Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21]CC3C=CC=CC=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:29]CC2C=CC=CC=2)[CH:12]=[C:11]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>C(OCC)(=O)C>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=2[OH:29])[CH:12]=[C:11]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[C:3]=1[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(OCc3ccccc3)cccc2OCc2ccccc2)nc1N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2O)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A suspension of tert-butyl 2-amino-6-[2,6-bis(benzyloxy)phenyl]-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]nicotinate (1.00 g, 1.052 mmol) and 10% Paradium-carbon (0.500 g) in 20 mL of ethyl acetate was stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. After paradium carbon was removed by filtration on Celite®, the filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]-6-(2,6-dihydroxyphenyl)nicotinate as a brown oil. (0.710 g, yield; 97%)
Reaction SMILES: Cl.[C:2](=[N:10][OH:11])([Cl:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:12]=[CH:13][CH:14]=[CH2:15].C(N(CC)CC)C>C(O)C>[ClH:9].[CH:13]([CH:14]1[O:11][N:10]=[C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:15]1)=[CH2:12]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C=CC=C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CC1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 27.0 g. of nicotinoyl chloride oxime hydrochloride and 30.2 g. of 1,3-butadiene in 500 ml. of absolute ethanol was added dropwise, over a one hour period, a solution of 29.3 g. of triethylamine in 200 ml. of ethanol. The reaction was stirred at room temperature for one hour, the solvent was removed by evaporation and the residue mixed with water and filtered. The solid was dissolved in diethyl ether and washed several times with water. The ether layer was separated, dried over sodium sulfate and filtered to remove solids (drying agent). Removal of the solvent left a red orange liquid which was dissolved in diethyl ether and HCl gas was bubbled in to form a white solid which was collected by filtration and recrystallized from ethanol. Recrystallization was repeated a second time. The hydrochloride salt melts at 201°-204°C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3([CH3:35])[CH2:32][C:31]3([F:34])[F:33])=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C@H:43]([NH:45][C:46]([NH2:48])=[O:47])[CH3:44])=[CH:39][CH:38]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[F:34][C:31]1([F:33])[CH2:32][C:30]1([C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:48][C:46]([NH:45][C@@H:43]([C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=3)[CH3:44])=[O:47])=[CH:3][C:4]=2[NH:10][N:9]=1)[CH3:35]
Reactant: CC1(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)CC1(F)F
Reactant: C[C@@H](NC(N)=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(C3(C)CC3(F)F)c2cn1)c1ccc(F)cc1

Procedure:
In a manner similar to that described in Scheme 6 and Example 30, 6-chloro-3-(2,2-difluoro-1-methylcyclopropyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine was reacted with (R)-1-(1-(4-fluorophenyl)ethyl)urea (Xantphos, Pd(OAc)2, Cs2CO3, dioxane, 80° C., overnight) and then deprotected with TFA to provide (R)-1-(3-(2,2-difluoro-1-methylcyclopropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea 2,2,2-trifluoroacetate. MS ESI calc'd. for C19H18F3N5O[M+1]+ 390, found 390.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30]Cl>C1COCC1.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:16]1=[O:21]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: O=C1CCCCN1C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCCN1C1CCCCC1
Reaction time: 0.25 h
Yield: 242 %

Procedure:
Add 1.8 M LDA (0.9 mL, 1.7 mmol) to solution of 1-cyclohexylpiperidin-2-one (300 mg, 1.7 mmol) in THF (5 mL) at −78° C. and stir for 15 minutes. Add 2,4-dichloro-1-(chloromethyl)benzene (640 mg, 3.3 mmol) and warm the reaction to room temperature. Quench the reaction with water and dilute with ethyl acetate. Dry the organic layer with sodium sulfate, filter and concentrate. Purify the residue by biotage chromatography to afford the title compound as a white solid (1.4 g, 81%): MS (APCI-pos mode) m/z (rel intensity): 340.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:33][CH2:32][C:19]5([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][CH2:20]5)[CH2:18][CH2:17]4)=[N:12][N:11]3[C:34]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]3[N:41](S(C4C=CC(C)=CC=4)(=O)=O)[CH:42]=[CH:43][C:36]=23)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][C:19]5([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:22][CH2:21][CH2:20]5)[CH2:32][CH2:33]4)=[N:12][N:11]3[C:34]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]3[NH:41][CH:42]=[CH:43][C:36]=23)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC7(CCCN(C(=O)OC(C)(C)C)C7)CC6)nn45)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(c3ccc4nc(-c5ccc(F)cc5)c(-c5ccnc6[nH]ccc56)n4n3)CC2)C1

