Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[I:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated at 65° C. under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v:v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.29 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0210 (M+H calculated for C19H16NO2FI requires 436.0196).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1Cl.[CH3:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH2:23])=[CH:14][CH:13]=1>C(O)C>[Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[NH:23][CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(CN)c2ccccc12
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: CCO
Product: COc1ccc(CNc2cn[nH]c(=O)c2Cl)c2ccccc12
Reaction time: 8 h

Procedure:
A mixture comprising 330 mg of 4,5-dichloro-3(2H)pyridazinone, 1.12 g of 4-methoxy-1-naphthylmethylamine and 30 ml of ethanol, was refluxed under stirring overnight. The solvent was evaporated under reduced pressure, and a mixture of ethyl acetate and ethyl ether was poured to the residue, whereupon precipitated crystals were collected by filtration. The product was recrystallized from a mixture of methanol/water to obtain 410 mg of the above identified command as slightly yellow crystals having a melting point of from 265° to 266° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(/[CH:14]=[CH:15]/[S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:34]([C:32]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:21]([NH:20][S:16](/[CH:15]=[CH:14]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:18])=[O:17])[CH:33]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 61 mg of ((E)-2-phenylvinyl)sulfonyl chloride were added to 5.0 mL of methylene chloride solution containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room, temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenoxy-2-(((E)-2-phenylvinyl)sulfonamido)benzoate.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[N:2][OH:3]
Reactant: COc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C=NO)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
A solution of hydroxylamine hydrochloride (10 g, 0.144 mol) in distilled water (20 ml) was added to 20%(w/v) aqueous sodium hydroxide solution (28 ml). 3-Methoxybenzaldehyde (14 ml, 0.12 mol) was added in one portion and the mixture was stirred for 2 hours at 0-5° C. The mixture was adjusted to pH7 and extracted with dichloromethane. The extracts were combined, dried (MgSO4) and the solvent removed by evaporation to give the title compound (18.7 g, 100%) as a colourless oil. NMR (CDCl3): 3.8 (s, 3H), 6.9 (m, 1H), 7.1 (m, 2H), 7.15 (m, 1H), 8.1 (s, 1H), 8.6 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28])([O-:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:27]([C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:26])[F:24])=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:28])=[O:29])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)c2ncccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c2ncccc12
Yield: 73.1 %

Procedure:
In a similar fashion using route 18 general procedure 27, 5-methoxy-quinolin-8-ylamine 586 (280 mg, 1.6 mmol), 2-nitro-4-(trifluoromethyl) benzenesulfonyl chloride (600 mg, 2.0 mmol), pyridine (0.39 ml, 4.8 mmol) DMAP (cat.) and DCM (15 ml) gave the title compound (500 mg, 73%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]5)=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 29.4 %

Procedure:
To a mixture of 0.0649 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.021 g (0.211 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0231 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-215) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.O=S(Cl)[Cl:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCCCCBr

Procedure:
A solution of 11-bromoundecanoic acid (10.00 g, 37.7 mmol) dissolved in CH2Cl2 (30 mL) was slowly added to a solution of SOCl2 (7.0 mL, 94.0 mmol) in CH2Cl2 (25 mL). The mixture was refluxed for 5 h, then concentrated in vacuo to give 11-bromoundecanoyl chloride, which was used without further purification: 1H NMR (CDCl3) δ 1.26 (bs, (CH2)5, 10 H), 1.34 (m, CH2CH2CH2Br, 2 H), 1.67 (m, CH2CH2COCl, 2 H), 1.81 (m, CH2CH2Br, 2 H), 2.85 (t, CH2COCl, J=7.2 Hz, 2 H), 3.36 (t, CH2Br, J=6.8 Hz, 2 H); 13C NMR (CDCl3) δ 24.89 (CH2CH2COCl), 27.95 (CH2CH2CH2Br), 28.21, 28.52, 28.84, 29.02, and 29.12 ((CH2)5), 32.64 (CH2CH2Br), 33.80 (CH2Br), 46.92 (CH2COCl), 173.47 (COCl).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1>C(OCC)(=O)C>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1nc(N)c2nc(C)n(CCOc3ccccc3)c2c1C
Temperature: 150 °C

