Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([OH:20])=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:43](N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.O>[CH2:1]([N:8]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:9]([C:11]1[C:12](=[O:20])[NH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1c[nH]c(=O)c(C(=O)N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a suspension of 5-benzylcarbamoyl-6-hydroxy-nicotinic acid 1.0 (3.67 mmol), EDAC.HCl 0.84 g (4.4 mmol), HOBT 0.59 g (4.4 mmol), in dimethylformamide (20 mL) was added benzylamine 0.47 g (4.4 mmol). The mixture was stirred overnight at room temperature. Water (20 mL) was added, and the reaction mixture was filtered. The solid product was then slurried in hot ethyl acetate. 1.1 g (81% yield). MS: m/z (APCI, AP+) 362.2 [M−]+. CHN Analysis: Calcd: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.49; H, 5.38; N, 11.64.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH2:22][CH3:23])[N:15]=2)[CH:3]=1.CO.[NH3:26]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:26])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH2:22][CH3:23])[N:15]=2)[CH:3]=1
Reactant: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Reactant: N
Solvent: CO
Product: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 40 °C
Yield: 100 %

Procedure:
A mixture of ethyl 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (147 mg, 439 μmol) in ammonia in methanol (7 N, 6.27 mL, 43.9 mmol) was heated to 40° C. for 16 h. The mixture was concentrated in vacuo to give 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (134 mg, 438 μmol, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (s, 1H), 9.16 (s, 1H), 8.82 (s, 1H), 8.18 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 2.69 (t, J=7.3 Hz, 2H), 2.29 (s, 3H), 1.76 (m, 1H), 0.95 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 305.9 [M+H].
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[C:9]([CH2:12]O)[S:10][CH:11]=1>>[Cl:3][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:6]([F:15])([F:14])[F:5])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(C(F)(F)F)cs1
Product: FC(F)(F)c1csc(CCl)c1
Reaction time: 3 h
Yield: 49.9 %

Procedure:
Thionyl chloride (4.89 g) was added to [4-(trifluoromethyl)thiophen-2-yl]methanol (500 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (275 mg).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccccn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and pyridine-2-sulfonyl chloride (133 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 221 mg, 95%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[NH:12][C:11](=O)[N:10]=[CH:9]2.C(Cl)(=O)C([Cl:25])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:25][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1cc2cnc(=O)[nH]c2cc1OCCOC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Yield: 97.8 %

Procedure:
To 6,7-bis(2-methoxy-ethoxy)-quinazolone (500 mg, 1.7 mmol), from Preparation 1, in CHCl3 (10 mL) containing one drop of DMF was added oxalylchloride (490 μL, 5.6 mmol) in several portions over 5 minutes. Once foaming ceased the solution was refluxed 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in 1,2-dichloroethane (20 mL) and washed two times with 80 mL saturated aqueous Na2CO3. The organic phase was dried over Na2SO4, and concentrated in vacuo to afford solid title product (520 mg, 92%; M.P. 108°-109° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[C:7](=[N:15]O)[CH2:6]2.S(=O)(=O)(O)O>C(O)(=O)C.O.[Pd]>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([NH2:15])[CH2:8]2
Reactant: COc1cc2c(cc1OC)C(=O)C(=NO)C2
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OC)CC(N)C2

Procedure:
A solution of 5,6-dimethoxy-2-hydroxyimino-1-indanone (0.27 moles, 6 g) in glacial acetic acid (500 ml) is added with 96% sulfuric acid (3.3 ml) and 10% Pd/C (1.5 g). The mixture is hydrogenated in a Parr apparatus (r.t., 35 psi). When the hydrogen absorption ceases, the catalyst is filtered off through celite, washing with methanol (70 ml). The solution is evaporated to dryness, to obtain a white solid which is dissolved in water, then extracted with ethyl acetate (2×70 ml). The aqueous solution is alkalinized with a 1M sodium hydroxide solution to pH=8-8.5. The product is extracted with methylene chloride (2×70 ml). The organic solution is dried over sodium sulfate and evaporated under vacuum to obtain the solid product. Yield: 4.6 g (88.5%)
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-])=O.Cl.[Cl:25]CCl>C(O)C.[Pd]>[ClH:25].[NH2:1][CH:4]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCCl
Reactant: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C1c2ccccc2Oc2ccccc21

