Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[N:7][C:6]=1[CH3:24])=O.[Li]>O1CCCC1>[F:23][C:20]([F:21])([F:22])[C:12]1[CH:11]=[C:10]([C:8]2[S:9][C:5]([CH2:3][OH:2])=[C:6]([CH3:24])[N:7]=2)[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=1
Reactant: COC(=O)c1sc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1C
Agent: [Li]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc1CO
Temperature: 0 °C
Yield: 95.1 %

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazole-5-carboxylic acid methyl ester (0.545 g, 1.42 mmol), is dissolved in anhydrous tetrahydrofuran (6 mL) and cooled to 0° C. with stirring under nitrogen. Lithium aluminumhydride, 1.0M in THF, (1.40 mL, 1.40 mmol) is added and the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is quenched with water, base, more water, and celite added, followed by dilution with ether. The mixture is filtered through a plug of celite and the two phases are separated. The organic layer is washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The [2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol (0.460 g, 1.35 mmol) is formed in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH2:10][C:9]([Cl:15])(S(Cl)(=O)=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[S:18]([O-])([O-:20])=[O:19].[Na+].[Na+].O>>[Cl:15][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]=1[S:18]([OH:20])=[O:19]
Reactant: O=C(O)C1=C(Cl)CC(Cl)(S(=O)(=O)Cl)C=C1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl

Procedure:
This compound is prepared following substantially the same procedure described in Example 1, Step A, using the following substances:2,4-dichloro-4-chlorosulfonylbenzoic acid 145 g. (0.5 mole)10N sodium hydroxide 145 ml.sodium sulfite 189 g. (1.5 mole)water 0.5 liter
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1)(=[O:24])=[O:23]
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cc1C
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2nc(Cl)c(NS(=O)(=O)c3ccccc3Cl)nc2cc1C
Yield: 71.3 %

Procedure:
According to Example 132, by use of 2,3-dichloro-6,7-dimethylquinoxaline (Compound HC) (300 mg, 1.32 mmol), dimethyl sulfoxide (5 mL), 2-chlorobenzenesulfonamide (253 mg, 1.32 mmol) and potassium carbonate (182 mg, 1.32 mmol), the mixture was stirred and reacted at 150° C. for 2 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-(3-chloro-6,7-dimethylquinoxalin-2-yl)benzenesulfonamide (360 mg, yield: 71%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19](=[O:52])[C@@H:20]([NH:34][C:35](=[O:51])[C@@H:36]([CH2:44][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:21][C:22]2[N:23](C(OC(C)(C)C)=O)[CH:24]=[N:25][CH:26]=2)[C@@H:9]([OH:17])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19](=[O:52])[C@@H:20]([NH:34][C:35](=[O:51])[C@@H:36]([CH2:44][C:45](=[O:50])[C:46]([CH3:48])([CH3:49])[CH3:47])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:21][C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)[C@@H:9]([OH:17])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1cncc1C[C@H](NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
408 mg (0.565 mmol) of (S)-N-[(1S,2S)-1-(cyclohexyl methyl)-2-hydroxy-3-(2-oxo-1-pyrrolidinyl)propyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-3-t-butoxycarbonylimidazole-4-propionamide were dissolved in 5.5 ml of methanol, treated with 23 mg of potassium carbonate and stirred at room temperature for 5 hours. Thereafter, the reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride extracts were dried over potassium carbonate and evaporated, and the residue was chromatographed on 35 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent, whereby there were obtained 280 mg (80%) of (S)-N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-(2-oxo-1-pyrrolidinyl)propyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-imidazole-4-propionamide as an amorphous solid, MS: 622 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(Br)ccc2oc(CO)c(C)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COc1c(Br)ccc2oc(C=O)c(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 0.21 g (0.77 mmole) of 5-bromo-4-methoxy-3-methyl-1-benzofuran-2-yl) methanol (Example 136, Step 1) in 6 mL of dichloromethane, 0.36 g (0.85 mmole, 1.1 eq) of Dess Martin periodinane was added. The reaction was stirred at room temperature for 2 hours and then diluted with 15 mL of ether. To the reaction was added 5 mL of 1NaOH and the mixture was stirred for 30 minutes. The reaction was diluted with ether and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.19 g of 5-bromo-4-methoxy-3-methyl-1-benzofuran-2-carbaldehyde. Yield 90.4%; m.p. 81-82° C.; MS: 268.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1csc(Nc2cc(O)ccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2cc(Oc3ccc(C#N)cc3)ccn2)n1
Yield: 22.2 %