Procedure:
A sealed tube containing anhydrous ammonium acetate (11.4 g) and 2,6,7-trimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (1.14 g) from Part C was heated to 150° C. for 40 hours. The reaction was allowed to cool to room temperature. The resulting reaction mixture was then dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The basic layer was washed twice with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and the solvents were removed under reduced pressure. The resulting orange solid was passed through a silica gel column using 94/6 dichloromethane/methanol as the eluant. Because NMR analysis indicated that the white solid contained ammonium acetate, the product was dissolved in chloroform and washed with 25% aqueous sodium hydroxide. The resulting basic aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with water, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting white solid was dried under vacuum at 60° C. for 24 hours to provide 2,6,7-trimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 176.0–177.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:8]2
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cccc2c1CCC(N1CCCC1)=C2
Yield: 99399.8 %

Procedure:
A mixture of 5-methoxy-2-tetralone (100 g, 0.68 mmol), pyrrolidine (85.7 ml, 1.03 mol) and p-toluenesulfonic acid (100 mg, catalytic) in benzene (1.2L) was heated at reflux under Dean-Stark conditions for 4 h. The mixture was cooled and the solvent evaporated to give the title compound as a brown oil (155 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O>[C:30]([O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:14][CH2:13]2)[CH2:16][CH2:17]1)(=[O:29])[CH:31]=[CH2:32]
Reactant: O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 1.44 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanol, 0.61 g of triethylamine, and 20 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 0.53 g of acryloyl chloride was added dropwise to the mixture under ice water cooling. The resultant mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=1/2) and recrystallized from hexane to obtain 0.91 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexyl acrylate (Y: 53.3%). The compound thus obtained had a purity of 98.8% by GC and 99.4% by HPLC. Furthermore, the phase transition temperature of this compound was as follows.
Reaction SMILES: C(Cl)Cl.[OH:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:28].[C:29]1(=[O:39])[O:34][C:32](=[O:33])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[C:32]([C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[C:29]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[C:20]([C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:28])=[O:39])([OH:34])=[O:33]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc([C@H]2Cc3c(cccc3C(F)(F)F)NC(=O)[C@H]2O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2Cc3c(cccc3C(F)(F)F)NC(=O)[C@H]2OC(=O)c2ccccc2C(=O)O)cc1
Temperature: 15 °C

Procedure:
Under argon, to dry methylene chloride (800 ml) and triethylamine (38 ml) was added DMAP (2.17 g) and (cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin -2-one (62.51 g). After stirring, the so-formed suspension was cooled to about 15° C. and phthalic anhydride (39.53 g) was added. The resulting solution was warmed to room temperature and stirred for 4 hours. Upon quenching with 500 ml of dilute hydrochloric acid the layers were separated and the crystallized product from the methylene chloride layer was filtered and washed and dried in vacuo to give 84.8 g (95.4%) of the title A compound as a white crystalline solid, m.p. 161°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH2:20][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCc1nccn1-c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCc1nccn1-c1ccc(F)cc1N
Reaction time: 2.5 h

Procedure:
Ethyl 3-[1-(4-fluoro-2-nitrophenyl)-1H-imidazol-2-yl]-propanoate as synthesized in above Production Example 91, 210 mg was dissolved in 1 mL of acetic acid and 1 mL of water, to which 533 mg of 85% sodium hyposulfite was added, followed by 2.5 hours' heating under reflux. The reaction liquid was allowed to cool off and rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, which was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. Distilling the solvent off under reduced pressure, 100 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5]Cl.[H-].[Na+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1ccc(CCl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)c(Cl)c1
Yield: 67.2 %

