Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([S:20]([NH:23][C:24]2[S:28][N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:6]=2[CH:19]=1.[CH2:29]([Zn]CC)[CH3:30]>CN1C(=O)CCC1.O.CCOC(C)=O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH2:29]([C:2]1[C:3]([S:20]([NH:23][C:24]2[S:28][N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])[C:6]=2[CH:19]=1)[CH3:30]
Reactant: CC[Zn]CC
Reactant: C[C@H](c1ccccc1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Br)cc21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc2c(cc1S(=O)(=O)Nc1ncns1)oc(=O)n2[C@H](C)c1ccccc1
Temperature: 120 °C

Procedure:
Into a solution of (R)-5-bromo-2-oxo-3-(1-phenylethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (38-1, 80 mg, 0.166 mmol, prepared from 35-3 by a reaction sequence analogous to that described herein) in NMP (831 ul) was added diethylzinc (1M in hexanes, 0.499 mmol) followed by chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7 mg, 8.9 umol). The reaction vessel was sealed and heated to 120° C. for 12 h, cooled to rt, diluted with 1 ml of H2O and 3 ml of EtOAc, filtered through celite, concentrated and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added) to yield 5-ethyl-2-oxo-3-[(1R)-1-phenylethyl]-N-1,2,4-thiadiazol-5-yl-2,3-dihydro-1,3-benzoxazole-6-sulfonamide (38-2). 1H NMR (499 MHz, DMSO): δ 8.44 (s, 1H); 7.75 (s, 1H); 7.46 (d, J=7.7 Hz, 2H); 7.36-7.38 (m, 3H); 7.06 (s, 1H); 5.63 (d, J=7.3 Hz, 1H); 2.92-2.94 (m, 2H); 1.88 (d, J=7.1 Hz, 3H); 1.09 (t, J=7.4 Hz, 3H). LRMS C19H18N404S2 [M+H] calc 431.1, obs 431.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30](Cl)[C:31]([O:33]CC)=O)=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:37][C:38]([NH2:40])=[S:39].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:39][C:38](=[NH:37])[NH:40][C:31]3=[O:33])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCCC2(C)CCc3cc(OC(C)=O)c(C(C)(C)C)cc3O2)cc1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2

Procedure:
The procedure described in Example 1(a) was repeated, except that 266 mg of ethyl 3-{4-[2-(6-acetoxy-7-t-butyl-2-methylchroman-2-yl)ethoxy]phenyl}-2-chloropropionate, 50 mg of thiourea and 4 ml of sulfolane were heated at 110°-120° C. for 4.5 hours. The product was treated as described in Example 1(a) except that the crude product was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of benzene and ethyl acetate, to give the title compound, melting at 175°-178° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 368. LCMS: 466.2.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2-].[Li+].[Li]C1C2N=CC=CC=2CCC1.[SiH3][N:25]=[C:26]=[S:27].Cl>O>[N:1]1[C:10]2[CH:9]([C:26](=[S:27])[NH2:25])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [SiH3]N=C=S
Reactant: c1cnc2c(c1)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [Li]C1CCCc2cccnc21
Solvent: O
Product: NC(=S)C1CCCc2cccnc21

