Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(SC1N=CNN=1)C.C(Cl)(Cl)=O.[CH2:13]([S:15][C:16]1[N:20]=[CH:19][N:18]([C:21](Cl)=[O:22])[N:17]=1)[CH3:14].[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1.N1C=CC=CC=1>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[C:21]([N:18]1[CH:19]=[N:20][C:16]([S:15][CH2:13][CH3:14])=[N:17]1)=[O:22])[CH2:25][CH3:26]
Reactant: CCSc1ncn(C(=O)Cl)n1
Reactant: CCCNCCC
Agent: CCSc1nc[nH]n1
Agent: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(SCC)n1
Reaction time: 0.5 h

Procedure:
A solution of 25.8 g. 3-ethylthio-1,2,4-triazole and 15.8 g. dry pyridine in 100 ml. dry tetrahydrofuran was added dropwise to 200 ml. of a 10% w/v solution of phosgene in dry tetrahydrofuran (20 g. phosgene, 1 molecular proportion), with stirring and cooling to maintain the reaction temperature at 25° - 30° C. The mixture was stirred at 25° - 30° C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. To the resulting solution of 3-ethylthio-1,2,4-triazole-1-carbonyl chloride was added dropwise a solution of 20.2 g. dipropylamine and 15.8 g. dry pyridine in 50 ml. dry tetrahydrofuran, with stirring and cooling to maintain the reaction temperature at 25° - 30° C. The mixture was stirred at 25° - 30° C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. The filtrate was evaporated under reduced pressure to remove solvent and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 130° C./0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[C:22](OC)[CH:21]=2)=[CH:11][C:10]=1[O:37][CH3:38])C1C=CC=CC=1.[H-].[Na+].[C:41](OC)(=[O:46])[CH2:42][C:43]([CH3:45])=[O:44].C([Li])CCC.C1C[O:57][CH2:56]C1>>[OH:44][C:43]1[CH2:45][C:17]([CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:37][CH3:38])[CH:11]=2)([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:57][CH3:56])[CH:21]=2)[O:36][C:41](=[O:46])[CH:42]=1
Reactant: C1CCOC1
Reactant: COc1cc(CCC(=O)CCc2ccc(OCc3ccccc3)c(OC)c2)ccc1OCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COc1cc(CCC2(CCc3ccc(O)c(OC)c3)CC(O)=CC(=O)O2)ccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared as described in General Method 6 using 3.72 g (7.3 mmol) of 1,5-bis-(4-benzyloxy-3-methoxy-phenyl)-pentan-3-one (prepared in Example I), 0.32 g (8.0 mmol) of 60% NaH dispersion in mineral oil, 0.85 g (7.3 mmol) of methyl acetoacetate, 5.0 mL (1.6 M, 8.0 mmol) of n-butyllithium and 100 mL of THF. The reaction mixture was stirred for 12 hours at room temperature and worked up in the usual manner.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CC(=O)OCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([CH:17]=[CH2:18])=[N:3][CH:4]=1
Reactant: COc1cc(Cl)ncc1Cl
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: c1ccncc1
Product: C=Cc1cc(OC)c(Cl)cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
To a solution of 2,5-dichloro-4-methoxy-pyridine (730 mg, 4.10 mmol) in DME (16 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (987 mg, 4.10 mmol) followed by 2 M aq. K2CO3 solution (4 mL) is added. The solution is degassed and put under argon before Pd(PPh3)4 (95 mg, 82 μmol) is added. The mixture is stirred for 18 h at 80° C. The mixture is cooled to rt, diluted with EA (200 mL) and washed with water and sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The remaining brown residue is purified by CC on silica gel eluting with heptane:EA 9:1 to give 5-chloro-4-methoxy-2-vinyl-pyridine (402 mg) as a pale yellow oil; LC-MS: tR=0.53 min, [M+1]+=169.98; 1H NMR (CDCl3): δ 3.98 (s, 3H), 5.52 (d, J=10.5 Hz, 1H), 6.20 (d, J=17.3 Hz, 1H), 6.76 (dd, J=17.3, 10.8 Hz, 1H), 6.88 (s, 1H), 8.41 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH2:16][OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](C=O)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-hydroxymethyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (2.31 g, 6.30 mmol, 1.0 eq.) was dissolved in CH2Cl2 (32 mL) and stirred at room temperature. Dess-Martin Periodinane (2.67 g, 6.30 mmol, 1.0 eq.) was added in one portion and the reaction is monitored by LC/MS and TLC. Upon completion, the reaction is diluted with EtOAc (200 mL) and extracted with 1M Na2S2O3 (100 mL), NaHCO3 (100 mL) and brine. The organic phase is dried over MgSO4, filtered and evaporated to provide 2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-formyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (1.41 g, 3.89 mmol, 62%) and used directly in the next step. HPLC-MS calcd. for C19H25FN2O4 (M+H+) 365.2, found 365.4.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[Mn]([O-])(=O)(=O)=[O:16].