Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].Br.Cl[C:12]1[CH:13]=[C:14]([CH3:22])[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[CH3:22][C:14]1[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=[C:12]([O:7][CH2:6][C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)[CH:13]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: CC1(CO)COC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(C)COC2)nn2c(N)nnc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
(3-Methyloxetan-3-yl)methanol (1.74 g) was initially charged in DMF (30 ml), admixed under argon with sodium hydride (408 mg) and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g) was dissolved in DMF (30 ml) and one equivalent of the alkoxide solution (10 ml) was added. After stirring at 45° C. for 30 min, a further 0.5 equivalent of alkoxide solution was added, followed by 0.5 eq. each after a further 30 and 60 min. Then the mixture was admixed with water, and the reaction mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 758 mg of the title compound were obtained. LC-MS rt: 0.49 min [M+H]+: 250.1 (met. b)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:23])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[C:5]1([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH2:22][CH3:24])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:23])[CH2:10][N:9]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OC)C(c1ccc(Br)cc1)=NCC(=O)N2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)NC(=O)CN=C2c1ccccc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 100 mg (0.267 mmol) of 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in 2 ml of anhydrous DMF, add under an inert atmosphere 48 mg (0.35 mmol) of K2CO3. After 30 minutes at room temperature, add dropwise 25 μl (0.4 mmol) of MeI. Allow to stand at room temperature for 12 hours. Add 30 ml of water. Extract three times with 30 ml of EtO2. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt 1/hexane 1). Recrystallize in EtO2. One obtains 78 mg of the abovenamed product as a white powder. Yield: 73%. 1H-NMR (CDCl3, 200 MHz): d 3.40 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.29 (AB system, ? d=1.014, JAB=10.7, 2H, CH2), 6.65 (s, 1H Ar), 6.78 (s, 1H Ar), 7.54 (s, 4H Ar).
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[C:14]([O:20][CH2:21][N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)[C:25]=2[CH:24]=[CH:23]1)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>[C:14]([O:20][CH2:21][N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([C:31]3[CH:32]=[N:33][N:34]([C@@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH:8]=[O:9])[CH:35]=3)[C:25]=2[CH:24]=[CH:23]1)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: O=C/C=C/C1CCCC1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.8 %

Procedure:
A solution of (2E)-3-cyclopentylacrylaldehyde (28, 345 mg, 2.50 mmol, 5.0 equiv), (2R)-2-bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methylpyrrolidine ((R)-35, 16 mg, 0.025 mmol, 0.05 equiv) and 4-nitrobenzoic acid (4.3 mg, 0.025 mmol, 0.05 equiv) in anhydrous chloroform (CHCl3, 2.0 mL, 25 mmol) was stirred at room temperature for 10 min before [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5, 0.150 g, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for 23 h. After LCMS showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by Combiflash with 0-80% EtOAc/hexane gradient elution to afford (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37, 169 mg, 211.8 mg theoretical, 80% yield) as a pale yellow foam. For (R)-37: C23H29N5O3 (MW, 423.51), LCMS (EI) m/e 424 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:13][CH2:14][Mg+].[Br-].[CH2:17]1COC[CH2:18]1>>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])([CH2:13][CH3:14])[CH2:17][CH3:18]
Reactant: CC[Mg+]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: [Br-]
Product: CCC(O)(CC)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a solution of methyl 2-bromo-4-methylbenzoate (10 g, 43.7 mmol) in THF (10 mL) was added dropwise EtMgBr (88 mL, 262 mmol) at 0° C. under nitrogen and then stirred at rt for 12 h. The reaction mixture was quenched with NH4Cl-saturated water and extracted with EA. The combined organic layer was washed with NaHCO3 solution and brine, dried over Na2SO4. The solution was concentrated and the residue was purified by column chromatography over silica gel eluted with PE-EA (10:1˜2:1) to provide 3-(2-bromo-4-methylphenyl)pentan-3-ol (8.09 g; yield 71.2%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H), 7.52 (s, 1H), 7.23 (d, 1H), 2.35 (s, 3H), 1.83 (m, 4H), 0.77 (t, 6H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][OH:13])[CH:4]=1)#[N:2]
Reactant: C=O
Reactant: N#Cc1c[nH]c2ccccc12
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cn(CO)c2ccccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
The mixture of 1.42 g of 3-cyano-1H-indole, 0.60 g of paraformaldehyde and 0.1 g of triethylamine was stirred at 130 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.69 g of 3-cyano-1H-indole-1-ylmethanol.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:73]([NH2:79])[C:74]1[O:78][CH:77]=[CH:76][CH:75]=1>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:79][CH2:73][C:74]4[O:78][CH:77]=[CH:76][CH:75]=4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCc1ccco1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Yield: 94.8 %