Procedure:
The tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate obtained in step 5.1 is dissolved in 3 ml of a mixture of methanol and tetrahydrofuran (2/1) and is treated using 0.09 ml (0.54 mmol) of a 6N aqueous solution of sodium hydroxide at 60° C. for 1 and a half hours. The solvent is evaporated under reduced pressure and the residue taken up in 3 ml of water. The product is extracted 2 times with 3 ml of dichloromethane. The organic phase is dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography on a silica gel column (4 g) by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 95/5/05 to 90/10/1) in order to give 0.06 g of tert-butyl 9-[2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane-2-carboxylate after crystallization in 10 ml of acetonitrile, filtration and drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].[I-].[K+]>C(O)CCC>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO

Procedure:
A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodide and 200 parts of butanol is stirred and refluxed overnight. The butanol is removed by evaporation in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol; mp. 97° C.
Reaction SMILES: [C:1]([C:4]1[N:12]2[C:7]([C:8]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[C:4]1([C:1](=[O:3])[CH3:2])[N:12]2[C:7]([C:8]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc2n1-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 1′-acetylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (600 mg, 1.57 mmol) in CH2Cl2 (6 mL) was added HCl in Dioxane (3.9 mL of 4 M, 15.7 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to give 1-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-ylethanone hydrochloride (499 mg, 99%) which was used without further purification. ESI-MS m/z calc. 282.1. found 283.3 (M+1)+; Retention time: 0.86 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH3:22])=[C:8]([Cl:23])[CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[CH:42][C:43]([C:46]([NH:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:47])=[N:44][CH:45]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:2]=2[C:40]2[CH:41]=[CH:42][C:43]([C:46]([NH:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:47])=[N:44][CH:45]=2)[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[CH3:22]
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C(F)(F)F)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(C(F)(F)F)cc3C)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
N-(2-bromo-4-(trifluoromethyl)benzyl)-2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine (3.9 g, 7.5 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate, prepared as in STEP A above, (3.2 g, 6.6 mmol), Pd(dppf)Cl2 (611 mg, 0.7 mmol), and K2CO3 (2.1 g, 14.9 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[C:13](=[O:24])[N:14]([CH2:20][C:21]([OH:23])=[O:22])[C:15]([CH3:19])=[C:16]([Cl:18])[N:17]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[C:13](=[O:24])[N:14]([CH2:20][C:21]([OH:23])=[O:22])[C:15]([CH3:19])=[C:16]([Cl:18])[N:17]=2)=[CH:5][CH:4]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)O
Reactant: COc1ccc(CN)cc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2nc(Cl)c(C)n(CC(=O)O)c2=O)cc1
Temperature: 60 °C

