Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)O1.Br[C:21](=[CH2:25])[CH2:22][CH2:23][OH:24].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:21](=[CH2:25])[CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C=C(Br)CCO
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(CCO)c1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Palladium acetate (100 mg, 0.6 mmol) was added to a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (8.0 g, 31 mmol) and 3-bromo-3-buten-1-ol (6.2 g, 41 mmol) in toluene (118 mL) and water (12 mL) followed by addition of 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (500 mg, 1 mmol). The mixture was stirred at 100° C. for 6 h. After cooling to RT, the mixture was diluted with EtOAc, washed with water and brine. The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in methylene chloride (0-50%) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]3[CH2:13][C:14]([CH3:24])([CH3:23])[O:15][C:16]=3[C:17]([C:19](OC)=[O:20])=[CH:18][C:9]=2[N:8]=1)=[O:5].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]3[CH2:13][C:14]([CH3:24])([CH3:23])[O:15][C:16]=3[C:17]([C:19]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([C:31]([F:30])([F:39])[F:40])[CH:33]=3)=[O:20])=[CH:18][C:9]=2[N:8]=1)=[O:5]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(NC(=O)c3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(F)(F)F)c3)cc3nc(NC(=O)c4c(F)cccc4Cl)[nH]c23)O1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 4.2 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-(2-chloro-6-fluorobenzamido)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-51, 0.200 g, 0.477 mmol), 3-trifloromethyl aniline (0.230 g, 1.43 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL). The reaction mass was stirred at RT for 4-5 h. The obtained crude was purified on preparative TLC using 4% DCM:MeOH as solvent system to afford 0.011 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.14 (s, 2H), 6.30 (s, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.56-7.70 (m, 4H), 7.86 (q, J=6.3 Hz, 1H), 8.15 (bs, 2H), 9.71 (s, 1H); MS [M+H]+: 547.06.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].O.O.O.O.O.O.[N+]([O-])([O-])=O.[Zn+2:16].[N+]([O-])([O-])=O>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:16].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:16].[Zn+2:16]
Reactant: O=P(O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
7,000 g of water and 553 g of 85% phosphoric acid were mixed, and 1,190 g of zinc nitrate hexahydrate was dissolved therein to obtain an aqueous zinc phosphate solution having a phosphorus/zinc molar ratio of 1.20.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[OH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>C(O)C.O>[CH2:2]([O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=CCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 10 h
Yield: 89 %

Procedure:
9.4 g of 8-bromo-1-octene, 9.0 g of ethyl p-hydroxybenzoate, and 7.6 g of potassium carbonate were refluxed in ethanol for 10 hours. Thereto added was an aqueous solution containing 2.4 g of sodium hydroxide, and then reflux was further continued for 10 hours. After conclusion of the reaction, the reaction solution was diluted with water, and the pH of the solution was lowered to 2 by dropping hydrochloric acid. The generated precipitate was collected, washed sufficiently with water, and dried, to obtain 10.8 g of the objective ether compound. (Yield: 89%)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[O:26])[CH2:16]2)[S:13][CH:14]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:26])[CH2:18]2)[S:13][CH:14]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CO[Si](C)(C)C(C)(C)C)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CO)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (719 mg, 1.09 mmol) (obtained as described in Example 20(1)) in anhydrous tetrahydrofuran (36 ml) were added sequentially acetic acid (0.19 ml, 3.3 mmol) and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (3.3 ml, 3.3 mmol) in an ice bath. The resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate and the aqueous layer was further extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (15:1) as the eluant to afford the desired compound p-nitrobenzyl (1R,5S,6S)-2-[1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (426.2 mg, yield 72%) as a yellow syrup.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]2=[CH:5][C:4]=1[C:14]#[N:15].[CH3:16][OH:17]>>[C:14]([C:4]1[CH:5]=[C:6]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]2=[N:8][C:3]=1[O:17][CH3:16])#[N:15]
Reactant: N#Cc1cc2c(nc1Cl)CCCCC2
Reactant: CO
Agent: [Na]
Product: COc1nc2c(cc1C#N)CCCCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
In an atmosphere of argon, metallic sodium (230.0 mg, 0.01 g atom) was dissolved in methanol (10.0 ml) at room temperature, a methanol solution (10.0 ml) of 2-chloro-3-cyano-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (1.03 g, 5.00 mmol) was added dropwise thereto at the same temperature and then the resulting mixture was stirred at 60° C. for 6 hours. After cooling, methanol was evaporated under reduced pressure, the thus obtained residue was mixed with water and extracted with chloroform, and the resulting organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (methylene chloride:hexane=2:1) to obtain the title compound (933.8 mg, 92.5%) as white powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1, method 1, step 1) (2.84 g, 10 mmol) and 3-aminopyrazole (0.83 g, 10 mmol) in acetic acid (20 mL) were refluxed for 4 h. The reaction mixture was cooled to rt and poured into ice water (200 mL), extracted with EtOAc, dried over MgSO4, filtered and concentrated, and triturated with toluene, and dried to give 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-α]pyrimidine (3.28 g, 99%) as a yellow solid. MS (ISP) 332.1 [(M+H)+]; mp 110-111° C.
Reaction SMILES: C(S(/N=C/[C@H]1CCCN1C(OC(C)(C)C)=O)=O)(C)(C)C.[NH2:21][CH:22]([C:35]1[CH:40]=[CH:39][C:38]([S:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)=[CH:37][CH:36]=1)[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[NH2:21][CH:22]([C:35]1[CH:40]=[CH:39][C:38]([S:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)=[CH:37][CH:36]=1)[C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)c1ccc(SCC2CC2)cc1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1/C=N/S(=O)C(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)c1ccc(SCC2CC2)cc1