Procedure:
A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), 1-hydroxybenzotriazole (14 mg, 0.1 mmol), and furfuryl amine (10 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. overnight, diluted with CH2Cl2 (3 mL), and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow oil. Et2O (5 mL) was added to dissolve the oil, and concentration afforded the title compound as a pale yellow solid (42 mg, 95% yield). LC/MS (ESI) retention time: 1.74 min, m/z 633 (MH+); 1H NMR (400 MHz, CDCl3 ) δ 1.29-1.44 (m, 3 H) 1.46-1.57 (m, 1 H) 1.69-1.81 (m,3 H) 1.86-1.97 (m, 1 H) 1.98-2.11 (m, 3 H) 2.27-2.37 (m, 1 H) 2.38-2.49 (m, 4 H) 2.61-2.78 (m, 2 H) 2.78-2.89 (m, 1 H) 3.66 (s, 4 H) 4.38 (s, 1 H) 4.66 (d, J=5.29 Hz, 2 H) 5.06 (s, 1 H) 6.22-6.41 (m, 2 H) 6.64 (t, J=5.04 Hz, 1 H) 6.81 (s, 1 H) 7.33-7.50 (m, 5 H) 7.51-7.61 (m, 1 H) 7.85 (d, J=8.31 Hz, 1 H) 7.97 (s, 1 H); 13C NMR (101 MHz, CDCl3) δ 26.20, 27.02, 33.27, 36.73, 37.04, 41.92, 49.45, 61.67, 66.94, 107.54, 108.90, 110.48, 116.84, 120.05, 121.19, 127.05, 127.95, 128.21, 129.24, 130.08, 130.96, 131.24, 133.24, 134.00, 135.18, 136.39, 142.15, 151.57, 167.74, 168.88.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N:9]([CH3:25])/[C:10](/[C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)=[CH:11]\[CH:12]=[N+:13](C)C.COC(O)C.[NH2:31][C:32]1[C:33]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:34][C:35]([O:42][CH3:43])=[C:36]([NH:38]C(N)=N)[CH:37]=1.CN(C)C(N(C)C)=N>COCCO.CCOC(C)=O>[CH3:43][O:42][C:35]1[CH:34]=[C:33]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)[C:32]([NH2:31])=[CH:37][C:36]=1[NH:38][C:25]1[N:9]=[C:10]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:11]=[CH:12][N:13]=1
Reactant: CN(C)/C(=C\C=[N+](C)C)c1cnn2ccccc12
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1NC(=N)N
Agent: CN(C)C(=N)N(C)C
Agent: COC(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: COCCO
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of [(Z)-3-(dimethylamino)-3-pyrazolo[1,5-a]pyridin-3-yl-prop-2-enylidene]-dimethyl-ammonium hexafluorophosphate (Intermediate 70, 116 mg, 0.3 mmol) in 2-s methoxyethanol (2 mL) was added dropwise to a stirred solution of 1-(5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)guanidine (Intermediate 72, 84 mg, 0.30 mmol) and 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) in 2-methoxyethanol (2 mL) at r.t. under N2. The resulting solution was sealed into a microwave tube and heated to 120° C. for 0.25 h then cooled to r.t. Further 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) was then added and the mixture was stirred at 120° C. for 0.25 h, then at 140° C. for 0.25 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (2×5 mL). The aqueous solution was extracted with EtOAc (5 mL) and the organic solution was washed with water (2×3 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (69 mg, 53%) as a yellow foam; 1H NMR: 2.25 (3H, d), 2.51 (4H, m), 2.87 (4H, t), 3.73 (3H, s), 4.37 (2H, s), 6.72 (1H, s), 7.07 (1H, m), 7.22 (1H, d), 7.33 (1H, s), 7.40 (1H, m), 7.98 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s), 8.79 (1H, d); m/z: ES+ MH+ 431.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.[CH:9]([OH:11])=O.[OH:12]O>C(O)C>[CH2:9]([OH:11])[CH:7]([OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OO
Reactant: C=CCCCCCC
Reactant: O=CO
Solvent: CCO
Product: CCCCCCC(O)CO

