Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[S-:11][C:12]#[N:13].[Na+].BrBr>C(O)(=O)C>[S:11]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1])[C:12]#[N:13]
Reactant: Cc1cc2cccnc2[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1[nH]c2ncccc2c1SC#N
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg (2.36 mmol) of 2-methylpyrrolo[2,3-b]pyridine and 920 mg (11.3 mmol) of sodium thiocyanate in 5 ml acetic acid was added 450 mg (2.8 mmol) bromine in 1 ml acetic acid at 5° C. The reaction mixture was stirred for 30 min at 5° C. and thereafter for 16 h at room temperature. The solid was filtered off. To the filtrate was added 20 ml water. The precipitated product was filtered off and washed with water giving 160 mg (37%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@:22]([OH:29])([CH2:26][CH2:27][OH:28])[C:23]([O-:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[K+].CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@:22]([OH:29])([CH2:26][CH2:27][OH:28])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(O)CCCCCCC)[C@@](O)(CCO)C(=O)[O-])C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(O)CCCCCCC)[C@@](O)(CCO)C(=O)O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
To a mixture of No. 5286993, potassium (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2,12-dihydroxy-2-(2-hydroxy-ethyl)-nonadec-4-enoate (40 mg, 0.0584 mmol) and methanol (2.0 mL) were added water (2.0 mL) and potassium carbonate (40 mg, 0.146 mmol), and the mixture was stirred at room temperature for 4 hours. After confirming the consumption of the starting materials by LCMS, water was added and the mixture was extracted with ethyl acetate. To the aqueous layer was then added 1 M hydrochloric acid until pH 7 was reached. The organic layer was washed with a saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure to obtain the title compound (15 mg, 41% yield, white solid).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:3]1=2.O1CCCC1.[OH-].[Na+]>O>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolve 900 mg. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboxylate in 20 cc. of tetrahydrofuran. Add 20 cc. 1 N aqueous sodium hydroxide. Stir at room temperature for 48 hours. Dilute with water and extract with ether. Acidify the aqueous fraction with hydrochloric acid and extract with ether. Evaporate the organic phase to obtain the title product (m.p. 275° C. dec.).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])(=[O:13])=[O:12])[CH2:23]1
Reactant: CC1CNCCN1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(N3CCNC(C)C3)cccc21
Yield: 38 %

Procedure:
The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and 3-methylpiperazine according to Method 1 to give 110 mg (38%) of a white solid: 1HNMR (CD3OD) δ 7.92–6.82 (m, 9H), 3.64–3.39 (m, 5H), 3.12–3.03 (m, 1H), 2.92–2.83 (m, 1H), 2.47 (s, 3H), 1.40 (d, J=7 Hz, 3H); MS (ESI) 370.0 (M+H)+; Purity (HPLC) 94%.
Reaction SMILES: [Sn].Cl.CO[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1OC)[NH:10][C:9](C)=[C:8]2CCN1CCN(C2C=CC=CC=2)CC1.COC1C=C2C(=CC=1OC)N[C@@H](C)[C@H]2CCN1CCN(C2C=CC=CC=2)CC1.N1C2C(=CC=CC=2)C=C1.B#B.C[O-].[Na+]>[Cr]([O-])([O-])=O.[Cu+2]>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: COc1cc2[nH]c(C)c(CCN3CCN(c4ccccc4)CC3)c2cc1OC
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: B#B
Product: c1ccc2c(c1)CCN2