Procedure:
4-Methoxybenzylamine (0.83 ml, 6.33 mmol) was added to a stirred solution of 3,5-dichloro-6-methyl-1-carboxymethylpyrazinone (0.50 g, 2.11 mmol) in dioxane (6 ml) and the resulting mixture was warmed to 60° C. After 16 h the reaction mixture was partitioned between chloroform and 10% citric acid solution and the organic layer was dried (Na2SO4) and evaporated in vacuo. The crude product was purified by flash column chromatography (eluting with 2% methanol/chloroform/2% acetic acid) to give after azeotroping dry with toluene/methanol the title compound as a white solid:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12][S:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[O:6])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:40])C=1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2[CH2:12][S:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:40])=[O:14])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(phenylsulfinyl)methyl]-1H-1,2,3-triazole-4-carboxamide (107 mg, 0.24 mmol) obtained in Example 313 was dissolved in THF (2.0 ml), m-chloroperbenzoic acid (purity 65%, 64 mg, 0.24 mmol, 1.0 eq.) was added with stirring at 0° C., and the mixture was stirred for 1 hr and at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (25 ml), washed with 5% aqueous sodium sulfite solution, 2% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added to the residue, and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (111 mg, 0.24 mmol, quant.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH:24]=[O:25])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCC[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: OCCC[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
A solution of 0.44 g of 3-[trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexyl]propanal in 20 ml of methanol/water (vol. 4:1) and 15 ml of dioxan is treated portionwise with 0.10 g of sodium borohydride. The reaction mixture is stirred at room temperature for 0.75 hour and concentrated. The residue is treated with water and extracted with diethyl ether. The ether phase is washed with water, dried over sodium sulphate, filtered and evaporated. 0.36 g of 3-[trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexyl]propanol is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CS([CH2:41][CH2:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[CH:48][CH:49]=1)(=O)=O>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:41][CH2:42][O:43][CH2:44][C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CS(=O)(=O)CCOCc1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCCN(c2nc3ccccc3n2CCOCc2ccco2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.6 mmol) and tetrahydrofuran (10 mL). Cool to -78° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (3.6 mL, 0.5 M in toluene, 1.8 mmol). After 30 minutes, add fur-2-ylmethyl 2-methanesulfonylethyl ether (1.8 mmol). Warm to ambient temperature and heat to reflux. After 18 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[N:11]=[CH:10]2)[CH:4]=1.[OH-].[Na+]>CO.O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]=[CH:10]2)[CH:4]=1
Reactant: COC(=O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of methyl 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylate (120 mg, 0.44 mmol) in methanol (2.5 mL) was added a 5 M solution of sodium hydroxide in water (2.5 mL) and the mixture was stirred at room temperature for 1 h. After removal of methanol under vacuum, the resulting solution was acidified with concentrated HCl (pH=5) and concentrated. The residue was taken up in acetone and insolubles were filtered off. The filtrate was evaporated to give the title compound (120 mg). MS (M+H) 258.2.
Reaction SMILES: [CH:1]([S:3][C@H:4]1[N:7]([C:8]([O:10][CH2:11][CH2:12][C@@H:13]([OH:15])[CH3:14])=[O:9])[C:6](=[O:16])[CH2:5]1)=[CH2:2].[C:17](OC(=O)C)(=[O:19])[CH3:18].CCN(CC)CC.C(OCC)(=O)C.C1C=CC=CC=1>C(Cl)Cl>[CH:1]([S:3][C@H:4]1[N:7]([C:8]([O:10][CH2:11][CH2:12][C@@H:13]([O:15][C:17](=[O:19])[CH3:18])[CH3:14])=[O:9])[C:6](=[O:16])[CH2:5]1)=[CH2:2]
Reactant: C=CS[C@@H]1CC(=O)N1C(=O)OCC[C@H](C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CS[C@@H]1CC(=O)N1C(=O)OCC[C@H](C)OC(C)=O
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A mixture of (4 R,S)-4-vinylthio-(1-hydroxyethyl-2-ethoxycarbonyl)-2-oxo-azetidine (1.01 g, 4.13 mmole), acetic anhydride (1 ml, 10.6 mmole), and Et3N (0.7 ml, 5 mmole) dissolved in methylene chloride (60 ml) was allowed to stand overnight at room temperature. The reaction mixture was then washed with brine (3 times), and dried on Na2SO4. Evaporation of the solvent left a residue which, after column chromatography (SiO2, 10% ethyl acetate-benzene), yielded 950 mg (3.31 mmole, 81%) of an oily product.
Reaction SMILES: C(OC(NC(C1C=CC(O)=C(COC)C=1)C(O)=O)=O)C1C=CC=CC=1.C(OC(Cl)=O)C(C)C.N[CH:35]1[C:41](=[O:42])[N:40]2[CH:36]1[S:37][C:38]([CH3:47])([CH3:46])[CH:39]2[C:43]([OH:45])=[O:44].C(N(CC)CC)C>O1CCCC1.O1CCCC1.O>[CH3:46][C:38]1([CH3:47])[S:37][CH:36]2[N:40]([C:41](=[O:42])[CH2:35]2)[CH:39]1[C:43]([OH:45])=[O:44]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: COCc1cc(C(NC(=O)OCc2ccccc2)C(=O)O)ccc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)SC2CC(=O)N2C1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
α-(Benzyloxycarbonyl)amino-4-hydroxy-3-(methoxymethyl)benzeneacetic acid (0.1 mole) is dissolved in tetrahydrofuran (THF). The temperature of the solution is maintained at about -10° C. and 0.2 mole of isobutylchloroformate is added. After stirring for about 30 minutes at -10° C., 0.1 mole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid in a 50/50 THF/water solution containing 0.1 mole of triethylamine is added to the above formed solution. This mixture is stirred for 30 minutes at -10° C. and then the temperature is raised to about 20° C. Stirring is continued for an additional 30 minutes. The pH is adjusted to 4.5 to 5.5, and the coupled product is extracted into ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the coupled product, 6-[[(benzyloxycarbonyl)amino]-hydroxy-3-(methoxymethyl)-phenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].Cl.O>CO>[OH:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][CH2:7]3
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 15 h
Yield: 46.5 %

