Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1>O1CCCC1>[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=3)=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: Cc1nccn1-c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(-n3ccnc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5.0 g of p-tetradecyloxy phenylacetyl chloride in 50 ml of tetrahydrofuran is added to a solution of 4.31 g of pyridine and 2.36 g of 4-(2-methyl-1H-imidazol-1-yl)benzenamine in 50 ml of tetrahydrofuran over 5 minutes. The mixture is stirred at ambient temperature for 1 hour, heated to reflux and allowed to stir at room temperature for 2 hours. The solvent is evaporated to a residue which is partitioned between chloroform and dilute sodium bicarbonate. The organic layer is separated, washed with water, dried and filtered through a pad of magnesium silicate. The solvent is evaporated to an oil which crystallizes from methyl alcohol:water to give 4.0 g of white solid Which is chromatographed on silica gel using ethyl acetate containing 0.1% ammonium hydroxide to give 3.9 g of the desired product as a white solid, m.p. 106°-109° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Si:35]([CH3:62])([CH3:61])[CH2:36][CH2:37][O:38][CH2:39][N:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH2:45][NH:46][CH2:47][C:48]1[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][N:52]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[C:2]1([CH2:1][O:8][C:9](=[O:10])[N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:46]([CH2:47][C:48]3[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][N:52]=3)[CH2:45][C:41]3[N:40]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:61])([CH3:62])[CH3:34])[CH:44]=[CH:43][N:42]=3)=[O:30])=[CH:32][CH:33]=2)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a solution of the compound 5 (137 mg) in dichloromethane (3 mL), the compound 2 (131 mg), 1-hydroxybenzotriazole (69 mg), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (86 mg) and diisopropylethylamine (105 μl) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was added by water and then extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100→dichloromethane:methanol=10:1) to obtain the title compound (225 mg) having the following physical properties.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14]O.S(Cl)([Cl:18])=O.[ClH:20]>>[Cl:20][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][Cl:18]
Reactant: Cl
Reactant: O=S(Cl)Cl
Reactant: OCCCOCCOCCOCCCO
Product: ClCCCOCCOCCOCCCCl

Procedure:
1.1 g, (4.9 mmol) 15 was added to 1.15 g (14.6 mmol) distilled pyridine in 30 mL dry benzene with stirring, followed by 1.8 g (14.6 mmol) thionyl chloride. The mixture was heated to reflux for 6 hours. After cooling in an ice bath, 5 mL 3M HCl was added with vigorous stirring. The organic layer was separated, washed 3× with a dilute brine solution, and dried (MgSO4) to yield a yellowish oil. After washing and removal of solvent, the dichloride was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:23]=O>C(O)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:23])=[CH:4][C:3]=1[C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=O
Reactant: CCCCCCC#Cc1cc(OC[C@@H]2CCCN2)cnc1Cl
Solvent: O=CO
Product: CCCCCCC#Cc1cc(OC[C@@H]2CCCN2C)cnc1Cl
Product: Cl
Temperature: 80 °C
Yield: 89 %

Procedure:
To 6-Chloro-5-(1-octynyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine from Example 140 above (330 mg, 0.78 mmol) was added formalin (37%, 4 mL) and formic acid (2 mL), and the mixture was heated at 80° C. for 10 h. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with CH2Cl2, which was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; CH2Cl2/MeOH/NH4OH, 10:1:0.1) to give the free base of the title compound (93 mg, 89% yield). The base was converted to the salt by treatment with HCl in Et2O to give the title compound: mp 223-225° C.; 1H NMR (D2O) δ0.83-0.93 (m, 3H), 1.20-1.30 (m, 4H), 1.34-1.46 (m, 2H), 1.48-1.68 (m, 2H), 1.96-2.20 (m, 3H), 2.28 (m, 1H), 2.34-2.45 (m, 2H), 2.94 (s, 3H), 3.18 (m, 1H), 3.64 (m, 1H), 3.83 (m, 1H), 4.24 (m, 1H), 4.36 (m, 1H), 7.43 (s, 1H), 8.68 (br s, 1H); MS (CI/NH3) m/z 335 (M+H)+. Anal. Calcd for C19H27ClN2O·1.5HCl·0.4 Et2O: C, 59.02; H, 7.81; N, 6.68. Found: C, 59.32; H, 7.54; N, 6.51. [α]25D +8.99 (c 0.14, MeOH).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[C:28]([N:32]1[CH2:37][CH:36]=[C:35]([Sn](C)(C)C)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[C:28]([N:32]1[CH2:33][CH:34]=[C:35]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:36][CH2:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Solvent: C1COCCO1
Product: CC(C)(C)N1CC=C(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Reaction time: 8 h

