Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11]C(C)C)=[O:10])[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.O.O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of isopropyl 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoate (product of step 26D, 16.1 g, 51.1 mmol) and lithium hydroxide hydrate (4.19 g, 102 mmol) in THF/water (100 mL/20 mL) was stirred at room temperature under nitrogen for 16 hours. The reaction was diluted with water, washed with ether, pH of aqueous fraction adjusted to ˜4, extracted with ether, combined organic fractions washed with saturated NaCl, dried (MgSO4) and evaporated giving 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoic acid as a light yellow syrup: 1H NMR (300 MHz, Chloroform-D) δ 5.89 (ddt, 1H, J=17.4, 10.4, 5.5), 5.25 (dd, 1H, J=17.4, 1.6Hz), 5.17 (dd, 1H, J=10.4, 1.6Hz), 4.30 (br d, 1H, J=6.2), 3.96 (dt, 2H, J=5.9, 1.5Hz), 3.46 (t, 2H, J=5.9Hz), 1.96-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.75-1.64 (m, 2H), 1.43 (s, 9H). LCMS m/z 274 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C(=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: NCCCN1CCOCC1
Solvent: CC(=O)N(C)C
Product: Ic1ccnc(NCCCN2CCOCC2)c1

Procedure:
A solution of 4-iodo-2-fluoropyridine (2.32 g, 10.00 mmol) and N-(3-aminopropyl)morpholine (4.2 ml, 26.00 mmol) in N,N-dimethylacetamide (30 ml) was heated to 100° C. for 20 hours before being concentrated in vacuo, to afford the crude title compound which was used without any further purification; Mass Spectrum: M+H+ 348.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:15][N:16](C)C(Cl)=O.C[Si](C#N)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[OH:1][C:2]1([C:8]2[N:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: [O-][n+]1ccccc1C1(O)CCOCC1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(C2(O)CCOCC2)n1
Temperature: 40 °C

Procedure:
To a stirred solution of 2-(4-hydroxytetrahydropyran-4-yl)pyridine-N-oxide (3.69 g, 18.91 mmol) in anhydrous dichloromethane was added dimethylcarbamoyl chloride (3.05 g, 28.4 mmol) and trimethylsilylcyanide (2.82 g, 28.4 mmol). The mixture was stirred for sixty hours at 40° C., after which time further aliquots of dimethyl carbamoyl chloride (3.05 g, 28.4 mmol) and trimethylsilylcyanide (2.82 g, 28.4 mmol) were added. After stirring at 40° C. for a further 24 hours, sodium carbonate solution (50 mL, 2 M aqueous solution) was added and the mixture stirred overnight. The resultant mixture was filtered and the layers partitioned. Sodium carbonate solution (50 mL, 2 M aqueous solution) was again added to the organic phase and stirred overnight. After separation of the phases, the organic layer was blown down at ambient temperature to give the title compound as a brown oil which was used in the next step without further purification; LC-MS Retention time 1.62 min, (M+H)+ 205.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:68])=[CH:53][CH:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH:56]([O:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:55]2)[CH:17]([CH3:69])[CH:16]([O:70][Si:71]([CH:78]([CH3:80])[CH3:79])([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:74])[CH3:73])[CH2:15][C:14]1=[O:81])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:68])=[CH:53][CH:54]2[CH2:59][CH2:58][C:57](=[O:60])[CH:56]([O:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:55]2)[CH:17]([CH3:69])[CH:16]([O:70][Si:71]([CH:78]([CH3:80])[CH3:79])([CH:72]([CH3:74])[CH3:73])[CH:75]([CH3:77])[CH3:76])[CH2:15][C:14]1=[O:81])[CH3:12]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccccc4)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(Oc4ccccc4)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride is added dimethyl sulfoxide dropwise, followed by a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-phenoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsiloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride. The reaction mixture is stirred for 30 min. at -78° C. and then triethylamine is added. The reaction temperature is raised to room temperature, reaction was poured into water, and extracted with ethyl acetate (three times). Combined organic layers are washed (water, sat'd NaHCO3), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography) gives the title compound.