Procedure:
Following the method of Example 1, Step D, 2-(4-methylthiazol-2-ylamino)pyridin-4-ol (0.100 g, 0.483 mmol), 4-fluorobenzonitrile (0.064 g, 0.531 mmol) and potassium carbonate (0.167 g, 1.21 mmol) were reacted to provide 4-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzonitrile (0.033 g; 20.0% yield) as white solid. 1H NMR (CDCl3) δ 8.27 (d, 1H), 7.72 (m, 1H), 7.70 (m, 1H), 7.18 (m, 1H), 7.16 (m, 1H), 6.52 (dd, 1H), 6.49 (m, 1H), 6.38 (s, 1H), 2.28 (d, 3H). HPLC (5 to 95) Rt=2.69 min; Mass spectrum (esi) m/z=309 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH2:8][CH:7]2O)([O-:3])=[O:2].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N+:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: COCC1(C)CC(O)c2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCC1(C)C=Cc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Yield: 99.1 %

Procedure:
To 10.1 g of 6-nitro-4-hydroxy-2-methoxymethyl-2,5,7,8-tetramethylchroman, 200 ml of benzene was added and 1.0 g of p-toluenesulfonic acid was added, followed by heating at reflux for 2 hours using a Dean-Stark apparatus. The reaction solution was poured into water and then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, 9.4 g of the objective oily compound was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CC=CC=1.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C1C=CC=CC=1>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][I:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: II
Reactant: OCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: ICCCOCc1ccccc1
Reaction time: 15 h
Yield: 53 %

Procedure:
To a solution of 83.3 g. (0.318 mole) triphenylphosphine in 200 ml. benzene was added, in four portions, 80 g. (0.318 mole) of iodine. The resultant mixture was stirred 3 hours and then 50 ml. (0.618 mole) of pyridine was added followed by the slow addition of 32 g. (0.192 mole) of 3-benzyloxypropanol in 250 ml. of benzene. The reaction was stirred 15 hours longer and then diluted with 40 ml. of methanol. The mixture was filtered through diatomaceous earth and the filtrate evaporated to an oil. Distillation of the crude oil yielded 28 g. (53%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(Cl)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.20 g of 5-chloro-2-hydroxymethyl-3-methylimidazo[5,4-b]pyrdine (prepared as described in Preparation 44), 2.83 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.51 ml of tributylphosphine, 1.53 g of 1,1'-(azodicarbonyl)di-piperidine and 25 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 2:1 to 1:1 by volume as the eluent, to give 1.29 g of the title compound, melting at 97°-99° C. (softening).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:14].[CH2:27](N(CC)CC)C.ClC(OC)=O>ClCCl.O>[CH3:27][O:24][C:23](=[O:25])[C:22](=[O:26])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:18]=1
Reactant: CCN(CC)CC
Reactant: O=C(COc1ccc2ccccc2c1)Nc1ccc(C(=O)C(=O)O)cc1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid (3.0 g) in dichloromethane (50 mL) and triethylamine (2.1 g ) was stirred at 0° C. and treated with methyl chloroformate (1.16 mL). The mixture was stirred for one hour and diluted with water, extracted with dichloromethane, dried (Na2SO4), filtered and evaporated. The residue was crystallized from dichloromethane-hexane to give 2.2 g of 4-[[2-(2-naphthalenyloxy) acetyl]amino]-alpha-oxobenzeneacetic acid methyl ester, mp 175°-176° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:27][CH2:26][CH2:25][C:5]2=[C:6]2[C:10]=1[NH:9][C:8]([C:11](=[O:14])[NH:12][CH3:13])=[C:7]2[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.O1CCCC1>[Pd].C(O)C>[CH3:13][NH:12][C:11]([C:8]1[NH:9][C:10]2[C:6]([C:7]=1[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]1[CH2:25][CH2:26][O:27][C:4]1=[CH:3][CH:2]=2)=[O:14]
Reactant: CNC(=O)c1[nH]c2c(Br)cc3c(c2c1CCNC(=O)OC(C)(C)C)CCO3
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1[nH]c2ccc3c(c2c1CCNC(=O)OC(C)(C)C)CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl {2-[5-bromo-7-(methylcarbamoyl)-1,6-dihydro-2H-furo[3,2-e]indol-8-yl]ethyl}carbamate (569 mg), triethylamine (0.724 mL), tetrahydrofuran (10.0 mL), and ethanol (30.0 mL) was added 10% palladium on carbon (50% water included, 284 mg) under an argon gas flow, followed by stirring at room temperature overnight under a hydrogen atmosphere (3.2 kgf/cm2). The catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to obtain tert-butyl {2-[7-(methylcarbamoyl)-1,6-dihydro-2H-furo[3,2-e]indol-8-yl]ethyl}carbamate (434 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][C:5]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:4][CH:3]=1.C(O)C>[Fe].C(O)(=O)C>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Temperature: 25 °C

