Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]([CH3:29])=[CH:27][S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]([CH3:29])=[CH:27][S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=[O:5].[C:13]([C:16]([CH2:23][Br:24])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(O)=[O:14].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:24][CH2:23][C:16]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[C:13]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=[O:5])=[O:14]
Reactant: CCOC(CBr)(OCC)C(=O)O
Reactant: NCC(=O)c1cccc(Br)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(CBr)(OCC)C(=O)NCC(=O)c1cccc(Br)c1
Reaction time: 18 h

Procedure:
The 2-amino-1-(3-bromophenyl)ethanone hydrochloride (4.6 g, 19 mmol), HO2CC(OEt)2CH2Br (5.0 g, 21 mmol), and NMM (12.5 mL, 113 mmol) were suspended in anhyd THF (270 mL) under N2 and PyBOP (10.8 g, 21 mmol) was added in one portion. The reaction mixture was stirred for 18 h and concentrated to ¼ vol and the precipitates were removed by filtration (HCl salt of NMM). The mother liquor was taken up in dichloromethane and washed with water. After concentration, the crude residue was subjected to flash chromatography (silica gel) eluting with 60% EtOAc/hexanes to give Intermediate J.1, 5.3 g (65%). 1H NMR (500 MHz, DMSO-d6): δ 8.27 (t, J=5.5 Hz, 1H), 8.14 (t, J=1.5 Hz, 1H), 8.00 (dt, J=7.9, 1.2 Hz, 1H), 7.87 (dd, J=8.8, 1.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 3.67 (s, 2H) 3.58-3.46 (m, 4H), 1.18 (t, J=7.0 Hz, 6H). LCMS: 2.2 min; LRMS: Calcd. for C15H19Br2NO4: 435.98. Found: 435.98 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>[Cl-].[Na+].O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[Cl:11])=[N:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cn2)c(Cl)c1
Yield: 55.5 %

Procedure:
1,2-Dichloro-4-nitrobenzene (19.2 g), 12.9 g of 5-chloropyridine-2-ol, and 10.4 g of potassium carbonate were added to 50 mL of dimethylacetamide, and the mixture was allowed to react at 90 to 110° C. for 15 hr. The reaction mixture was cooled, ethyl acetate and brine were then added thereto, followed by separation and washing with brine. The ethyl acetate layer was concentrated, and the precipitated crystals were collected by filtration. The filtrate was concentrated, and the crude product thus obtained was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 15.75 g of 5-chloro-2-(2-chloro-4-nitrophenoxy)pyridine (yield 55.2%).
Reaction SMILES: [C:1]([N:5]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].Cl>C(Cl)Cl.O1CCOCC1>[CH2:7]1[C:8]2([CH2:13][CH2:12][NH:11][CH2:10]2)[CH2:9][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:6]1
Reactant: CCC(=O)N1CCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(=O)N1CCC2(CCNC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-propanoyl-3,7-diazaspiro[4.4]nonane-7-carboxylate (153 mg, 0.54 mmol) in DCM (0.5 mL) was added a solution of hydrogen chloride (1.4 mL of 4 M, 5.4 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the crude product was dried on the high vacuum for 1 h to yield 1-(3,7-diazaspiro[4.4]nonan-3-yl)propan-1-one as an off white gum. LC/MS m/z 183.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([SiH2:9][O:10][C:11]([CH3:27])([CH3:26])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20]OS(C)(=O)=O)[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]>CCO>[C:5]([SiH2:9][O:10][C:11]([CH3:26])([CH3:27])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: NC1CC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCOS(C)(=O)=O)ccc1Cl
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCNC2CC2)ccc1Cl
Temperature: 25 °C
Yield: 54.7 %

