Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>>[Cl:22][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccccc1-c1cccc2[nH]c(=O)n(C)c12
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccccc1-c1cccc2nc(Cl)n(C)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
A mixture of 190 mg (0.753 mmol) of 7-(2-ethylphenyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 1.5 mL of phosphorus oxychloride was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into ice and neutralized by 12 N sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 3-10% ethylacetate/n-hexane gradient mixture to give 123 mg (60%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Br:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Br:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Brc1cc(Br)c2c(c1)CCN2
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 165° C.; 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J=1.8 Hz, 1 H), 7.29 (d, J=1.8 Hz, 1 H), 7.02 (s, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 4.06 (app. q, J=8.0 Hz, 1 H), 3.15 (t, J=8.1 Hz, 2 H), 1.99-1.74 (m, 2 H), 1.11-0.99 (m, 1 H), 0.94 (t, J=7.5 Hz, 3 H), 0.88-0.73 (m, 1 H), 0.57-0.46 (m, 2 H), 0.39-0.27 (m, 1 H); HRMS (CI) calcd for C18H19N3OBr2Cl (M+H)+: 485.9583; found m/z 485.9604.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH2:5]>>[CH2:3]=[CH:2][CH2:1][S:4](=[O:5])[S:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCS
Reactant: O
Product: C=CCSS(=O)CC=C

Procedure:
First prepare a 1/400 dilution of allyl mercaptan by adding 1.25 ml (a quarter teaspoon) of food grade allyl mercaptan to 500 ml of distilled water.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:7]([C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=1)[CH3:8])=[CH2:6])[CH3:2].CCOC(C)=O.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH:7]([C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[CH:13][CH:14]=1)[CH3:8])[CH3:2]
Reactant: C=C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 91 %

Procedure:
TEA (0.076 mL, 0.542 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-acrylic acid ethyl ester (158 mg, 0.493 mmol) in thioacetic acid (2 mL) at 0° C. under argon. The mixture was stirred at 45° C. over night. EtOAc was added and the solution was washed with NaHCO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 5:1→1:1) gave slightly unpure 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-butyric acid ethyl ester (178 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]C(=O)N(C)C)=[CH:8][C:7]=1[CH3:18].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:18]
Reactant: COC(=O)CCc1ccc(SC(=O)N(C)C)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccc(S)cc1C
Temperature: 25 °C
Yield: 118.3 %

Procedure:
3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methyl ester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and to this is added sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol). The reaction is heated to reflux under nitrogen and monitored by TLC. After complete conversion, 20 h., the reaction is allowed to cool to room temperature. The reaction is neutralized with 1N HCl (7.23 mL) and diluted with ethyl acetate (150 mL). The two phases are separated and the organic layer is washed with water (75 mL), then brine (75 mL). The organic layer is then dried over anhydrous sodium sulfate, then concentrated to yield 4.43 g crude product that is used without further purification.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13].[N:16]#[C:17][NH2:18]>>[ClH:1].[CH2:6]([C:5]1[N:14]=[C:17]([NH2:18])[NH:16][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]
Reactant: N#CN
Reactant: C#CCCCCCCC(N)C(=O)OC
Agent: Cl
Product: C#CCCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-dec-9-ynoic acid methyl ester hydrochloride (1.50 g, 6.42 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.774 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (400 MHz, CD3OD) δ 6.09 (s, 1H), δ 2.19 (t, 2H), δ 1.95 (t, 1H), 1.93 (m, 2H), δ 1.39-1.11 (m, 8H) ppm; 13C NMR (75 MHz, CD3OD) δ 148.5, 131.0, 110.1, 83.9, 68.3, 28.6, 28.5, 28.4, 28.3, 25.7, 17.8 ppm; HRMS (ESI) calcd for C11H18N3 (M+) 192.1495. Found 192.1495.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([CH2:20][CH2:21][CH3:22])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:20][CH2:21][CH3:22])[C:10]([OH:12])=[O:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCC[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C
Yield: 66.3 %

Procedure:
The crude (S)-benzyl 2-(dibenzylamino)pentanoate (3) (2.2 Kg) was dissolved in methanol (5.5 L). A previously prepared, cold (0-5° C.) solution of sodium hydroxide (568 g; 14.2 mol) in water (6 L) was added to the solution of (3), and the resulting mixture heated at 90° C. for 20 hours. The reaction mixture was then allowed to cool to ambient temperature, and the methanol evaporated under reduced pressure. The residue was diluted with water (25 L), and extracted with methyl t-butyl ether/hexane (1:1; 2×5 L) to remove the benzyl alcohol formed in the hydrolysis. The basic aqueous layer was acidified to pH 2 with 6M aqueous hydrochloric acid (4 L), then extracted with ethyl acetate (2×8 L). The combined organic extracts were dried over sodium sulfate and the solvent removed under reduced pressure, to afford a semi solid, which was washed with hexanes (8 L) to provide 1.12 Kg of (S)-2-(dibenzylamino)pentanoic acid, a compound of formula (4), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15](Cl)[CH3:16])[CH2:11][CH2:10]1.Cl.[CH3:19][NH2:20]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:20][CH3:19])[CH2:11][CH2:10]1
Reactant: CN
Reactant: COc1ccccc1N1CCN(C(C)Cl)CC1
Agent: Cl
Solvent: CCO
Product: CNCCN1CCN(c2ccccc2OC)CC1