Procedure:
The title compound was prepared from tert-butyl (2R)-2-{(E)-[(tert-butylsulphinyl)imino]methyl}pyrrolidine-1-carboxylate using conditions described in Examples 5 and 6 and with the Grignard reagent described in Example 7. Data identical to those described for tert-butyl (2S)-2-(amino{4-[(cyclopropylmethyl)thio]phenyl}methyl)pyrrolidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][CH2:33][CH:34]1[CH2:36][CH2:35]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: NCC1CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)NCC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (aminomethyl)cyclopropane.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][C@H:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:45]([C:46]([OH:48])=O)=[CH:44][N:43]=2)[CH2:38][C@H:37]1[O:56][CH3:57])=[O:34].CCN(CC)CC.[C:65]([NH2:74])([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([CH3:67])[CH3:66]>CN(C=O)C.O>[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][C@H:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:50]=[C:49]([C:45]([C:46]([NH:74][C:65]([CH3:67])([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH3:66])=[O:48])=[CH:44][N:43]=2)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:38][C@H:37]1[O:56][CH3:57])=[O:34]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)O
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
HATU (87 mg, 24 mmol) was added to a solution of 118 mg (0.24 mmol) Cis(±)-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(ethoxycarbonyl)nicotinic acid (Example 197), 0.040 ml (28 mmol) Et3N and 33 mg (0.24 mmol) cumylamine in 3 ml DMF. After stirring at room temperature overnight, the mixture was diluted with water and extracted with EtOAc. The EtOAc was washed 2 times with water and once with brine before being dried (MgSO4) and concentrated to give 103 mg of a solid. MS (ES) MH+: 616 for C30H35Cl2N5O5.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].CN[CH2:15][C:16]1C=CC=C[C:17]=1N>C1COCC1>[CH3:9][N:8]1[CH2:12][C:11]2[C:7](=[CH:6][CH:15]=[CH:16][CH:17]=2)[NH:3][C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNCc1ccccc1N
Solvent: C1CCOC1
Product: CN1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,1'-Carbonyl-diimidazole (16.7 g) is added to a solution of 2-(methylaminomethyl)-aniline (11.2 g) in anhydrous THF (30 ml) under nitrogen. The reaction mixture is refluxed for about 24 hours, stirred for 48 hours at RT and filtered. The filtered precipitate is suspended in 2N HCl for about 40 minutes, filtered, and the filtered solid washed with water and air dried, affording the desired product, M.P. 202-206.5 C., used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: Oc1ccc(Br)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=3)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](=[O:42])[NH:27][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=3)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3cn(CCN4CCOCC4)nc3c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3cn(CCN4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
To a solution of Intermediate 24b (86 mg, 0.23 mmol) in THF (10 mL) was added DIPEA (80 μL, 0.46 mmol), followed by the dropwise addition of a solution of 2,2,2-trichloroethylchloroformate (32 μL, 0.23 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by FCC, using 0-20% MeOH in EtOAc, gave the title compound (32 mg, 26%) as a yellow solid. LCMS (Method 4): Rt 2.64, m/z 543, 545 [MH+].
Reaction SMILES: Cl.[CH3:2][CH:3]([C:5]1[CH:6]=[C:7]2[C:17](=[CH:18][N:19]=1)[O:16][C:10]1([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20])[CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:44]1[C:48]([C:49]2[CH:50]=[C:51]([C:61](O)=[O:62])[CH:52]=[C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:54]=2)=[N:47][N:46]=[N:45]1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:17](=[CH:18][N:19]=1)[O:16][C:10]1([CH2:11][CH2:12][N:13]([C:61]([C:51]3[CH:52]=[C:53]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:54]=[C:49]([C:48]4[NH:47][N:46]=[N:45][N:44]=4)[CH:50]=3)=[O:62])[CH2:14][CH2:15]1)[CH2:9][C:8]2=[O:20])[CH3:2]
Reactant: CC(C)c1cc2c(cn1)OC1(CCNCC1)CC2=O
Reactant: O=C(O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc2c(cn1)OC1(CCN(C(=O)c3cc(-c4ccccc4)cc(-c4nnn[nH]4)c3)CC1)CC2=O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6-(1-Methylethyl)spiro[7-azachroman-2,4′-piperidin]-4-one hydrochloride (94 mg), 1-hydroxybenzotriazole monohydrate (36 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57 mg), triethylamine (73 μL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 5-(tetrazol-5-yl)biphenyl-3-carboxylic acid (50 mg), and stirred at 90° C. for 1 hour and 30 minutes. Water was added to the reaction liquid, the formed precipitate was taken out through filtration, washed with hexane/ethyl acetate=2/1, and dried to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.50 (1.0H, s), 8.38 (1.0H, s), 8.04 (1.0H, s), 7.87 (1.0H, s), 7.79 (2.0H, d, J=7.6 Hz), 7.54 (2H, t, J=7.6 Hz), 7.45 (1.011, t, J=7.6 Hz), 7.40 (1.0H, s), 4.40-4.22 (1.0H, m), 3.65-3.20 (3.0H, m), 3.01 (1.0H, q, J=6.8 Hz), 2.97 (2.0H, s), 2.15-2.05 (1.0H, m), 1.95-1.78 (3.0H, m), 1.18 (6.0H, d, J=6.8 Hz). MS [M+H]+=509.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>C(O)C>[CH2:20]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 64 %

