Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]2[C:23](=[O:24])[N:22]([C:25]([CH:37]([CH3:39])[CH3:38])([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:26](=[O:28])[NH2:27])[C:21]3[CH:40]=[CH:41][CH:42]=[CH:43][C:20]=3[N:19]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[C:18]2=[O:50])=[O:15])[CH:8]=1)(C)(C)C.Cl.CCOCC>O1CCOCC1>[CH:37]([C:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([C:26](=[O:28])[NH2:27])[N:22]1[C:23](=[O:24])[CH:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:51])=[O:5])[C:18](=[O:50])[N:19]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[C:20]2[CH:43]=[CH:42][CH:41]=[CH:40][C:21]1=2)([CH3:39])[CH3:38]
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)Nc3cccc(C(=O)OC(C)(C)C)c3)C(=O)N(c3cccnc3)c3ccccc32)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)Nc3cccc(C(=O)O)c3)C(=O)N(c3cccnc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-{1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-ureido)-benzoic acid tert butyl ester (115 mg, 0.224 mmol) and 4N HCl in dioxane (1 ml) was stirred at rt for 1.75 h after which time a further 1 ml of 4N HCl in dioxane was added and the reaction mixture stirred at rt overnight. Ether (20 ml) was added and the resultant precipitate was triturated with ether (3×30 ml) to afford the title compound as a white powder. 1H NMR (300 MHz, CDCl3).s 1H NMR (300 MHz, CDCl-3). s 8.61 (s, 1H), 8.56 (d, 1H, J=8.2), 7.91 (d, 1H, J=8.2), 6.91-7.83 (m, 16H), 6.41 (d, 1H, J=7.9), 5.43 (d, 1H, J=7.9), 4.91 (sept, 1H, J=6.8), 4.60 (d, 1H, J=11.8), 4.18 (d, 1H, J=11.8), 3.86 (s, 3H), 1.06 (m, 6H). Low resolution MS (FAB) m/e 637 (m+).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:13]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(=O)Oc1ccc(OC)cc1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
18.6 g (0.12 mole) of triethylphosphite was heated at 125°-130° in a flask with a reflux condensor. 18.6 g (0.10 mole) of 4-methoxyphenyl chloroformate (prepared according to M. J. Zatik and R. D. Schuetz, J. Org. Chem. 32 (1967) 300) was added dropwise. The reaction flask was heated additionally at about 120° for 11/2 hours and left at room temperature overnight. The product was distilled to give 25.8 g (89%) of diethyl 4-methoxyphenoxycarbonylphosphonate. B.p.0.03 174°-8°, nD21 1.4940. Analysis for C12H17O6P. Found (calculated): C 49.79 (50.00), H 6.01 (5.95), P 10.54 (10.75). NMR (CDCl3)δ: 1.42 (t, CH3), 3.78 (s, OCH3), 4.13-4.63 (CH2), 6.77-7.33 (aromatic). IR (neat) cm- : 1740 (CO), 1275, 1255, 1190, 1030.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccccn2c1=O
Product: O=c1n(CCC#Cc2ccccn2)nc2ccccn12
Yield: 23513.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol) and 2-bromopyridine (65 mg, 0.41 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (87 mmol, 23%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a yellow solid (M.P.=95.5-96° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:6]=2[CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc2cc(N)ccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
In a 250 ml round-bottomed flask fitted with a Teflon stirrer and a reflux condenser, methyl 5-nitrobenzo[b]thiophene-2-carboxylate (10 g, 42.18 mmole) was dissolved in ethanol (100 ml). Tin (II) chloride dihydrate (5 equivalents, 47.60 g, 211 mmole) was added in one lot and the resulting slurry was reluxed for 18 hours while being stirred. The reaction mixture was cooled to room temperature, transferred to a 2000 ml Erlenmeyer flask, and carefully quenched with 5% sodium bicarbonate solution (aprroximately 700 ml) until effervescense was no longer detected. The resulting precipitate was filtered off and air-dried. The dried solid was dissolved in hot ethanol (500 ml), and filtered to remove undissolved material. The filtrate was evaporated in vacuo to give 8.564 g (96%) of methyl 5-aminobenzo[b]thiophene-2-carboxylate.