Procedure:
8 ml of ethanol were added to a mixture of 8.9 g of 4-(o-methoxyphenyl)-1-chloroethyl-piperazine .HCl in 20 g of an aqueous solution of 34.88% methylamine and the mixture was stirred for 1 hour at room temperature and then for 4 hours at reflux. The ethanol was evaporated and after cooling the mixture, 5 g of sodium hydroxide pellets were added thereto. The mixture was extracted with ethyl ether and the extracts were dried over potassium carbonate and the solvent was evaporated. The oily residue was distilled to obtain 2.6 g of 4-(o-methoxyphenyl)-1-(β-methylaminoethyl)-piperazine in the form of a yellow oil boiling at 153°C under 0.2 mm Hg. The oil was soluble in ethanol and ethyl ether and slightly soluble in water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH3:21][C:22]1([CH3:34])[CH2:26][C:25](=[O:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23]1>C1COCC1>[CH3:21][C:22]1([CH3:34])[CH2:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:27])[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23]1
Reactant: CC1(C)C=C(c2ccccc2)C(=O)C1
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C2(O)CC(C)(C)C=C2c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-bromothioanisole (2.51 g, 12.3 mmol) in THF (20 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyl lithium in hexane (4.8 mL, 12.0 mmol). The resulting suspension was stirred at this temperature for 1 h and then a solution of 4,4-dimethyl-2-phenyl-2-cyclopenten-1-one from Step 2 (1.25 g, 6.7 mmol) in THF (20 mL) was added slowly via cannula to the cold reaction. The reaction was stirred for 15 min at −78° C. and then for 30 min. at r.t. The reaction was stopped by dilution with NH4OAc buffer 25% w/v and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes to give the title compound as a colorless gum.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH:29]4[O:34][C:33]5[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=5[O:31][CH2:30]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl- 1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol- 3-yl)-1-piperidinyl]methyl-1,4benzodioxan as off-white crystals, 2.22 g, m.p.=8687° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(OCC)(=O)C>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1cc(-c2ccccc2)ccc1O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1cc(-c2ccccc2)ccc1OC(=O)OCC
Reaction time: 8 h
Yield: 93.1 %

Procedure:
At 5 to 10° C., 18.4 g (0.17 mol) of ethyl chloroformate are added dropwise with cooling to a solution of 36.3 g (0.17 mol) of 4-hydroxy-3-propyl-biphenyl in 160 ml of ethyl acetate and 17.2 g (0.17 mol) of triethylamine. The solution is left standing overnight at 20° C. and washed with water and dilute hydrochloric acid, and the organic phase is dried and concentrated 45 g (yield 93.2% of theory) of (4-phenyl-2-propyl-phenyl) ethyl carbonate are obtained as a pale oil of log p=4.76 (pH=2.3).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>>[N+:13]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Product: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
D-Phenylalanine (12.0 g, 73 mmol) and potassium nitrate (11 g, 109 mmol) were loaded into a teflon HF apparatus commonly used for the deprotection of peptides. The mixture was treated with liquid HF at approximately 0° C. for one hour. After removal of the HF by vacuum, the residue was dissolved in water and treated with concentrated ammonia until pH 6. The precipitate was recrystallized from hot water. Yield 9.31 g (61%) of a nearly white solid, mp 236.5°-237° C., [α]D25 =-8.63° (c=1.7, 1N HCl).
Reaction SMILES: [OH:1][C@@H:2]([CH2:36][C@@H:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH2:39])[C@@H:3]([NH:8][C:9]([C@@H:11]([NH:18]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]>C(Cl)Cl.N1CCCCC1>[NH2:18][C@@H:11]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:9]([NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C@@H:2]([OH:1])[CH2:36][C@@H:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH2:39])=[O:10]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C

