Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](OCCCC)=[O:2].[CH3:8][C:9]1[C:14]([CH3:15])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:11][C:10]=1[Cl:20].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[Cl:20][C:10]1[C:9]([CH3:8])=[C:14]([C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[CH:15]=[N:1][OH:2]
Reactant: Cc1c(Cl)ccc(S(C)(=O)=O)c1C
Reactant: CCCCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)ccc(S(C)(=O)=O)c1C=NO
Temperature: 0 °C

Procedure:
A solution of 12.7 g (119 mmol) of n-butyl nitrite (97% pure) and 20 g (92 mmol) of 2,3-dimethyl-4-methylsulfonylchlorobenzene in 100 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 16.8 g (147 mmol) of potassium tert-butoxide in 70 ml of dimethylformamide is added dropwise at this temperature, over a period of 30 minutes. The reaction is monitored by HPLC. For work-up, initially 50 ml of water are added, and the pH is subsequently adjusted to 5-6 using approximately 30 ml of glacial acetic acid. The reaction mixture is subsequently poured into 0.7 kg of ice-water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 18.4 g of a light-beige crude product which is purified by recrystallization from approximately 30 ml of toluene.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].CS(C)=O.C([N:20](CC1C=CC=CC=1)[CH2:21][CH2:22][NH2:23])C1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[F:5][C:4]([F:7])([F:6])[CH:3]1[CH2:2][NH:23][CH2:22][CH2:21][NH:20]1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(CBr)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: FC(F)(F)C1CNCCN1
Reaction time: 21 h

Procedure:
A 12.3 g portion of bromo-3,3,3-trifluoropropanone was slowly added to 50 ml of dimethyl sulfoxide and stirred under a dry atmosphere for 21 hours and then diluted to 100 ml with ethanol. A solution of 31 g of N,N-dibenzylethylenediamine in 100 ml of ethanol was added dropwise and the mixture was stirred for 8 hours. A 2.43 g portion of sodium borohydride was added over 30 minutes, this mixture was stirred overnight then the ethanol was removed. The dimethyl sulfoxide residue was dissolved in water and extracted with dichloromethane. The extracts were combined, washed with water and brine and then subjected to flash chromatography on a silica gel column, eluting with ether:hexane (3:7). The 2-(trifluoromethyl)dibenzylpiperazine was dissolved in 25 ml of ethanol in an argon flushed Parr bottle. A 0.63 g portion of 10% palladium on carbon was added and the mixture was shaken under 47 lbs. of hydrogen pressure overnight at 40° C. Filtration and evaporation of the solvent gave 0.55 g of 2-(trifluoromethyl)piperazine as a semi-solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[C:29]#[CH:30].Cl>C(Cl)Cl.C1N2CCN(CC2)C1>[CH2:1]([C@H:8]1[CH2:9][O:10][CH2:11][C@H:12]([NH:20][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[C:13](=[O:19])[O:14][C@@H:15]([CH3:18])[C@@H:16]1[O:17]/[CH:30]=[CH:29]/[C:28]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: C#CC(=O)OCc1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O/C=C/C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (360 mg, 0.949 mmol, 1.00 equiv) in CH2Cl2 (9.5 mL, 0.1 M) at 0° C. (ice water bath) were added benzyl propiolate (228 mg, 1.42 mmol, 1.5 equiv) and DABCO (5 mg, 0.05 mmol, 0.05 equiv). The resulting solution was stirred at 0° C. for 20 min and then poured into 0.1 N HCl (20 mL). The mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a white crystalline solid. The solid was purified by automated silica gel column chromatography (5-25% acetone in hexanes) to provide (E)-benzyl 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)acrylate (490 mg, 96%) as a white solid: IR (ATR) 3344, 2982, 2941, 1752, 1717, 1690, 1638, 1527, 1454, 1381, 1205, 1079, 833, 751, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=12.2 Hz, 1H), 7.40-7.09 (m, 10H), 5.44 (d, J=12.2 Hz, 1H), 5.16 (s, 2H), 5.09 (d, J=8.2 Hz, 1H), 5.01 (dd, J=9.3, 6.4 Hz, 1H), 4.64 (dd, J=15.3, 7.5 Hz, 1H), 3.91 (dd, J=11.6, 7.5 Hz, 1H), 3.73 (t, J=9.2 Hz, 1H), 3.45 (dt, J=10.6, 8.5 Hz, 2H), 3.28 (dd, J=11.3, 7.5 Hz, 1H), 2.92 (dd, J=13.8, 3.5 Hz, 1H), 2.34 (t, J=12.4 Hz, 1H), 2.05 (s, 1H), 1.51-1.35 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 172.15, 167.40, 163.21, 138.54, 136.22, 129.10, 128.57, 128.25, 128.19, 126.48, 98.54, 89.01, 80.31, 73.94, 72.60, 71.36, 65.87, 52.72, 46.48, 35.21, 28.26, 18.74; HRMS-ESI (m/z) [M+Na]+ calc'd for C30H37NO8Na, 562.2411. found, 562.2427.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[N:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:24]1([CH:30]2[CH2:35][CH2:34][N:33]([C:6]3[N:5]=[C:4]4[N:11]([C:16]5[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=5[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]4=[C:2]([Cl:1])[N:7]=3)[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2c(Cl)nc(N3CCC(N4CCCCC4)CC3)nc2N1c1c(F)cccc1F
Yield: 115 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.56 mmol) in DCM (10 mL) were added 1,4′-bipiperidine (270 mg, 1.61 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (298 mg, 83%). LC-MS m/z 463 (M+H)+.
Reaction SMILES: C(OC(NCC1C=C(NC(=O)COC2C=CC([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=CC=2)C=CC=1)=O)C1C=CC=CC=1.[Si:60]([O:67][CH:68]([CH3:79])[CH2:69][C:70]1[CH:75]=[CH:74][C:73](B(O)O)=[CH:72][CH:71]=1)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>>[C:48]([O:47][C:45]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:56])[CH3:57])=[O:53])[C:40]1[C:41]2[C:36](=[CH:35][C:34]([NH:33][CH:29]([C:73]3[CH:74]=[CH:75][C:70]([CH2:69][CH:68]([O:67][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:61])[CH3:62])[CH3:79])=[CH:71][CH:72]=3)[C:30]([OH:32])=[O:31])=[CH:43][CH:42]=2)[CH:37]=[CH:38][N:39]=1)=[O:46])([CH3:50])([CH3:51])[CH3:49]
Reactant: CC(Cc1ccc(B(O)O)cc1)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Product: CC(Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc1)O[Si](C)(C)C(C)(C)C
Yield: 65 %

