Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:38])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(SC)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(S(C)=O)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of 10-chloro-7-(1-ethylpropyl)-1-[2-methyl-4-(methylthio)phenyl]-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (106 mg, 0.248 mmol) in dichloromethane (2.5 mL) was added m-chloroperbenzoic acid (47.0 mg, 0.272 mmol), and the mixture was stirred at 0° C. for 2 hr. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (32.1 mg, 0.0723 mmol, 29%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[CH:37]=[C:38]2[C:43]([NH:44][CH:45]([CH:47]3[CH2:49][CH2:48]3)[CH3:46])=[C:42]([C:50]([NH2:52])=[O:51])[CH:41]=[N:40][N:39]2[CH:53]=1.CN1CC(=O)OB([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][N:65]=2)OC(=O)C1.C(=O)([O-])[O-].[K+].[K+]>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].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:47]1([CH:45]([NH:44][C:43]2[C:38]3[N:39]([CH:53]=[C:36]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][N:65]=4)[CH:37]=3)[N:40]=[CH:41][C:42]=2[C:50]([NH2:52])=[O:51])[CH3:46])[CH2:49][CH2:48]1
Reactant: CC(Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reactant: CN1CC(=O)OB(c2ccccn2)OC(=O)C1
Agent: [Cu+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CC(Nc1c(C(N)=O)cnn2cc(-c3ccccn3)cc12)C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
Pd2 dba3 (0.850 mg, 0.928 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.770 mg, 3.71 mmol) were added to a degassed (nitrogen bubbled through for ca. 10 min) solution of (+/−)-6-bromo-4-(1-cyclopropylethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 9, 20 mg, 0.062 mmol), 6-methyl-2-(pyridin-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione (21.72 mg, 0.093 mmol), potassium carbonate (42.8 mg, 0.309 mmol) and copper (II) acetate (5.62 mg, 0.031 mmol). The vial was sealed (screw-cap) and immersed in an oil bath pre-heated to 100° C. The reaction was allowed to stir at this temperature for 2 hrs. After cooling to rt, the mixture was filtered and purified by direct injection onto a preparative HPLC (condition A) to give the title compound (7.63 mg, 0.023 mmol, 36.4% yield). HPLC (condition I): retention time=5.08 minutes. LC/MS (M+H)+=m/z 322.2. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.99 Hz), 8.40-8.49 (1 H, m), 8.32-8.40 (1 H, m), 8.28 (1 H, s), 7.76 (1 H, td, J=6.59, 1.25 Hz), 7.68 (1 H, d, J=1.94 Hz), 7.52 (1 H, d, J=1.94 Hz), 4.12 (1 H, quin, J=6.45 Hz), 1.52 (2 H, d, J=6.38 Hz), 1.14-1.29 (1 H, m), 0.58-0.75 (1 H, m), 0.35-0.51 (1 H, m).
Reaction SMILES: [O-][Si]([O-])=O.[Mg+2].C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:22][C:23]([C@H:25]1[C@@H:29]2[C@@H:30]3[C@@:43]([CH3:46])([CH2:44][CH2:45][C@@:28]2([CH2:52][OH:53])[CH2:27][CH2:26]1)[C@@:42]1([CH3:47])[C@@H:33]([C@:34]2([CH3:51])[C@@H:39]([CH2:40][CH2:41]1)[C:38]([CH3:49])([CH3:48])[C@@H:37]([OH:50])[CH2:36][CH2:35]2)[CH2:32][CH2:31]3)=[CH2:24]>C(Cl)Cl>[CH3:24][C:23]([C@H:25]1[C@@H:29]2[C@H:30]3[C@@:43]([CH3:46])([CH2:44][CH2:45][C@@:28]2([CH:52]=[O:53])[CH2:27][CH2:26]1)[C@:42]1([CH3:47])[CH2:41][CH2:40][C@H:39]2[C:38]([CH3:49])([CH3:48])[C:37](=[O:50])[CH:36]=[CH:35][C@:34]2([CH3:51])[C@H:33]1[CH2:32][CH2:31]3)=[CH2:22]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: O=[Si]([O-])[O-]
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@@H](CC[C@@H]4[C@@]5(C)C=CC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 2 h
Yield: 75 %

