Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.O>CN(C)C=O>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[C:15]4[C:10]([CH2:11][CH2:12][NH:13][C:14]4=[O:17])=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C1NCCc2ccc(N3CCNCC3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
7-Piperazin-1-yl-3,4-dihydro-2H-isoquinolin 1-one (100 mg) synthesized according to the method described in J. Med. Chem., 39, 4583 (1996) was dissolved in N, N-dimethylformamide (5 ml). Potassium carbonate (71 mg) and 4-chloro benzyl bromide (106 mg) were added to the solution. The mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1) to give 7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one (75 mg).
Reaction SMILES: [C:1](Cl)([C:3](Cl)=O)=O.[OH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[N:12]2>CS(C)=O>[N:12]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[C:13]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[N:12]3)[CH2:3][CH2:1][CH2:9][CH2:10][CH2:11]1.[O:19]=[C:14]1[C:13]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[N:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]=[O:7])[CH:10]=2)[NH:15]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]c2ccc(CO)cc2nc1-c1cccs1
Solvent: CS(C)=O
Product: O=Cc1ccc2[nH]c(=O)c(-c3cccs3)nc2c1
Product: O=c1[nH]c2ccc(CN3CCCCC3)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared first via Swern oxidation with DMSO and (COCl)2 of 6-Hydroxymethyl-3-thiophen-2-yl-1H-quinoxalin-2-one to form 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-carbaldehyde. The 6-carboxaldehyde compound then undergoes reductive amination with piperidine in acetonitrile in the presence of NaCNBH3 and acetic acid to afford, after an aqueous workup and purification, 6-Piperidin-1-ylmethyl-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(OCC)(=O)C>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:16]([C:17](=[O:19])[NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: NCCN1CCCCC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of 27.9 g (75 mmol) 3-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid, (Bachem Inc., Torrance, Calif. 90505) 16.5 mL (150 mmol) 4-methylmorpholine, and 28.5 g (75 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 110 mL dry DMF was stirred in an ice-bath for 30 minutes. Next, 10.7 mL (75 mmol) of 1-(2-aminoethyl)piperidine (Aldrich, Milwaukee, Wis.) was added, and the resulting solution was warmed to 25° C. and stirred 60 minutes. The mixture was poured into 200 mL ethyl acetate, and washed sequentially with 200 mL each of 2.5% aqueous HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure to give 33.7 g (94%) of (S)-[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester as a pale amber solid; mp 54-61° C.
Reaction SMILES: Cl[Sn]Cl.Cl.S(=O)(=O)(O)[OH:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][C:12]=1[F:19]>O.C(OCC)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:6])=[CH:13][C:12]=1[F:19]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 59 g (0.31 mol) of anhydrous SnCl2 and 320 cm3 of diethyl ether was placed on an ice water bath and saturated with hydrogen chloride gas generated by the drop-wise addition of concentrated sulfuric acid to concentrated hydrochloric acid until the SnCl2 assumed a liquid state and the mixture was dried with concentrated sulfuric acid. 31 g (0.16 mol) of 4-bromo-3-fluorobenzonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 300 cm3 of water was added to the reaction product and the mixture was stirred over a hot water bath at 50° C. The diethyl ether was distilled off. The oily layer was separated out and the aqueous layer was extracted with ether. The two layers were combined, washed with water, and dried overnight with anhydrous Na2SO4. Diethyl ether was distilled off the resulting dried mixture. Diethyl ether was distilled off the distillation residue. The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg) to yield 26 g (0.13 mol) of 4-bromo-3-fluorobenzaldehyde.