Procedure:
314 g (2.80 mol) of 1-octene were reacted with 330 g (7.17 mol) of formic acid and 232 g (3.41 mol) of a 50% strength aqueous H2O2 solution in accordance with Example 4. 575 g of ethanol were employed for the Marlon AS3 acid-catalyzed transesterification, and the main fraction obtained after the workup by distillation was >99.5% pure, virtually odorless 1,2-octanediol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>CO>[C:22]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1)(=[O:24])[CH3:23].[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Product: CCC(=O)[O-]
Yield: 37.3 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 50 mg (0.21 mmol) of 4-acetylamino-benzenesulfonyl chloride. After trituration in hot methanol, 35 mg (38%) of 8-(4-acetylamino-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of an orange-brown solid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:26][CH2:27][C:28](Cl)=[O:29].O>C(OCC)(=O)C>[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:28](=[O:29])[CH2:27][Cl:26])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCl)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.68 ml of triethylamine were added to a solution of 3.00 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine in 60 ml of ethyl acetate, and the resulting mixture was cooled with ice, after which 0.96 ml of 2-chloroacetyl chloride was added. The reaction mixture was then stirred at room temperature for 1 hour, after which it was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 3.40 g (yield 87%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:49])[CH:6]([NH:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](=[O:48])[NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[CH:31][C:30]=2[C:39]([N:41]2[CH2:45][CH2:44][CH2:43][CH:42]2[CH2:46][OH:47])=[O:40])=[CH:21][CH:20]=1)=[O:17])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:2]=[CH2:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:49])[CH:6]([NH:15][C:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]([N:28]2[C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[CH:31][C:30]=3[C:39](=[O:40])[N:41]3[CH2:45][CH2:44][CH2:43][C@H:42]3[C@@H:46]2[OH:47])=[O:48])=[CH:23][CH:24]=1)=[O:17])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2CO)cc1)C(=O)OCC=C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)N2c3cc(OC)c(OC)cc3C(=O)N3CCC[C@H]3[C@@H]2O)cc1)C(=O)OCC=C
Yield: 66 %

Procedure:
The alcohol 44 (0.55 g, 0.8 mmol) was reacted (Method B) with pyridinium dichromate (0.36 g, 0.96 mmol) and 4 Å molecular sieves (0.4 g) in anhydrous CH2Cl2 (4 mL). The product was obtained (flash column chromatography 80% EtOAc/20% n-hexane) as a white foam (0.36 g, 66%). 1H NMR (CDCl3) δ 7.22 (m, 3H), 7.07 (d, J=7.5 Hz, 2H), 6.50 (s, 1H), 5.95 (m, 3H), 5.70 (dd, J=3, 10 Hz, 1H); 5.30 (m, 5H), 4.90 (d, J=13 Hz, 1H), 4.60 (m, 4H), 4.45 (m, 1H), 3.92 (s, 3H), 3.55 (m, 8H), 2.50 (m, 2H), 2.30 (m, 1H), 2.10 (m, 4H).
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>O1CCOCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:18]1[NH:17][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Oc1ncnc2ncccc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CC(Nc1ncnc3ncccc13)C2
Yield: 23 %

Procedure:
Using 4-hydroxypyrido[2,3-d]pyrimidine (150 mg, 1.0 mmol) (see J. Am. Chem. Soc., 77, 2256 (1955)), phosphorus oxychloride (1.0 ml), 2-aminoindan (270 mg, 2.0 mmol), triethylamine (1.4 ml, 10 mmol), and dry dioxane (5 ml), a similar procedure to Product ion Example 203 was carried out. The product obtained was purified by silica gel chromatography (ethyl acetate:methanol=19:1) to obtain the title compound (60 mg, 0.23 mmol) having the following physical properties:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][OH:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(OCC)C>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of (S)-methyl 5-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (12 g, 46 mmol) in DMF (100 mL) was added imidazole (7.8 g, 115 mmol, 2.5 equiv.). TBS-Cl (8.25 g, 55 mmol, 1.2 equiv.) was then added in 3 portions. The reaction was complete in 30 min. Diethyl ether (200 mL) and brine (300 mL) were added to the reaction solution. The organic layer was further washed with brine (300 mL), dried, and concentrated to give (S)-methyl 5-(tert-butoxycarbonylamino)-6-(tert-butyldimethylsilyloxy)hexanoate (15.9 g, 92%) as a colorless oil. LRMS (M-Boc+H+) m/z 276.1.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[Cl:25])[C:5](OCC)=[O:6])(=O)[CH3:2].[NH2:26][NH:27]C(N)=S.C[O-].[Na+]>CO>[Cl:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[C:5]([OH:6])=[N:26][NH:27][C:1]=1[CH3:2]
Reactant: CCOC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Reactant: NNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCCCCCCc2c(O)n[nH]c2C)c(Cl)c1
Yield: 55.2 %

