Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:34])[C:24]=2[N:23]=[C:22]1[CH2:35][CH2:36][CH2:37][CH3:38]>ClCCl>[NH2:34][C:25]1[C:24]2[N:23]=[C:22]([CH2:35][CH2:36][CH2:37][CH3:38])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:7]3[C:6]4[CH:5]=[CH:4][N:3]=[CH:2][C:11]=4[CH:10]=[CH:9][CH:8]=3)(=[O:14])=[O:13])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A suspension of isoquinoline-5-sulfonyl chloride hydrochloride (0.83 g in 50 ml of pyridine, 3.1 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol) and dichloromethane (175 ml). The solution turned a bright yellow color and was maintained at room temperature for 4 hours. An additional 0.18 g of isoquinoline-5-sulfonyl chloride hydrochloride was added and the reaction was maintained an additional 60 hours. The yellow solution was concentrated in vacuo, dissolved in dichloromethane, and washed sequentially with saturated aqueous sodium bicarbonate and water. The organic fraction was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol) to provide 0.7 g of N5-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-isoquinolinesulfonamide as a white crystalline solid, m.p. 96.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (d, J=0.7 Hz, 1H), 8.64(d, J=6.1 Hz, 1H), 8.41-8.35 (m, 2H), 8.30 (dd, J=7.4, 1.2 Hz, 1H), 8.11 (t, J=5.6 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.41 (dt, J=7.7, 1.2 Hz, 1H), 7.22 (dt, J=7.6, 1.2 Hz, 1H), 6.47 (broad s, 2H), 4.38 (t, J=7.5 Hz, 2H), 2.86-2.74 (m, 4H), 1.78-1.63 (m, 4H), 1.50-1.34 (m, 4H), 0.94 (t, J=7.4 Hz, 3H); MS (E1) m/e 502.2151 (502.2151 calcd for C27H30N6O2S). Anal calcd for C27H30N6O2S: C, 64.52; H, 6.02; N, 16.72. Found: C, 64.03; H, 6.03; N, 16.55.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:12])[CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1cccc(S(C)(=O)=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1cccc(CBr)c1

Procedure:
A solution of 1.0 g of 3-methanesulphonyltoluene in 5.9 ml of tetrachloromethane was admixed with 1.05 g of N-bromosuccinimide 11.8 mg of 2,2′-azoisobutyronitrile at 25° C. and subsequently refluxed for 5 hours. After decanting the orange precipitate was washed with tetrachloromethane and the combined organic phases were concentrated under reduced pressure. The 3-bromomethylphenyl methyl sulphone thus obtained was used in the next stage without further clarification. 100 mg of (E/Z)-N′-(4-bromo-2-cyano-5-hydroxyphenyl)-N,N-dimethylformimidamide are suspended in 1.5 ml of acetone together with the bromide freshly prepared above and after admixture of 95.4 mg of potassium carbonate refluxed for 3 hours. After cooling to 25° C., the reaction mixture was admixed with 25 ml of water and washed twice with 25 ml of ethyl acetate each time. The combined organic phases were washed with 25 ml of saturated sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel with ethyl acetate to obtain 166 mg of (E/Z)-N′-[2-Cyano-5-(3-methanesulphonylbenzyloxy)-4-bromophenyl]-N,N-dimethylformamidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[C:11]1([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([C:6]3[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
In 4 ml of ethanol was dissolved 415 mg of 2,4-dichloro-6-methylpyrimidine, and the solution was cooled with ice-water. To the solution were added 503 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 664 mg of diisopropylethylamine, followed by stirring overnight under cooling with ice. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=10/1 to 3/1) to give 491 mg of 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[S-:12][C:13]#[N:14].[NH4+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][C:13]#[N:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: COc1ccc2cc[nH]c2c1
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(SC#N)c[nH]c2c1
Yield: 28.8 %

Procedure:
Using the procedure described in Tetrahedron Letters 40 (1999), 1195-1196, 6-methoxy-1H-indole (1.0 g, 6.8 mmole) and ammonium thiocyanate (0.621 g, 8.1 mmole) were dissolved in methanol (35 ml) and treated with ceric ammonium nitrate (8.56 g, 15.6 mmole)in methanol (175 ml) at room temperature. The reaction mixture was stirred for 15 m and then diluted with water (700 ml) and extracted with methylene chloride (4×125 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel) using ethyl acetate:hexane (1:9) as the eluting solvent to afford 6-methoxy-3-thiocyanato-1H-indole (0.40 g 29% yield).
