Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.S(Cl)([Cl:16])(=O)=O>>[Cl:16][C:9]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=S(=O)(Cl)Cl
Product: Oc1ccc(Cl)c(OC(F)(F)F)c1

Procedure:
A solution of 3-trifluoromethoxyphenol and sulfuryl chloride is stirred at room temperature until conversion of starting material to product is complete. The excess of sulfuryl chloride is evaporated using a rotary evaporator. The residue is dissolved in dichloromethane and washed with water. The organic layer is separated, dried over MgSO4, filtered and concentrated to yield crude 4-chloro-3-trifluoromethoxyphenol. The crude product is purified over a silica gel column using to give purified product that is used with or without further purification in the following reaction.
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:12]=[CH:11][C:10]=1[C:25]([F:28])([F:27])[F:26].S(=O)(=O)(O)O.[N+:34]([O-])([OH:36])=[O:35]>C(OCCCC)(=O)C>[N+:34]([C:22]1[CH:23]=[CH:24][C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([C:25]([F:26])([F:27])[F:28])=[C:9]([Cl:8])[CH:14]=2)=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])([O-:36])=[O:35]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 85 %

Procedure:
Acetic anhydride (37.7 g) was added to 3-(2-chloro-α,α,α-trifluoro-4-tolyloxy)-benzoic acid (86% strength, 45 g) in n-butyl acetate (85.8 g) at 35° C. Sulphuric acid (98%, 12.2 g) was added slowly and the mixture cooled to 0° C. Nitric acid (90%, 10.4 g) was then added slowly over about 3 hours such that the temperature was maintained at -5 to 0° C. On completion of the nitric acid addition the reaction was quenched with water (60 g) at 0° C. The mixture was warmed to 50-60° C. and the aqueous layer removed. The solvent layer was washed with water (2×100 g) at 60° C. and the aqueous layer removed. The solvent and acetic acid were removed by distillation to give 2-nitro-5-(2-chloro-α,α,α-trifluoro-4-tolyloxy) benzoic acid (85%), 2'-nitro isomer (7.5 to 8.5 pph), total dinitro's (~0.5 pph).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].[N+:26]([C:29]1[CH:39]=[CH:38][CH:37]=[C:31]2[C:32]([O:34][C:35](=O)[C:30]=12)=[O:33])([O-:28])=[O:27].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:26]([C:29]1[CH:39]=[CH:38][CH:37]=[C:31]2[C:30]=1[C:35](=[O:34])[N:2]([C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10])[C:32]2=[O:33])([O-:28])=[O:27]
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)N1
Temperature: 130 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a mixture of 4 (0.326 g, 0.881 mmol), 3-nitrophthalic anhydride (0.211 g, 1.093 mmol) and sodium acetate (0.097 g, 1.181 mmol) was added acetic acid (4.0 mL) and the resulting mixture was stirred overnight at 130° C. After 20 h, the mixture was carefully neutralized with sodium bicarbonate and extracted into DCM. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 5 (0.241 g, 54%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:16]([O:18][CH2:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:16]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)OCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of 2-(benzyloxy)-2-oxoethyl 3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-methoxybenzoate (0.508 g, 1.029 mmol) in MeOH (30 m) and EtOAc (3 ml), 10% w/w Pd/C (a catalytic amount) was added, and the mixture was hydrogenated in a Parr apparatus at 20 psi for 3 hours. The catalyst was filtered off and the filtrate was evaporated to dryness affording 2-(3-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-4-methoxybenzoyloxy)acetic acid (0.387 g, 0.959 mmol, 93% yield, MS/ESI+not detectable [MH]+). This product was used without any further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][C:11]([O:13]CC2C=CC=CC=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][CH2:8][N:9]([C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CN(CCc1ccccc1)C(=O)CCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN(CCc1ccccc1)C(=O)CCc1ccccc1
Yield: 99.1 %