Procedure:
The tin and hydrochloric acid reduction of 5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-1-piperazinyl)ethyl]indole to cis-5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-1-piperazinyl)ethyl]indoline suffers from low productivity in that it has not been possible to isolate more than 60-65% of crude product. Furthermore, this crude material is contaminated with 6-7% of trans-isomer and 1-2% of starting material. Purification by two recrystallizations is required to provide pure cis-isomer in 9% overall yield. Alternate methods of reducing the starting indole such as electrochemical-lead electrodes, diborane and sodium methoxide, and catalytic reduction with copper chromite catalyst provide from 50/50 cis/trans mixtures to 70/30 cis/trans mixtures of indoline. The stereoselectivity of the novel process of the present invention is thus completely unexpected particularly in view of the fact that ionic hydrogenation usually results in the formation of the thermodynamically more stable trans-isomer.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[CH:5]=[C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9](=[O:16])[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7]1)[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[CH:5]([C:6]1[CH:11]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH3:23]
Reactant: C1COCCN1
Reactant: CCN(CC)C(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Product: CCN(CC)C(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCOCC1

Procedure:
Synthesized as in Example 51 from Intermediate 21 (1.84 g, 5.8 mmol) and morpholine (1.06 g, 12.2 mmol). This gave 1.65 g (70%) of pure product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)=[CH:10][CH:9]=1.Cl.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:25]1([CH2:28][NH:29][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[N:21][C:13]=2[O:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:23][CH:22]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: NCC1CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C(NCC1CC1)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reaction time: 0.08 h

Procedure:
To a 100 mL round-bottomed flask was added 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (0.333 g, 1.08 mmol), cyclopropylmethanamine hydrochloride (0.116 g, 1.08 mmol), and TEA (0.4500 mL, 3.25 mmol) in DMF to stir for 5 min. EDC (0.2314 g, 1.19 mmol) and HOBT (0.1870 g, 1.19 mmol) was then added and allowed to stir overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (1×10 mL), saturated sodium chloride (1×10 mL), saturated sodium bicarbonate (1×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide N-(cyclopropylmethyl)-2-(4-(pyridin-2-ylamino)phenoxy)nicotinamide. MS (ESI, pos. ion) m/z: 361.1 (M+1). IC50 (uM) 0.831.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[N:2]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1

Procedure:
prepared by reaction of 1H-indazol-6-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.CO[C:12]1[CH2:17][N:16]([CH3:18])[CH2:15][C:14](=[O:19])[CH:13]=1.CO.Cl>CCOCC.C1COCC1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:12]2[CH2:17][N:16]([CH3:18])[CH2:15][C:14](=[O:19])[CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: COC1=CC(=O)CN(C)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(=O)CN(C)C2)cc1

Procedure:
A solution of p-tolyl magnesium bromide (0.23 M) in ether (150 ml) was treated with a solution of 5-methoxy-1-methyl-1,6-dihydro-3[2H]pyridone (28.2 g, 0.2 M) in THF (200 ml) at such a rate as to maintain a gentle reflux. After 1 hour the reaction mixture was poured on to methanol (500 ml) and treated with 12 N hydrochloric acid (50 ml). Removal of the resulting crystals by filtration followed by air-drying gave the title compound (21 g) as the hydrochloride five quarters hydrate.
Reaction SMILES: [OH-:1].[Na+].Cl[P:4]1(=[O:22])[O:9][CH:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1.Cl>O>[OH:1][P:4]1(=[O:22])[O:9][CH:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1
Reactant: [OH-]
Reactant: CC1(C)COP(=O)(Cl)OC1c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)COP(=O)(O)OC1c1ccc2ccccc2c1
Temperature: 101 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Sodium hydroxide (14.9 g, 0.373 mol) was dissolved in water (150 ml). To this solution was added little by little 2-chloro-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane-2-one (38.6 g, 0.124 mol) with heating to 100 to 102° C. and stirring for 30 min. The solution was stirred at the same temperature for 20 min, and the reaction solution was cooled to 45° C. Concentrated hydrochloric acid (37 ml) was added thereto to adjust the solution to acidic. The solution was stirred at 15° C. for 30 min. The crystals were collected by filtration, washed with water and then ether, and dried under reduced pressure at 60° C. to give the title compound as pale ocher crystals having the melting point of 237 to 238° C. (33.87 g, yield 93.2%).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:19])[CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:20]([O:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:19])[CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc2cc(C(O)Cn3ccnc3)ccc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2cc(C(Cn3ccnc3)OC(=O)c3ccccc3)ccc2c1