[K+]>O.CC(C)=O>[N+:12]([C:8]1[C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]2[O:2][CH2:1][O:11][C:10]=2[CH:9]=1)([O-:14])=[O:13]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 3,4-(methylenedioxy)-6-nitrobenzaldehyde (25 g, 128 mmol) and potassium permanganate (40 g, 253 mmol) in a mixture of 300 mL water and 200 mL acetone was stirred overnight at ambient temperature and then heated to 100° C. for 1 hour. The reaction mixture was filtered through Celite®, acetone was removed in vacuo, and the product precipitated from the water solution by acidification to pH 1.2 with concentrated hydrochloric acid to give 6-nitro-benzo[1,3]dioxole-5-carboxylic acid [19.88 g (73%)].
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:32]([NH:42][C@H:43]([C:45](O)=[O:46])[CH3:44])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(Cl)Cl>[C:32]([NH:42][C@H:43]([C:45]([N:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:46])[CH3:44])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNc1ccc2c(c1)CCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@H](C)NC(=O)OCc1ccccc1)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl N-(5-indanyl)-glycinate (10.6 g, 48.4 mmol) and N,N'-dicyclohexylcarbodiimide (10.5 g, 50.8 mmol) in 200 ml CH2Cl2 at 0° C. was added dropwise a solution of N-carbobenzyloxy-L-alanine (11.3 g, 50.8 mmol) in 100 ml CH2Cl2. After the addition was completed the solution was stirred 10 min., warmed to room temperature and stirred overnight. The solution was filtered and concentrated in vacuo. The residue was dissolved in ether, filtered, washed with saturated NaHCO3, 10% aqueous HCl (5x), brine and dried MgSO4). Concentration of the volatiles in vacuo provided the product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[C:12]([NH:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)(=[O:14])[CH3:13].Cl>C(Cl)CCl>[C:12]([NH:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:10])=[O:11])[CH:22]=2)[CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NC1Cc2ccccc2C1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC1Cc2ccc(C(=O)CCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
137.3 g (1.03 mol) of anhydrous aluminium chloride and 34.2 g (0.34 mol) of succinic anhydride are suspended in 500 ml of ethylene chloride and 54.5 g (0.311 mol) of 2-acetamido-indane are introduced at room temperature, with vigorous stirring. The mixture is stirred at room temperature for a further 2 hours, ice and 150 ml of concentrated hydrochloric acid are added, and the ethylene chloride is removed by steam distillation. On cooling, 4-(2-acetamido-indan-5-yl)-4-oxobutyric acid crystallises out from the aqueous solution. The acid is purified by being dissolved in 2N sodium hydroxide solution, the solution is filtered and the acid is reprecipitated by means of hydrochloric acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=O)[CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:11]1
Reactant: C#Cc1ccccn1
Reactant: CC1CC(=O)CC(C)C1
Product: CC1C=C(C#Cc2ccccn2)CC(C)C1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 3,5-dimethylcyclohexanone (6.0 mmol, 0.85 mL); yields 2-[(3,5-dimethyl-1-cyclohexen-1-yl)ethynyl]pyridine as a transparent yellow oil (500 mg, 39% overall yield) as a mixture of diastereomers. 1H NMR (CDCl3, 300 MHz) δ 8.57 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.19 (m, 1H), 6.15 (br s, 1H), 2.29 (m, 2H), 1.80 (br m, 2H), 1.00 (m, 6H), 0.88 (br m, 2H). MS (EI ionization) 211 (M+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:17]=[N:18][N:19]([CH2:21][Si](C)(C)C)[CH:20]=3)=[CH:14][C:13]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:37][CH2:36][C:35]([CH3:43])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[N:30][CH:31]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][C:13]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:37][CH2:36][C:35]([CH3:43])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[N:28][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cn(C[Si](C)(C)C)nn3)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cn(C)nn3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-[1-(trimethylsilylmethyl)triazol-4-yl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (95 mg, 0.1529 mmol) in 1 mL of THF was cooled to 0° C. Water (5 drops) was added followed by tetra butyl ammonium fluoride (0.153 mL, 1.0 M solution in THF). The reaction was stirred at rt for 18 hours, another 0.2 mL of tetra butyl ammonium fluoride solution added and stirred for another 24 hours. The reaction was filtered through a pad of keiselguhr and the solvent removed under vacuum to yield a brown gum. The crude material was purified by preperative HPLC to give the product as a brown gum 63 mg, 75% yield.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:16]=1[C:17]([N:19]([CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1)=[O:18])C.C(=O)(O)[O-].[Na+].[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:45]([C:15]1[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[CH:32][C:16]=1[C:17]([N:19]([CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1)=[O:18])(=[O:49])=[O:47])[CH3:3]