Procedure:
Cyclopropylamine (1.14 mL, 16.3 mmol) was added to a sol. of methanesulfonic acid 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl ester (1.76 g, 4.65 mmol) in EtOH (46 mL). The mixture was heated to reflux for 2 h, and cyclopropylamine (0.57 mL, 8.2 mmol) was added again. The mixture was heated to reflux overnight, and was allowed to cool to rt. The solvents were removed under reduced pressure, and the residue was purified by FC (EtOAc/heptane 50:50→7M NH3/MeOH) to yield the title compound (865 mg, 68%). LC-MS: tR=0.92 min; ES+: 340.39.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([NH:18][C:19]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]=2)=[O:20])[CH:9]=1>O1CCOCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:18][C:19]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:26]=2)=[O:20])[CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccco2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) was added to a dioxane (3.0 mL) suspension of the obtained methyl 4-(furan-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate (76 mg) at room temperature, followed by stirring at the same temperature for 3 hours and 20 minutes. A 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) was added to the reaction mixture at room temperature, followed by stirring at 50 to 55° C. for 4 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. To the obtained residue, 1 mol/L hydrochloric acid (1.5 mL) was added. The solid substance was collected by filtration to obtain 69 mg of 4-(furan-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC1(C)C(C)(C)OB([C:51]2[CH:65]=[CH:64][CH:63]=[CH:62][C:52]=2[CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])O1.[I:67][C:68]1[O:69][CH:70]=[C:71](I)[N:72]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I:67][C:68]1[O:69][CH:70]=[C:71]([C:51]2[CH:65]=[CH:64][CH:63]=[CH:62][C:52]=2[CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:58])([CH3:59])[CH3:60])[N:72]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Ic1coc(I)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1coc(I)n1
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
Palladium(II) acetate (35.0 mg, 0.156 mmol) and Xantphos (90 mg, 0.156 mmol) was added to degassed THF (3 ml) and let stir for 5 minutes then transferred to a separate rxn vessel that contained tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (1142 mg, 3.43 mmol), 2,4-diiodooxazole (1000 mg, 3.12 mmol), Potassium phosphate (1985 mg, 9.35 mmol) and degassed Tetrahydrofuran (THF) (12 mL). The rxn vessel was capped and heated to 80° for 16 hours. Filtered and the residue was purified via Biotage (0% to 100% DCM:Hex; 50 g-HP-silica gel column) to obtain 460 mg of tert-butyl 2-(2-iodooxazol-4-yl)benzylcarbamate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 4.39 (d, J=5.31 Hz, 2H) 5.40 (br. s., 1H) 7.31-7.45 (m, 2H) 7.53 (dd, J=19.45, 7.07 Hz, 2H) 7.94 (s, 1H); MS[MH]+=401.1
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C-:20]#[N:21].[K+]>Cl.O>[C:20]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:21]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 93.8 %

Procedure:
3-Amino-5-nitrobenzoic acid (3.64 g, 20 mM) was dissolved in concentrated hydrochloric acid (20 ml), diluted with water (75 ml), cooled to 0°, and added over 30 minutes to a solution of NANO2 (1.38g, 20 mM) in water (10 ml). The pH was adjusted to 6.2 with saturated Na2CO3 solution. A mixture of CuSO4.5H2O (10 g, 42 mM) in water (40 ml) and KCN (10 g, 154 mM) in water (20 ml) was heated to 65°, the solution of diazonium salt added over 15 minutes, and the mixture refluxed for 40 minutes. After cooling, and acidifying with 2M hydrochloric acid, the organics were extracted into ethyl acetate (2×200 ml). The combined extracts were washed with aqueous NaH2PO4, water, brine, and dried over Na2SO4. Evaporation gave 3-cyano-5-nitrobenzoic acid (3.6 g, 94%).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][CH2:29][C@@H:30]([CH2:32][OH:33])[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C1C=CN=CC=1)C.CO>N1C=CC=CC=1>[CH2:21]([O:28][CH2:29][C@H:30]([CH2:32][O:33][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: CCN(CC)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Product: O[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Trityl chloride (56 g) was added portionswise to a solution of 1-O-benzyl-(R)-glycerol (36.4 g, 0.2 mol) and 4-diethylaminopyridine (1 g) in pyridine (300 mL) under stirring and cooling with ice. After 20 h stirring methanol (50 mL) was added, the mixture was stirred for 30 min and concentrated in vacuo to half of the original volume. Ethyl acetate (500 mL) was added and the mixture extracted with water (3×250 mL). The organic layer was briefly dried with MgSO4, filtered and evaporated in vacuo. The residue 4 was codistilled with toluene (200 ml portions) to remove the residual pyridine and used for further synthesis.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([F:14])([F:13])[F:12])[CH2:9][N:8]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:18]([O:17][C:15]([N:8]1[CH2:9][C@@H:10]([C:11]([F:12])([F:13])[F:14])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
In 92 ml of ethanol, is dissolved 15.8 g (45.8 mmol) of trans-1-benzyloxycarbonyl-4-trifluoromethylpyrrolidine-3-carboxylic acid ethyl ester. To the above solution, is added 46 ml of 2N sodium hydroxide on cooling with ice. The mixture is stirred at 0° C. for 1 hour and then concentrated under reduced pressure. The residue is dissolved in 100 ml of water. The solution is washed with diethyl ether. The water phase is adjusted to pH 3 with citric acid. The solution is extracted twice with dichloromethane. The organic phases were put together and dried over anhydrous magnesium sulfate. The dried organic phase was concentrated under reduced pressure to give 13.84 g of the objective substance as a colorless powder (yield 95.3%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([CH3:27])=[N:29][CH:30]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cn1

Procedure:
The title compound, off-white solid (77 mg, 69%), MS (ISP) m/z=448.4 [(M+H)+], mp 202° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 6-methyl-nicotinic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:32][CH:33]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(-c5ccccn5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-pyridin-2-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-pyridin-2-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]C(O)(C)C)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(-c2ccc(OCCCCCCCCCC)cc2)cc1