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1CCCCC1>[NH:27]1[CH2:28][CH2:29][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=4[CH2:3][C:2]([NH2:1])=[O:41])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-1-carboxylate (I141) in DCM (20 mL) was added TFA (4.0 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue taken up in EtOAc (10 mL) and 2 M NaOH (10 mL). The organic layer was extracted with EtOAc (2×10 mL), and the combined layers washed with water (10 mL), brine (10 mL) and dried over MgSO4. The solvent was removed in vacuo to give a yellow solid. The solid was suspended in cyclohexane and filtered to give a brown solid (42 mg). The product was purified further by RP-HPLC (Waters, 0-80% CH3CN in H2O over 20 minutes at a flow rate of 10 mL/min). Fractions containing product were basified (pH 10) with 2 M NaOH and extracted with EtOAc. The combined organic layers were washed with brine (10 mL), dried (MgSO4) and the solvent removed in vacuo to give the title compound (35) (17 mg, 27%) as a brown oil; 1H-NMR (400 MHz, d4-MeOD) δ 8.56 (d, J=0.6 Hz, 1H), 7.73-7.68 (m, 2H), 7.33-7.16 (m, 6H), 3.67 (s, 2H), 3.60-3.46 (m, 2H), 3.42-3.33 (m, 2H), 3.14 (m, 5H), 2.45 (dtd, J=10.1, 7.1, 3.4 Hz, 1H), 2.18-2.05 (m, 1H); LCMS Method C: rt 4.84 min; m/z 470.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[CH2:7]1[O:9][CH2:8]1>O>[OH-:6].[OH:6][CH2:5][CH2:4][N+:2]([CH2:7][CH2:8][OH:9])([CH3:3])[CH3:1]
Reactant: CN(C)CCO
Reactant: C1CO1
Solvent: O
Product: C[N+](C)(CCO)CCO
Product: [OH-]

Procedure:
The procedure of Example 1 was followed except that about 356 grams of DMEA, 400 grams of de-ionized water, and 170 grams of ethylene oxide were used. At the end of the nitrogen purge, about 9 grams of aminoethylethanolamine (AEEA) was added. The product is a clear and colorless solution, and no color change was observed after one month of standing at room temperature.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([Si:26]([CH3:29])([CH3:28])[CH3:27])[O:24][CH:25]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CC=C[CH:31]=1.[C:36](=[O:39])(O)[O-:37].[Na+].C(OCC)C>C(OC(=O)C)(=O)C.O>[C:36]([O:37][CH:20]([C:21]1[CH:22]=[C:23]([Si:26]([CH3:27])([CH3:28])[CH3:29])[O:24][CH:25]=1)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:4])(=[O:39])[CH3:31]
Reactant: c1ccncc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCc1coc([Si](C)(C)C)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC(CCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(12-t-butyldimethylsiloxydodecyl)-2-trimethylsilylfuran (0.46 g, 1.0 mmol) and pyridine (0.3 ml) in acetic anhydride (4 ml) was stirred at 0° under nitrogen for 1/2 hour, then 3.5 hours at room temperature. Approximately 1 ml saturated sodium bicarbonate solution was added to the reaction mixture, which was subsequently poured into ethyl ether and water. The organic portion was washed successively three times with water, once with saturated sodium bicarbonate solution, once with water, once with 10% copper sulfate solution, twice with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale oil. The acetate (20% ethyl ether/hexane) was purified by flash chromatography (silica, 7% ethyl ether/petroleum ether) to give a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.[Br:25][C:26]1[C:27]([C:33]#[N:34])=[N:28][CH:29]=[C:30](F)[CH:31]=1.Cl>CN1C(=O)CCC1.ClCCl>[Br:25][C:26]1[CH:31]=[C:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:29]=[N:28][C:27]=1[C:33]#[N:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ncc(F)cc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Temperature: 120 °C

Procedure:
