Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:10]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCCCc1ccc(CCN)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCCc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1

Procedure:
By the reaction of ethyl 6-[4-(2-aminoethyl)-phenyl]-hexane-carboxylate hydrochloride with 4-chlorobenzoyl chloride, there is obtained 6-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-hexane-carboxylic acid; m.p. 140°-143° C., after recrystallization from ethanol/diethyl ether.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[S:21][C:22]=1[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:18]3[C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[S:21][C:22]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: Cc1sc2ccccc2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4ccccc34)c(C)nc12
Temperature: 130 °C
Yield: 32.7 %

Procedure:
217 mg of 8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (11.0 mmol), 227 mg of 3-bromo-2-methyl-benzo[b]thiophene (1.0 mmol), 26.2 mg of triphenylphosphine (0.1 mmol) and 650 mg of cesium carbonate (2.0 mmol) are placed into a reaction vial with 3 ml of dry DMF. N2 gas is bubbled in for 10 min and 34 mg of palladium acetate (0.05 mmol) is added. The reaction vial is capped with a Teflon cap and heated at 130° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt:2M NH3 in MeOH=10:2:1) to give the title compound 119 mg (33%). mass spectrum (m/e): 364; 1H-NMR (CDCl3): 7.86 (m, 1H), 7.31 (m, 3H), 6.72 (s, 1H), 3.44 (m, 1H), 2.47 (s, 3H), 2.42 (s, 3H), 1.90 (m, 4H), 0.95 m, 6H) ppm.
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[OH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:33]([CH2:34][CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:36][CH3:37])=[CH:28][C:27]=1[C:26](=O)[C@H:25]3[CH2:39][CH:40]=[CH2:41].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:37][O:36][C:29]1[CH:30]=[CH:31][C:32]2[C@@H:33]3[C@H:24]([C@H:21]4[C@@:19]([CH2:35][CH2:34]3)([CH3:20])[C@@H:18]([OH:17])[CH2:23][CH2:22]4)[C@H:25]([CH2:39][CH:40]=[CH2:41])[CH2:26][C:27]=2[CH:28]=1
Reactant: C=CC[C@@H]1C(=O)c2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Triethylsilane (5 ml) and boron trifluoride diethyl etherate (5 ml) were added to a solution of 17β-hydroxy-3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-6-one (1.0 g, 2.9 mmol) in dichloromethane (20 mL) at 0° C. The resulting mixture was warmed to room temperature and stirred for 18 hours. After the reaction was completed, 10% aqueous potassium carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol (935 mg, Yield 98%).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[N:13]=1)(OC(C)(C)C)=O>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[N:13]=1
Reactant: CCCCc1nc(CCCNC(=O)OC(C)(C)C)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(CCCN)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 106.2 %