Procedure:
A mixture of 100 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 94 mg of 1-tert-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (COMPOUND PPA-2) in 2 mL of dry dioxane was evacuated and purged three times with Ar. Pd(Ph3P)4 (23 mg) was added and the mixture was evacuated and purged again with Ar. The mixture was heated to reflux and stirred at this temperature overnight, then filtered through Celite and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH, to yield the title compound. The HCl salt was prepared by dissolving this compound in CH2Cl2, adding 1 eq 1M HCl in Et2O, and concentrating. Mass spectrum (ESI) 540 (M+1).
Reaction SMILES: [NH:1]1[C:5](B(O)O)=[CH:4][CH:3]=[N:2]1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O.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>[C:14]([O:13][C:11](=[O:12])[CH2:10][N:2]1[CH:3]=[CH:4][C:5]([C:25]2[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[N:1]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OB(O)c1ccn[nH]1
Reactant: Nc1ncc(Br)cn1
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: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc(-c2cnc(N)nc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1H-pyrazol-5-ylboronic acid (0.2 g, 2 mmol) in N,N-dimethylformamide (1.0 mL) were added 1,1-dimethylethyl bromoacetate (0.38 g, 2 mmol) and potassium carbonate (0.74 g, 0.0054 mol). The reaction mixture was stirred overnight at RT. To the reaction mixture was added 5-bromopyrimidin-2-amine (0.40 g, 2.3 mmol) and tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol). The resulting mixture was stirred at 100° C. for 2 h. After cooling to RT, the reaction mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by RP-HPLC to afford the desired product. LCMS: (M+H)=276.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([SH:13])=[CH:11][CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13][CH3:18])=[CH:11][CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(S)n1-c1ncccc1Cl
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)n1-c1ncccc1Cl
Yield: 64.2 %

Procedure:
A mixture of 0.50 g of 1-(3-chloro-2-pyridinyl)-5-mercapto-1H-pyrrole-2-carbaldehyde, 0.36 g of methyl iodide, 0.43 g of potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at room temperature for 1 day Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.34 g of 1-(3-chloro-2-pyridinyl)-5-methylthio-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:14]
Reactant: NO
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc2ccccc2c1

Procedure:
2-Cyanonaphthalenes are prepared by refluxing 2-formylnaphthalene with hydroxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding which is refluxed with acetic anhydride in the presence of an acid catalyst to furnish 2-cyanonaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13]C)[C:5]=1[CH:15]=[O:16].B(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH:15]=[O:16]
Reactant: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a suspension of 95.3 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester in 250 ml of dichloromethane were added 800 ml of a 1M solution of boron trichloride in dichloromethane over 40 min at a temperature of 5°-10° C. The mixture was allowed to warm to 20° C. within 30 min and stirring was continued at room temperature for 4 h. The clear solution was cooled to 5° C. and then poured into a mixture of 1.5 l of ice-water and 0.5 l of dichloromethane. The layers were separated and the aqueous phase was back-extracted with 0.4 l of dichloromethane. The organic layers were washed with water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from ethyl acetate/hexane provided 77.3 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester as colorless crystals of m.p. 118°-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23]/[NH:22][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(c1cccc(Br)c1)c1ncccc1O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(C)(C)N/N=C(/c1cccc(Br)c1)c1ncccc1O
Yield: 24.3 %