Reaction SMILES: [C:1]([C:5]1[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2I)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:22]1([P:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CCOCC>[C:1]([C:5]1[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[P:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1=N[C@H](c2ccccc2I)CO1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C1=N[C@H](c2ccccc2P(c2ccccc2)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 4a (94 mg, 0.286 mmol) in 4 mL ether was added t-BuLi (1.7 M solution, 0.34 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 min before diphenylchlorophosphine (2.43 g, 11.0 mmol) was added slowly. The solution was allowed to warm to rt and was stirred overnight. Water was added. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 5a as a colorless oil (40%). [α]20D=−50.9 (c=2.0, CHCl3); 1H NMR (CD2Cl2, 360 MHz) δ 7.40-7.26 (m, 12H), 7.19 (dt, J=1.5 Hz, J=7.5 Hz, 1H), 6.93-6.89 (m, 1H), 5.82-5.75 (m, 1H), 4.24 (dd, J=is 8.4 Hz, J=10.2 Hz, 1H), 3.64 (dt, J=0.5 Hz, J=8.4 Hz, 1H), 1.28 (s, 9H); 13C NMR (CD2Cl2, 90 MHz) δ 175.8, 148.4 (d, J=24.0 Hz), 136.9 (d, J=10.2 Hz), 135.4-134.2 (m), 130.0-129.3 (m), 127.9 (br s), 126.8 (br s), 75.4 (d, J=4.4 Hz), 67.5 (m), 33.9, 28.3; 31P NMR (CD2Cl2, 145 MHz) δ-14.97; HRMS (M++1) m/z calculated for C25H27NOP 388.18248, found 388.17930.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].[O:14]=[C:15]1[N:20]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]3[NH:26][C:27](=[O:29])[NH:28][C:24]=3[CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[C:36]([F:38])[C:35](F)=[C:34]([F:40])[CH:33]=2)[CH:17]=[CH:16]1>CN(C=O)C>[F:38][C:36]1[CH:37]=[C:32]([C:18]2[CH:17]=[CH:16][C:15](=[O:14])[N:20]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]4[NH:26][C:27](=[O:29])[NH:28][C:24]=4[CH:23]=3)[N:19]=2)[CH:33]=[C:34]([F:40])[C:35]=1[O:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCN(CCCO)CC1
Reactant: O=c1[nH]c2ccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2c(F)cc(-c3ccc(=O)n(Cc4ccc5[nH]c(=O)[nH]c5c4)n3)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
170 mg (1.08 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-ol are dissolved in 20 ml of DMF, 64.5 mg (1.61 mmol) of NaH in paraffin oil (60%) are added under nitrogen, and the mixture is stirred at room temperature. After 10 min, 200 mg (0.54 mmol) of 5-[6-oxo-3-(3,4,5-tri-fluorophenyl)-6H-pyridazin-1-ylmethyl]-1,3-dihydrobenzimidazol-2-one are added, and the mixture is stirred at room temperature under a nitrogen atmosphere. The reaction is monitored by means of HPLC. After 3 h, the reaction is terminated. The mixture is neutralised using 1N HCl. The mixture is evaporated to dryness, the residue is dissolved in 100 ml of ethyl acetate and 30 ml of water, the aqueous phase is separated off and neutralised using sodium hydrogencarbonate and subsequently extracted. A precipitate deposits in the process and is separated off. The residue is stirred with methanol, filtered off with suction and dried in vacuo.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CCO.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>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (120 mg, 0.388 mmol) was dissolved in toluene/EtOH (3 ml/0.15 ml), and then 1-bromo-4-fluorobenzene (0.05 ml, 0.466 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol), and K2CO3 (107 mg, 0.776 mmol) were sequentially added thereto. The resulting mixture was stirred at 100° C. under nitrogen stream for 2 hours. Distilled water (3 ml) was added to the resulting reaction liquid, followed by extraction with MC (10 ml×3). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (6% EtOAc/Hexanes), to obtain 48 mg of colorless oil (45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([Cl:28])[N:22]=1.Cl>C(OCCO)C.C(OCC)(=O)C>[ClH:28].[NH2:20][C:21]1[N:22]=[C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Nc1cccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Temperature: 20 °C
