Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[C:9]([CH2:31][CH2:32][CH3:33])=[C:10]([CH:18]=[CH:19][C:20]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:6][O:7][C:8]1[C:9]([CH2:31][CH2:32][CH3:33])=[C:10]([CH:18]=[CH:19][C:20]=1[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[CH2:1])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: [Li]CCCC
Reactant: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2OC)c1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccccc1OC)c1ccc(OCCCCC#N)c(CCC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.56 g of methyltriphenylphosphonium bromide in 10 ml of dry tetrahydrofuran were added 0.88 ml of a 1.6 molar n-butyllithium solution in hexane. After stirring for 3 hours under a nitrogen atmosphere, 0.5 g of 5-[3-methoxy-4-(2-methoxybenzoyl)-2-propylphenoxy]pentanenitrile were added in 5 ml of tetrahydrofuran. The reaction was stirred for 40 hours at 25° C. and then at 65° C. for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by preparative thin layer chromatography using a solvent system of 10% ethyl acetate in hexane. The appropriate band was isolated, extracted with ethyl acetate, dried over sodium sulfate, and evaporated in vacuo providing 50 mg of the desired title product as an oil.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[NH2:21].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:21]/[C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: Nc1c(F)cccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (10.0 g, 60.0 mmol) and 2-chloro-6-fluorophenylamine (8.7 g, 60.0 mmol) in DCM (200 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (25 mL, 180 mmol) was added, followed by titanium (IV) chloride solution (1 N in DCM, 36 mL, 36 mmol) dropwise. The reaction mixture was stirred at 0° C. then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:51]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:53][CH:52]=1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:60]6[CH2:61][CH2:62][N:57]([C:54]7[CH:55]=[CH:56][N:51]=[CH:52][CH:53]=7)[CH2:58][CH2:59]6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ccncc5)CC4)cc3F)cn2)cc1
Yield: 146.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 1-(4-pyridyl)piperazine (38.5 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone as a yellow solid (142 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-286) as a yellow powder (51.2 mg, 74%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:18][C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[S:20])[CH3:17]>C(OCC)C>[CH2:16]([N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:20][C:19]1=[N:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:17]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCNC(=S)NCc1ccccn1
Solvent: CCOCC
Product: CCN1C(=NCc2ccccn2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3 g of 1-ethyl-3-(2-pyridylmethyl)-thiourea were reacted according to the prescription given in Example 23 and 150 ml of diethyl ether were added to the reaction mixture. The hygroscopic 3-ethyl-4-(4-chloro-3-sulfamoylphenyl)-2-(2-pyridylmethylimino)-1,3-thiazolidine-4-ol-hydrobromide which had separated as crystals was rapidly filtered off, dissolved in 50 ml of water and converted into the end product as described in Example 28. Colorless solid body, decomposition beginning at 135° C., γC=N 1615 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:20]=[N:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH3:16])=[O:12])=[C:4]([CH3:21])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:20]=[N+:19]([O-:30])[CH:18]=[CH:17][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH3:16])=[O:12])=[C:4]([CH3:21])[CH:3]=1
Reactant: CCONC(=O)c1ccncc1Nc1ccc(Br)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCONC(=O)c1cc[n+]([O-])cc1Nc1ccc(Br)cc1C
Yield: 44 %

Procedure:
3-[(4-Bromo-2-methylphenyl)amino]-N-ethoxyisonicotinamide 3b (80.0 mg, 0.228 mmol) was dissolved in 4 ml dry DCM and 3-chloroperbenzoic acid (73% pure, 60 mg) was added at ambient temperature. After 2 h the solvent was removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 37 mg (101 μmol; 44% yield) of pure desired product.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH2:14]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:14][C:6]1[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:2]#[N:3]
Reactant: N#C[Cu]
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(N)c(C#N)c1
Yield: 88.5 %

Procedure:
Heat a mixture of copper (I) cyanide (2.5 g, 28.02 mmol), and 2-bromo4-isopropyl-phenylamine (5.0 g, 23.35 mmol) in 1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute the reaction mixture with 100 ml of ethyl acetate and wash the dark solution twice with 28% aqueous ammonium hydroxide, twice with saturated aqueous sodium chloride (brine) and twice with water. Collect the organic layer, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue via flash chromatography eluting with a step gradient starting with hexanes and going to 80% hexanes with 20% ethyl acetate to obtain 3.31 g (20.66 mmol, 88% yield) of the title compound as an orange oil: Mass Spectrum (m/e): 161(M+1).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:30])([F:31])[F:17])[CH:20]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=425.99.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)[O:16][CH2:15][CH2:14][N:13]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].O>C(O)C>[C:32]([O:31][C:29]([N:13]1[CH2:12][C@@H:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[C@@H:17]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]2)[O:16][CH2:15][CH2:14]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C1CCN(C[C@H]2OCCN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN2CCC(C(=O)O)CC2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
2 M Aqueous sodium hydroxide solution (0.2 mL) was added dropwise to a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-{[4-(methoxycarbonyl)piperidin-1-yl]methyl}-1,4-oxazepane-4-carboxylate (110 mg) in ethanol (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. The obtained aqueous layer was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (70 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].[Na]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:18][CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1ccc(OCc2ccccc2)cn1
Yield: 94 %