Procedure:
A 5,6,7,8-tetrahydroquinoline (0.01 mole) in the solvent indicated (approx. 15 ml) at 0° C. under nitrogen was treated with an alkyl lithium or a lithium amide (0.01 mole). To this solution of the 5,6,7,8-tetrahydro-8-lithioquinoline was added, at around 0° C. under nitrogen, the silyl isothiocyanate (0.01 mole) and the mixture was stirred 15 minutes. H2O(10 ml) and 2N HCl (15 ml) were added and the acid layer was separated and washed with ethyl acetate. The aqueous solution was basified (Na2CO3) and extracted with chloroform. The chloroform extracts were dried (MgSO4) and evaporated to give the 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide. In this manner the thioamides in the table were prepared.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>N1C=CC=CC=1.[Cu]=O>[C:5](=[C:4]1[CH:3]=[CH:2][CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:7]1)=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=Cc1cccc(Br)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(OC2=CC=CC(=C=O)C2)c1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 3-bromobenzaldehyde (1.000 g; 5.4 mmol), methyl 3-hydroxybenzoate (987 mg; 6.5 mmol) and potassium carbonate (1.494 g; 10.8 mmol) in dry pyridine (8 mL) is stirred under argon at RT. Copper (II) oxide (860 mg; 10.8 mmol) is added and the reaction mixture is refluxed for 12 hours. After cooling to RT, CH2Cl2 (50 mL) is added and the mixture is filtered through celite. The filter cake is washed with fresh CH2Cl2 (50 mL). The combined organics are concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate/hexanes, 1:10 to 1:4) to yield methyl 3-(3-carbonylphenoxy)benzoate (776 mg; 56%) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([O:16]COC)=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[C:12]([O:24]COC)[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:8]([O:7][C:5]([C:4]1[C:12]([OH:24])=[C:13]([C:20]([F:22])([F:23])[F:21])[CH:14]=[C:15]([OH:16])[C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=2)=[CH:33][CH:34]=1)=[O:6])([CH3:11])([CH3:9])[CH3:10]
Reactant: COCOc1cc(C(F)(F)F)c(OCOC)c(C(=O)OC(C)(C)C)c1CBr
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Product: CC(C)(C)OC(=O)c1c(O)c(C(F)(F)F)cc(O)c1COc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Yield: 17 %

Procedure:
According to a method similar to Example (40-2), Example (8-3) and Example (17-4), from tert-butyl 2-(bromomethyl)-3,6-bis(methoxymethoxy)-5-(trifluoromethyl)benzoate (154 mg, 0.34 mmol) obtained in Example (87-1) and methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (80 mg, 0.33 mmol) obtained in Example (6-2), the title compound was obtained (25 mg, three-step total yield: 17%).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:16])([CH3:15])[CH3:14].N>C(#N)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:24])[NH2:3])=[CH:19][C:18]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
165 mg (1.02 mmol) of 1,1'-carbonylbis(1H-imidazole) were added to a solution of 355 mg (0.783 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 74C) in 7.0 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes, after which 0.46 ml of 29% v/v aqueous ammonia was added. The reaction mixture was stirred at room temperature for 1 hour, after which the mixture was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel using ethyl acetate as the eluent, to give 327 mg (yield 92%) of the title compound as a colorless foam-like substance.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:30][CH2:31][C@H:32]1[C@H:37]([OH:38])[CH2:36][CH2:35][CH2:34][O:33]1)[CH2:15][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][CH3:29].C(O)(C)C>CC(C)=O.C(OCC)(=O)C>[CH2:14]([O:30][CH2:31][CH:32]1[C:37](=[O:38])[CH2:36][CH2:35][CH2:34][O:33]1)[CH2:15][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][CH3:29]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1OCCC[C@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOCC1OCCCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of Jones reagent (1.34 g as chromic anhydride) were added, whilst ice-cooling, to a solution of 4.30 g of dl-trans-2-hexadecyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 2) in 20 ml of acetone. The mixture was then stirred at room temperature for 2 hours, after which 2 ml of isopropanol were added. The reaction mixture was then stirred for a further 10 minutes, after which it was diluted with 50 ml of ethyl acetate and then washed, in turn, with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was removed by distillation. The resulting oily residue, 4.5 g, was subjected to column chromatography through 100 g of silica gel. The fraction eluted with mixtures of ethyl acetate and hexane ranging from 1:10 to 3:20 by volume gave 3.73 g of the title compound, melting at 42°-43.5° C. (hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Brc1ccc(-c2ccccc2)nc1