Reaction SMILES: [I-].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:18])[CH3:17])[CH:13]=[C:12]([C:19](=[O:21])[CH3:20])[CH:11]=2)[CH:6]=[C:5]([CH3:22])[N+:4]=1[CH3:23].CO.O.[OH-].[Na+]>O>[NH2:2][C:3]1[N:4]([CH3:23])[C:5]([CH3:22])=[CH:6][C:7](=[N:9][C:10]2[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)[N:8]=1
Reactant: CC(=O)c1cc(Nc2cc(C)[n+](C)c(N)n2)cc(C(C)=O)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(N=c2cc(C)n(C)c(N)n2)cc(C(C)=O)c1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A suspension of 21 g (49.3 mmole) of 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium iodide (compound No. 2, synthesized as described in section 6.1) in 1:1 methanol/water (750 mL) at 60° C. was treated with excess 2N NaOH with cooling to maintain about 60° C. An additional 200 mL of water was added and the mixture was cooled in ice and filtered to give 14.69 g 2-amino-4-(3,5-diacetylphenyl)imino-1,4-dihydro-1,6-dimethylpyrimidine as yellow crystals, mp 219-220°.
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:28])[C:14]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[OH:15])[CH2:8][CH2:7]1.Cl.Cl.N[CH:33]1[CH2:38]CN(CC2CCCCCC2)C[CH2:34]1>>[CH:4]1([CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:28])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:15])[CH2:10][CH2:11]2)[CH2:38][CH2:33][CH2:34][CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2cccc(F)c2)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1cccc(F)c1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-(3-fluorophenyl)-2-cyclopentyl-2-hydroxyacetic acid obtained in Example 53 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].COC(OC)OC.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:19][CH2:20][CH2:21][CH2:22][OH:23])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=[N+]([O-])c1cccc(CNCCCO)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of m-nitrobenzaldehyde (94.23 mmol) and trimethylorthoformate (15.5 mL, 141 mmol) in MeOH (300 mL) is added dropwise 3-amino-1-propanol (7.21 mL, 94.23 mmol) at room temperature. The reaction is allowed to stir at room temperature for 5 hours followed by cooling to 0° C. in an ice bath. Sodium borohydride (3.56 g, 94.23 mmol) is added in two portions and when the bubbling stops the solvent is evaporated. The resulting residue is partitioned between ethyl acetate (75 mL) and water (75 mL). The aqueous layer is extracted twice with ethyl acetate (75 mL) The ethyl acetate extracts are collected and washed twice with Brine (50 mL), dried over MgSO41 filtered, and concentrated. Drying will give the title compound.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C(Cl)Cl.O>[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: CC(C)(C)NN
Reactant: COc1cccc(C(=O)Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C(=O)NNC(C)(C)C)c1C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mol) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50% aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mol) in methylene chloride (1 L) and sodium hydroxide (50% aqueous, 80 g) diluted with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4×500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g, 96% yield). 1H-NMR (CDCl3)δppm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38](=O)[CH:39]([CH3:41])[CH3:40]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)C=O
Product: CC(C)CN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure F using isobutyraldehyde. The final product was obtained in 41% yield.