Procedure:
Ethyl α-nitro-9H-xanthene-9-acetate (7.5 g, 24 mmol) is dissolved in 150 mL of ethanol and 2 mL of concentrated hydrochloric acid and hydrogenated over 1.0 g of 20% palladium on carbon (53 hours, 51 pounds per square inch (psi)). The filtered solution is stripped of solvent and washed with dichloromethane. This gives 4.83 g of the title compound. An additional crop, 0.61 g is obtained after cooling the dichloromethane wash. The crops are combined and used in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:16]([CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([C@@H:28]2[CH2:32][C@H:31]([S:33]CC3C=CC(OC)=CC=3)[CH2:30][N:29]2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])=[O:27])[CH2:22][CH2:21]1)(=[O:18])[NH2:17]>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:16]([CH2:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]([C@@H:28]2[CH2:32][C@H:31]([SH:33])[CH2:30][N:29]2[C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=2)=[O:44])=[O:27])[CH2:24][CH2:25]1)(=[O:18])[NH2:17]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.88 ml of trifluoroacetic acid and 94 μl of trifluoromethanesulfonic acid were added to a suspension of 305 mg of (2S,4S)-2-(4-carbamoylmethyl-1-piperazinylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 10) in 577 μl of anisole, whilst ice-cooling, and then the resulting mixture was stirred at room temperature for 1 hour. It was then treated in a similar manner to that described in Example 13(1), to give 316 mg of the title compound as a powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][Si@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].I[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:15]([Si@H:12]1[CH2:11][CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH3:19])=[CH:22][CH:23]=3)=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)[CH2:16][CH3:17]
Reactant: ICCc1ccccc1
Reactant: C#Cc1ccc([C@H]2CC[Si@H](CCC)CC2)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCC[Si@H]1CC[C@H](c2ccc(C#Cc3ccc(CC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 mg of tetrakis (triphenylphosphine) palladium (0) and 50 mg of copper (I) iodide were added to a mixture of 1.21 g (5.00 mmol) of trans-4-(p-ethynylphenyl)-1-n-propyl-1-silacyclohexane, 1.50 g (6.46 mmol) of p-iodoethylbenzene and 30 ml of triethylamine. The reaction mixture was stirred for 20 hours at room temperature. After a conventional after treatment, purification was conducted by means of silica-gel column chromatography to obtain 1.30 g (yield 75%) of the target product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (528 mg) in 2-propanol (10 mL) were added 4-[(cis-2-hydroxycyclohexyl)amino]thiazol-2(5H)-one (500 mg) and piperidinium acetate (230 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (153 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:31]=[N:30][C:29]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:36][CH2:37][N:32]([C:29]4[N:30]=[N:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:33][CH2:34]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(Cl)nn2)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(Cl)nn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(6-chloro-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(6-chloro-3-pyridazinyl)-4-piperidinecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 572.2 [M]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a light brown solid (303 mg).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH2:6][CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>ClCCl>[Cl:5][S:1]([NH:6][CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:3])=[O:2]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCNS(=O)(=O)Cl)OCC
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sulfuryl dichloride (1.1 g, 8.15 mmol, 1.47 equiv) in dichloromethane (10 mL). This was followed by the addition of a solution of diethyl 2-aminoethylphosphonate (intermediate 1.9) (1.0 g, 5.52 mmol, 1.00 equiv) and triethylamine (800 mg, 7.92 mmol, 1.43 equiv) in dichloromethane (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of ice water. The organic layer was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.5 g (crude) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:3]=1[CH:4]=O.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[Cl:1][C:2]1[C:3]2[C:6]([CH:7]=[CH:8][CH:9]=1)=[N:10][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:4]=2
Reactant: C[Si](C)(C)C#CCCN
Reactant: O=Cc1c(Cl)cccc1[N+](=O)[O-]
Product: C[Si](C)(C)C#CCCn1cc2c(Cl)cccc2n1
Yield: 42.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 149(A), from 2-chloro-6-nitro-benzaldehyde (210 mg, 1.13 mmol) and 4-trimethylsilanyl-but-3-ynylamine (210 mg, 1.50 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 4-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48 mmol, 43%) as a yellow oil.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:17]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:18])[CH:7]=[C:8]2[C:12]=1[C:11]([CH3:14])([CH3:13])[CH2:10][C:9]2([CH3:16])[CH3:15].[CH2:38]([O:40][C:41]([C:43]1[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41](=[O:42])[C:43]1[CH:50]=[CH:49][C:46](/[CH:47]=[C:17](/[C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([O:3][CH3:2])[CH:5]=2)[C:11]([CH3:14])([CH3:13])[CH2:10][C:9]3([CH3:15])[CH3:16])\[CH3:18])=[CH:45][CH:44]=1)[CH3:39]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: COc1cc(C(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc2c1C(C)(C)CC2(C)C
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc(OC)c3c(c2)C(C)(C)CC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(7-methoxy-1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(7-methoxy-1,1,3,3-tetramethyl-5-indanyl)-propenyl]-benzoic acid ethyl ester of melting point 72°-73° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[CH:25]([C:27]1[NH:31][N:30]=[N:29][N:28]=1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:25][C:27]1[NH:31][N:30]=[N:29][N:28]=1
Reactant: O=Cc1nnn[nH]1
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=Cc3nnn[nH]3)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 5-formyltetrazole by the method of Example 1.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:23]([F:24])=[CH:22][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:34]OC(OC)N(C)C>C1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]3[C:13]([C:14](=[O:15])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:34][N:25]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:22][C:23]=2[F:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 88.1 %