Yield: 98.2 %

Procedure:
3-Amino-N-(4-nitrophenyl)benzamide (B1) (1.0 g, 3.89 mmol) and 4-chloro-6-methyl-2-pyrimidinylamine (A8) (569 mg, 3.89 mmol) were dissolved in warm 2-ethoxyethanol. (20 mL). Two drops c.HCl was then added to the reaction mixture and refluxed for 1 h. by this time TLC and mass spec. showed completion of the reaction. The reaction mixture was diluted with ethyl acetate and cooled to 20° C. The resulting precipitate was filtered, washed with more EtOAc and recrystallized from MeOH/EtOAc/Charcoal/Celite to give B2 (1.531 g, 98%); m.p (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 12.86 (br s, 1H, N+H), 10.90 (s, 1H, NH), 10.80 (br s, 1H, NH), 8.30-8.26 (m, 2H, ArH), 8.11-8.08 (m, 4H, ArH), 7.80-7.78 (br m, 3H, ArH & NH2), 7.56 (t, J=7.8 Hz, 1H, ArH), 2.30 (s, 3H, CH3); mass APCl+365.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[C:4]([F:16])[CH:3]=1.[CH2:17]([NH:19][C:20](=[O:34])[CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:18].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]([CH:10]([CH2:13][CH3:14])[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:24][CH2:23][N:22]([CH:21]([C:20](=[O:34])[NH:19][CH2:17][CH3:18])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)=[CH:3][C:4]=1[F:16])=[O:15])[CH3:12]
Reactant: CCNC(=O)C(c1ccccc1)N1CCNCC1
Reactant: CCC(CC)C(=O)Nc1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)C(CC)CC)c(F)c2)CC1
Temperature: 110 °C
Yield: 12.6 %

Procedure:
To a solution of N-(4-bromo-2-fluoro-phenyl)-2-ethyl-butyramide (20 mg, 0.07 mmol), N-ethyl-2-phenyl-2-piperazin-1-yl-acetamide (18 mg, 0.07 mmol), Pd2(dba)3 (10 mg), and 2-(dicyclohexylphosphino)biphenyl (1 mg) in toluene was added sodium tert-butoxide (20 mg). The mixture was heated in a focused microwave at 110° C. for 1.5 h. The crude reaction mixture was purified by reverse phase HPLC (Agilent method) to provide the title compound (4 mg, 13%). MS (ESI): mass calcd. for C26H35FN4O2, 454.27. m/z found, 455.4 [M+H]+. 1H NMR (CDCl3): 8.10 (dd, J=9.6, 8.9, 1H), 7.38-7.30 (m, 3H), 7.14-6.99 (m, 2H), 6.68-6.59 (m, 2H), 3.88 (s, 1H), 3.43-3.29 (m, 2H), 3.21-3.10 (m, 4H), 2.66-2.55 (m, 4H), 2.12-2.00 (m, 1H), 1.79-1.67 (m, 2H), 1.66-1.47 (m, 2H), 1.18 (t, J=7.2, 3H), 0.98 (t, J=7.4, 6H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[N:25][N:24]=[C:23]2[CH2:30]O)=[C:11]([CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:13])(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[N:25][N:24]=[C:23]2[CH2:30][N:36]2[C:32](=[O:42])[C:33]3=[CH:41][CH:40]=[CH:39][CH:38]=[C:34]3[C:35]2=[O:37])=[C:11]([CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:13])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCc1nnc(CO)n1-c1ccc(S(=O)(=O)C(C)C)cc1C(=O)c1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(S(=O)(=O)C(C)C)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 3, a mixture of 5-isopropylsulfonyl-2'-fluoro-2-[3-(hydroxymethyl)-5-propyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 5-isopropylsulfonyl-2'-fluoro-2-[3-(phthalimidomethyl)-5-propyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>CO.[Rh]>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2
Yield: 68.9 %

Procedure:
A solution of naphthyridine 1-4 (2.72 g) in methanol (20 mL) was hydrogenated in the presence of 5% rhodium on carbon (2.1 g; containing 63% of water) under 40 psi of hydrogen at 5° C. for 10 hours. The catalyst was filtered through Solka Flok and washed with methanol (25 mL twice). The filtrate and washings were combined, concentrated in vacuo, and dissolved in methanol (6.8 mL). To the solution was added water (6.8 mL) slowly at ambient temperature. The resulting solid was collected by filtration, washed with a mixture of water and methanol (2:1; 5 mL), and dried under vacuum to give the desired crystalline tetrahydronaphthyridine 1-5 (1.9 g). The mother liquor yielded an additional 5% of 1-5; m.p. 95.2-96.3° C.