Procedure:
To a suspension of freshly activated powdered 4A molecular sieves (1.2 g), celite (1.2 g), florisil (1.2 g), sodium acetate (500 mg) and pyridinium chlorochromate (1.2 g) in CH2Cl2 (25 mL) add betulin (500 mg). The mixture is to be stirred for 2 hrs, and then filtered through a short column of silica gel. The filtrate is evaporated in vacuo. The residue is then subjected to column chromatography to afford betulone aldehyde (370 mg) as white solid.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].O.[NH2:23][C:24]1[N:33]=[C:32]([C:34]([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[N:25]=1>C(O)C.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]>[NH2:23][C:24]1[N:33]=[C:32]([C:34]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:44]2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:3]=3[CH2:4][NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:30]=2)[N:25]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: CC(C)(C)NCc1cc(F)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 120 °C

Procedure:
184 mg of (2-bromo-4,5-difluorobenzyl)-tert-butylamine, 166 mg of potassium carbonate, 11 μl of water and 25 mg of [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride are added to a solution of 250 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 10 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated. and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)=[O:16])[C:5](=[O:13])[N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC>[O:13]=[C:5]1[C:4]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)=[O:16])=[CH:3][C:2]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:7][N:6]1[CH2:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=C(Cc1cc(Br)cn(CC(F)(F)F)c1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C(Cc1cc(-c2ccccc2)cn(CC(F)(F)F)c1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 85 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
1,1′-Bis(diphenylphospino)ferrocene palladium(II)dichloride dichloromethane complex (5 mg, 0.006 mmol) was added to a solution of 1-(1-{[5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg, 0.097 mmol), phenyl boronic acid (14 mg, 0.117 mmol), and potassium phosphate (45 mg, 0.214 mmol), in DME (2 mL) and heated to 85° C. After 24 h, water was added and the mixture was extracted with ethyl acetate (3×). The organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [99%-85% dichloromethane/methanol] gave the title compound (25 mg). MS 512.1861 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>ClCCl.CN(C=O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][C:18]=1[NH:23][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N)c(NC(=O)c2cc(Br)ccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Method 6—Step a A mixture of 5-Bromo-2-fluoro-benzoic acid (1.50 g, 6.85 mmol), 4-methoxy-benzene-1,2-diamine dihydrochloride (1.77 g, 8.49 mmol), HATU (2.73 g, 7.19 mmol) and TEA (2.88 mL, 20.76 mmol) in dichloromethane (20 mL) and DMF (5 mL) was stirred at room temperature overnight, then water was added (50 mL), mixture was stirred for 2 h and left standing at room temperature overnight. The precipitate obtained was filtered off and dried to afford 1.45 g of the title compound (50%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10](C(OC(C)(C)C)=O)[N:11]([CH2:35][CH2:36][CH3:37])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]>FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][N:11]([CH2:35][CH2:36][CH3:37])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCCN(C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)N(C(=O)OC(C)(C)C)c1cccc(C(=N)N)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(Nc1cccc(C(=N)N)c1)C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 40 %

Procedure:
0.5 g (0.803 mmol) of 408 is dissolved in 5.0 ml of trifluoroacetic acid and stirred at 5C for 18 h. After customary work-up, 0.15 g (99.3%) of 1 is thus obtained as crystals having a melting point of 215-216° C.; MS(FAB)=467.
Reaction SMILES: COCCO[CH2:6][O:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[Cl-].[In+3].[Cl-].[Cl-]>C(#N)C>[S:11]1[C:10]2[CH2:9][CH2:8][O:7][CH2:6][C:14]=2[CH:13]=[CH:12]1
Reactant: COCCOCOCCc1cccs1
Agent: [Cl-]
Agent: [In+3]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.7 %

Procedure:
11.0 g of 2-[2-(2-methoxyethoxymethoxy)ethyl]thiophene obtained in Example 20 and 1.1 g of indium(III) chloride were added to 750 mL of acetonitrile, and the resulting mixture was refluxed for 5 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. To the residue, 100 mL of water and 150 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 70 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 2.9 g (yield of 41%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [S:1]([N:11]1[CH2:14][C:13]([CH2:17][OH:18])(CO)[CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH-].[Na+].[O:21]1CCOCC1.O=O>O.[Pt]>[S:1]([N:11]1[CH2:12][CH:13]([C:17]([OH:18])=[O:21])[CH2:14]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N2CC(CO)(CO)C2)cc1
Reactant: C1COCCO1
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(C(=O)O)C2)cc1