Procedure:
Under a static nitrogen atmosphere 2.30 g (4.5 mmol) of 5-[4′-[[3-(N-Boc-3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 68 was dissolved in 30 mL of 4N HCl in dioxane at ambient temperature and allowed to stir overnight. The solvents were removed in vacuo; the residue was triturated with diethyl ether and filtered providing 1.99 g (98%) of 5-[4′-[[3-(3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl] (1,1′-biphenyl)-2-yl]-1H-tetrazole as the hydrochloride salt: NMR (DMSO-d6) δ 0.85 (t, J=7 Hz, 3H), 1.22–1.38 (m, 2H), 1.59 (t, J=8 Hz, 2H), 1.96 (t, J=8 Hz, 2H), 2.71–2.79 (m, 2H) 2.80–2.92 (m, 4H), 5.40 (s, 2H) 7.10 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H) 7.52 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 2H); MS (FAB) m/e (rel intensity) 417 (60), 389 (10), 357 (10), 263 (5), 235 (10), 207 (100), 166 (40), 136 (15); HRMS. Calc'd for M+H: 417.2515. Found: 417.2510.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:13]3[CH2:17][CH:16]4[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH:15]4[CH2:14]3)[CH:9]=2)[N:4]=[CH:3]1.FC(F)(F)C(O)=O>ClCCl.CO>[CH2:14]1[CH:15]2[CH2:20][NH:19][CH2:18][CH:16]2[CH2:17][N:13]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][N:2]([CH3:1])[C:11]2=[O:12]
Reactant: Cn1cnc2ccc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)cc2c1=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc2ccc(N3CC4CNCC4C3)cc2c1=O
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of tert-butyl 5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate 20A) (80 mg, 0.22 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and the reaction allowed to stand overnight. The reaction was diluted with methanol and passed through a scx cartridge (500 mg) to afford 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-methylquinazolin-4(3H)-one (58 mg, 0.21 mmol).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[O:35][CH:36]([CH3:38])[CH3:37]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CC(C)Oc1c(N)ncnc1Cl
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(C)C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-isopropoxy-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=505, obsd=505).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6].N([O-])=O.[Na+].[Sn](Cl)Cl.[C:21]([C:29](=[CH:32][NH:33]C1C=CC=CC=1)[C:30]#[N:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.Cl.CCOC(C)=O>[NH2:33][C:32]1[N:1]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6])[N:31]=[CH:30][C:29]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3ccccc3)c2N)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 20.7 %

Procedure:
To a stirred solution of 3-amino-N-methoxy-4-methyl-benzamide 1 (104 mg, 0.58 mmol) in water (2 ml) at 0° C. was added conc. HCl (2 mL) followed by the addition of sodium nitrite (44 mg, 0.63 mmol). The reaction mixture was stirred at 0° C. for 40 minutes then a solution of tin(II)chloride (245 mg, 1.30 mmol) in conc. HCl (1 mL) was added and the mixture was stirred for 40 minutes then allowed to stand at −20° C. for 20 hours before it was warmed to RT and concentrated to a white solid. The solid was triturated with ethanol, the solids were removed, and 2-benzoyl-3-phenylamino-acrylonitrile 5 (144 mg, 0.58 mmol, preparation: Grothaus, J. Am. Chem. Soc. 58, 1334 (1936)) was added and the mixture heated (bath T=65-70° C.) for 16 hr. The mixture was cooled to RT, concentrated and purified by flash chromatography, eluting with 1:1 EtOAc/hexanes to remove impurities then 100% EtOAc to give 3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-methoxy-4-methyl-benzamide 6 as an off-white solid (41 mg, 0.12 mmol, 28%). HPLC (4 minute gradient) tR1.93 min; MS m/z 351.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 11.88 (s 1H, NH), 7.803 (m, 4H), 7.56 (m, 4H), 7.01 (s, 2H, NH2), 3.32 (s, 3H), 2.162 (s, 3H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 187.6, 151.9, 141.2, 139.7, 139.6, 135.7, 131.4, 131.2, 130.9, 128.5, 128.1, 127.8, 126.4, 102.6, 63.2, 17.2 ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (5.7 g, 16.34 mmol) and commercially available 3-nitrophenylboronic acid (3.274 g, 19.61 mmol) according to the general procedure VI. Obtained as a white solid (6.6 g, 92%). MS (ISP) 436.2 [(M+H)+]; mp 164° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Br:15][C:16]1[N:17]=[C:18]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)c1ccn2c(-c3cccc(Br)n3)cnc2c1F
Yield: 60 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (194 mg, 1.0 mmol) was coupled with 2,6-dibromopyridine (403 mg, 1.7 mmol) using Cs2CO3 (652 mg, 2.0 mmol), as described in Example 4, affording 2-[3-(6-bromopyridin-2-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as a white amorphous solid (210 mg, 60%): m/z (ES+) 350, 352 (100%, [MH]+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[C:9]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[CH:8][CH2:7]1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:3][CH2:4][C:6]1[CH:11]([CH3:12])[CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=2)[CH:9]([C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)[CH2:8][CH:7]=1
Reactant: CCOC(=O)C1CC=C(c2ccc(O)cc2)C(Cc2ccc(OCCN3CCCCC3)cc2)C1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC1C(CO)=CCC(c2ccc(O)cc2)C1Cc1ccc(OCCN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-(4-Hydroxy-phenyl)-6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-3-enecarboxylic acid ethyl ester (38.4 mg, 0.0803 mmol, 1.0 eq.) in DCM (2 mL) at 0° C. was added DIBAL (1.5 M in toluene, 0.215 mL) and was stirred at 0° C. for 10 min, then at 25° C. for 30 min. The reaction mixture was quenched at 0° C. with brine, extracted with DCM, dried over MgSO4, then purified on SiO2 (15% MeOH/DCM) to yield 4-[4-hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-3-enyl]-phenol as yellowish foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:26]1[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]1)[N:8]([CH:14]([CH3:15])[CH3:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: CC(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C(C)C)c3c2F)CCN1
Yield: 48.2 %