Reaction SMILES: C[C@H]1CO[C@@]2(O[C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H]2C)CC1.C[C:32]1[C@@H]2[C@]3(C)[C@@H](C[C@@H]2[O:34][C:33]=1CC[C@H](CO)C)[C@@H]1CC=C2C[C@@H](O)CC[C@]2(C)[C@H]1CC3>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:25][CH:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C:19](=[CH:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH:8]=[C:7]2[C:33](=[O:34])[CH3:32])[CH2:24]1
Reactant: CC1=C(CC[C@@H](C)CO)O[C@H]2C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@@H]12
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC=C4CC(O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In this method too tigogenin is converted by conventional method to pseudodiosgenin and finally pseudodiosgenin is oxidized with chromium trioxide in acetic acid to give 3-hydroxy-5-pregnen-16-en-20-one.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[N:45]1([CH2:51][CH2:52][S:53]([C:56]2[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:60][C:59]4[CH:58]=[CH:57][C:56]([S:53]([CH2:52][CH2:51][N:45]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]5)(=[O:55])=[O:54])=[CH:62][CH:61]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(S(=O)(=O)CCN2CCCCC2)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(S(=O)(=O)CCN5CCCCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(2-(piperidin-1-yl)ethylsulfonyl)aniline (which may be prepared via: Tetrahedron Letters, 48 (51), 9040-9043, 2007) as the aniline component. (6%, MS=631.3 (M+H))
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][O:14][C:12]1[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[C:4]([CH:13]=1)[C:3]([OH:25])=[O:2]
Reactant: COC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(OCCc2ccc(Cl)cc2Cl)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
500 mg 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalic acid dimethyl ester were dissolved in 50 ml of MeOH:water/3:1. Then 1 g of lithium hydroxide monohydrate was added the solution, and the reaction was stirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT and then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethylacetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[F:13][C:14]([F:22])([F:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>CO>[CH3:1][O:2][C:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:15]([C:14]([F:22])([F:21])[F:13])=[CH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1)=[O:12]
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: COC(=O)C#CC(F)(F)F
Solvent: CO
Product: COC(=O)C=C(Nc1ccc(CC(=O)OC)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Into 30 ml of methanol were dissolved 2.17 g (13.2 mmol) of methyl-p-aminophenylacetate, and, under stirring and cooling with ice, a solution of 2.00 g (13.2 mmol) of methyl 3- trifluoromethylpropiolate in 10 ml of methanol was added dropwise. After 30 minutes, solvent was distilled off to obtain methyl 3-(4-methoxycarbonylmethylphenylamino)-3-trifluoromethylacrylate (4.17 g) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[C:27]([OH:29])=[O:28])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:31][O:28][C:27]([C@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]1[S:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:16])=[O:17])=[O:29]
Reactant: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 335.8 %

Procedure:
A solution of the title A compound, (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (5.55 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmol) in methanol (260 mL) is heated under nitrogen at reflux for 4 hours. The solution is allowed to stand overnight at room temperature which results in the formation of a crystalline solid. The crystals are collected by vacuum filtration and dried at high vacuum. A second crop of crystals is obtained from the mother liquor that is isolated and dried at high vacuum. A combined yield of 3.84 g of (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester is obtained as a pure crystalline product: [M+1]+=424.27.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[O:13])[CH2:6][CH2:5]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:22]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[CH2:11][CH:12]=[O:13])[CH2:8][CH2:9]1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(CC=O)[C@H]1CC[C@H](CCO)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC[C@H]1CC[C@H](C(CC=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 1-(trans-4-(2-hydroxyethyl)cyclohexyl)-3-oxopropylcarbamate (1.88 g, 6.28 mmol) in DCM (60 mL) was added DMAP (cat. amount), followed by addition of TEA (2.63 mL, 18.84 mmol) and acetic anhydride (0.89 mL, 9.42 mmol) at 0° C. under N2. The mixture was stirred at rt for 3 h, and diluted with DCM, quenched by addition of aqueous NaHCO3 solution. The organic phase was separated and dried over Na2SO4. Purification by flash column chromatography (eluent: 40% EtOAc in hexanes) gave the product as colorless gel (1.90 g, 88.6%).