Reaction SMILES: [C:1]1([S:7][C:8](=[CH2:11])[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8](=[CH2:11])[CH2:9][OH:10])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CO)Sc1ccccc1
Solvent: ClCCl
Product: C=C(CO)S(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of 0.91 g (5.5 mmol) of 2-(phenylthio)-2-propenyl alcohol in 60 mL of CH2Cl2 at -78° C. was added 1.11 g (5.5 mmol) of 85% m-chloroperbenzoic acid. The reaction mixture was stirred for 1 hour at -78° C. The cooling bath was removed and the mixture allowed to warm to room temperature. The mixture was filtered, and then extracted with three 50-mL portions of saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The residue was flash chromatographed on silica gel (230-400 mesh, 4×12-cm packed column) with 80% EtOAc/Skelly B as eluant, to give 0.57 g (57%) of the sulfoxide as a colorless oil; IR (neat) cm-1 3360, 1440, 1030, 990, 930, 750, 690; 1H NNR (CDCl3) δ4.00 (s, 1 H, allylic), 4.15 (s, 1H, allylic), 4.40 (bs, 1H, OH), 5.90 (t, J=1 Hz, 1H, vinyl), 6.05 (s, 1H, vinyl), 7.35-7.80 (m, 5H, phenyl).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16](Br)[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.[F-].[K+]>O1CCOCC1.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>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH:20]=[CH2:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nc(NCc2ccccc2)c2scc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
N-Benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (200 mg, 0.56 mmol) was dissolved in dioxane (2.5 mL) and nitrogen was flown for 20 minutes. After adding Pd(PPh3)4 (41 mg, 0.036 mmol) and tributyl(vinyl)tin (0.18 mL, 0.62 mmol), the mixture was stirred at 120° C. for 7 hours. The reaction mixture was cooled to room temperature and stirred for 2 hours after adding 10% potassium fluoride aqueous solution (5 mL). The reaction solution was filtered with celite and washed with ethyl acetate. The aqueous layer was separated from the organic layer and extracted once more with ethyl acetate. The combined organic layer was concentrated by drying with MgSO4. Purification of the mixture by silica gel chromatography (DCM/MeOH=97/3) yielded the target compound (95 mg, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](N2C=CN=C2)=[O:40])=[CH:34][C:33]=1[O:46][CH3:47]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:40])=[CH:34][C:33]=1[O:46][CH3:47]
Reactant: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1OC
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 64.6 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (50.5 mg, 0.119 mmol) and 4-[(imidazole-1-carbonyl)-amino]-2-methoxy-benzoic acid methyl ester (325.2 mg, 1.181 mmol) in CH2Cl2 (8 mL) was stirred at reflux for 16 hrs. The reaction mixture was then purified by flash column to give rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester (48.5 mg, 64.6%). HRMS (ES+) m/z Calcd for C32H31Cl2F2N3O4+H [(M+H)+]: 630.1733; Found: 630.1738.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:9](OCC)(OCC)([O:11][CH2:12][CH3:13])[CH3:10]>CC(O)=O>[CH2:9]([O:11][CH2:12][CH:13]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Product: CCOCC=C(C#N)C(=O)OCC
Temperature: 135 °C
Yield: 82.6 %

Procedure:
To a stirred solution of Ethyl cyanoacetate (46.8 g, 414 mMol) and Triethyl orthoacetate (84.4 g, 520 mMol), in a 250 mL round bottom flask fitted with a short path distillation head, was added HOAc (1.2 mL, 21 mMol). The reaction was slowly heated to 135° C. and maintained at that temperature to distill off the ethyl alcohol that was produced. (Distillation started at ˜106° C.) At 15 min. intervals HOAc (1.2 mL, 21 mMol) was added to the reaction for an additional three times. The reaction was then slowly heated to 150° C. then cooled back down to ˜80° C. The title product (62.64 g, 82%) was obtained by short path distillation under high vacuum (bp 128° C., HV) as a pale yellow crystalline solid. (Note; Cooling to the condensor was shut off to prevent plugging.): 1H NMR (400 MHz, CDCl3) δ 4.27 (q, 2H), 4.22 (q, 2H), 2.61 (s, 3H), 1.43 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:52](Cl)[CH2:53]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:52][CH3:53])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCCCl
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccc(F)c(F)c3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccc(F)c(F)c2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 1.50 g 4-((S)-4-Carboxy-2-{[5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3,4-difluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml dichloromethane were added 481 mg EDC, 306 mg DMAP and 617 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 520 mg MS (ES+): m/e=746.
