Chem. Soc., Perkin Trans. 1, 1993, 2391) in 125 mL of dry THF was added dropwise to a stirred suspension of 1.26 g (33 mmol) of lithium aluminum hydride in 125 mL of dry THF. The solution was stirred for 2 hours at room temperature, and carefully quenched with 1.26 mL of water, 1.26 mL of 15% NaOH, and 3.78 mL of water. After stirring for 30 minutes, the mixture was filtered through Celite, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography eluting with 9:1 chloroform:methanol gave 1.67 g (58%) of the title compound. 13C NMR (base, CDCl3): δ 25.3, 39.7, 41.8, 51.1, 51.6, 57.1, 62.3, 62.9, 63.3, 71.3, 127.0, 128.2, 128.7, 129.2, 138.3. m/z (MH+) 261.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[N:5]=1)[CH3:3].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:5]2[C:6]3[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])=[CH:17][CH:18]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC(C)c1nc2c([nH]1)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(=O)CCC2
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To Intermediate 56 (2nd alternative preparation) (5.4 g) in Toluene (120 mL) was added 1-(bromomethyl)-4-iodobenzene (9.00 g) and tetrabutylammonium bromide (4.88 g) then sodium hydroxide, 5M aq (66.7 mL). The mixture was then stirred at room temperature, stirring vigorously to mix the phases for 1.5 h. The mixture was partitioned between ethyl acetate and water. The brown solid was filtered. The 2 phases were separated and the aqueous layer extracted well with ethyl acetate. The combined organics were dried (hydrophobic frit) and evaporated. The sample was loaded in dichloromethane and purified by column chromatography (silica) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product 6.65 g as a brown oil. LC/MS MH+ 395, Rt 2.88 min (5 min run).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].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.[CH3:40][NH:41][C:42](=[O:66])[C:43]1[CH:48]=[C:47]([O:49][C:50]2[CH:65]=[CH:64][C:53]3[N:54]=[C:55]([NH:57][C@H:58]4[CH2:63][CH2:62][CH2:61][NH:60][CH2:59]4)[S:56][C:52]=3[CH:51]=2)[CH:46]=[CH:45][N:44]=1>CC(N(C)C)=O>[C:1]([N:60]1[CH2:61][CH2:62][CH2:63][C@H:58]([NH:57][C:55]2[S:56][C:52]3[CH:51]=[C:50]([O:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([C:42]([NH:41][CH3:40])=[O:66])[CH:48]=4)[CH:65]=[CH:64][C:53]=3[N:54]=2)[CH2:59]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)C(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To the reaction solution of isobutyric acid (4 μl, 40 μmol), HATU (15 mg, 40 μmol) and DIEA (14 μL, 80 μmol) in 400 μl of DMA was added (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (6 μL, 30 μmol). The reaction solution was stirred at room temperature for 16 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (6.8 mg, 15 μmol) as white powder. ES/MS m/z 454.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1.ClCCl.[NH2:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:29][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccon1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride (512.8 mg, 1.031 mmol), dichloromethane (1718 μl), and 3-aminoisoxazole (114 μl, 1.546 mmol) to give a thick suspension. Pyridine (3437 μl) was added relatively quickly, leading to thinner suspension. After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-50% 3:1 EtOAc/EtOH in heptane with 10% DCM) to give 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (419.2 mg, 0.846 mmol, 82% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=11.74 (br. s., 1H), 8.74 (d, J=1.9 Hz, 1H), 8.47 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 7.90 (dd, J=2.2, 8.9 Hz, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 3.74-3.71 (m, 3H), 3.32 (s, 3H). m/z (ESI) 495.0 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[S:28][CH:27]=1)=[O:25])[C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].NN>CO.C1COCC1>[NH2:3][CH2:12][CH:13]([NH:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[S:28][CH:27]=1)=[O:25])[C:14]([CH3:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15]
Reactant: Cn1nccc1-c1cc(C(=O)NC(CN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccc2)cs1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)NC(CN)C(C)(C)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-{1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-methyl-2-phenylpropyl}-5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide (96 mg, 0.20 mmol) in MeOH/THF (20 mL, 3:1) at RT was added hydrazine (45 μL, 1.43 mmol). After stirring for 18 h at RT, the reaction mixture was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.