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(SC(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(SC(F)(F)F)cn1
Reaction time: 2 h

Procedure:
0.82 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.63 g of 2-ethylsulfanyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethylsulfanyl-pyridin-2-yl)-benzamide and 10 mL of chloroform under ice cooling, and the mixture was stirred for 2 hours under ice cooling. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.62 g of 2-ethylsulfonyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethylsulfanyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 10) and 0.04 g of 2-ethylsulfonyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethylsulfinyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 11).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][N:12](CC3C=CN=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[Se](=O)=[O:23]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccncc2)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc2[nH]ncc2c1O

Procedure:
3 g of 4-hydroxy-1-(4-picolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.01 mol) is dissolved in 20 ml of acetic acid. 2.2 g of selenium dioxide (0.02 mol) and 2-3 drops of water are added. The mixture is refluxed for 30 minutes and then filtered off. 4-Hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates on cooling. Recrystallization from acetic acid yields 1.8 g (87%), m.p. 275°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Sn](C)(C)C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][N:23]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:22]2[N:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][N:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)c1nn(Cc2ccccc2)c2ccccc12
Reactant: Cc1cnc(Cl)nc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cnc(-c2nn(Cc3ccccc3)c3ccccc23)nc1C
Temperature: 25 °C

Procedure:
640 mg of 1-benzyl-3-trimethylstannylindazole (1.72 mmol), 212 mg of 2-chloro-4,5-dimethylpyrimidine* (1.49 mmol) and 72 mg (0.10 mmol) of Pd(PPh3)2Cl2 (5.8 mol %) in 20 ml of toluene were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification was carried out by chromatography over silica gel using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([NH2:23])[CH2:16][CH2:15][CH2:14][C:13]2=1>>[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([NH:23][C:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:8])[CH2:16][CH2:15][CH2:14][C:13]2=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1c[nH]cn1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide was prepared from 4-imidazole carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid (4% yield). 1H-NMR (CDCl3): δ 9.19 (s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.37 (d, 1H), 7.17 (d, 1H), 7.05 (dd, 1H), 6.60 (d, 1H), 5.25 (m, 1H), 2.62 (m, 2H), 2.21 (m, 1H), 1.91 (m, 3H); MS m/z 313 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:5]([N+:20]([O-])=O)[CH:4]=1.Cl[Sn]Cl>C(O)C.O>[NH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)c(N)c1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
2-(4-Methoxy-2-nitrophenyl)-4H-chromen-4-one (1.5 g, 5.04 mmol) was dissolved in ethanol (30 mL) and heated at reflux. SnCl2 (4.97 g , 26.23 mmol) was added. The mixture was heated under reflux for 20 min. The reaction mixture was cooled to rt diluted with water, neutralized and extracted with ethyl acetate to give the crude compound. This was purified by column chromatography using 3% MeOH in CH2Cl2 to give 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (790 mg, 58%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27].O>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:26](=[O:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)OC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(C3(C(=O)OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.6 %

Procedure:
To 1-(biphenyl-4-yl)cyclopropanecarboxylic acid isopropyl ester (10.2 g, 36 mmol) in CH2Cl2 (100 mL) was added aluminum chloride (10.2 g, 76.5 mmol) followed by acetyl chloride (5.97 g, 76.5 mmol). The solution was stirred at room temperature for 1.5 hours then slowly poured into water. The organic layer was separated and extracted 1 time with sodium potassium tartrate solution (20 g in 250 mL water). The organic layer was dried and evaporated to yield 12.6 g of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)C1=NO)[CH2:8]2.[C:13]1(S(Cl)(=O)=O)C=CC=C[CH:14]=1.[OH-:23].[Na+]>>[CH3:13][CH2:14][CH2:6][CH2:5][C:10](=[O:23])[CH2:1][CH2:8][CH2:7][CH2:9][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: ON=C1C2CC3CC(C2)CC1C3
Agent: [Na+]
Product: CCCCCCC(=O)CCCC
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a suspension of 3 grams (18 mmol) of 2-adamantanone oxime in 36 ml of 20% aqueous sodium hydroxide were added 5 grams (28 mmol) of benzenesulfonyl chloride with vigorous stirring at a temperature of 20°-30° C. The temperature was maintained below 30° C. until the exothermic reaction ceased, then raised to 55° C. and held there for 2 hours. The reaction mixture was worked up leaving 2 grams of 4-azatricyclo[4.3.1.13,8 ]undecan-5-one as white crystals melting at 306°-308° C. (recrystallized from hexane).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:31][CH2:30]2)[CH:21]=1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1.O1CCCC1>O.CO>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:30][CH2:31]2)[CH:21]=1
Reactant: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CC1
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Cl)cc1OC1CC1
Yield: 60.6 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 313 mg (0.677 mmol) of 3-chloro-2-(3-cyclopropoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 42-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained crude solid was dissolved by adding small amounts of tetrahydrofuran and methanol, followed by addition of water, and the solid precipitated by ultrasonic wave treatment was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 136 mg of the title compound as a white solid. (Yield: 61%)
Reaction SMILES: [CH3:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:13]N1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.O.C([NH:49][C@H:50]([C:57]([N:59]1[CH2:66][CH2:65][CH2:64][C@H:60]1[C:61]([NH2:63])=[O:62])=[O:58])[CH2:51][C:52]1[N:56]=[CH:55][NH:54][CH:53]=1)(=O)C1NC(=O)NC(=[O:43])C=1>CN(C)C=O.C(N(CC)CC)C>[OH2:5].[OH2:13].[OH2:43].[CH3:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([NH:49][C@H:50]([C:57]([N:59]1[CH2:66][CH2:65][CH2:64][C@H:60]1[C:61]([NH2:63])=[O:62])=[O:58])[CH2:51][C:52]1[N:56]=[CH:55][NH:54][CH:53]=1)=[O:6]
Reactant: Cc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Reactant: On1nnc2ccccc21
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1cc(=O)[nH]c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(N)=O)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 100 ml of dimethylformamide are added, while stirring at room temperature, 17.0 g of 5-methyl orotic acid, 14.4 g of 1-hydroxybenzotriazole and 27.8 ml of triethylamine. After 10 minutes the mixture is chilled in an ice bath and 10 minutes later a solution of 20.6 g of N,N'-dicyclohexyl-carbodiimide in 30 ml of dimethylformamide and then L-histidyl-L-prolinamide dihydrobromide (obtained as described in Example 2 from 38.5 g of N-benzyloxycarbonyl-L-histidyl-L-prolinamide) and a further amount of 100 ml of dimethylformamide are added. The mixture is stirred for 30 minutes in the ice bath and then for 12 hours at room temperature and thereafter worked up as described in Example 2 until and including the preliminary purification with a cationic exchanger. The residue of the ammoniacal solution is recrystallized from 110 ml of ethanol. After chilling for 24 hours to 0° C. the product is filtrated by suction and dried over phosphorous pentoxide. 2 g portions of this material are dissolved in methanol/water (1:1) and chromatographed over a column of 350 g basic aluminium oxide. The elution is controlled by measuring the ultraviolet absorption spectrum at 254 nm and the fractions containing the pure main product are combined and evaporated under reduced pressure. The residue is dissolved in methanol, filtered, evaporated to dryness, redissolved in water and lyophylized. Thus, 14.4 g (30.4% of the theoretical yield) of 5-methyl-orotyl-L-histidyl-L-prolinamide trihydrate melting at 222° - 227° C. with decomposition are obtained.