Procedure:
1.15 g of sodium hydroxide was dissolved in 100 ml of ethyl alcohol. Then, 2.0 g of 4-(4'-hydroxyphenyl) benzoic acid and 2.45 ml of 1-bromooctane were added to the solution and refluxed for 16 hours. 50 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another 2 hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. Filtration and recrystallization from ethyl alcohol gave 1.95 g of pure product (yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[CH:4](Cl)Cl.S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[CH:4]=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Fc1cc(C(Cl)Cl)c(Cl)cc1Cl
Product: O=Cc1cc(F)c(Cl)cc1Cl

Procedure:
reacting 2,4-dichloro-5-fluorobenzal chloride of the formula ##STR13## with sulphuric acid to obtain 2,4-dichloro-5-fluorobenzaldehyde of the formula ##STR14## then chlorinating to give the compound of formula (I).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[S:8][CH2:9][C:10]([F:13])([F:12])[F:11].[FH:15].[Sb](Cl)(Cl)(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([F:15])[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)CSC1C=CC=CC1(Cl)Cl
Reactant: F
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: FC(Sc1ccccc1Cl)C(F)(F)F
Reaction time: 3 h

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 24.7 g (0.094 mol) of 1,1-dichloro-2,2,2-trifluoroethylthiobenzene which are subsequently condensed with 50 g of hydrogen fluoride. 4.2 g (0.014 mol; corresponding to 15 mol%) of antimony pentachloride are added at a temperature of 20° C. The resultant hydrogen chloride is removed from the reactor through the reflux condenser. After 3 hours a further 1.4 g (5 mol%) and after 4 hours a further 2.8 g (10 mol%) of antimony pentachloride are added. After a total reaction time of 5 hours, the hydrogen fluoride is removed by distillation, the residue is dissolved in 150 ml of methylene chloride and the solution is extracted with water. The solution is separated by distillation, affording 1-chloro-1,2,2,2-tetrafluoroethylthiobenzene. Boiling point 178°-179° C., nD20 =1.4732.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C1=CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=CCC1
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1,2,3,6-tetrahydropyridine (1.5 g, 18.04 mmol, Aldrich) and triethylamine (36.12 mmol, 5.05 mL) in methylene chloride (60 mL) at 0° C., methane sulfonyl chloride (1.82 mL, 23.45 mmol, Aldrich) was added and the mixture was stirred for 2.5 hours. The reaction was quenched with water and the mixture was extracted with methylene chloride. The extracts were dried with MgSO4 and the solvent was removed under reduced pressure to give the desired product as an off-white solid. 2.20 g, 76%. MS (ES) MH+=162.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CO.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cccc(CCOc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(CCOc2ccc(N)cc2)n1
Yield: 90.5 %

Procedure:
To a solution of 2.8 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]nitrobenzene in the mixture consisting of 30 ml of methanol and 20 ml of ethyl acetate is added 0.5 g of 10% palladium carbon, and then the mixture is shaken in a stream of hydrogen. After absorption of hydrogen ceased, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 2.24 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]aniline as yellowish brown powder.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][CH:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (48 mg, 72%), MS (ISP) m/z=415.5 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and 3-methyl-butyric acid.