Procedure:
A mixture is prepared of 2,5-dibromopyridine (10 g, 42.21 mmol), phenylboronic acid (5.1 g, 42.21 mmol), and potassium carbonate (11.7 g, 84.42 mmol) in 100 mL dimethoxyethane and 40 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, tetrakis(triphenylphosphine)palladium(0) was added (244 mg, 2.11 mmol) and the mixture is heated to reflux under nitrogen overnight. The mixture is cooled and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue is purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[C:19](=O)[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:19][O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C2[C@@H]3OC(=O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C2[C@@H]3OCC(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the solution of compound of example 27 (424 mg, 1 mmol) in THF (20 mL) under stirring to 0° C., under nitrogen, was added LAH (132.8 mg, 3.5 mmol) and stirred at room temperature (25° C.) for 15 hours. The reaction mixture was quenched with water (3×50 mL), stirred for 10-15 minutes and added ethyl acetate (3×100 mL). The separated ethyl acetate layer was dried over sodium sulphate. The product was obtained by concentrating the ethyl acetate portion. It was dried under vacuum. Crude product was washed with petroleum ether which was crystallized using ethyl acetate (2 mL) and petroleum ether (5-6 drops) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH:14]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH2:37][CH2:38]O)[C:28]=1[CH3:40])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:14]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH2:37][CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)[C:28]=1[CH3:40])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(C(c2ccccc2)c2ccccc2)c2cc(Cl)ccc2n1CCO
Reactant: COC(=O)CCc1ccc(O)cc1
Product: Cc1c(C(c2ccccc2)c2ccccc2)c2cc(Cl)ccc2n1CCOc1ccc(CCC(=O)O)cc1

Procedure:
The methyl ester of the title compound was prepared from methyl 3-(4-hydroxyphenyl)propionate and 2-(3-benzhydryl-5-chloro-2-methyl-1H-indol-1-yl)ethanol according to Step 2 of the procedures for Example 2.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[N:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:23]3[N:22]=[N:21][S:20][CH:24]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1csnn1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1csnn1
Yield: 52 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,2,3-thiadiazole-4-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 70°-72° C., in a 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].CO[C:13]1(OC)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[C:4]2[O:10][C:13]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC1(OC)CCCCCC1
Reactant: COc1cccc(O)c1O
Product: COc1cccc2c1OC1(CCCCCC1)O2

Procedure:
Substantially the same procedure as in Reference Example 63 was repeated using 3-methoxycatechol (18 g) and dimethoxycycloheptane (24.35 g) to give Compound IIbm-a (28.0 g, 93.5%) as a colorless solid.
Reaction SMILES: FC1C(F)=CC=CC=1O.BrCCCCCCCCCO.[F:21][C:22]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C(F)=CC=CC=1OCCCCCCCCC(O)=O.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:23]1[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:22]=1[F:21])[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1cccc(F)c1F
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1cccc(F)c1F
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1cccc(F)c1F

Procedure:
The title compound, m/e=415.5 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, 2,3-difluorophenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(2,3-difluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(2,3-difluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(2,3-difluoro-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:30]([O:32][C:33](=[O:46])[CH:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:46])[CH:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:38][CH:37]=1)[CH3:31]
Reactant: OCC=C(c1ccccc1)c1ccccn1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccccc2)c2ccccn2)cc1)OCC
Yield: 100.4 %

Procedure:
Reaction of 3-phenyl-3-(pyridin-2-yl)-prop-2-en-1-ol (320 mg, 1.5 mmol), tributylphosphine (0.42 mL, 1.6 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (380 mg, 1.6 mmol) and azodicarboxylic dipiperidide (403 mg, 1.6 mmol) in an identical manner to Example 3 gave the title compound (650 mg).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C@H:15]2[CH2:20][CH2:19][C@H:18]([CH3:21])[CH2:17][CH2:16]2)=[O:13])=[N:8][CH:7]=1)(=[O:5])=[O:4].[C:28](NC1SC(S(Cl)(=O)=O)=C(C)N=1)(=O)C.S(Cl)(Cl)(=O)=O>>[CH3:1][NH:2][S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C@H:15]2[CH2:20][CH2:19][C@H:18]([CH3:21])[CH2:17][CH2:16]2)=[O:13])=[N:8][C:7]=1[CH3:28])(=[O:4])=[O:5]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Solvent: O=S(=O)(Cl)Cl
Product: CNS(=O)(=O)c1sc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)nc1C