Procedure:
A mixture of 11.1 g (0.03 m) of ethyl 2-acetyl-8-(2-chloro-4-methoxyphenoxy)octanoate, 2.73 g (0.03 m) of thiosemicarbazide and 1.62 g (0.03 m) of sodium methoxide in 15 ml of methanol was heated at reflux for 24 hours. The solid product was collected, washed with 50% aqueous ethanol and recrystallized from ethanol to give 5.6 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-5-methyl-1H-pyrazol-3-ol, m.p. 145°-146° C.; MIC=6 microg/ml (herpes 2). (During this reaction the thiocarbamyl group (CSNH2) of the thiosemicarbazide was cleaved so that the reaction product is the same as that obtained when unsubstituted hydrazine is used.)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].C(N(C(C)C)C(C)C)C.[CH3:60][C:61]1([CH3:68])[CH2:65][C:64](=[O:66])[O:63][C:62]1=[O:67]>O1CCOCC1>[CH3:41][O:40][C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:4][CH2:3][N:2]([CH3:1])[C:64](=[O:66])[CH2:65][C:61]([CH3:68])([CH3:60])[C:62]([OH:63])=[O:67])=[O:16])=[O:24])=[CH:31][CH:30]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC(CC)N(CCN(C)C(=O)CC(C)(C)C(=O)O)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a mixture of 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 48 mg of N-ethyl-N-isopropylpropan-2-amine and 4 mL of dioxane was added 44 mg of 3,3-dimethyldihydrofuran-2,5-dione, followed by stirring overnight at 65° C. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 200 mg of 4-[(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)(methyl)amino]-2,2-dimethyl-4-oxobutanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([Cl:19])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a soln of 2-(3,4-dichlorophenyl)pent-4-enoic acid (2.34 g, 9.53 mmol) in methylene chloride (25.0 mL) was added oxalyl chloride (1.61 mL, 19.0 mmol) followed by N,N-dimethylformamide (73.8 uL, 0.953 mmol) After 1 hr of stirring at rt, the solution was concentrated to provide 2-(3,4-dichlorophenyl)pent-4-enoyl chloride as a yellow oil (2.70 g, quantative). 1H NMR (400 MHz, CDCl3) δ 7.49-7.42 (d, J=8.3 Hz, 1H), 7.40-7.36 (d, J=2.2 Hz, 1H), 7.17-7.10 (dd, J=8.3, 2.2 Hz, 1H), 5.73-5.57 (ddt, J=17.1, 10.2, 6.9 Hz, 1H), 5.15-5.06 (m, 2H), 4.06-3.97 (t, J=7.6 Hz, 1H), 2.97-2.83 (m, 1H), 2.61-2.49 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])OC(=O)[CH:3]=1.[C:15]1([CH:21]=[CH:22]N2CCOCC2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCOCC1>C1(C)C=CC=CC=1>[CH3:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:3])[CH:1]=[CH:22][C:21]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Reactant: C(=CN1CCOCC1)c1ccccc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)ccc(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 18.1 %

Procedure:
Under a dry nitrogen atmosphere a solution of commercial ethyl 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylate (19.6 g, 0.1 mole) in toluene (20 ml) was added dropwise to a stirred solution of 4-(2-phenylethenyl)morpholine (14.3 g, 0.076 mole) in toluene (200 ml). Preparation of the morpholine derivative is described in U.S. Pat. No. 3,922,237. After the addition, the reaction mixture was heated at reflux for approximately 20 hours. The reaction mixture was then cooled and concentrated under reduced pressure, leaving a residue. The residue was heated at 170° under a dry nitrogen atmosphere for 3.5 hours, allowed to cool to room temperature, and then filtered. The filtrate was purified by column chromatography on silica gel, elution first with n-hexane: ethyl acetate, and finally ethyl acetate, to give ethyl 2,4-dimethyl-[1,1'-biphenyl]-3-carboxylate (3.5 g) as a yellow oil.