Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH:9]([CH3:13])[C:10]([OH:12])=[O:11]>>[CH3:1][S:2][CH2:3][CH2:4][O:5][CH:9]([CH3:13])[C:10]([OH:12])=[O:11]
Reactant: CSCCO
Reactant: CC(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CSCCOC(C)C(=O)O
Yield: 77.9 %

Procedure:
Addition of 2-methylthioethanol (10.0 g, 0.108 mol) to sodium hydride (9.54 g of a 60% dispersion in mineral oil, 0.238 mol, washed twice with hexane) followed by reaction with 2-bromopropionic acid (16.6 g, 0.108 mol) gave 13.81 g (78% yield) of the title compound as a clear oil; bp 80-90° C./0.2 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ ppm: 1.49 (3H, d, J=7.0 Hz, CH3), 2.18 (3H, s, SCH3), 2.76 (2H, t, J=6.6 Hz, CH2), 3.74 (2H, t, J=6.6 Hz, CH2), 4.07 (1H, d, J=7.0 Hz, OCH).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH:11]=O)=[CH:9][C:4]=2[CH2:3][O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O.CCOC(C)=O>[CH3:11][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[CH2:1][O:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=CNc1ccc2c(c1)COC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of N-(1,3-dihydro-2-benzofuran-5-yl)formamide (250 mg, 1.5 mmol) in THF (20 mL) was added LAH (1.9 mL, 2.4 M in THF, 4.6 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The solution was diluted with water (0.5 mL) and EtOAc (30 mL), dried (Na2SO4), and concentrated to give 220 mg (96%) of the title compound as a yellow oil. [M+H] Calc'd for C9H11NO, 150. Found, 150.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.C(OC([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][C@@H:46]1[CH3:51])=O)(C)(C)C>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[N:6]=[CH:7][C:2]([N:48]6[CH2:49][CH2:50][NH:45][C@@H:46]([CH3:51])[CH2:47]6)=[N:3][CH:4]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCN[C@@H](C)C5)cn3)C4)n[nH]c2c1
Yield: 25.8 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (200 mg, 386 μmol) and (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (155 mg, 773 μmol) using the method from Example 61. After purification by HPLC Method E and deprotection using HCl/dioxan, the title compound (58 mg, 25% yield over two steps) was obtained as off-white solid (HCl-salt).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.Cl[C:27]1[C:32]([S:33]([N:36]([C:46]([O:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47])[C:37]2[C:42]([O:43][CH3:44])=[N:41][C:40]([CH3:45])=[CH:39][N:38]=2)(=[O:35])=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1>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.C1(C)C=CC=CC=1.C(O)C>[CH2:49]([O:48][C:46]([N:36]([C:37]1[C:42]([O:43][CH3:44])=[N:41][C:40]([CH3:45])=[CH:39][N:38]=1)[S:33]([C:32]1[C:27]([C:7]2[CH:12]=[CH:11][C:10]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:9][CH:8]=2)=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:35])=[O:34])=[O:47])[CH:50]([CH3:52])[CH3:51]
Reactant: Clc1ncccn1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(B(O)O)cc1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Yield: 17.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (60 mg) was added to a deoxygenated solution of sodium carbonate (233 mg), 1,4-benzenediboronic acid (165 mg), 2-chloropyrimidine (114.5 mg) and 2-chloro-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (414 mg) in a mixture of water (1.6 ml), ethanol (4 ml) and toluene (8 ml). The mixture was stirred and heated under argon under reflux for 16 hours and then allowed to cool to ambient temperature. Water (15 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated sodium chloride solution and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 25-100% ethyl acetate/hexane to give N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[pyrimidin-2-yl]phenyl)pyridine-3-sulphonamide (95 mg) as a solid, mass spectrum (+ve ESP): 535 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[N:14]1.[H-].[Na+].[CH3:22]I.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][O:19][CH3:22])[CH:15]=[N:14]1
Reactant: CI
Reactant: OCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]methanol (1.5 g), sodium hydride (0.15 g) and methyl iodide (0.7 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 2 hours and left over the weekend. The mixture was added to water and extracted with ether. The extract was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methoxymethyl-2H-1,2,3-triazole, m.p. 32°-33°. (Compound 20)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>ClCCl.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: Nc1cccccc1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1cccccc1=O)C(=O)OCC