Procedure:
50 g (0.21 mol) of 5-benzyloxy-2-chloromethylpyridine (CAS 127590-90-3; D. I. Scopes, N. F. Norman, D. E. Bays, D. Belton, J. Brain et al., J. Med. Chem., 1992, 35, 490-501) in solution in 150 ml of methanol are added to the solution of sodium methoxide prepared by adding 6.4 g (0.28 mol) of sodium to 150 ml of methanol. After refluxing for 3 hours under nitrogen, the solution is concentrated to dryness. The oil obtained is taken up in ethyl acetate. The solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and then concentrated to dryness. 46 g (94%) of a brown oil are obtained.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1>O>[F:27][C:25]([F:26])([F:28])[S:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:7][C:4]2[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=2)=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: Nc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccc(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 190 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
A mixture of 0,277 mol of 1,4-benzenediamine, 0,017 mol of methyl 2-hydroxy benzoate and 10 grams of potassium carbonate is stirred for 1 hour at 190° C. Then there are added 0,049 mol of 1-chloro-4-(trifluoromethylsulfonyl)benzene and stirring at 190° C. is continued for 3 hours. The reaction mixture is cooled and stirred in 2000 ml of water. The precipitated product is filtered off, washed with water, dried and crystallized from a mixture of ethanol and water, yielding 2.3 grams of N-[4-(trifluoromethylsulfonyl)phenyl]-1,4-benzenediamine. (interm. 6)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][CH2:12][O:8]2)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: COc1ccc(Br)cc1C=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCCO1
Yield: 84.3 %

Procedure:
A mixture of 5-bromo-o-anisaldehyde (10.0 g, 46.5 mmol), propane-1,3-diol (3.90 g, 51.2 mmol) and BF3-Et2O(0.15 ml) in toluene (50 ml) was refluxed in a Dean-Stark apparatus for 3 h. The reaction mixture was cooled, diluted with ether. The organic layer was washed successively with sat. NaHCO3 aq., water and brine, dried (MgSO4), and concentrated in vacuo to give crude product. The residue was distilled to give Compound 38 (10.7 g, 84%) as a colorless oil.
Reaction SMILES: O.NN.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1>C(O)C.[Pd]>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1
Reactant: Cc1cccc(C)c1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1Oc1ccc(N)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 190.7 %

Procedure:
In a 50 mL round-bottomed flask 2-[(2,6-dimethylphenyl)oxy]-5-nitropyridine (Intermediate 41, 555.9 mg) was dissolved in ethanol (10 mL) to give a pale orange solution. Palladium on carbon (230 mg, 0.216 mmol) and hydrazine hydrate (0.416 mL, 4.32 mmol) were added. The reaction mixture was stirred at 90° C. After 3 hours the reaction was completed. The reaction mixture was filtered and the organic phase was evaporated under vacuum to afford 929.9 mg of a dark orange solid that was charged on a 10 g SCX cartridge. It was then flushed with 200 mL of ethanol followed by 50 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as dark orange solid (447.6 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1>>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared starting from Intermediate 96c and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety) using analogous procedures to those described in Example 3. LCMS (Method 5): Rt 5.33 min, m/z 647 [MH+]. 1H NMR (400 MHz, CD3OD): 0.64-0.74 (6H, m), 1.34 (9H, s), 1.41-1.72 (3H, m), 1.75-2.19 (6H, m), 2.21-2.31 (1H, m), 2.42 (3H, s), 3.22-3.35 (2H, m), 4.90-4.98 (1H, m), 5.45 (1H, t, J=4.1 Hz), 6.37 (1H, s), 7.19-7.40 (9H, m), 7.62 (1H, dd, J=9.9, 0.8 Hz), 7.89 (1H, d, J=2.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:23])[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:10]=[C:9]([C:24]#[N:25])[CH:8]=[CH:7][C:6]=1[S:5]2.C(N(CC)CC)C.[SH2:33]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:23])[CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[C:11]1[CH:10]=[C:9]([C:24](=[S:33])[NH2:25])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: S
Reactant: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (31.07 g) and triethylamine (11.8 cc) in anhydrous pyridine (300 cc) is saturated with hydrogen sulphide for 4 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C. The mixture is outgassed by bubbling nitrogen through for 2 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (5×200 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column (height: 38 cm; diameter: 6.5 cm) of silica gel (0.06-0.2 mm), eluting with a mixture of cyclohexane and ethyl acetate in proportions (by volume) of 70:30 (6 liters), 50:50 (4 liters) and 30:70 (4 liters), then with pure ethyl acetate (2 liters) and finally with a 90:10 mixture (6 liters) of ethyl acetate and methanol, collecting 50-cc fractions. The first 13.3 liters are discarded and fractions 6 to 94 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinethiocarboxamide (21.43 g).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[C:7]([CH2:9][OH:10])#[N:8].C(N(CC)CC)C>C(COC)OC>[C:7]([CH2:9][O:10][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])#[N:8]
Reactant: CC(Br)C(=O)Br
Reactant: N#CCO
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC(Br)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
215.9 g (1 mole) of α-bromopropionyl bromide are dissolved in 500 ml of dimethoxy ethane and to the resulting solution are slowly added 62.8 g (1.1 moles) of cyanomethanol at 10° C. Then 111.3 g (1.1 moles) of triethylamine are added dropwise at 10°-20° C. The reaction mixture is stirred for 10 minutes at room temperature and filtered over hyflo. The filtrate is concentrated and the residue is distilled in a water jet vacuum, yielding as main fraction 107 g (55.7%) of α-bromopropionic acid cyanomethyl ester with a boiling point of 109° C./17 torr and having the formula ##STR6##
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH:14]1[CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:1]1([O:11][CH2:13][CH:14]2[CH2:16][O:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc2c(OCC3CO3)cccc2c1