Reaction SMILES: [OH:1][CH:2]([C:16]1[N:17]=[C:18]([CH2:28][CH2:29][CH2:30][CH3:31])[N:19](C(OC(C)(C)C)=O)[CH:20]=1)[CH:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([OH:6])=[O:5].C(OCC)(=O)C.[ClH:38]>>[ClH:38].[OH:1][CH:2]([C:16]1[N:17]=[C:18]([CH2:28][CH2:29][CH2:30][CH3:31])[NH:19][CH:20]=1)[CH:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: CCCCc1nc(C(O)C(C(=O)O)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(O)C(C(=O)O)c2ccc3c(c2)OCO3)c[nH]1

Procedure:
A solution of (2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionic acid (250 mg) in 4N hydrogen chloride-ethyl acetate solution (3 ml) was stirred at ambient temperature for 18 hours. The solution was evaporated in vacuo and then the residue was solidified with ether. Resulting powder was collected by filtration and dried to afford (2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1H-imidazol-4-yl)propionic acid hydrochloride (65 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1.C(O)(=O)C.Br>O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A mixture of the title A compound, 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene (16.4 g, 60 mmol), acetic acid (AcOH; 100 mL) and aqueous 48% hydrobromic acid (HBr; 100 mL) is heated at 120° C. for 16 h. The mixture is cooled to RT, diluted with water (200 mL) and the precipitated product is collected by vacuum filtration, washed with water and hexanes and dried in vacuo to afford 3,5-dimethyl-4-(4′-hydroxyphenoxy)nitrobenzene: NMR (CDCl3) 2.22 (s, 6H), 6.62 (d, 2H, J=8.7), 6.77 (d, 2H, J=8.7), 8.0 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=1>C([O-])(O)=O.[Na+]>[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[C:42]([C:47]([F:48])([F:49])[F:50])[CH:41]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(CC(=O)Nc2ccc(OC)cc2C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 20.2 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of 2-(4-(methoxycarbonyl)phenyl)acetic acid (300 mg, 1.54 mmol) were added HOBt (417 mg, 3.09 mmol), EDC (593 mg, 3.09 mmol) and DIEA (539 μL, 3.09 mmol). After 1.5 h, 4-methoxy-2-(trifluoromethyl)aniline (325 mg, 1.70 mmol) was added. After stirring for 14 h, the mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 114 mg (31%) of methyl 4-(2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-2-oxoethyl)benzoate INT-54. LCMS-ESI (m/z) calculated for C18H16F3NO4: 367; found 368 [M+H]+, tR=3.27 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.40 (t, J=14.6 Hz, 2H), 7.13 (s, 1H), 7.09-6.96 (m, 2H), 3.92 (d, J=10.8 Hz, 3H), 3.81 (m, 5H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[N:18]=[C:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1csc(-c2nc(O)c3ccccc3n2)n1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1csc(-c2nc(Cl)c3ccccc3n2)n1
Temperature: 100 °C

Procedure:
Compound 50 (100 mg, 0.37 mmol) was added to phosphorous oxychloride (2 mL) and heated to 100° C. for 2 h. The reaction mixture was then poured on ice with vigorous stirring and made basic with NaOH (aq). The resulting slurry was extracted with ether (3×20 mL) and the combined organic phases were dried (MgSO4) and filtered. Removal of the solvent in vacuo afforded the title compound in quantitative yield. LC/MS>95%, m/z (ESI+)=290 (MH+).