Procedure:
Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (0.84 g) in methanol (18 ml) containing concentrated hydrochloric acid (1.2 ml) and water (0.8 ml) and allow the mixture to stand at room temperature for 15 hours. Add water and extract the mixture with ether. Wash, dry and evaporate the ethanol solution and dissolve the residue in a little benzene. Filter through a column of alumina (25 g) with benzene-ether (7.3). Evaporate the eluates and recrystallize the residue from etherhexane to obtain the title compound (372 mg), m.p. 123°-124.5° or in an alternate form, m.p. 131°-132°; ultraviolet absorption maximum at 241 mμ (ε16,600); infrared absorption peaks at 6μ, 7.9 μ, 9.4 μ.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][C:10](=[CH2:14])[CH2:11]CO.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:11][C:10]([CH3:14])=[CH2:9])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: C/C=C(/C)C(=O)OC
Reactant: C=C(C)CCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C=C(C)CCOC(=O)/C(C)=C\C

Procedure:
A mixture of 20.0 g. of methyl angelate, 22.65 g. of 3-methyl-3-butenyl alcohol, 100 ml. of toluene and 0.8 g. of dioctyltin laurate was reacted under the same conditions as in Example 6. The reaction mixture was subjected to single distillation to obtain 39.5 g. of a distillate boiling at 104° C. (32 mmHg).
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.O>CN(C=O)C>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(CC(=O)O)C2CC2)ccc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
To a solution of 5-(cyclopropyl(4-fluoro-3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.00 g) in DMF (20 mL) was added water (2.0 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.10 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O>C1(O)CCCC1>[NH2:1][C:2]1([C:7]([O:9][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1(C(=O)O)CCCC1
Agent: O=S(=O)(O)O
Agent: OC1CCCC1
Product: NC1(C(=O)OC2CCCC2)CCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-aminocyclopentanecarboxylic acid (2.58 g, 19.97 mmol) in cyclopentanol (20 ml), was added concentrated sulfuric acid (2.15 g, 21.97 mmol) and the mixture stirred overnight at 70° C. The reaction was allowed to cool to RT and the cyclopentanol removed under reduced pressure. The residue was dissolved in EtOAc (30 ml) and washed with sat. NaHCO3 (30 ml) and water (3×20 ml) then dried (MgSO4), filtered and concentrated in vacuo to leave a dark yellow oil. Purification by column chromatography (15% 1.2 M NH3/MeOH in EtOAc) afforded the desired product (1.97 g, 50% yield).