Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(CC)CC.[NH2:37][CH2:38][CH2:39][OH:40].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:38][CH2:39][OH:40])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and 2-amino ethanol (40 mg, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 76 mg (68%) of the title compound as an off white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14].[CH3:32][S:33]([CH:36](O)[CH3:37])(=[O:35])=[O:34].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14]
Reactant: CC(O)S(C)(=O)=O
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(O)c2ccccc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCS(C)(=O)=O)c2ccccc2c1O

Procedure:
10 g (0.023 mol) of 1,4-dihydroxy-N-n-hexadecyl-2-naphthamide, 5.7 g (0.046 mol) of methylsulfonylethanol and 4.4 g (0.023 mol) of p-toluenesulfonic acid were added to 50 ml of dehydrated toluene. The mixture was refluxed with heating for 5 hours and the water produced was removed. Toluene was removed under reduced pressure. 100 ml of methanol was added to the mixture. The crystals thus deposited were collected by filtration to obtain 10.8 g (88%) of Coupler (2). Melting Point: 107° to 109° C. (recrystallized from methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+]>COCCOC.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>[Cl:14][C:6]1[CH:5]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(Br)c2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C)cc3)c2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of compound ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68 mmol), Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (325 mg) as thick oil.
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2C=CC=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.8 g (22.6 mmol) 3-pyridyl-methyltriphenylphosphonium chloride in 40 mL dry tetrahydrofuran at 0° C. is added slowly 9.0 mL (22.5 mmol) of 2.5 M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 hour, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-(formylmethyl)-8-(t-butyldimethylsiloxy)octanoate in 10 mL dry tetrahydrofuran is added slowly and then stirred for 16 hours. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporation and the residue is purified by silica gel chromatography using 1:1 hexane, ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsiloxy)octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:29][C:30]=1[O:36][CH3:37])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1OC

Procedure:
In analogy to the procedure described in example 1 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-methoxy-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as light yellow solid. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 4-chloro-1H-indole-2,3-dione, and (2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compound was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.48 (t, 1H), 7.08 (d, 1H), 6.67 (d, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 268.6 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(OC)[C:21](=[O:30])[C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH2:29].C([Li])CCC.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[NH2:29])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)c2cc(Cl)ccc2N)C1
Temperature: -78 °C
Yield: 23.3 %

Procedure:
In tetrahydrofuran (15 ml) were dissolved N-tert-butoxycarbonyl-5-bromo-1,2,3,4-tetrahydroisoquinoline (0.9 g) and N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (0.68 g). The solution was cooled to −78° C., to which was added dropwise, while stirring, n-butyl lithium (1.6 mol, hexane solution) (9 ml) over 30 minutes. To the reaction mixture was added water (50 ml) to decompose, followed by extraction with ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(N-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)carbonyl-4-chloro-aniline (0.26 g) as a yellow crystalline product. m.p.: 159-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH2:27][CH2:28][C:29]1([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:46][C:47]([CH:50]([CH3:52])[CH3:51])=[N:48][N:49]=3)(=[O:43])=[O:42])=[CH:37][CH:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:27][CH2:28][C:29]1([C:35]2[CH:36]=[CH:37][C:38]([S:41](=[O:43])(=[O:42])[NH:44][C:45]3[S:46][C:47]([CH:50]([CH3:52])[CH3:51])=[N:48][N:49]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:8])[CH3:2]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(C3(CN)CCCCC3)cc2)s1
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NCC1(c2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)CCCCC1
Yield: 94.6 %

Procedure:
55 mg of 2-ethoxy-4-trifluoromethyl-benzoic acid (example 1g), 85 mg Totu and 100 mg N,N-diisopropylethylamine were dissolved in cold dimethylformamide. After 30 minutes 100 mg of 4-(1-aminomethyl-cyclohexyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide hydrochloride were added and the mixture stirred over night. After evaporation of the solvent the residue was purified by chromatography on silica gel with the eluents dichloromethane:methanol=98:2 to obtain 134 mg of an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)([CH2:25][CH:26]([CH3:28])[CH3:27])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:25]\[CH:26]([CH3:28])[CH3:27])/[C:18]([CH3:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(O)(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2,5-trimethylhexanoate (280 mg, 0.7 mmol) was dissolved in 10 mL MeOH and 5 mL H2SO4 and heated at 90° C. for 12 h. After 12 h, diluted with water and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 1:9 EtOAc/hexane. Obtained 220 mg (82% yield) of (E)-methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate. MS found: (M+H)+=381.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12].C1OC(C2C=CSC=2)OC1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>C(=O)(O)[O-].[Na+]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])(=[O:13])=[O:12]
Reactant: NCCCCO
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc(C2OCCO2)cs1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCCO)c1sccc1C1OCCO1
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride, prepared from thiophene-3-carboxaldehyde ethylene acetal (20.0 g, 128 mmol) as described in Example 6, Step A, was combined with 4-amino-1-butanol (17.1 g, 192 mmol) and triethylamine (15 g, 148 mmol). The reaction was stirred for 1 h, a saturated aqueous solution of sodium bicarbonate (200 mL) was added and this mixture was stirred for 1 h. The organic layer was separated, dried (MgSO4), and evaporated to a residue which was purified by column chromatography (silica, 50% ethyl acetate/hexane to ethyl acetate, gradient) to give an oil (26.45 g, 62%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[C:18]1([NH:24][C:25](=[O:26])[O:14][C:9]2[CH:10]=[C:11]([Cl:13])[CH:12]=[C:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:15][CH2:16][CH3:17])[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(COc1cc(O)cc(Cl)c1)OCC
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(COc1cc(Cl)cc(OC(=O)Nc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Diethoxyethoxy)-5-chlorophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-diethoxyethoxy)-5-chlorophenyl] N-phenylcarbamate as the residue.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Solvent: Cc1ccccc1
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.) in toluene (200 ml.) is added benzoyl chloride (1.4 g.). The mixture is refluxed for 18 hours, cooled to room temperature and the precipitate collected, washed with hexane and dried to afford 2.8 g. (65% yield) of 3-(3-carbomethoxythioureido)-4-benzamidobenzophenone as a gray solid, m.p. 191°-192° C., dec.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:6][C:7]1[CH:8]=[C:9]([C:12](=[O:17])C(Cl)(Cl)Cl)[NH:10][CH:11]=1>C(#N)C>[I:6][C:7]1[CH:8]=[C:9]([C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[NH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(c1cc(I)c[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Pyrrolidine (3 mL, 35.62 mmol) was added to a stirred solution of 4-iodo-2(trichloroacetyl)pyrrole (10 g, 29.69 mmol) in acetonitrile (50 mL) at room temperature. The mixture was stirred at room temperature for 1 hr. The white precipitate was filtered and washed with acetonitrile (25 mL) to give title compound as a white solid (7.3 g, 86%).; Mass Spec FIA MS 291.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
Step C (1): A mixture of 3-methyl-1H-1,2,4-triazole (15.0 g, 181 mmol), 1,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80° C. for 48 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol, 17% yield) as an off-white solid. Pure fractions of the more polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (6.23 g, 28.0 mmol, 15% yield) as an off-white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10][CH2:11][CH2:12][CH2:13][O:14]C1CCCCO1>CO>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Agent: Cl
Solvent: CO
Product: OCCCSc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.2 %