Reaction SMILES: [C:1]([C:4]1([CH2:7][CH2:8][C:9]([O:11]C)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+]>O1CCCC1.CN(C)C=O>[CH2:5]1[C:4]2([CH2:7][CH2:8][C:9](=[O:11])[CH2:2][C:1]2=[O:3])[CH2:6]1
Reactant: COC(=O)CCC1(C(C)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCC2(CC2)C(=O)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
74.5 g of methyl 3-(1-acetylcyclopropyl)propionate (0.32 mol) are dissolved in 1 l of tetrahydrofuran and the solution is treated portionwise with 14.3 g of sodium hydride (55% suspension in oil, 0.32 mol) at room temperature. After 1 hour, the reaction mixture is diluted with 200 ml of dimethylformamide and warmed to 70° C. After 8 hours, tetrahydrofuran is removed in vacuo, and the residue is poured into 2 N hydrochloric acid and extracted with diethyl ether. The organic phase is dried over sodium sulfate and concentrated, and column chromatography over silica gel (methylene chloride:ethanol 9:1 as eluent) gives spiro[2.5]octane-4,6-dione in the form of white crystals of melting point 116-118° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:8]([F:20])([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][OH:18]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: OCc1cc(F)ccc1OC(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: OCc1cc(F)ccc1OC(F)(F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 85 %

Procedure:
473 mg (1.36 mmol) of {2-[(4-bromophenyl)(difluoro)methoxy]-5-fluorophenyl}methanol from Example 39A are dissolved in 8 ml of 1,2-dimethoxyethane and, under argon, 362.6 mg (1.91 mmol) of 4-trifluoromethylphenylboronic acid, 67 mg of bis(triphenylphosphine)-palladium(II) chloride and 1.5 ml of a 2 M solution of sodium carbonate in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 5 g of Celite, washed with dichloromethane and concentrated. The resulting crude product is purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 532 mg (1.29 mmol, 90% purity, 85% yield) of a colorless oil are obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]3[CH:31]=[CH:30][C:22]4[O:23]C(C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:45]>CO.C1COCC1.CO>[ClH:45].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([OH:27])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CCCc3ccccc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(CCCc3ccccc3)c3ccc(O)c(C(=O)O)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(3-phenylpropyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (147 mg, 0.26 mmol) in MeOH/THF (9 ml, (2/1)) was added an aqueous solution of NaOH (0.3 mL, 5N). The reaction mixture was stirred at rt for 48 hrs. Then a solution of HCl in MeOH (2.5 mL, 1.25M) was added and the solvents were 5 removed under reduced pressure. The residue was taken up with water (5 mL), extracted with Et2O (2×5 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved in a solution of HCl in Et2O (2 mL, 1N). Evaporation of the solvent gave 60 mg (32%) of the title compound as a brown foam. HPLC, Rt: 4.8 min (purity: 78.1%). LC/MS, M+(ESI): 518.4, M−(ESI): 516.3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C:13]([O:15]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:17].[OH-]>CO.C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C:13]([NH2:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 50 mg of methyl (2R-cis)-3-(benzyloxymethyl)oxirane carboxylate in 3 ml of MeOH was added 1 ml of concentrated NH4OH with rapid stirring. The mixture was allowed to stir for two days. The reaction was then diluted with 20 ml of CHCl3 and the organic layer separated and washed three times with 10 ml of 0.1N HCl. The combined organic layers were dried over MgSO4, filtered and evaporated to yield a pale yellow residue. Flash chromatography (7 mm column, 5% MeOH: CHCl3) afforded 24.2 mg of a clear oil which solidified upon standing. 1H NMR (CDCl3) 7.4-7.2 (m, 5), 6.08 (br, 1), 5.64 (br, 1), 4.58 (dd, 2, J=12, 15 Hz), 3.8 (m, 1), 3.5-3.4 (m, 3). Mass Spectra: EI: M-41 (--CONH2) Calc. 163.0758, Found 163.0745.