Procedure:
A methanol solution (20 mL) of benzyl N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycinate (1.3 g, 3.24 mmol) and palladium on carbon (10%, 180 mg) was stirred under 1 atmosphere of hydrogen gas for 18 hours. The reaction was purged with nitrogen and filtered through a pad of diatomaceous earth and evaporated to give N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycine (1.0 g) in quantitative yield. LRMS: (M+NH3)+ =326.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[CH:4][CH:3]=1.[N:11]([CH2:14][CH2:15][O:16][CH3:17])=[C:12]=[O:13]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH:10][C:12]([NH:11][CH2:14][CH2:15][O:16][CH3:17])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: COCCN=C=O
Reactant: NNC(=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Product: COCCNC(=O)NNC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
At 50° C., 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide were substantially suspended in 30 ml of dry THF. 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane dissolved in 30 ml of THF were then added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was triturated with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 4.87 g (100% of theory) of the title compound.
Reaction SMILES: Cl[C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[CH:3]Cl.C(OCC)C.CN(CCN(C)C)C.C([Li])CCC>CCCCC.C(O)C>[C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)#[CH:3]
Reactant: ClC=C(Cl)Oc1ccc(-c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Solvent: CCO
Product: C#COc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.9 %

Procedure:
To a two-necked, round-bottomed flask (100 mL) equipped with a nitrogen inlet adapter and rubber septum was added the vinyl ether 2 (2.0 g, 7.6 mmol, 1 eq), anhydrous diethyl ether (30 mL), and TMEDA (23 mmol, 3.3 mL, 3 eq), and then cooled at −78° C. 2.5 M n-Butyllithium (9.0 mL, 23 mmol, 3 eq) was then added drop-wise to the reaction mixture for over 5 min. The reaction mixture was then maintained at −78 C for 1 h and at −40° C. for 40 min, and then cooled to −78° C. while 10% ethanol in pentane (10 mL) was added drop-wise. After 10 min, the reaction mixture was then diluted with n-pentane (20 mL) and the washed with saturated solution of ammonium chloride (25 mL). The organic phase was later washed twice with water (20 mL) and then finally with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give brown oil. The oil was purified by column chromatography with hexane as the eluent to yield 3 as dark brown oil (0.84 g, 70%) that later crystallized out as brown amorphous solid: mp 48-49° C. The compound was placed in a round bottom flask and was flushed with nitrogen and kept at −78° C. to avoid the decomposition if it was not to be used immediately. 1H NMR (300 MHz, CDCl3): 7.64-7.52 (m, 4H, HAr), 7.48-7.41 (m, 2H, HAr), 7.40-7.34 (m, 3H, HAr), 2.13 (s, 1H, ≡—H) ppm; 13C NMR (75 MHz, CDCl3): 155.0, 140.1, 138.0, 128.9, 128.4, 127.4, 127.0, 115.4, 84.5, 33.5 ppm; IR (cm−1): 3317 (≡C—H), 3029, 2927, 2174 (C≡C), 1606, 1512, 1484, 1208, 1166, 1062, 1008, 941, 838, 641, 548, 450; HRMS (ESI) Calculated for C14H10 [M−H]− 193.0654. Found 193.0651; Elemental analysis Calculated. for C14H10O.0.13H2O: C, 85.54; H, 5.26. found: C, 85.54; H, 5.38.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C(=O)C)([CH3:11])[CH3:10])=[CH:4][C:3]=1[F:16].[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:10])([NH2:12])[CH3:11])=[CH:4][C:3]=1[F:16]
Reactant: CC(=O)NC(C)(C)Cc1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(N)Cc1ccc(Cl)c(F)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 17.4 %

Procedure:
A mixture of N-(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)acetamide (3.36 g, 13.80 mmol) and concentrated hydrochloric acid (60 mL) was heated at 120° C. for 16.5 h. The mixture was cooled to rt and poured into ice water and the resulting mixture was adjusted to pH>12 with NaOH and extracted with EtOAc (80 mL×5). The combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in concentrated hydrochloric acid (60 mL) and the mixture was stirred at 120° C. for 20 h. The reaction mixture was cooled to rt and 100 mL of water was added. The resulting mixture was washed with EtOAc (50 mL×3). The aqueous phase was adjusted to pH>11 with NaOH and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (80 mL×2), dried over anhydrous Na2SO4 (20 g) and concentrated in vacuo to give the tile compound as a yellow solid (0.484 g, 17.4%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].Cl>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:16]=[CH:15][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][CH2:9][N:8]3[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCCN1CCCC1Cc1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCN1CCCC1Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cc2)cc1
Temperature: 5 °C
Reaction time: 18 h
Yield: 187.2 %