Procedure:
A mixture of 2-amino-2,4,6-cycloheptatrien-1-one (2 g), described by W. Von E. Doering and L. H. Knox, J. Amer. Chem. Soc., 73, 828 (1951), and diethyl ethoxymethylenemalonate (20 ml) was heated at 140° C. for 2 hr. The reaction was cooled and subjected to chromatography on silica gel using dichloromethane-ethyl acetate (4:1) as the eluant. The pure fractions were pooled to give 4.13 g of 2-[(7-oxo-1,3,5-cycloheptatrien-1-yl)aminomethylene]-propanedioic acid diethyl ester; mp 66°-68° C.; nmr (CDCl3) δ1.35 (m, 6H), 4.35 (m, 2H), 7.35 (m, 5H), 8.4 (d, 1H), 11.4 (broad, 1H); ir (CHCl3) 3230, 1700, 1665, 1580 cm-1 ; uv λ max (MeOH) 356 nm (ε13,770), 292 (9,880), 277 (10,680), 213 (17,020) with shoulders at 338 and 236 nm.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(OCC)(=O)C>[Cl:17][S:18]([NH:21][C:22]([N:14]1[CH2:15][C@H:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[C:13]1=[O:16])=[O:23])(=[O:20])=[O:19]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Cl)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5.19 g (0.0236 mol) of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 160 ml of ethyl acetate was added with stirring at room temperature 2.05 g (0.0236 mol) of chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature to form a solution of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0° C., 80 ml of dichloromethane was added followed by 9.9 ml (0.0707 mol) of triethylamine and a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, hydrazide (obtained from a suspension of 3.99 g (0.0236 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, hydrazide in 50 ml of ethyl acetate and 8.75 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (8.75 ml=0.0472 mol)). The mixture was stirred at room temperature overnight, then ice water was added and stirring was continued for an additional 30 minutes. The aqueous phase was layered with ethyl acetate and acidified to pH 2.5. The precipitate crystallized after stirring for one hour, yielding 6.6 g of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>O.CO>[CH2:3]([O:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A solution of potassium hydroxide (1.3 g, 22.2 mol) in water (20 m) was added to a stirred solution of ethyl 2-ethoxy-3-(3-nitrophenyl)acrylate (5.6 g, 21.1 mmol) in methanol (100 ml) and the resulting mixture heated to reflux overnight. The methanol was then evaporated in vacuo and the residue diluted with water (150 ml). The solution was washed with dichloromethane (2×80 ml), filtered through a pad of celite and then acidified by the addition of 3M HCl to pH 3. The mixture was refrigerated for 18 h then the precipitated solid was collected by filtration, washed with water (3×30 ml) and dried in vacuo at 40° C. The resulting solid was recrystallized from ethyl acetate and heptane to give 2-ethoxy-3-(3-nitrophenyl)acrylic acid as a yellow solid (3.06 g, 61%).
Reaction SMILES: [OH: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].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (1S,2S)-2-hydroxycyclohexylcarbamate (1.30 g, 6.04 mmol), 4-nitrobenzoic acid (1.11 g, 6.64 mmol), triphenylphosphine (1.74 g, 6.64 mmol) in THF (30 mL) was added diethylazo dicarboxylate (1.05 ml, 6.64 mmol) and the resulting solution was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give an orange oil that was purified by column chromatography (hexanes/ethyl acetate, 8:1) to give (1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl 4-nitrobenzoate (1.95 g, 89%).
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:18])[CH2:3]1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:18])[CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)C(F)C1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C(F)C1
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of compound 136 (0.07 g, 0.283 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.16 g, 0.566 mmol) at room temperature and stirred for overnight (16 h). Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 137 (0.09 g, 90%) as a solid. mp 115-117° C.; 1H NMR (DMSO-d6) δ 1.79-2.09 (m, 4H), 2.26 (s, 3H), 2.74-2.90 (m, 2H), 3.13-3.17 (m, 1H), 4.68 (dddd, 1H, J=4.8, 9.6, 9.6, 48.5 Hz), 6.23 (brs, 2H), 6.65 (d, 1H, J=8.1 Hz), 6.99 (s, 1H), 7.09 (t, 1H, J=4.2 Hz), 7.17 (d, 1H, J=1.5 Hz), 7.28 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.70 (d, 1H, J=3.3 Hz), 10.72 (s, 1H); ESI-MS m/z (%): 357 (MH+, 100), 179 (52); ESI-HRMS calculated for C19H22FN4S (MH+), Calculated: 357.1547, Observed: 357.1543.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C.CCOC(C)=O>[N+:18]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]#[N:15])([O-:20])=[O:19]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of sodium thiophenolate (16.29 g, 123.3 mmol) in 150 mL of DMF was heated at 100° C. with 4-chloro-3-nitrobenzonitrile (15.0 g, 82.2 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane giving a yellow solid (4.0 g, 19%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[CH:12]=2)[CH2:7][N:6]1[C:28](=[O:42])[C@@H:29]([NH:34][C:35]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:4].[CH3:43]O.[OH-].[Na+]>O1CCCC1>[CH3:43][C@@:5]1([C:3]([OH:2])=[O:4])[CH2:9][C@@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[CH:12]=2)[CH2:7][N:6]1[C:28](=[O:42])[C@@H:29]([NH:34][C:35]([NH:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: CO
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@H]3CN(C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@](C)(C(=O)O)C3)cc(-n3cccn3)nc2c1
Reaction time: 1 h