Procedure:
A mixture of 1-naphthyl alcohol, chloromethyloxirane, potassium carbonate and methylethylketone was heated at reflux for 5 hours to give 2-(1-naphthyloxy)methyloxirane. This intermediate was treated with 4-benzylpiperidine to give the title compound.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH3:14])[CH3:13])[CH:8]([CH3:15])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH3:13][N:12]([CH3:14])[CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH:8]1[CH3:15]
Reactant: CCOC(=O)N1CCC(N(C)C)C(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC1CNCCC1N(C)C
Temperature: 110 °C
Reaction time: 48 h

Procedure:
1-Carbethoxy-4-dimethylamino-3-methylpiperidine (3.5 g, 16.3 mmol) was suspended in 5 M NaOH solution (20 ml), stirred at 110° C. for 48 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-dimethylamino-3-methylpiperidine. Yield 1.0 g (43%), C8H18N2, m/z 143 (M+1), PMR (CDCl3): 0.96 (dd, 3H), 1.3 (m, 1H), 1.5 (m, 1H), 1.74 (m, 1H), 2.08 (m, 1H), 2.24 (s, 6H), 2.38 (m, 1H), 2.16 (bs, 1H, D2O exchangeable), 2.86 (m, 1H), 3.16 (m, 1H), 3.68 (m, 1H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]N(C(C)C)C(C)C>>[Cl:14][CH:5]([CH3:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CC(C)N(Cl)C(C)C
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CC(Cl)CCCC(=O)O

Procedure:
135 parts by mass of the caproic acid were added to 1,000 parts by mass of 84% sulfuric acid and an equivalent amount of N-chlorodiisopropylamine and were reacted for 5 hours at 25° C. to obtain 163 parts by mass of 5-chlorocaproic acid.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15][C:16](=[O:21])[C:17](Br)([F:19])[F:18])[CH3:14]>CS(C)=O.[Cu]>[CH2:13]([O:15][C:16](=[O:21])[C:17]([C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1)([F:19])[F:18])[CH3:14]
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cc(C)c(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
To a solution of 4-iodo-2-methyl-6-nitroaniline (2.78 g, 10 mmol) and 2-bromo-2,2-difluoroacetic acid ethyl ester (2.03 g, 10 mmol) in anhydrous DMSO (20 mL) was added copper powder (1.28 g, 20 mmol). The mixture was purged with N2 and heated at 60° C. in a sealed vial for 14 h. After being cooled to the room temperature, the reaction mixture was poured into 20% aqueous NH4Cl solution (300 mL). The resulting mixture was basified to pH=8.5 with saturated aqueous Na2CO3 solution and was extracted with EtOAc (3×100 mL). The organic extract was washed with brine (2×30 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (40:1 hexanes/EtOAc) to afford the title compound (1.79 g, 65%). 1H NMR (CDCl3) δ 1.36 (t, 3H), 2.30 (s, 3H), 4.36 (q, 2H), 6.41 (br s, 2H NH), 7.51 (s, 1H), 8.33 (s, 1H). ESI-MS m/z 275 (MH+), 255 (M-F)+, 297 (M+Na)+, 549 (2M+1)+ and 571 (2M+Na)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:27].C(O)C>>[NH2:27][C:9]1[C:10]([F:21])=[C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:12]=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CN1CCN(c2cc3c(c(F)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reactant: N
Solvent: CCO
Product: CN1CCN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
In a sealed tube, 1-cyclopropyl-5,6-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was aminated with ammonia/ethanol as in Example 13 to give 5-amino-1-cyclopropyl-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxlic acid. m.p 216°-218° C.