Procedure:
According to the procedure for the preparation of 66D, 77C (200 mg, 0.68 mmol) afforded 295 mg (65%) of 77D as an off-white solid. MS (ESI) m/z 666.4(M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:11][CH:10]=1.[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(COC2CCCCO2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 4-(tetrahydropyranyloxy)methyl-2'-nitro-1,1'-biphenyl (4.12 g, 13.2 mmol) in 100 mL of methanol was hydrogenated at 40 psi in the presence of 5% palladium on carbon. After 2 hours, uptake of hydrogen was complete. The reaction mixture was filtered through diatomacious earth, and the filter cake washed with methanol. The filtrate was evaporated under vacuum to yield 3.57 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=O)=[CH:14][CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19]/[C:20](=[N:39]\[OH:40])/[C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:14][CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)cc1

Procedure:
In analogy to example 151, step 3, 2-chloro-5-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=549.2 [M−H]−.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.Br[CH2:30][C:31]1[CH:35]=[C:34]([CH3:36])[O:33][N:32]=1.C(OC([N:44]1[CH2:49][CH2:48][O:47][C@H:46]([CH2:50][C:51]2[CH:56]=[C:55]([F:57])[C:54]([OH:58])=[CH:53][C:52]=2[F:59])[CH2:45]1)=O)(C)(C)C>>[F:59][C:52]1[CH:53]=[C:54]([O:58][CH2:30][C:31]2[CH:35]=[C:34]([CH3:36])[O:33][N:32]=2)[C:55]([F:57])=[CH:56][C:51]=1[CH2:50][C@H:46]1[O:47][CH2:48][CH2:49][NH:44][CH2:45]1
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(F)c(O)cc2F)C1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Cc1cc(COc2cc(F)c(C[C@@H]3CNCCO3)cc2F)no1