This example describes the procedure for conversion of (A1) to (A3) as shown in Scheme 1. Tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate was purchased from Small Molecules, Inc. (CAS: 365996-30-1, Hoboken, N.J.). DIPEA (18.5 mL, 106 mmol) and tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (17.7 g, 82.7 mmol) were added to 3-bromo-5-fluoropyridine-2-carbonitrile (Frontier Scientific; CAS: 950670-18-5, Logan, Utah) (16.4 g, 81.6 mmol) dissolved in NMP (16.3 mL) in a 150 mL sealed tube. The reaction was heated to 120° C. for 24 hours before cooling to ambient temperature. Hydrochloric acid (1.0 M in water, 100 mL, 100 mmol) was added. Dichloromethane was then added dropwise until a freely stirring suspension was formed. The precipitate was collected by filtration, washed with cold diethyl ether (30 mL), and dried under reduced pressure to afford a portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)-amino]cyclohexyl}carbamate. The mother liquors were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and water to yield an additional portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate. MS ESI calc'd. for C17H24BrN4O2 [M+H]+ 395 and 397. found 395 and 397. 1H NMR (500 MHz, CD3OD) δ 8.02 (d, J=2.3 Hz, 1H), 7.23 (br s, 1H), 6.59-6.46 (m, 1H), 3.83 (s, 1H), 1.65 (s, 6H), 1.56-1.17 (m, 11H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].CCCCCCC>C(O)(C)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:24][C@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Br)c1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1nc(-c2ccn(C[C@@H](C)c3ccccc3)n2)sc1C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide and 2-(bromo-1-methyl-ethyl)-benzene as described in Example 90 and isolated by chiral separation (90:10, heptane:isopropyl alcohol). 1H NMR (400 MHz, CDCl3) δ 7.20-7.39 (m, 8H), 7.13 (d, J=4 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 6.68 (d, J=2 Hz, 1H), 5.98-6.04 (bm, 1H), 4.62 (d, J=8 Hz, 2H), 4.17-4.32 (m, 2H), 3.33-3.44 (m, 1H), 2.75 (s, 3H), 1.29 (d, J=4 Hz, 3H); MS (M+H)+=417.2; Rt=1.32 min; HRMS (M+H)+=417.17.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:4]1[S:3][C:2]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2cccs2)s1
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-chlorothiophene (4.11 g), thiophene-2-boronic acid (4.00 g), tetrakis(triphenylphosphine)palladium (0) (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) in dimethoxyethane (100 ml) was heated under reflux under argon atmosphere for 2.5 hours. The reaction mixture was cooled, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-chloro-2-thienyl)thiophene (3.37 g) as pale yellow oil. (2) The above 2-(5-chloro-2-thienyl)thiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were used and treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[F:5][C:6]([F:17])([F:16])[C:7](=O)[CH:8](Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CN(C=O)C.O>[NH2:1][C:2]1[O:3][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:6]([F:5])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc(N)nc1C(F)(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a suspension of urea (13.5 g) in DMF (50 mL) was added ethyl 4,4,4-trifluoro-2-chloroacetoacetate (10 mL) and the resulting reaction mixture was heated at 120° C. for 3 days. Then, the reaction mixture was cooled to RT and diluted with H2O (100 mL). Then, the reaction mixture was stirred at 0° C. for 1 h. The resulting precipitate was filtered, washed with H2O and dried in vacuo to yield ethyl 2-amino-4-trifluoromethyloxazole-5-carboxylate (A-1) as a white powder (9.8 g, 74% yield). LCMS (ESI) calcd for [M+1]+ 225.1. found 225.1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]#[N:19])(=[O:28])=[O:27])[N:3]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: Brc1n[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1S(=O)(=O)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) in 2 ml CH2Cl2 was added triethylamine (308 mg, 3.05 mmol) and 2-cyanobenzene-1-sulfonyl chloride (205 mg, 1.02 mmol). The reaction mixture was stirred overnight at room temperature. After completion the reaction mixture was concentrated under reduced pressure and the product was purified on SiO2 using 0% to 50% ethyl acetate in heptane as the eluent to give 3-bromo-1-(2-cyanophenylsulfonyl)-1H-indazole (360 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1>>[ClH:1].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: Clc1ccnc2ccccc12
Product: Cl
Product: c1ccc2c(c1)CN(c1ccnc3ccccc13)C2

Procedure:
The title compound m.p. 264-267° C. and MS: m/e=247.3 (M+H+), was prepared from 4-chloroquinoline and 2,3-dihydro-1H-isoindole.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:36]1[C:45]2[C:44](=[O:46])[NH:43][CH:42]=[CH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:43]4[C:44](=[O:46])[C:45]5[N:36]=[CH:37][CH:38]=[CH:39][C:40]=5[CH:41]=[CH:42]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=c1[nH]ccc2cccnc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cccnc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A suspension of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (27.0 mg, 0.051 mmol), 1,7-naphthyridin-8(7H)-one (22.4 mg, 0.153 mmol) and Cs2CO3 (66.5 mg, 0.204 mmol) in anhydrous DMF (1.0 mL) was heated in a microwave at 150° C. for 50 min. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 90% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H32ClN4O4S: 639.2; found: 639.3.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][C:6]=1Br.C([Li])CCC.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.Cl.[CH2:27]([O:29]CC)[CH3:28]>CN(C)C(=O)C>[C:27]([C:2]1[O:3][CH:4]=[CH:5][C:6]=1[B:13]([OH:18])[OH:14])(=[O:29])[CH3:28]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccoc1Br
Reactant: CCOCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)N(C)C
Product: CC(=O)c1occc1B(O)O
Temperature: -70 °C

Procedure:
2,3-Dibromofuran (5.00 g) was dissolved in anhydrous diethyl ether (200 mL) and cooled to −70° C., under an atmosphere of nitrogen. n-Butyllithium (2.5M solution in hexanes, 10.2 mL) was added and the resultant mixture was stirred at −70° C. for 50 minutes. A solution of anhydrous N,N-dimethylacetamide (2.3 mL) in diethyl ether (20 mL) was added and the mixture was warmed to −10° C. The solution was re-cooled to −70° C. and n-butyllithium (2.5M solution in hexanes, 11 mL) was added and the resultant mixture stirred at −70° C. for 1 hour. Tri-isopropyl borate (6.2 mL) was added and the reaction mixture was stirred while the temperature rose from −70° C. to 0° C. The mixture was acidified with 4M hydrochloric acid, extracted into ether, dried (MgSO4) and filtered. The filtrate was concentrated to give an oil which was triturated with tert-butyl methyl ether and the solid obtained was collected by filtration and dried under vacuum to give 2-acetyl-furan-3-boronic acid (0.760 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: OCCCCl
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCSc1ccc(F)cc1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Part A: A solution of 10 g (78 mmol) of 4-fluorothiophenol and 8 g (86 mM) of 3-chloro-1-propanol in 80 mL of anhydrous DMF was purged with nitrogen for 20 min., then treated with 32 g (234 mM) of potassium carbonate. After one hour, the reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine (3×), dried (MgSO4), and concentrated to afford 16 g of crude product. The crude product was chromatographed on silica gel using 30-45% ethyl acetate/hexane to yield 12 g of pure 3-[(4-fluorophenyl)thio]propan-1-ol, m/z=203 (M+NH4).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:55]([OH:57])=[O:56])[CH2:43][CH2:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:40])[CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:58]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:59]([C:71](ON1C(=O)CCC1=O)=[O:72])[CH2:60][C:61](=[O:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CCN(CC)CC.CS(C)=O>CN(C=O)C>[NH:58]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:59]([C:71]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:55]([OH:57])=[O:56])[CH2:43][CH2:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:40])[CH2:30][O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:27])[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:72])[CH2:60][C:61](=[O:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
Boc-Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (54.5 g, 61.7 mmol) was treated with HCl in THF (1.5 liters; 4.1 N; 40 min) and worked up as usual to give HCl.H-Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (46.3 g, 56.6 mmol) as a white powder. It was then stirred in DMF (500 ml) with Boc-Asp(OBzl)-OSu (23.7 g, 56 mmol) at 0° for 2 hours in the presence of Et3N (16 ml). The mixture was further stirred at 25° for 15 hours during which time 7.4 ml more of Et3N was added. The product was worked up as usual and crystallized from CH2Cl2 and petroleum ether: yield, 50.35 g (82.7%); mp 111°-113°; [α]D25 =+7.21° (c 1, DMSO).