Procedure:
2-(4-Aminobenzyl)-1-propylpyrrolidine (300 mg, 1.37 mmol) was dissolved in pyridine-dichloromethane (1:2, 9 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (300 mg, 0.24 mmol) was added and the solution stirred at 5° C. for 18 h. The solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane-2% methanol) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (180 mg, 30%).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[C@H:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ncccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1 g) was dissolved in DMF (30 ml). Sodium hydride (120 mg, 60%) was added, and the suspension was stirred at room temperature for 20 min. Ethyl bromoacetate (500 mg) was added, and the mixture was stirred for 2 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentration to give ethyl (R)-2-{1-[1-(acenaphthen-1-yl)piperidin-4-yl]-1,2-dihydro-2-oxo-imidazo[4,5-b]pyridin-3-yl}acetate. 40% Methylamine-methanol solution (20 ml) was added, the mixture was stirred at room temperature for 2 hr, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.86 g) as a white powder.
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:34]([CH:36]1[C:38]([CH3:40])([CH3:39])[CH:37]1[C:41]([O:43][CH2:44][CH3:45])=[O:42])=O.C1(C)C=CC=CC=1>CCCCCC.O1CCCC1.O>[CH:34]([CH:36]1[C:38]([CH3:40])([CH3:39])[CH:37]1[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC=CC1C(C(=O)OCC)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
64.5 g of a 15% strength solution of butyl-lithium in n-hexane were added dropwise to a suspension of 68.3 g (0.15 mol) of n-octyl-triphenylphosphonium bromide in 300 ml of absolute tetrahydrofuran at 0°-5° C., with the exclusion of air. After one hour, 25.5 g (0.15 mol) of ethyl 2-formyl-3,3-dimethylcyclopropanecarboxylate were slowly added, and the mixture was further stirred for 18 hours at room temperature. The mixture was shaken after the addition of 400 ml of toluene and 300 ml of water, the water was separated off and the organic phase was washed once again with 200 ml of water. The toluene solution was then dried over sodium sulphate and the solvent was distilled off in vacuo. The residue was stirred with 300 ml of petroleum ether (40°-60° C.), the solution was filtered off from the undissolved triphenylphosphine oxide, and the filtrate was again concentrated by evaporation in vacuo. The residue was distilled in vacuo. 22.6 g (57% of theory) of ethyl 2-(1-nonen-1-yl)-3,3-dimethylcyclopropanecarboxylate with a boiling point of 90° C./0.01 mm Hg were thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19]([O:20][CH2:21]C)=[CH:18][CH:17]=[C:16]([N+:23]([O-])=O)[C:10]=1[CH:11]=[CH:12][N+]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=C([N+]([O-])=O)C=1C=C[N+]([O-])=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:10]=1[CH:11]=[CH:12][NH:23]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(C=C[N+](=O)[O-])c1OCc1ccccc1
Agent: COc1ccc([N+](=O)[O-])c(C=C[N+](=O)[O-])c1OCc1ccccc1
Product: COc1ccc2[nH]ccc2c1OCc1ccccc1

Procedure:
This compound is obtained according to the operating method described in Example lc, in which the 2-benzyloxy-3-ethoxy-6,β-dinitrostyrene is replaced with 2-benzyloxy-3-methoxy-6,β-dinitrostyrene. A white powder (yield =86%, m.p. =83°-84° C.) is obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)O)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:25])=O>O1CCCC1>[CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([CH:14]([Cl:25])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1nnc2ccc(C(O)c3cccc(Cl)c3)cc21
Solvent: C1CCOC1
Product: CCCCn1nnc2ccc(C(Cl)c3cccc(Cl)c3)cc21
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a stirred solution of 6.5 parts of 1-butyl-α-(3-chlorophenyl)-1H-benzotriazole-6-methanol in 45 parts of tetrahydrofuran were added 3.7 parts of thionyl chloride at room temperature. After stirring for 1 hour, the reaction mixture was concentrated. The product was extracted with ethyl acetate. The extract was washed with a diluted sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 6.2 parts (88.3%) of 1-butyl-6-[chloro(3-chlorophenyl)methyl]-1H-benzotriazole as a residue (int. 73).
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH3:1][C:2]([S:5][CH2:8][CH2:7][C:6]#[N:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)S
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)SCCC#N

Procedure:
β-(2-Methyl-2-propylmercapto)propionitrile was prepared according to the procedure of Example 1 using 2-methyl-2-propanethiol according to the procedure of Example 1 using 2-methyl-2-propanethiol (25.0 g; 0.28 moles), acrylonitrile (14.9 g; 0.28 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[Cl:13][CH2:14][C:15](O)=[O:16].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[Cl:13][CH2:14][C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])=[O:16]
Reactant: CC1=C(C)C(=O)N(CCO)C1=O
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(CCOC(=O)CCl)C1=O
Yield: 83.9 %