Procedure:
A solution of 1.26 g. 1-[2-hydroxy-2-(6-methyl-2-naphthyl)ethyl]imidazole in 20 ml. pyridine is treated dropwise with stirring with 0.72 ml. of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml. water, extracted with ethyl acetate and the extracts washed, dried (MgSO4) and evaporated in vacuo to remove residual pyridine and afford 1-[2-benzoyloxy-2-(6-methyl-2-naphthyl)ethyl)imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give the hydrochloride salt.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:15][CH:16]=1.[Br:28]CC(C1C=C(C(OC)=S)SC=1C)=O.NC(NC1C=NC2C(C=1)=CC=CC=2)=S>>[BrH:28].[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:15][CH:16]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Agent: COC(=O)c1cc(-c2csc(Nc3cnc4ccccc4c3)n2)c(SC)s1
Agent: NC(=S)Nc1cnc2ccccc2c1
Product: Br

Procedure:
Methyl 5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was allowed to react with amino(3-quinolylamino)methane-1-thione (59.1 mg) as described in Example 154, step (a) to give 107.5 mg (78% yield) of methyl 5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.75 (s, 3H), 3.84 (s, 3H), 7.52 (s, 1H), 7.92-8.05 (m, 2H), 8.22 (s, 1H), 9.22 (m, 2H); Mass Spectrum (ESI) m/z calcd. for C19H15N3O2S3, 413.54 (M+H), found 414.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14]>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.ClCCCl>[CH2:14]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH:13]=[CH2:12]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=CCc1ccc(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 84.9 %

Procedure:
To 1-chloro-4-methyl-2-nitrobenzene (2.00 g, 11.7 mmol), allyltributylstannane (5.79 g, 17.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.818 g, 1.17 mmol) in two 25-mL reaction vials was added 1,2-dichloroethane (20 mL). The vials were capped and heated at 120° C. for 45 minutes in a Biotage Initiator® microwave reactor with an external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was loaded onto a Celite® cartridge. The crude material was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent followed by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent. The combined acetonitrile/water fractions were concentrated, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, and dried in a vacuum oven to provide the title compound as a yellow liquid (1.76 g, 84%): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=0.9 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 5.96 (ddt, J=16.6, 10.1, 6.4 Hz, 1H), 5.08 (ddq, J=18.5, 17.0, 1.5 Hz, 2H), 3.64 (d, J=6.4 Hz, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 149.09, 137.62, 135.35, 133.81, 131.81, 131.72, 124.94, 116.81, 36.62, 20.72; EIMS m/z 176 ([M]+).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22]([NH:24][CH:25]([C:32]#[N:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.[NH2:41][OH:42]>C(O)C>[NH2:33]/[C:32](=[N:41]\[OH:42])/[C@H:25]([NH:24][C:22]([CH:18]1[N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:9][CH:10]=2)(=[O:15])=[O:16])[CH2:21][CH2:20][S:19]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#CC(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N/C(=N\O)[C@H](NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (92 μl, 0.66 mmol) was slowly added to a suspension of product Ic, e.g., 3-(biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-1,3-thiazolidine-2-carboxamide, and hydroxylamine.hydrochloride (46 mg, 0.66 mmol) in ethanol (5 mL), under stirring. The reaction mixture was heated under reflux for 16 h, and then cooled to RT. The solvents were removed and the resulting solid was suspended in water and extracted with three portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording intermediate Id, e.g., N-[(1R,2Z)-2-amino-2-(hydroxyimino)-1-phenylethyl]-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (272 mg, quantitative yield) which was directly used in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:21][C:22]1[C:23]([CH3:48])=[C:24]([CH:34]2[CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[CH2:35]2)[C:25]([O:31][CH2:32][CH3:33])=[C:26]([CH:28](Cl)[CH3:29])[CH:27]=1>CN(C)C=O.O>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:28]([C:26]3[C:25]([O:31][CH2:32][CH3:33])=[C:24]([CH:34]4[CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:39])[CH2:35]4)[C:23]([CH3:48])=[C:22]([Cl:21])[CH:27]=3)[CH3:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (11.5 mg, 0.0708 mmol), cesium carbonate (34 mg, 0.10 mmol) and potassium iodide (1.2 mg, 0.0071 mmol) in N,N-dimethylformamide (0.2 mL) was added benzyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate (30 mg, 0.07 mmol). The mixture was stirred at 140° C. for 1 hour, cooled and then diluted with water, extracted with ether. The combined organic layers were dried over MgSO4 and concentrated to afford the crude product which was used in the next step directly. LCMS calculated for C29H31ClN5O4 (M+H)+: m/z=548.2; Found: 548.2.
Reaction SMILES: [C:1]([C:9]1[C:10]([O:24][CH2:25][CH3:26])=[C:11]2[CH:17]=[N:16][N:15](CC3OC=CC=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O>[C:1]([C:9]1[C:10]([O:24][CH2:25][CH3:26])=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1c(C(=O)c2ccccc2)cnc2[nH]ncc12
Reaction time: 1 h