Procedure:
Compound 73 (12.90 g, 0.033 mol) and sodium hydroxide ( ) was boiled for 1 h in toluene (100 ml) under a dry nitrogen atmosphere and the resultant toluene/acetone mixture removed in a Dean-Stark apparatus. As the toluene mixture was removed fresh toluene was added to the reaction mixture. TLC analysis (dichloromethane) revealed a complete reaction. The sodium hydroxide was filtered off and the toluene washed with water, dried (MgSO4) and removed in vacuo to leave a metallic-beige solid.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][NH:10][NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:11][N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=2)[C:17](=[O:16])[CH:18]=1
Reactant: CC(C)(C)c1ccc(CNN)cc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2[nH]c(N)cc2=O)cc1

Procedure:
24.6 g of p-tert.butylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 22 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 24° to 30° C. After stirring overn the solvent was distilled off in vacuo and the oily residue solidified after addition of 50 ml of petroleum ether. The compound identified above was filtered off and recrystallised from ethanol. Melting point: 126°, 8 g (24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([F:19])[C:13]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([O:11][C:12]3[C:13]([F:20])=[C:14]([F:19])[C:15]([I:18])=[CH:16][C:17]=3[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1Oc1ccc(I)c(F)c1F
Agent: O=S(=O)(O)O
Product: O=c1c2cc(Br)ccc2oc2c(F)c(F)c(I)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a 250 mL flask charged with 5-bromo-2-(2,3-difluoro-4-iodophenoxy)benzoic acid (9.1 g, 20.0 mmol) was added sulfuric acid (21.32 mL, 400 mmol). The resulting slurry was heated at 100° C. for 2.5 h. The mixture was cooled to rt and poured into 1 L of ice water. The resulting tan slurry was stirred vigorously for 3 hours. The mixture was filtered through a Buchner funnel and the derived solid was dried under a stream of air for 6 hours to provide 7-bromo-3,4-difluoro-2-iodo-9H-xanthen-9-one (8.10 g, 18.54 mmol, 93% yield) as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:19]1[C:23]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN>C(#N)C>[CH3:23][NH:19][C:14]([C:11]1[S:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:13][CH:12]=1)=[O:16]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Agent: CN
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a heterogeneous mixture of 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (1.0 g, 4.1 mmol), 1-hydroxybenzotriazole hydrate (0.63 g, 4.1 mmol), N,N-diisopropylethylamine (4.3 mL, 24 mmol), methylamine hydrochloride (0.83 g, 12 mmol) in anhydrous acetonitrile (20 mL), was added WSCDI (2.4 g, 12 mmol) at room temperature under a nitrogen atmosphere and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. To the residue was added saturated aqueous sodium bicarbonate solution (20 mL), ethyl acetate (6 mL), and heptane (2 mL). The solid that separates out was filtered, washed with water (2×2 mL) and diethyl ether (2×4 mL), and dried to give tert-butyl 5-(methylcarbamoyl)thiazol-2-ylcarbamate (0.77 g, 73% yield) as a white solid. MS found: (M+H)+=258; 1H NMR (400 MHz, methanol-d4) δ ppm 7.83 (s, 1H), 2.87 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[CH2:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:39]([C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[C@@H:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:47])=[CH:49][CH:50]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])C[C@@H](c1ccc(Cl)cc1)[C@H]1CCCC[C@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9.1 g (32.1 mmol) of rac-(1S*)-cis-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanol, 16.8 g (64.2 mmol) of triphenylphosphine and 10.8 g (64.2 mmol) of p-nitrobenzoic acid are dissolved in 180 ml of tetrahydrofuran. To this solution is added dropwise with 30 minutes a solution of 11.3 g (64.2 mmol) of diethyl azodicarboxylate in 80 ml of tetrahydrofuran and the mixture is subsequently stirred at room temperature for 5 hours. After distilling off the solvent the residue obtained is chromatographed on a 30-fold amount of silica gel while eluting with toluene/hexane (1:2). By recrystallization of the product obtained from methylene chloride/hexane there is obtained rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexyl p-nitrobenzoate in the form of colourless crystals of m.p. 146°-148°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Methyl 2-hydroxy-5-acetylbenzoate (12 g, 61.7 mmol) in DMF (200 ml) was added cesium carbonate (24.15 g, 74.1 mmol) and MeI (9.64 g, 68 mmol). The reaction mixture was stirred for 16 hours at 0° C. and then diluted with ethyl acetate, washed with aq Na2S2O5, brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (ethyl acetate:hexane 1:2) to provide the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[C:5]([CH3:24])[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[ClH:44]>>[ClH:44].[ClH:44].[CH3:24][C:5]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[C:2]([CH3:1])[NH:3][N:4]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1-c1ccc2nccc(N3CCN(C)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]c(C)c1-c1ccc2nccc(N3CCN(C)CC3)c2c1

Procedure:
75 mg 6-(3,5-dimethyl-1-trityl-1H-pyrazolyl)-4-(4-methylpiperazin-1-yl)quinoline obtained in Example 171 and 1 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 147 mg of the title compound as pale yellow crystals.