Reaction SMILES: [CH2:1]([P:3]([OH:9])([CH2:5][C:6]([OH:8])=[O:7])=[O:4])[CH3:2].[OH-].[Na+:11]>>[Na+:11].[CH2:1]([P:3]([OH:9])([CH2:5][C:6]([O-:8])=[O:7])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCP(=O)(O)CC(=O)[O-]
Yield: 98 %

Procedure:
An aqueous solution of 304 g (2 mol) of 2-(ethylhydroxyphosphinyl)acetic acid (prepared as in Example 9) is reacted with about 160 g of a 50% aqueous solution of sodium hydroxide and the water is distilled off in vacuo to leave 384 g (98% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid sodium salt as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][OH:13])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:13][CH2:12][C@@H:8]2[O:7][C:6]3[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=[C:2]([Cl:1])[C:11]=3[O:10][CH2:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1

Procedure:
Preparation according to Preparation 22 using [(2S)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.33 g, 1.2 mmol), DCM (10 ml), p-toluenesulfonyl chloride (0.34 g, 1.8 mmol), TEA (0.18 ml, 1.8 mmol) and 4-DMAP (0.15 g, 1.2 mmol). Yield: 0.47 g. MS m/z (rel. intensity, 70 eV) 344 (28), 342 (bp), 340 (74), 263 (18), 233 (31). Molecular ion not found, however fragmentation consistent with the title compound. Used directly in the next step (Example 38) without further analysis.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:36])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]3[C:32]4[C:27](=[C:28]([C:33](=[O:35])[NH2:34])[CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH:16]=2)[N:12]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([NH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[CH2:21][NH:22][C:23]2[C:32]3[C:27](=[C:28]([C:33]([NH2:34])=[O:35])[CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][N:24]=2)=[O:36])[N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cs1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4csc(N)n4)c3)ncnc12
Reaction time: 8 h

Procedure:
64 mg (0.12 mmol) of (4-{3-[(8-Carbamoyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl}-thiazol-2-yl)-carbamic acid tert-butyl ester were dissolved in 1.0 ml dioxane and 620 μl 4 N HCl in dioxane were added. The mixture was stirred overnight and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 59.3 %

Procedure:
11.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 120 ml of acetone, and 7.56 g of sodium bicarbonate are added thereto. 6.4 g of 4-nitrobenzoyl chloride are added to the mixture under ice-cooling and under stirring, and said mixture is stirred at room temperature for 2 hours. After the reaction, 10 ml of water are added to the mixture to dissolve inorganic materials, and said mixture is evaporated under reduced pressure to remove acetone. The oil thus obtained is extracted with ethyl acetate, and the extract is washed with water, dried and then eveporated to remove solvent. 9.3 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-nitrobenzoyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[CH:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: OCc1cccc2cc[nH]c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl Indole-7-carboxylate was prepared according to literature procedure {Batcho B. and Leimgruber, K., Org. Syn. Vol IIV, page 34-40). To a solution of methyl 7-indolecarboxylate (13 g, 74.2 mmol) in 250 ml of anhydrous THF was added LiAlH4 (10.9 g, 0.288 mol) in portions, and reaction mixture was heated to reflux for 2 h. After cooling to room temperature, the excess hydride was quenched by addition of water (12 mL), 15% NaOH (12 mL) and water (26 mL). The solids were removed by filtration through a pad of Celite and filtrate was evaporated in vacuo to yield (1H-indol-7-yl)-methanol (10.7 g, 98%). 1HNMR (CDCl3). To a solution of the alcohol, (1H-indol-7-yl)-methanol (8.0 g, 54.3 mmol) in 400 mL of methylene chloride was added activated manganese (IV) oxide (85%, 41.0 g, 0.40 mol), and stirred at ambient temperature for 72 h. After additional of 200 mL of methylene chloride and 400 mL of methanol to the reaction mixture, the whole mixture was filtered through a pad of silica gel to remove solid materials. The filtrate was concentrated to afford a crude product, which was purified by a column chromatography on silica gel to yield 1H-indole-7-carbaldehyde, K-87 (6.55 g, 83%). 1HNMR (CDCl3).