Procedure:
To N-(6-methyl-3′-nitrobiphenyl-3-yl)-3-(trifluoromethyl)benzamide (1.00 g, 2.50 mmol) was added ethanol (18 mL) and acetic acid (1.7 mL) and iron (770 mg). The resulting mixture was heated to reflux until LCMS indicated complete reduction, typically 2-4 hours. The reaction was cooled to ambient temperature, and the unreacted iron was removed by filtration. The ethanolic filtrate was evaporated to dryness and EtOAc was added to the residue. The resulting rust-like particulates were removed by filtration through a small pad of diatomaceous earth, and the filtrate was evaporated to dryness to leave the crude aniline. The compound was recovered in quantitative yield and was used without further purification in the subsequent reaction. MS (EI) m/z=371 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:13][NH:14][NH2:15]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:12])[N:14]([CH3:13])[NH2:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N=C=S)cc1
Reactant: CNN
Solvent: CCO
Product: CCOc1ccc(NC(=S)N(C)N)cc1
Yield: 79.5 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.5 g (0.0698 mole) of 4-ethoxyphenyl isothiocyanate and 3.22 g (0.0698 mole) of methylhydrazine in 100 ml of ethanol yielded 12.5 g of 4-(4-ethoxyphenyl)-2-methyl-3-thiosemicarbazide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH2:37][CH3:38])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH2:37][CH3:38])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of 18.3 (0.040 g, 0.077 mmol) in THF/MeOH (2/1) (1.5 mL) was added LiOH (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford 18 (0.0130 g, 34% yield). MS ESI (neg.) m/e: 489.2 (M−H)+.
Reaction SMILES: [CH2:1]([CH:8]([CH2:14][C:15]#[C:16]C)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](C(CC#CC)C(O)=O)C1C=CC=CC=1>>[CH2:1]([C:8]([CH3:18])([CH2:14][C:15]#[CH:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#CCC(Cc1ccccc1)C(=O)O
Reactant: CC#CCC(Cc1ccccc1)C(=O)OCC
Product: C#CCC(C)(Cc1ccccc1)C(=O)O

Procedure:
By replacing ethyl 2-benzyl-2-methyl-5-trimethylsilylpent-4-ynoate with ethyl 2-benzylhex-4-ynoate, 2-benzylhex-4-ynoic acid was prepared; IR: 3300-2500, 1710 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:27](=[O:28])[C@@H:19]([NH:18][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Brc1ccc2c(c1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(Br)cc21
Reaction time: 60 h
Yield: 42.8 %