Procedure:
The title compound was synthesized in analogy to Example 78, intermediate (a), using 3-(bromomethyl)-5-methylisoxazol and (R)-2-(2,5-difluoro-4-hydroxy-benzyl)-morpholine-4-carboxylic acid tert-butyl ester as starting materials.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][C:24]2([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][C:24]2([NH:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NS(C)(=O)=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.75 mL, 9.75 mmol) was added to a 0° C. solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (2.75 g, 8.13 mmol), 4-dimethylaminopyridine (DMAP, 2.75 g) and pyridine (11 mL) in dichloromethane (28 mL). The solution was stirred at 0° C. for 2 h, then at rt for 1 h. The reaction was washed with water (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a light yellow oil. Purification by flash chromatography (silica gel, 20% methanol/ethyl acetate) afforded N-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamide as a white solid (2.72 g, 80%).
Reaction SMILES: C([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([C:21]3[CH2:22][CH2:23][O:24][CH2:25][CH:26]=3)[N:13]2[N:12]=1)[CH3:10])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:13]2[N:12]=1)[CH3:10]
Reactant: CC(OCc1ccccc1)c1nn2c(C3=CCOCC3)ncc2c(=O)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(O)c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of compound 13 (900 mg, 2.55 mmol) in MeOH (30 mL) was added Pd(OH)2/C (120 mg). The mixture was stirred at 75° C. under H2 (50 psi) overnight. The suspension was filtered through Celite, washed with MeOH (20 mL×2). The combined organic phases were concentrated in vacuo to afford compound 14 (540 mg, 80% yield) as a white solid. LC-MS: m/z 265 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 9.07 (br. s, 1H), 7.85 (s, 1H), 4.84 (q, J=6.4 Hz, 1H), 4.11 (m, 2H), 3.59 (m, 2H), 3.44˜3.39 (m, 1H), 2.14˜2.06 (m, 3H), 1.92˜1.88 (m, 2H), 1.64 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH2:11]([C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22](OCC)=[O:23])=[C:17]2[CH:16]=[CH:15][CH:14]=1)[CH3:12]>C1C=CC=CC=1>[CH2:11]([C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:23])=[C:17]2[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)c1cnn2c(CC)cccc12
Agent: [Na]
Solvent: c1ccccc1
Product: CCc1cccc2c(C(=O)OC3CN4CCC3CC4)cnn12
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
After suspension of 140 mg (1.10 mmol) of 3-quinuclidinol in 20 ml of benzene was refluxed for 0.5 hour by using a Dean-Stark apparatus, 0.05 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 1.5 hours. Unreacted sodium was removed and 80 mg (0.37 mmol) of ethyl 7-ethylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 12 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 100 mg (0.33 mmol) of the title compound were obtained as an oily substance (yield: 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:51][O:52][C:53]1[N:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[CH:58][CH:57]=[C:56]2[NH2:63]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:19])[NH:63][C:56]2[C:55]3[C:60](=[CH:61][CH:62]=[C:53]([O:52][CH3:51])[N:54]=3)[N:59]=[CH:58][CH:57]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccc2nccc(N)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2nccc(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 118.9 %

Procedure:
A solution of acid (d) (7.9 g, 30 mmol) and triethylamine (4.2 ml, 3.03 g, 30 mmol) in N,N-dimethylformamide (50 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (HATU) (9.5 g, 25 mmol). After 0.25 hours, amine (c) (3.5 g, 20 mmol) was added and the mixture heated at 50° C. overnight. Evaporation afforded an oil which was partitioned between ethyl acetate and dilute brine. Drying and evaporation afforded an oil (10 g) which was chromatographed on silica eluting with a 0–5% methanol in ethyl acetate gradient, affording an oil (6.0 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:13]([CH:14]=O)=[CH:12][C:5]2[B:6]([OH:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:13]([CH:14]=[N:16][OH:17])=[CH:12][C:5]2[B:6]([OH:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1
Reactant: CC1(C)OB(O)c2cc(C=O)c(Cl)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2cc(C=NO)c(Cl)cc21
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (200 mg, 0.89 mmol) and NH2OH.HCl (74 mg, 1.07 mmol) in THF (12 mL) and H2O (3 mL) at rt was added NaOAc (110 mg, 1.34 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to give crude compound 5-chloro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:19](=[O:20])[NH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:21].[NH4+].[Cl-].[CH2:24](Cl)Cl>>[Br:1][C:2]1[C:19]([O:20][CH3:24])=[N:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:21]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)c(Br)c(O)c2CC1
Reactant: ClCCl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1nc2c(c(O)c1Br)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.17 h
Yield: 67 %