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[C:11](=[O:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:11](=[O:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)N(Cc1ccc(C(C)(C)C)cc1)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(N(Cc3ccc(C(C)(C)C)cc3)C(=O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A mixture of methyl N-[4-(tert-butyl)benzyl]-N-(4′-methoxybiphenyl-4-yl)oxamate (230 mg, 0.533 mmol), methanol (1.5 ml), 2N aqueous sodium hydroxide (0.8 ml) and tetrahydrofuran (1.5 ml) was stirred at room temperature for 10 minutes. The reaction mixture was adjusted to pH 5-6 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (160 mg, 71.9%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[NH:19]1[CH2:22][CH:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20]1>C(O)C>[CH3:31][N:23]([CH:21]1[CH2:20][N:19]([C:2]2[C:3]3[N:4]([N:8]=[N:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:22]1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Reactant: Clc1nccn2nnnc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CN(c2nccn3nnnc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A 2 L round bottom flask was charged with 8-chlorotetrazolo[1,5-a]pyrazine (100 g, 0.64 mol), triethylamine (195 g, 1.93 mol) and ethanol (1 L). To the above was added tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride (146 g, 0.66 mol) at 25° C. The resulting mixture was stirred at 25° C. for 1 h. Work-up: the resulting crystalline solid was collected by filtration, washed with ethanol (200 mL), and dried to afford 176 g (91%) of the product as a white solid. MS m/z: 306 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:41]([NH2:44])([CH3:43])[CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1>>[CH3:40][O:39][C:37]1[CH:36]=[C:35]([C:41]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:42])[CH3:43])[CH:34]=[C:33]([O:32][CH3:31])[CH:38]=1
Reactant: COc1cc(OC)cc(C(C)(C)N)c1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: COc1cc(OC)cc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(3,5-dimethoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10d) as starting materials, in relative proportions similar to those used in than Example, the title compound was obtained in a yield of 83%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][N:10]=2)[CH2:4]1.O[C:17]1[CH:21]=[CH:20][O:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:19]1[CH:20]=[CH:21][C:17]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][N:10]=3)[CH2:4]2)=[N:18]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1cc(Br)ccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
To a stirred solution of 5(R)-hydroxymethyl-3-(4-bromo-pyrid-2-yl)oxazolidin-2-one (EP 694543; 3.75 g, 13.7 mmol), 3-hydroxyisoxazole (1.28 g, 15.1 mmol) and triphenylphosphine(4.31 g, 16.4 mmol) in anhydrous THF (83 ml), was added dropwise diisopropyl azodicarboxylate(3.20 g, 3.11 ml, 15.8 mmol) and stirred at room temperature for 5h. The solvent was then removed by rotary evaporation and purification by MPLC (Merck 9385 silica, eluting with CH2Cl2) and trituration with diethyl ether gave the title compound as a white solid (2.93 g, 63%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)/[C:10](=[CH:13]/[N:14](C)C)/[CH2:9][CH2:8][O:7][C:6]=2[CH:17]=1.Cl.Cl.[NH2:20]N>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:10]([CH2:9][CH2:8][O:7][C:6]=2[CH:17]=1)=[CH:13][NH:14][N:20]=3
Reactant: CN(C)/C=C1\CCOc2cc(Br)ccc2C1=O
Reactant: NN
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Brc1ccc2c(c1)OCCc1c[nH]nc1-2
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a suspension of 8-bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one (5.32 g, 17.9 mmol) in isopropyl alcohol (50 mL) was added powdered hydrazine dihydrochloride (3.77 g, 35.9 mmol) at room temperature, then the mixture stirred for 2 h. The reaction mixture was diluted with water (20 mL) and then heated at 100° C. for 2 h before cooling to room temperature. The reaction mixture was concentrated in vacuo to remove the volatile solvent. The resulting suspension was filtered and the filtrate washed with water and dried under vacuum at 40° C. to yield 8-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a pale yellow solid (4.28 g, 90%). 1H NMR δ (ppm) (DMSO-d): 8.07 (1H, d, J=8.52 Hz), 7.64 (1H, s), 7.30-7.24 (1H, m), 7.21 (1H, d, J=2.07 Hz), 4.24 (2H, dd, J=5.63, 4.50 Hz), 3.00 (2H, t, J=5.09 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Cl:27][C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1Cl

Procedure:
A mixture of ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro -2-oxo-3-quinolinecarboxylate (1.0 g), phosphorus oxychloride (5 ml) and pyridine (0.5 ml) was refluxed for 16 hours. The mixture was concentrated under reduced pressure. Water was added to the residue to obtain ethyl 2,6-dichloro-4-(2-chlorophenyl)-3-quinolinecarboxylate (0.7 g). The product was dissolved in methanol (20 ml), to which 28% sodium methoxide-methanol solution (0.5 ml) was added. The mixture was refluxed for 3 hours, and then diluted with water to obtain methyl 6-chloro-4-(2-chlorophenyl) -2-methoxy-3-quinolinecarboxylate as crystals (0.61 g, 61.0%). Recrystallization from methanol gave colorless needles. mp 151°-152° C.