Procedure:
The 6-bromoindoline (1050 mg, 5.30 mmol), N—BOC-phenylalanine (1.41 g, 5.30 mmol), N-ethyl-N-isopropylpropan-2-amine (2.02 ml, 12.2 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.41 g, 6.36 mmol) (HBTU) were dissolved in DMF. The reaction mixture was stirred for 2.5 days. The reaction was diluted with water and then extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with 1M lithium chloride solution (2×70 mL) and brine (1×70 mL) and dried over magnesium sulfate. The crude product was then recrystallyzed using ethyl acetate:hexanes to give (S)-tert-butyl 1-(6-bromoindolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (1.01 g, 42.8% yield). MS ESI (pos.) m/e: 445.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C)C=O>[CH2:20]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10])[CH:19]=[CH2:18]
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 1-(2-hydroxy-4-methyl-phenyl)-ethanone (10 g, 67 mmol) in dimethylformamide (100 mL) was added potassium carbonate (18.4 g, 133 mmol), followed by allyl bromide (5.75 mL, 67 mmol). The reaction was stirred at room temperature for 16 hours. The residue was partitioned between ethyl acetate (200 mL) and water (800 mL), the organics were separated, and washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. After cooling the concentrate to room temperature the title compound crystallised as colourless platelets, 12.40 g, in a 98% yield. LCMS (2 min acidic) 1.20 min 72-100% pure by UV, ES+/AP+ 191. 1HNMR (400 MHz, CDCl3) δ ppm 2.37 (s, 3H), 2.63 (s, 3H), 4.61-4.66 (m, 2H), 5.33 (dq, 1H), 5.44 (dq, 1H), 6.10 (m, 1H), 6.76 (s, 1H), 6.80-6.83 (m, 1H), 7.68 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)[NH:5][C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7]>CCCCC>[CH:10]12[CH2:18][CH:14]3[CH2:13][CH:12]([CH2:17][CH:16]([CH2:15]3)[CH:9]1[O:8][C:6]([NH:5][C@H:4]([C:3]([OH:30])=[O:2])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=1)=[O:7])[CH2:11]2
Reactant: COC(=O)[C@H](Cc1ccc2ccccc2n1)NC(=O)OC1C2CC3CC(C2)CC1C3
Solvent: CCCCC
Product: O=C(N[C@@H](Cc1ccc2ccccc2n1)C(=O)O)OC1C2CC3CC(C2)CC1C3
Yield: 52 %

Procedure:
Method was as described for Example 30, Step 5, but using N-(2-adamantyloxy-carbonyl)-3-(quinolin-yl)-alanine methylester (1.0 g, 2 mmol) to obtain N-(2-adamantyloxy-carbonyl)-3-(quinolin-yl)-alanine (0.41 g, 42.4%) as a solid from n-pentane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][O:19][CH3:20])=[CH:13][N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Oc1ccc(OCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(OCc2ccccc2)nc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 mL) was added NaH (60% in mineral oil; 0.6 g, 15 mmol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (0.88 g, 11 mmol, 1.1 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH4Cl(sat.) solution; The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-(benzyloxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. MS (ESI) m/z 246.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[OH2:22]>C(O)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][NH:3][C:2](=[O:22])[CH:12]=1
Reactant: O
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(I)cc1F
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Yield: 59 %

Procedure:
Ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate (2.03 g, 4.83 mmol) was dissolved in acetic acid (75 mL), to which was added water (25 mL). This solution was heated at reflux for 14 h. The mixture was allowed to cool, then refrigerated, and a cream solid crystallised out. This material was isolated by filtration, washed well with water and hexanes, then dried to afford ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a white solid (1.14 g, 59%), m.p. (acetone/MeOH) 262-264° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.59 (br s, 1H), 9.32 (s, 1H), 8.10 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.61 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 5.38 (d, J=1.3 Hz, 1H), 7.26-7.33 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H). Anal. Calcd for C14H12FIN2O3: C, 41.8; H, 3.0; N, 7.0. Found: C, 41.9; H, 2.8; N, 7.0.