Procedure:
In 2 ml of benzene was suspended 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate, and 100 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 7 hours. Subsequently, the crystals thus deposited were collected by filtration and washed with 2 ml of dithyl ether to obtain 180 mg (yield 88.1%) of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 233°-236° C.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16]2)=[CH:11][C:10]=1[O:22][CH:23]([CH3:25])[CH3:24])([O-:8])=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][CH:3]3[CH2:2][O:1][CH2:4]3)[CH2:16]2)=[CH:11][C:10]=1[O:22][CH:23]([CH3:25])[CH3:24])([O-:8])=[O:7]
Reactant: O=C1COC1
Reactant: CC(C)Oc1cc(N2CCC[C@@H](N)C2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)Oc1cc(N2CCC[C@@H](NC3COC3)C2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
2 ml of 3-oxetanone are added, at a temperature of about 20° C., to a solution of 1.50 g of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-amine in 54 ml of 1,4-dichloroethane, under an argon atmosphere. After stirring of the mixture, 3.69 g of sodium triacetoxyborohydride are added in small portions and the reaction mixture is heated at 70° C. for 3 h. After returning to ambient temperature, 70 ml of a dilute sodium hydrogen carbonate solution are added. The aqueous phase is extracted twice with 80 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain an orangey-coloured oily residue. The residue is purified by chromatography on silica gel, using a dichloromethane/isopropanol (98/2 to 94/6) elution gradient, so as to obtain 1.2 g of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine in the form of an orangey-coloured gum.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:22])=[C:18](F)[CH:19]=2)[C:14](=[O:23])[C:13]([C:24]([OH:26])=[O:25])=[CH:12]1)[CH3:10]>N1C=CC=CC=1>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:22])=[C:18]([N:7]3[CH2:6][CH2:5][NH:4][CH:3]([CH2:2][F:1])[CH2:8]3)[CH:19]=2)[C:14](=[O:23])[C:13]([C:24]([OH:26])=[O:25])=[CH:12]1)[CH3:10]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: FCC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)cc21
Temperature: 75 °C
Yield: 36 %

Procedure:
A mixture of 400 mg of 2-(fluoromethyl)piperazine and 200 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 3 ml of pyridine was stirred and heated at 75° C., under nitrogen, in a pressure bottle for 3 hours. The pyridine was removed and replaced with methanol. This mixture was chromatographed on silica gel, eluting with methanol:chloroform (2:8). The solid was recrystallized from methanol, giving 100 mg of the desired product, mp 177°-180° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH:13](OCC)=[O:14]>>[Cl:1][C:2](=[CH:13][OH:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4]
Reactant: CCOC=O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Product: O=C(C(Cl)=CO)c1ccc(Cl)cc1Cl

Procedure:
The above starting material is prepared according to the literature method of Example 1A by reacting 2-chloro-1-(2,4-dichlorophenyl)-ethan-1-one with ethyl formate, m.p. 162°.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([C:14]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=3[C:21]([F:24])([F:23])[F:22])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[BH4-].[Na+]>CO>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([F:24])([F:22])[F:23])=[C:14]([CH2:12][C:10]2[S:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH:19]=1
Reactant: O=C(c1ccc(-c2ccccc2)s1)c1cc(Br)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml)-acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0° C. Thereto was added dropwise boron trifluoride.diethyl ether complex (0.52 ml). The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the desired 5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg) as colorless oil.