Procedure:
The title compound was prepared in a similar manner to 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonic acid methylamide using 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride as the sulfonyl chloride.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C([O-])(=O)C.[Na+].Br[C:11]1[C:12]([NH:14][C:15](=[O:17])[CH:16]=1)=[O:13]>CO>[CH2:1]([NH:4][C:11]1[C:12]([NH:14][C:15](=[O:17])[CH:16]=1)=[O:13])[CH2:2][CH3:3]
Reactant: O=C1C=C(Br)C(=O)N1
Reactant: CCCN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCNC1=CC(=O)NC1=O
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To propylamine (75 μL, 1.09 mmol) and sodium acetate (92 mg, 1.12 mmol) in methanol (15 mL) was added bromomaleimide (200 mg, 1.12 mmol) dropwise in methanol (15 mL). After 10 minutes, solvent was removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow waxy solid (82 mg, 0.53 mmol) in 49% yield. δH (500 MHz, CDCl3) 7.36 (s, 1H, NH), 5.45 (s, 1H, NH), 4.80 (d, 1H, J=1.3, H-5), 3.14 (dt, 2H, J=6.2 and 7.2, H2-3), 1.71-1.63 (m, 2H, H2-2), 0.99 (t, 3H, J=7.4, H3-1); δc (125 MHz, CDCl3) 172.31 (C═O), 167.73 (C═O), 149.83 (C4), 85.29 (C5), 46.16 (C3), 21.91 (C2), 11.42 (C1); IR (solid, cm−1) 3190 (m), 2962 (m), 1693 (m), 1627 (s); MS (EI) m/z (relative intensity): 154 (M+, 60), 125 (98), 84 (100); Exact Mass Calcd for [C7H10N2O2]+ requires m/z 154.0737 Found 154.0734 (EI); UV (Acetonitrile) ε240=7400 and ε348=5700 cm−1M−1 d3.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[CH3:11][C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:13][CH3:14])=[C:2]([CH:7]=1)[CH:23]=[O:24])([CH3:12])[CH:9]=[CH2:10]
Reactant: C=CC(C)(C)c1ccc(OC)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)(C)c1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-Bromo-4-(1,1-dimethyl-allyl)-1-methoxy-benzene (3.1 g, 0.012 mol) in dry THF (50 mL) was cooled to −78° C. under argon. n-BuLi (2.5M, 5.1 mL, 0.0128 mol) was added keeping the temperature below −70° C. The yellow mixture was stirred for another 15 min and quenched with dry DMF (1.4 mL, 0.018 mol). The cooling bath was removed and the mixture was allowed to warm to 25° C. A saturated solution of NaHCO3 (30 mL) was added and then extracted with EtOAc (3×50 mL). The organic phase was dried (Na2SO4) and evaporated to yellow oil. Yield: 2.31 g (94%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)(=[O:4])=[O:3].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)(=[O:3])=[O:4])=[O:28])[N:19]=1
Reactant: Cn1nnnc1-c1ccccc1S(N)(=O)=O
Reactant: COc1cc(Cl)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2nnnn2C)n1
Temperature: 0 °C
Yield: 87 %

Procedure:
To 0.48 g of 5-(2-aminosulfonylphenyl)-1-methyl-1H-tetrazole and 0.56 g of phenyl N-(4-chloro-6-methoxypyrimidine-2-yl)carbamate in 20 mL of dry acetonitrile at ambient temperature was added, with stirring, 0.3 mL of DBU. After stirring 16 hours the mixture was then poured into 25 g of ice followed by the addition of 10 mL of 2N hydrochloric acid. The precipitate thus formed was removed by filtration, washed with water and dried to yield 0.74 g of the desired product m.p. 225°-227° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][OH:9])[NH:5][C:4](=[O:6])[CH2:3]1.CO[C:12](OC)([CH3:14])[CH3:13].B(F)(F)F.CCOCC>C(Cl)Cl>[O:6]=[C:4]1[N:5]2[C:2]([CH3:1])([CH2:7][CH2:8][O:9][C:12]2([CH3:14])[CH3:13])[CH2:3]1
Reactant: COC(C)(C)OC
Reactant: CC1(CCO)CC(=O)N1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC12CCOC(C)(C)N1C(=O)C2

Procedure:
A solution of 4-methyl-4-(2-hydroxyethyl)-2-azetidinone (0.016 mole) and 2,2-dimethoxypropane (1.69 g, 0.016 mole) in 25 ml anhydrous methylene chloride is treated with boron trifluoride etherate (0.201 ml, 0.002 mole) at 25° C. The resulting solution is stirred for ten minutes. Removal of the solvent under reduced pressure and chromatography of the crude product on silica gel using 2:1 ethyl acetate/benzene as eluting solvent gives 8-oxo-2,2,6-trimethyl-3-oxa-1-azabicyclo[4.2.0]-octane.