Procedure:
NBS (0.668 mmol, 119 mg) was added in one portion to a stirred solution of tert-butyl 4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.607 mmol, 170 mg) in DCM (3 ml) at room temperature. After 3 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified purified by column chromatography to provide 180 mg (83%) of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. Ag2CO3 (0.42 mmol, 116 mg) was added to a solution of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (75.0 mg, 0.21 mmol) in DCM (1.5 ml) at room temperature. After 10 min of stirring, Mel (0.23 mmol, 15 μl) was added. After 5 h of stirring, sat. aq. NH4Cl was added and the mixture was extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 52 mg (67%) of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. The correct regioselectivity was confirmed by NOESY. 1H-NMR (CDCl3) δ 13.21 (1H), 3.85 (3H), 3.65 (2H), 3.55 (2H), 3.05 (2H), 2.85 (2H), 1.49 (9H) ppm. To a solution of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (51 mg, 0.137 mmol) was added HC1 (2 N in Et2O, 3 ml) at room temperature. After 10 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to provide 33 mg (89%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-4-ol. 1H-NMR (CDCl3) δ 12.02 (br s, 1H), 9.21 (br s, 1H), 3.79 (3H), 3.25 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.92 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3].[OH:24]O.[OH-].[Na+]>CO.O.[Cl-].[Na+].O>[O:24]1[C@:9]23[C@:4]([CH2:1][C:2]#[CH:3])([CH2:5][CH2:6][C:7](=[O:23])[CH:8]12)[C@@H:21]1[C@H:12]([C@H:13]2[C@@:17]([CH2:19][CH2:20]1)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3
Reactant: OO
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CC[C@]12CCC(=O)C3O[C@@]31CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 650 mg of 10-(2-propynyl)estr-4-ene-3,17-dione in 5 ml of methanol at 15° C. is added 0.6 ml of 30% hydrogen peroxide. A solution of 46 mg of sodium hydroxide in 0.4 ml of water is then added dropwise. After 1 hour at 15° C., the solution is stirred for 2 hours at 25° C. before it is poured into brine. The aqueous mixture is then extracted with ether and the ether solution is dried and concentrated. The residual material obtained is recrystallized from methanol to give 4,5β-epoxy-10-(2-propynyl)estrane-3,17-dione. This epoxide is added to 5 ml of acetic acid containing 0.1 ml of concentrated sulfuric acid and the mixture is stirred at 25° C. for 4 hours before it is poured into ice. The solid which forms is separated by filtration and recrystallized from ethyl acetate to give 4-hydroxy-10-(2-propynyl)estr-4-ene-3,17-dione. This compound has the following structural formula ##STR15##
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][C:32]1[C:33]([F:41])=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[C:35]#[N:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:31][C:32]3[C:39]([F:40])=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=3[F:41])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)c(CCl)c1F
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 80 mg (0.20 mmol) of rac-(1-{[(7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl)carbonyl]amino}-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 141A and 56 mg (0.27 mmol) of 3-(chloromethyl)-2,4-difluorobenzonitrile from Example 135A in 3 ml of DMF was admixed with 129 mg (0.396 mmol) of caesium carbonate. The resulting suspension was stirred at RT for 72 h and then diluted with dichloromethane (15 ml) and extracted with saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic phase was concentrated under reduced pressure, which gave a crude product that contained the target compound in a multicomponent mixture (20% pure). This crude material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[OH:17])[CH3:2].[H-].[Na+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1OCCN1CCCCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 16.4 %

Procedure:
3-(4-tert-Butyl-2-hydroxyphenyl)acrylic acid ethyl ester (59.0 mg, 0.238 mmol) and NaH (47.5 mg, 60% disp. oil, 5 eq) were added in anhydrous DMF. The reaction mixture was cooled down to 0° C. 1-(2-Chloroethyl)piperidine hydrochloride (87.6 mg 0.476 mmol, 2 eq) was added. The mixture was heated to 90° C. The reaction was stirred for 12 hr at 90° C. The reaction was quenched by adding H2O. The reaction mixture extracted with EtOAc and then washed with H2O and brine. The residue was purified with column chromatography (EtOAc) to give a yellow liquid (14.0 mg, 16.4%).