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-hydroxypyridine (0.79 g), t-butylhydrazine hydrochloride (0.53 g), triethylamine (1.2 mL) and ethanol (13 mL) was refluxed for 5 hours. The reaction mixture was poured into water, and subjected to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate), followed by evaporating the solvent under reduced pressure. The residue was purified by means of a silica gel column (ethyl acetate--hexane) to afford (E)-2-(3-bromo-α-t-butylhydrazinobenzyl)-3-hydroxypyridine (0.60 g) and (Z)-2-(3-bromo-α-t-butylhydrazonobenzyl)-3-hydroxypyridine (0.24 g) (compounds 27 and 26).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:28][C@H:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[C:12]([CH:27]=1)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:14])#[N:7].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN1CCN(C)C1=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:28][C@H:29]2[CH2:33][CH2:32][N:31]([C:2]([O:4][CH3:5])=[O:3])[CH2:30]2)=[C:12]([CH:27]=1)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:14])#[N:7]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@H]2CCNC2)cc1OC
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: COC(=O)N1CC[C@H](Nc2ccc(C#N)cc2C(=O)NCc2ccc(OC)c(OC)c2)C1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of methyl chloroformate (26 mg) in chloroform (2 mL) was added dropwise to a mixture of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (80 mg) and triethylamine (43 mg) in a mixture of chloroform (2 mL) and 1,3-dimethyl-2-imidazolidinone (1 mL) under cooling on an ice bath. The reaction mixture was stirred for 2 hours at same temperature and the reaction was quenched by addition of 3-(N,N-dimethylamino)propylamine (0.1 mL). The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with 70% ethyl acetate in hexane. The obtained crystals were recrystallized from a mixture of 2-propanol and diisopropyl ether to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidin-3-ylamino]benzamide (55 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([NH2:18])[CH:5]=1.N1C=CC=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[C:6]([NH:18][S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N+:26]([O-:28])=[O:27])(=[O:36])=[O:37])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester (817.3 mg, 3.07 mmol) in dichloromethane (10 ml), pyridine (0.373 ml, 4.60 mmol) and 2-nitrobenzenesulfonyl chloride (815 mg, 3.68 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 4 hours. Pyridine (0.050 ml) and 2-nitrobenzenesulfonyl chloride (135 mg) were added, and stirring was continued for 2 hours. The reaction mixture was concentrated under reduced pressure, water (30 ml) was added, and then extraction was performed with ethyl acetate (20 ml×3 times). The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the crystallized residue was suspended in n-hexane-ethyl acetate (4:1), filtered, and dried to obtain 4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O>[C:30]([CH2:29][CH2:28][CH2:27][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.51 g, 1.61 mmol) and dimethylformamide (15 mL). Add sodium hydride (0.086 g, 60% in oil, 2.15 mmol). Heat to 80° C. After 15 minutes, add ethyl 4-bromobutyrate (0.35 mL, 2.45 mmol) and continue heating at 80° C. After 18 hours, cool and partition the reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give (1-(3-carboethoxypropyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine.
Reaction SMILES: C(S([NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=CN=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:13]=1)=O)(C)(C)C.[ClH:33].[CH2:34](OCC)[CH3:35]>CO>[Cl-:33].[CH3:18][O:17][C:15](=[O:16])[C:14]([N:12]1[CH:13]=[C:9]([C@H:8]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:30])[F:32])=[CH:35][CH:34]=2)[NH3+:7])[N:10]=[N:11]1)([CH3:19])[CH3:20]
Reactant: COC(=O)C(C)(C)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reactant: Cl
Reactant: CCOCC
Solvent: CO
Product: COC(=O)C(C)(C)n1cc([C@@H]([NH3+])c2ccc(OCC(F)(F)F)cc2)nn1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
To a solution of 0.12 g (0.25 mmol) methyl 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoate in 1.0 ml MeOH was added 0.96 mL (1.9 mmol) 2.0M HCl in diethyl ether. After 30 min at room temperature, the reaction mixture was concentrated in vacuo to afford (S)-[1-(2-methoxy-1,1-dimethyl-2-oxoethyl)-1H-1,2,3-triazol-4-yl][4-(2,2,2-trifluoroethoxy)phenyl]methanaminium chloride. ES-MS [M+1]+=374.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[N:7]=1
Reactant: CCOC(=O)c1c(Cl)nc(Cl)nc1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(Cl)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a solution of ethyl 2,4-dichloro-6-((1,3-dioxoisoindolin-2-yl)methyl)pyrimidine-5-carboxylate (45.3 mg, 0.119 mmol) in MeCN (1 mL) was added m-toluidine (0.020 mL, 0.187 mmol) and N,N-diisopropylethylamine (0.037 mL, 0.212 mmol). The mixture was stirred at RT for 12 h. Saturated aq NaHCO3 was added to the mixture, which was subsequently extracted with EtOAc. The organic layers were washed again with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a pale brown solid (37.1 mg, 69%). 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (t, J=7.2 Hz, 3H), 2.36 (s, 3H), 4.52 (q, J=7.2 Hz, 2H), 5.20 (s, 2H), 6.97-6.98 (m, 1H), 7.23-7.27 (m, 1H), 7.33 (br s, 1H), 7.45-7.47 (m, 1H), 7.73-7.78 (m, 2H), 7.89-7.94 (m, 2H), 10.67 (br s, 1H).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[S:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1SC(C(OC)=O)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[S:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)s1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1ccc(Br)s1
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)s1
Yield: 94 %

Procedure:
Methyl 5-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)thiophene-2-carboxylate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (89 mg, 0.134 mmol) and methyl 5-bromothiophene-2-carboxylate following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (65 mg, 94%): 1H NMR (CDCl3, 400 MHz) δ 7.72 (d, 1H, J=3.6 Hz), 7.26-7.23 (m, 4H), 7.17-7.14 (m, 3H), 4.80 (t, 1H, J=6.0 Hz), 3.89 (s, 3H), 2.58 (t, 2H, J=7.6 Hz), 1.95-1.87 (m, 2H), 1.68-1.56 (m, 2H), 1.38-1.27 (m, 6H), 0.88 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.4, 150.8, 147.9, 141.3, 139.2, 137.7, 133.5, 133.3, 130.7, 129.2, 129.2, 128.5, 73.7, 57.5, 41.4, 41.0, 36.5, 34.2, 30.8, 30.9, 30.2, 23.3, 0.2, 0.0.