Procedure:
A mixture of 0.68 g of 6,7,8-trifluoro-1,4-dihydro-1-isopropyl-4-oxoquinoline-3-carboxylic acid, 0.72 g of 2-methyl piperazine and 10 ml of pyridine was treated in the same manner as described for Example 4 to give 0.42 g of the title compound as colorless crystals. M.p. 217°-218° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[C:13]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Br)C=C>O1CCCC1>[CH2:3]([CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:13]([O:30][CH2:31][CH3:32])=[O:29])[CH:2]=[CH2:1]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCCCCCC(=O)OCC
Solvent: C=CCBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCC(CCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of n-butyl lithium (hexane, 0.048 mol) in 120 mL of anhydrous tetrahydrofuran at 0° C. and under argon atmosphere, diisopropylamine was added (6.8 mL, 0.048 mol). Afterwards, ethyl hexadecanoate (11.3 g, 0.04 mol) in tetrahydrofuran (15 mL) was added dropwise and the homogeneous solution was stirred for 1 h at the same temperature. Next, allyl bromide (4.0 mL, 0.048 mol) was added and the resulting mixture was stirred at room temperature for 12 h. The mixture was poured on water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent evaporated to afford 11.9 g of an oil. The product was chromatographed (silica gel, hexane: ethyl acetate, 3%) to afford 8.7 g of a colorless oil (67% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](OC(=O)C)(=[O:11])[CH3:10]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Br)c1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
To a dichloromethane solution (15 ml) of 3-bromoaniline (1 g), acetic anhydride (659 μl) was added, followed by stirring at room temperature for 14 hours. This was washed with water (20 ml), and the organic layer was dried over sodium sulfate. After filtering off the sodium sulfate, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=200/1), to obtain the desired compound (1.19 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH3:38]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH3:38])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CI
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-methoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)-propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[Li+].[CH3:15]C([N-]C(C)C)C.CCCCCC.CN(CCN(C)C)C.CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(CC(=O)O)cc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CSc1ccc(C(C)C(=O)O)cc1Cl
Reaction time: 0.25 h

Procedure:
2-(3-chloro-4-(methylthio)phenyl)acetic acid is then alkylated in alpha-position analogous to Vazquez et al. (Eur. J. Med. Chem. Chim. Ther. (1997), 32, 6, 529-53). A solution of the acid (1.05 mmol) in dry THF (3 mL) is cooled to −78° C. under an argon atmosphere and stirred. Within 15 min, a solution of LDA in hexane (2 M, 1.6 mL, 3.2 mmol) and TMEDA (0.3 mL, 1.9 mmol) is added dropwise and the resulting mixture is slowly stirred for 3 h at −78° C. Methyl iodide (0.17 mL, 2.7 mmol) is added slowly under stirring and the mixture is stirred for another 16 h at room temperature. The reaction mixture is then neutralized applying a saturated aqueous solution of NH4Cl (10 mL). The organic layer is separated and the aqueous alkaline one is acidified with HCl (5 N) and then extracted with diethyl ether (3×20 mL). The combined organic layers are dried over Na2SO4 and then concentrated in vacuo. Purification of the crude product by column chromatography (hexane/ethyl acetate 4:1) yields the desired 2-(3-chloro-4-(methylthio)phenyl)propanoic acid (d).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: CO
Reactant: O=C(O)C=Cc1ccccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccccc1O
Yield: 92 %