Procedure:
1.3 g of fluoren-9-ylmethyl [(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamate in 30 ml of methylene chloride and 2 ml of piperidine were stirred at room temperature for 1.5 hours. Thereafter, the solvent was evaporated and the residue was triturated with hexane. The (S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamide so obtained was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[CH:22]([O:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].I[CH2:36][C:37]#[N:38]>C1COCC1>[C:37]([CH2:36][N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:10]([CH:22]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=3)[CH3:23])[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)#[N:38]
Reactant: N#CCI
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(CC#N)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VIII-B-1) (25 mg, 0.053 mmol) in THF (2 mL) was added NaH (2.4 mg, 55% purity, 0.056 mmol). After 10 min. 2-iodo acetonitrile (13 mg, 0.079 mmol) was added and stirring was continued at RT overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:33])([F:32])[F:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3C(F)(F)F)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-trifluoromethyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:28]([Cu])#[N:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:9]2=[C:10]([C:28]#[N:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 508 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=[O:13])[CH2:5]1.O>C(O)C>[OH:13][CH:6]1[CH2:5][C:4]([CH3:14])([CH3:3])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]1=2
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(O)c2sccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.97 g, 25.5 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno-[3,2-b]pyran-7-one (3.1 g, 17.0 mmol) in ethanol (50 mL) and stirred at rt for 2 h. An additional 0.97 g of sodium borohydride was added and the mixture was stirred 16 h. The mixture was poured into water and extracted with dichloromethane. The dichloromethane solution was washed with water (5×) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product, 2.96 g (95%), as a brown oil: IR (neat): 3373, 2976, 1561 and 1400 cm-1 ; MS: m/z 185 (MH+); 1H NMR (CDCl3): δ1.34 (s, 3H), 1.45 (s, 3H), 1.87 (m, 1H), 1.94 (d, J=7.0 Hz, 1H, exchanges with D2O), 2.16 (m, 1H), 4.88 (m, 1H), 6.57 (d, J=5.4 Hz, 1H), 7.13 (d, J=5.4 Hz, 1H). This oil was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14](OC)=[O:15])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:14][OH:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(Br)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 5-bromo-[1,1′-biphenyl]-2-carboxylate (2.2 g, 6.9 mmol) in THF (50 mL) was cooled to 0° C. LiAlH4 (380 mg, 10 mmol) was added slowly. The reaction mixture was stirred at RT for 2 h, after which water (1 mL) was added slowly to quench the reaction. The solid was removed by filtration and the filtrate was concentrated in vacuo to provide (5-bromo-[1,1′-biphenyl]-2-yl)methanol as a white solid that was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH:32]([CH3:36])[C:33](O)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C>>[C:26]1([CH:32]([CH3:36])[C:33]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: CC(C(=O)Nc1cccc(-c2n[nH]c3ccc(C(N)=O)cc23)c1)c1ccccc1
Yield: 18.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-phenylpropionic acid (97 μL, 0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 40 mg (17% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 10.3 (s, 1H), 8.6 (s, 1H), 8.2 (br s, 1H), 8.35 (br s, 1H), 7.94 (dd, 1H), 7.7 (m, 2H), 7.6 (d, 1H), 7.5–7.3 (m, 5H), 7.25 (m, 1H), 3.8 (s, 1H), 1.4 (d, 3H); ES-MS (m/z) 385 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:24])([F:23])[O:22][C:18]=3[CH:17]=2)=[S:14])=[O:11])[CH:7]=[C:6]([CH3:27])[N:5]=1.[CH3:28]I.O>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([CH3:27])[N:5]=1)[C:10]([NH:12][CH:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]2[O:20][C:21]([F:24])([F:23])[O:22][C:18]=2[CH:17]=1)[S:14][CH3:28])=[O:11]
Reactant: Cc1cc(C(=O)NC(=S)Nc2ccc3c(c2)OC(F)(F)O3)cc(Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(NC(=O)c1cc(C)nc(Cl)c1)Nc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH, 60% (2.2 g; 0.0550 mol) was stirred in THF (170 ml) on an ice bath under N2. Intermediate D1 (19.3 g; 0.500 mol) was then added and stirred for 1 hour at 0° C. CH3I (7.8 g; 0.0550 mol) was then added and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the THF was evaporated in vacuo. The precipitate was filtered off, washed with water and dried. Yield: 22.86 g of intermediate D2.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.C(=O)(O)O.[NH2:17][C:18]([NH2:20])=[NH:19]>C(O)C>[NH2:20][C:18]1[N:19]=[C:8]([OH:10])[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:17]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(O)c2c(n1)CCCC2
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a solution of ethyl 2-oxocyclohexane carboxylate (41 g, 241 mmol) in ethanol (200 ml) was added guanidine carbonate (26.0 g, 289 mmol) under stirring at room temperature. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The precipitated crystals were filtered and washed with water, followed with methanol. The crystals were dried in vacuo to give the object compound (35.5 g, 89%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:42]([N:45]=[C:46]=[O:47])([CH3:44])[CH3:43].C(N(CC)CC)C.ClCCl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:46]([NH:45][CH:42]([CH3:44])[CH3:43])=[O:47])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)N=C=O
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)NC(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with isopropyl isocyanate/triethylamine/dichloromethane as described in Example 93 to provide the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.82 (3H, d), 0.98 (3H, d), 1.1 (3H, d), 1.35-1.42 (1H, m), 1.90-1.95 (1H, m), 2.4 (1H, t), 2.65-2.80 (3H, m), 2.9-3.0 (2H, m), 3.3-3.4 (1H, m), 3.50-3.63 (6H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.05 (1H, br d), 5.45 (1H, d), 6.18 (2H, s), 6.92 (2H, d), 7.0 (1H, d), 7.18 (2H, d), 7.22 (1H, s), 7.3 (2H, d), 7.58 (1H, d); MS: 678 (MH+); C32H43N3O11S.