Procedure:
With stirring, 169.2 g (1 mole) of N-(2-hydroxyethyl)dimethylmaleimide, 113.4 g (1.2 moles) of chloroacetic acid and 11.8 g of concentrated sulfuric acid are heated to reflux in 1000 ml of toluene using a water separator. The formation of water ceases after about 2 hours and 18 ml have separated. The reaction solution is washed with saturated sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator at 40° C. The residue is dried for 2 hours at 60° C./0.1 mm, affording 206 g of a colourless liquid.
Reaction SMILES: F[C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=C\C1NC=CC=1OC>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.CN(C=O)C.CCN(CC)CC>[N:7]1[C:6](=[O:11])[CH:5]=[C:4]2[C:8]=1[CH:9]=[CH:10][CH:2]=[CH:3]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C=c2ccccc2=N1

Procedure:
Using Method C above, Ethyl-[(3R,4S,5R)-4-ethynyl-2,2,6-trimethyl-[1,3]-dioxan-5-yl]-carbamic acid tert-butyl ester (148.5 mg, 0.50 mmol) (Example 123C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (96 mg, 0.25 mmol) (Starting Material 6) using (Ph3P)4Pd (23.1 mg, 8 mol %) and Cul (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 5 h to give the coupling product (137.2 mg, 99.2% after flash column purification). This coupling product (125 mg) was then treated with 50% of trifluoroacetic acid/CH2Cl2 (5 mL) and 0.5 mL of water at r.t. for 1 h. The reaction mixture was concentrated to about 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic layer was washed with brine and dried with Na2SO4. After concentration, the crude product (113.6 mg) was triturated with AcOEt/hexanes and the precipitate was collected by filtration to offer (Z)-1,3-Dihydro-4-[(3R,4S,5R)-3,5-dihydroxy-4-ethylamino-1-hexynyl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (LLLLL) as a brown-orange solid. (Yield 29.5 mg, 31.6%). The filtrate was then purified via flash column chromatography (5%-10% MeOH in CH2Cl2) to give (R)-(Z)-1,3-Dihydro-4-[(5-ethylamino-6-methyl)-6H-pyran-2-yl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (MMMMM). (Yield 33.6 mg, 37.6%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[N+:14]([O-])=O)(=[O:3])[NH2:2]>[Ni].CO>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[NH2:14])(=[O:3])[NH2:2]
Reactant: COc1ccc([N+](=O)[O-])c(OCC(N)=O)c1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)c(OCC(N)=O)c1

Procedure:
930 mg of 2-carbamoylmethoxy-4-methoxynitrobenzene are hydrogenated in the presence of 300 mg of Raney nickel in 30 ml of methanol at room temperature under normal pressure for 12 h. The reaction mixture is filtered over Hyflo® and concentrated. Recrystallization of the crude product from methanol gives 2-carbamoylmethoxy-4-methoxyaniline of mp 139°-140° C.; Rf (O)=0.25.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH:10]=2)[CH:5]=[C:4]([OH:20])[C:3]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1.C(N(CC)CC)C.O.Cl>CS(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]([CH:16]=[O:17])([CH3:19])[CH3:18])[CH:10]=2)[CH:5]=[C:4]([OH:20])[C:3]=1[N:21]1[S:25](=[O:26])(=[O:27])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: CC(C)(CO)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-[1-fluoro-3-hydroxy-7-(5-hydroxy-4,4-dimethylpentyl)-naphthalen-2-yl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.00 g, 2.23 mmol) in anhydrous DMSO (10 ml) at room temperature was added triethylamine (2.17 mL, 15.6 mmol) followed by a slow addition of a solution of sulfur trioxide pyridine complex (1.28 g, 8.02 mmol) in anhydrous DMSO (12 mL). The reaction mixture was stirred for 30 min and cold water (70 mL) was slowly added. The above content was acidified with 3 N HCl to pH 2.5, extracted twice with EtOAc, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a light brown solid. Retention time=1.22 min (Method A); MS (M−H)−=407.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH3:10].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH3:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc([N+](=O)[O-])cn1
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.13 g, 10.0 mmol) and iodomethane (1.25 mL, 20.0 mmol) in DMF (12 mL), NaH (60% in mineral oil, 0.600 g, 15.0 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give 1-methyl-4-nitro-1H-pyrazole as a solid (1.11 g).