Procedure:
87 g. of 5-benzoyl-4-ethoxy-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.25 mol.) are dissolved in 300 ml. of conc. sulfuric acid within 15 to 20 minutes with vigorous stirring. The temperature rises to 40°-45°. Stirring is continued for 1 hour. The dark colored mixture is then added to 3700 ml. of cold water. Stirring is continued for 2 hours and the dark by-products are filtered off. The filtrate is made alkaline with 25% aqueous ammonia. The white precipitate of 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine is filtered off, yield 44.8 g. (66%), m.p. 202°-203° (butanol).
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 300 mg (1.19 mmol) of ethyl (1R,2S)-2-aminocyclohexanecarboxylate HBr salt (Xu, Daquiang et al., Tetrahedron:Asymmetry (1988), 9(10) 1635) dissolved in 8 mL DMF was added 192 mg (1.19 mmol) of indole-2-carboxylic acid, 228 mg (1.19 mmol) of EDCI, 161 mg (1.19 mmol) of HOBT and 0.458 mL (4.16 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to provide ethyl (1R,2S)-2-[(1H-indol-2-ylcarbonyl)amino]cyclohexane-carboxylate.
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=[CH:7][CH:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[CH2:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.[Cl-].[Na+]>[OH:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=[CH:7][CH:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[CH2:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(C=CC1CCC(=O)N1CC(=O)CCCCC(=O)O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: CCCCCC(O)C=CC1CCC(=O)N1CC(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
To a solution of 13 (100 mg, 0.25 mmol) in methanol (3 mL) was added potassium carbonate (220 mg, 1.59 mmol). The reaction mixture was stirred at room temperature for five hours before it was acidified with 10% hydrochloric acid to pH 2. It was then diluted with saturated aqueous sodium chloride and extracted with ether three times. The combined ether layer was washed with saturated sodium chloride and dried over magnesium sulfate. Removal of the solvent afforded 70 mg of 7-[2-(3-hydroxy-1-octen-1-yl)-5-oxopyrrolidin-1-yl]-6-oxo-1-heptanoic acid (14). IR (CH2Cl2): 3600-2500 (br), 1720, 1690 cm-1 ; PMR (CDCl3): δ5.67 (bs, 2H, --CO2H and --OH), 5.67-5.17 (m, 2H), 4.33-3.56 (m, 4H), 2.57-2.13 (m, 6H), 1.90-1.07 (m, 14H), and 0.90 (t, 3H); MS: m/z 335 (M+ --H2O).