Procedure:
Using 0.28 g of 3-chloro-4-(trifluoromethyl)benzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.25 g of 2-(3-chloro-4-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (39)).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:13])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([F:13])[CH:6]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium cyanide (1.3 g, 20 mmol) was added to a solution of 4-bromo-2-fluorobenzylbromide (5.00 g, 18.7 mmol) in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate) to give (4-bromo-2-fluorophenyl)acetonitrile in colorless solid form (3.75 g, yield: 94%).
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[Cl:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:8]3[N:9]=[C:5]([NH:4][C:32]([C:30]4[S:31][C:27]([Cl:26])=[CH:28][CH:29]=4)=[O:33])[S:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:20][CH2:21]1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Br
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
In analogy to example 47.3, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide (example 47.2) was coupled with 5-chlorthiophene-2-carboxylic acid, using general method D, to give 5-chloro-thiophene-2-carboxylic acid (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Light orange solid. MS 468.5 ([M+H]+)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC4C=CC([N+]([O-])=O)=CC=4)=[O:19])[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1.O1CCCC1.C(N(CC)C(C)C)(C)C.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([N:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:19])[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N1CCCCC1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitrophenyl 2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (30 mg, 0.00007 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) was added N,N-diisopropylethylamine (25.0 μL, 0.000144 mol) and piperidine (10 μL, 0.0001 mol). After stirring at rt for 16 h, the crude reaction mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 364.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[Cl:24]N1C(=O)CCC1=O>ClCCCl.CO>[Cl:24][C:10]1[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[C:7]2[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[CH:9]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClCCCl
Product: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A suspension of 1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (2.0 g, 6.1 mmol, from Step 4) and N-chlorosuccinimide (0.91 g, 6.8 mmol, Aldrich) in 1,2-dichloroethane (40 mL) was heated at 60° C. overnight. Flash chromatography, eluting with a gradient from 0-5% MeOH/DCM (0.5% NH4OH), afforded an orange solid which was refluxed in 10 mL MeOH for 15 minutes. The product was isolated by filtration. Yield: (2.2 g, 80%). 1H NMR (500 MHz, d6-DMSO) δ 8.23 (s, 1H), 8.01-7.96 (m, 2H), 7.80-7.74 (m, 1H), 7.68-7.61 (m, 2H), 7.22 (s, 1H), 2.86 (s, 3H), 2.62 (s, 3H); LCMS (M+H)+: 361.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][N:7]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:6]1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[CH2:18]([O:17][C:15]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Temperature: 35 °C
Reaction time: 6 h
Yield: 88.9 %

Procedure:
To a solution of (6) (300 mg; 0.9 mmol) in a mixture dioxane/water (6 mL; 9:1) was added a 2 M solution of NaOH (0.90 mL; 1.8 mmol). The reaction mixture was stirred at 35° C. for 6 hours. Solvents were removed in vacuo. The residue was diluted in water (15 mL) and was washed with diethyl ether (3×10 mL). The aqueous phase was acidified with 2N HCl and was extracted with ethyl acetate (3×15 mL). The ethyl acetate extracts were combined, dried over MgSO4, and concentrated to give 254 mg (0.8 mmol, 89%) of (7) as a colorless gum.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[NH2:18].[O-:19][C:20]#[N:21].[K+].[OH-].[Na+]>O>[CH3:17][O:16][C:15]1[C:7]([O:6][CH3:5])=[C:8]2[C:9]([C:10](=[O:12])[NH:21][C:20](=[O:19])[NH:18]2)=[CH:13][CH:14]=1
Reactant: N#C[O-]
Reactant: COc1ccc(C(=O)O)c(N)c1OC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(=O)[nH]c(=O)[nH]c2c1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Acetic acid (177.4 ml., 3.1 moles) was added to a vigorously stirred suspension of 3,4-dimethoxyanthranilic acid (436.5 g., 2.21 moles) in 10 liters of water. Then 2.24 liters of 20% potassium cyanate (5.53 moles) solution was gradually added and the mixture was stirred for one hour at 40° C. After cooling the reaction mixture to 20° C., 3.54 kg. sodium hydroxide pellets were added maintaining the temperature below 40° C. The reaction mixture was heated to 90° C. for 45 minutes and then slowly cooled in an ice bath. The sodium salt of the product was filtered, resuspended in 6 liters of water, acidified with concentrated hydrochloric acid (370 ml.), cooled and filtered to yield 404 grams (82%) of the product. Recrystallization from dimethylformamide gave colorless crystals, M.P. 314°-6° C.