Procedure:
(2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylate was treated with methanol (6.0 mL), tetrahydrofuran (3.0 mL) and 1N sodium hydroxide (6. mL). After 1 hour at room temperature, the reaction mixture was concentrated, acidified with 1N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were then washed with brine and dried (MgSO4). The ethyl acetate layer was then filtered and evaporated to dryness to give (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2C=1)=[O:5])[CH3:2].[CH:14]([Cl:17])(Cl)Cl.[Cl:18]N1C(=O)CCC1=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:18])=[CH:13][C:8]=2[C:14]=1[Cl:17])=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CCOC(=O)c1[nH]c2sc(Cl)cc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a 0° C. solution of 6H-thieno[2,3-b]pyrrole-5carboxylic acid ethyl ester (180 mg, 0.92 mmol) in acetic add (2 mL) and CHCl3 (2 mL) was added N-chlorosuccinimide (294 mg, 2.2 mmol) over 30 min. The reaction mixture was slowly allowed to warm to room temperature over several hours, stirred overnight, concentrated to remove the chloroform, diluted with water, basified with 5 N NaOH, and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The product was purified by Chromatron-chromatography (4:1 hexanes:ether) and obtained as a white solid (180 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1CO
Solvent: ClCCl
Product: Nc1ncc(Br)cc1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
To a solution of 2-amino-3-(hydroxymethyl)pyridine (13.0 g, 116.0 mmole) in CH2Cl2 (300 mL) at RT was added NBS (22.71 g, 127.6 mmole). After stirring at RT for 45 min the reaction solution was concentrated and the residue was dissolved in CHCl3. The resulting suspension was filtered and the filtrate was concentrated to a dark oil. Purification on silica gel (EtOAc) afforded the title compound (78%, 18.36 g) as a tan solid: MS (ES) m/e 204 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][NH:27][CH2:25][CH3:26])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:10]1[C:15](O)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].[CH2:18](Cl)CCl>>[OH:9][C:4]1[C:5]2[C:14]([CH3:15])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:10])([CH3:17])[C:6]=2[C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: ClCCCl
Reactant: Cc1cccc(O)c1
Reactant: Cc1ccc(O)cc1C
Product: Cc1cc(O)c2c(c1C)C(C)(C)CCC2(C)C

Procedure:
Employing procedures and materials similar to those described in Example 1, except that 3,4-dimethylphenol was substituted for m-cresol, and the reaction was carried out in the presence of ethylene dichloride as solvent, there was obtained 1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene, 15% theor., GLC purity 100%, exhibiting the expected spectral data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 50 °C

Procedure:
467.3 g of 2-cyano-4'-methylbiphenyl, prepared above, are dissolved in 4.7 l of 1,2-dichloroethane in the presence of 467.3 g of N-bromosuccinimide and 9.3 g of benzoyl peroxide. The mixture is heated very gradually so as to have good control over the exothermic effect. It is subsequently refluxed for 4 h, cooled to 50° C. and then washed 3 times with hot water and dried and the organic phase is concentrated to give cream-colored crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][C:34]=1[CH:35]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCCCC>ClCCl>[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][C:34]=1[CH:35]=[C:20]([Br:24])[Br:21])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of triphenylphosphine (15.7 g) and carbon tetrabromide (9.93 g) in dry dichloromethane (100 mL) is cooled to 0° C. and stirred for 30 minutes. A solution of 2,4-dibenzyloxybenzaldehyde (4.76 g) in dichloromethane (30 mL) is added and the solution stirred at 0° C. for 2 hours. The solution is treated with pentane to precipitate triphenylphosphine oxide. The filtrate is evaporated to give 1-(2,4-dibenzyloxyphenyl)-2,2-dibromoethylene as a yellow oil (4.85 g, 67%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17]Br)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][O:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(Br)nc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.50 g), tert-butyl(2-bromoethyl)carbamate (2.32 g), cesium carbonate (3.65) and N,N-dimethylformamide (30 mL) was stirred at 40° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.47 g).
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)#[N:2].C(OC(C)(C)C)=O>>[NH2:24][C:23]1[C:3]([C:1]#[N:2])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(N)c2C#N)C1
Yield: 100 %

Procedure:
Prepared as in example 100b from tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 220e) in 100% yield as an oil. MS 232 [M+H-Boc]+.