Procedure:
N-Tosyl-3,3-bishydroxymethyl azetidine (10 g, 0.037 mol) was suspended in distilled water (100 ml) and 30% NaOH (3 ml) added. Dioxane (50 ml) was then added in order to obtain a homogeneous solution, followed by 1 g of a 5% Pt/C catalyst. This mixture was heated under reflux with rapid stirring whilst a stream of oxygen was bubbled through at the rate of 600 ml.min-1. The pH of the solution was maintained at 9-12 with 30% NaOH and the course of the oxidation followed by 'H nmr. After 24 h another 1 g of catalyst was added and after 48 h a further 2 g was added at which point all of the starting diol had been converted. In order to achieve conversion of any intermediates, a further 1 g catalyst was added after 120 h. After a total reaction time of 144 h, 5 g catalyst had been added and 10 ml 30% NaOH (0.074 mol). The solution was filtered whilst hot and the catalyst washed with dil NaOH and water. The filtrate and washings were then acidified with 4N HCl and extracted with ether (×3). The combined ether extracts were dried and evaporated to leave a white solid which, on recrystallisation from ethyl acetate, gave N-Tosyl azetidine 3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12](=O)[C:11](=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C(N2CCCC(=O)C(=O)C2)=O)=CC=1.Br.Br.[NH2:39][CH2:40][C:41]([NH2:43])=[NH:42].[OH-].[Na+]>CO.C(OCC)(=O)C>[NH2:43][C:41]1[CH:40]=[N:39][C:12]2[CH2:13][CH2:14][N:8]([C:6](=[O:7])[C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10][C:11]=2[N:42]=1
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2)CCC1=O
Reactant: N=C(N)CN
Agent: Br
Agent: O=C1CCCN(C(=O)c2ccc(Cl)cc2)CC1=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc2c(n1)CCN(C(=O)c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
53 mg (0.2 mol) of a mixture of 1-(4-chloro-benzoyl)-hexahydroazepine-4,5-dione and 1-(4-chloro-benzoyl)-hexahydroazepine-3,4-dione [prepared from 1-(4-chloro-benzoyl)-hexahydroazepine-4-one by selenium dioxide oxidation in dioxane/water] and 47 gm (0.2 mol) of 2-amino-acetamidine dihydrobromide were dissolved in 700 ml of methanol, and 200 ml of 2 N sodium hydroxide were added dropwise to the solution at 5° C. The mixture was stirred at room temperature for one hour, then concentrated by evaporation and then, after addition of more sodium hydroxide, extracted with chloroform. The dried extract solution was concentrated by evaporation and chromatographed on silicagel with ethyl acetate/methanol (10:1) as the mobile phase. The crystals obtained thereby were digested with ethyl acetate and suction-filtered.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:27]#[C:26][CH:23]3[CH2:25][CH2:24]3)[CH:7]=2)[C:9]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[N:10]1)([CH2:15][CH3:16])[CH3:14]
Reactant: C#CC1CC1
Reactant: CCC(C)n1cc(-c2ccnc(Br)c2)c(-c2ccc(Cl)s2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)n1cc(-c2ccnc(C#CC3CC3)c2)c(-c2ccc(Cl)s2)n1
Temperature: 120 °C
Reaction time: 0.05 h
Yield: 50.9 %

Procedure:
To a solution of 2-bromo-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.18 mmol) in 2 mL of tetrahydrofurane was added cyclopropylacetylene (0.71 mmol), copper iodide (0.053 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.053 mmol) and N,N-diisopropylethlamine (0.88 mmol). The resulting mixture was stirred in the microwave at 120° C. for 3 min. The solvent was then evaporated and the residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 2:1) to afford 35 mg of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(cyclopropylethynyl)pyridine (51% yield).
Reaction SMILES: [N:1]([C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11]
Reactant: [H][H]
Reactant: C[C@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O