Procedure:
1M Hydrochloric acid (170 mL) was added to a solution of 2-[3-(2,4-difluorophenyl)sulfanylpropoxy]oxane (Intermediate 26) (10.8 g, 37 mmol) in methanol (170 mL) and stirred at ambient temperature for 40 minutes. The methanol was removed under reduced pressure and the remaining aqueous phase taken to pH 6. The solution was extracted with ethyl acetate (3×50 mL) and the combined organics washed with brine (50 mL), dried (MgSO4) and the solvent removed under reduced pressure to afford the product (7.5 g, 99%). 1H NMR δ (400 MHz, CDCl3): 1.38 (t, 1H), 1.83 (quintet, 2H), 2.97 (t, 2H), 3.77 (q, 2H), 6.81-6.87 (m, 2H), 7.38-7.45 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[CH:29]=1)([CH3:27])[CH3:26].C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)no1)C(F)(F)F
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (144 mg, 0.46 mmol) in anhydrous THF (5.6 mL), was added 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 259A (161 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (31 mg, 0.25 mmol). The mixture was stirred at rt for 15 h. To the suspension was added diethyl ether. Sonication and filtration afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (134 mg, 55%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.28-7.54 (m, 5H), 6.89 (s, 1H), 3.99 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[Br:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14](Br)[CH:13]=1.[Br-].[Li+]>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:17]=1
Reactant: C1CCNC1
Reactant: COCOc1cc(Br)cc(Br)c1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cc(Br)cc(N2CCCC2)c1
Temperature: 78 °C
Yield: 16.8 %

Procedure:
A solution of pyrrolidine (1.66 g, 23.27 mmol), in dry tetrahydrofuran (20 ml) was cooled to −78° C. under argon atmosphere. A solution of n-BuLi (15.5 ml, 1.5 M in hexanes) was added via slow drop-wise addition over 5 minutes. After complete addition the cooling bath was removed and the mixture allowed to warm to ice bath temperature over 30 minutes. A second oven dried flask was charged with 1,3-dibromo-5-methoxymethoxy-benzene (5.74 g, 19.4 mmol) and lithium bromide (1.68 g, 19.4 mmol) and taken up in dry tetrahydrofuran (10 ml). This flask was then cooled to 78° C. under argon. The contents of the first flask (slurry containing the lithio salt of pyrrolidine) was taken up in a syringe with wide bore needle and added via drop-wise addition to the second flask (over 10 minutes). The mixture was allowed to slowly warm to ambient temperature over night. The mixture was quenched via the addition of 1 N HCl (23 ml), saturated aqueous NH4Cl (34 ml) and water (40 ml). Ethyl acetate (80 ml) was added and the material shaken in a separtatory funnel. The ethyl acetate phase was collected and washed with an equal volume of 50% diluted brine solution. The aqueous phases were back extracted with ethyl acetate (2×50 ml), the organics combined, dried (MgSO4), filtered and stripped to provide a yellow remainder. The oil was purified by silica gel chromatography using 4%-8% EtOAc in hexanes as eluant to provide 930 mg of 1-(3-Bromo-5-methoxymethoxy-phenyl)-pyrrolidine as a light yellow mobile oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
A mixture of 4-(4-chlorophenyl)piperazine (6.63 g, 33.7 mmol) and sulfamide (3.89 g, 40.5 mmol) in water (10 ml) was heated at 120° C. After 96 h, the reaction mixture was cooled to RT, diluted with ethyl acetate (100 ml). Water (100 ml) was added and the reaction mixture was stirred vigorously for several minutes. The solid was filtered to give [4-(4-chlorophenyl)-piperazine-1-sulfonyl]amine as a white powder (59%), mp 218.0-220.0° C.