Procedure:
A solution of 200 g (1.218 mole) of 2-hydroxycinnamic acid in 2 L of anhydrous methanol was treated with 10 drops of concentrated sulfuric acid. This solution was refluxed for 72 hr., using a Soxhlet extractor charged with 200 g of 3A molecular sieves. The methanolic solution was then concentrated under reduced pressure and cooled to afford 200 g (92%) of white crystals, which were used directly in the next step without additional purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1.CN.Cl>C(O)C>[NH2:21][CH2:20][C@@H:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: CN
Agent: Cl
Solvent: CCO
Product: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 61.5 °C
Reaction time: 2 h

Procedure:
1360 g of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (VI) are suspended in 10.2 l of ethanol at 22° C., and 1103 g of methylamine solution (40% strength in water) are added. The reaction mixture is then heated to 60 to 63° C., and the resulting solution is stirred at this temperature for 2 hours. After cooling to 55 to 60° C., a total of 2348 g of hydrochloric acid solution (20% strength in water) is added until the pH is 2.7, after which the product starts to crystallize. After cooling to 20° C., the precipitated reaction product is filtered off with suction, washed with methanol and then dried.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1
Reactant: ClCCN1CCOCC1
Reactant: Brc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cn(CCN2CCOCC2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-imidazole (217 mg, 1.48 mmol) and cesium carbonate (875 mg, 2.69 mmol) in dimethylformamide (5 mL) was stirred for 30 minutes. 4-(2-Chloro-ethyl)-morpholine hydrochloride (250 mg, 1.34 mmol) was added and the mixture was heated to 50° C. After heating overnight the reaction was concentrated by rotary evaporation. The residue was suspended in a mixture of dichloromethane and methanol and filtered. The filtrate was concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol to afford 4-[2-(4-Bromo-imidazol-1-yl)-ethyl]-morpholine (148 mg, 42%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([C:30]67OCC(C)(C[O:35]6)[CH2:32][O:31]7)[CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[Na+]>CO>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([C:30]([O:31][CH3:32])=[O:35])[CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC12COC(c3cncc(C4(O)CCN(CC56CC(c7ccccc75)c5ccccc56)CC4)c3)(OC1)OC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a heterogeneous solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(5-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-3-pyridyl)piperidin-4-ol (0.970 g, 1.90 mmol) in methanol (5 mL) under nitrogen was added sulfuric acid (0.21 mL, 2 eq). The suspension dissolved as the acid was added. The reaction was stirred for 24 h and basified with 2.5N NaOH (25 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (65 mL, eluent: 20% hexane in ethyl acetate) to yield 0.560 g (67%) of the title compound as a white solid. TLC analysis (Rf 0.21, 20% hexane in ethyl acetate). 1H NMR (CDCl3, 300 MHz) 9.10 (d, J=1.8 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.38 (t, J=2.1Hz, 1H), 7.27 (m, 2H), 7.18 (m, 2H), 6.95 (m, 4H), 4.29 (br s, 1H), 3.95 (s, 3H), 3.49 (s, 2H), 2.95 (m, 2H), 2.73 (m, 2H), 2.63 (s, 2H), 2.15 (m, 2H), 1.76 (m, 2H) MS (CI, CH4) m/z 441 (M+1,100), 469 (M+29,15), 423 (11), 145 (9), 103 (11), 85 (20) The free base was dissolved in ether containing methylene chloride and acidified with ethereal HCl. The hydrochloride salt was precipitated with ether dilution, filtered, rinsed with fresh ether and dried in vacuo (60° C., 10 pascal, 18 h) to yield a white solid, mp 243°-247° C. (dec).