Procedure:
A solution of the (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (620 mg) in ethanol (25 ml) was hydrogenated at 70 psi of hydrogen gas in presence of 10% palladium on carbon (150 mg) for 12 hours. After filtration to remove the catalyst, the filtrate was concentrated under reduced pressure to provide (R)-1-(5-aminohexyl)-3,7-dimethylxanthine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[C:16]([CH3:17])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)[CH:14]=[N:13]1
Reactant: COc1nc(Br)ccc1N
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Product: COc1nc(-c2cnn(C)c2C)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 6-bromo-2-methoxypyridin-3-amine and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The crude residue was purified using silica gel column chromatography eluting with 1-10% MeOH/aqueous ammonia (10/1) in DCM.
Reaction SMILES: [CH3:1][C:2]1([C:18]([O:20]C)=[O:19])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.[OH-].[Na+].C(#N)C.CO>CO>[CH3:1][C:2]1([C:18]([OH:20])=[O:19])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[S:10][C:5]=2[C:4](=[O:17])[NH:3]1
Reactant: COC(=O)C1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CC1(C(=O)O)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A mixture of methyl 2-methyl-4-oxo-6-(pyridin-4-yl)-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2-carboxylate (0.152 g, 0.500 mmol) and 2 M sodium hydroxide (0.75 mL, 1.5 mmol) in methanol (10 mL) was stirred at room temperature for 3 h, and the resulting suspension was stored at −20° C. for 65 h. Then, the reaction mixture was warmed to room temperature, and the precipitate was collected by filtration and washed with methanol (1 mL) to give a yellow solid. This yellow solid was partitioned between ethyl acetate (25 mL) and water (10 mL), and the ethyl acetate layer was extracted with water (2×5 mL). The combined aqueous layers were acidified with acetic acid to a pH of 5 to 6, and the resulting orange precipitate was collected by filtration and washed with water to give an orange solid. Trituration with acetonitrile/methanol gave the title compound (0.031 g, 21%) as an orange solid:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])=[O:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of methyl 3-formylbenzoate (6.15 g, 37.46 mmol) in methanol (61.5 mL) and 2 M sodium hydroxide aqueous solution (37.5 mL, 75 mmol) was stirred at r.t. for 1 h, Thin layer chromatography (Petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was acidified with 80 mL of 1 M hydrochloric acid aqueous solution to pH=2 and the resulting mixture was concentrated in vacuo. The residue was extracted with ethyl acetate for 3 times and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 5.59 g of 3-formylbenzoic acid as a white solid. Yield: 99.5%.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([NH:35][S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([OH:25])([C:21]([O:23]C)=[O:22])[CH:18]([OH:26])[C:17]4[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([NH:35][S:36]([N:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([OH:25])([C:21]([OH:23])=[O:22])[CH:18]([OH:26])[C:17]4[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(O)Cn2c(c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)C)cc32)-c2ccc(OC)cc2C1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C(O)C(O)(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 80 °C
Yield: 74 %

Procedure:
To a solution of methyl rac-(5R,6S)-13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-5,6-dihydroxy-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carboxylate (57 mg, 0.10 mmol) in MeOH/THF (1:1, 2 mL) was added 1M NaOH aq. (0.5 mL). The reaction was sealed and heated at 80° C. for 20 min with microwave irradiation. The reaction was quenched with 1N HCl aq. (0.5 mL), diluted with H2O and concentrated to remove the organic solvents. The resulting precipitates were collected by filtration and dried under vacuum to yield rac-(5R,6S)-13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-5,6-dihydroxy-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (42 mg, 0.074 mmol, 73%) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ 0.73-2.20 (m, 10H), 2.92-3.05 (m, 1H), 3.02 (s, 6H), 3.54 (d, J=14.8 Hz, 1H), 3.93 (s, 3H), 4.71 (d, J=14.8 Hz, 1H), 4.94 (s, 1H), 7.05 (dd, J=8.4, 2.6 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.5 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.05 (d, J=1.5 Hz, 1H). LCMS: m/e 572 (M+H)+, ret time 3.34 min, column B, 4 minute gradient.
Reaction SMILES: [O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([OH:16])=[O:15])[CH3:13])=[CH:3]1.[OH-].[Na+].[CH3:28]I.O>CN(P(N(C)C)N(C)C)C>[O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([O:16][CH3:28])=[O:15])[CH3:13])=[CH:3]1
Reactant: CC(C(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CI
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 20 g (0.06 m) of 3-oxopregn-4-ene-20-carboxylic acid in 100 ml of hexamethyl phosphorus triamide is added 5.0 g (0.12 m) of sodium hydroxide as a 25% solution. The solution is stirred for 30 minutes after which 34 g (0.24 m) of methyliodide is added and stirring is continued for an additional 30 minutes. The reaction mixture is poured into 500 ml of water, and the product is collected and recrystallized from acetone to yield methyl 3-oxopregn-4-ene-20-carboxylate, M.P. 175°-177° C.