Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 4-chlorophenol:
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(C#N)ccc2C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2cc(C(=N)NO)ccc2C1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A mixture of 1,1-dimethylethyl 8-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 32) (0.195 g, 0.711 mmol), hydroxylamine hydrochloride (0.099 g, 1.422 mmol) and sodium bicarbonate (0.299 g, 3.55 mmol) in ethanol (5 ml) was stirred and heated at 60° C. for 3 hours. The reaction mixture was cooled, evaporated and dissolved in EtOAc/water (40 ml of each, some warming needed) and the organics dried (magnesium sulphate) and evaporated to give the title compound (210 mgs) as a white solid. MS (ES) C15H21N3O4 requires 307; found 308 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([CH3:24])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[Cl:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32][C:4]([C:6]2[N:7]=[C:8]([CH3:24])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([F:21])([F:23])[F:22])[CH:13]=3)[C:10]=2[CH3:11])=[O:5])[CH:29]=[CH:28][N:27]=1
Reactant: CCOC(=O)c1nc(C)n(-c2ccc(OC)c(C(F)(F)F)c2)c1C
Reactant: Cc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(-n2c(C)nc(C(=O)Cc3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-(4-Methoxy-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.8 g, 2.3 mmol) and 2-chloro-4-methylpyridine (0.36 g, 2.8 mmol) were dissolved in 10 mL toluene. This solution was dropped to a cold (0° C.) mixture of potassium bis(trimethylsilyl)amide (1.17 g, 5.84 mmol) in 15 mL toluene. The reaction mixture was stirred for 90 min. at 0° C. 0.4 mL acetic acid were added, and the mixture extracted with water, saturated NaHCO3-Solution and brine. The aqueous layer was washed with toluene (100 mL). The combined organic extracts were dried with sodium sulfate and filtered. The solvent was evaporated, and the crude product [(0.8 g, 81%), [MS: m/e=424.5 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:23]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:24]([C:40]([NH:42][C@H:43]([C:48](O)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:23]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:24]([C:40]([NH:42][C@H:43]([C:48]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Yield: 47.7 %

Procedure:
compound A416. Same procedure as above with Trp-NHCH2Ph (63.03 mg, 0.215 mmol), N-Boc-Tyr(Bn)-Asn-OH (105.0 mg, 0.216 mmol), EDC (44 mg, 0.226 mmol) and HOBt (31 mg, 0.226 mmol) in CH2Cl2/DMF (1.5 mL/1.5 mL). After treatment, the crude residue was triturated with CH2Cl2/pentane to afford a white solid (78 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300 MHz, DMSO-d6) δ 1.29 (s, 9H, (CH3)3), 2.30-3.26 (m, 6H, CH2 Tyr, CH2 Trp, CH2 Asn), 4.08 (m, 1H, CHα), 4.24 (s, 2H, NCH2Ph), 4.49 (m, 1H, CHα), 4.56 (m, 1H, CHα), 5.03 (broad s, 2H, OCH2Ph), 6.88-7.56 (m, 17H), 8.17 (d, J=8 Hz, 1H, NH), 8.23 (d, J=8 Hz, 1H, NH), 8.51 (t, J=6 Hz, 1H, NH), 10.84 (s, 1H, NH). 13C NMR (75 MHz, CD3OD) δ 28.5 (CH2 Trp), 28.6 ((CH3)3), 37.3, 38.1 (CH2 Tyr, CH2 Asn), 44.1 (NCH2Ph), 51.7, 55.9, 57.6 (CHα Tyr, Asn, Trp), 71.0 (OCH2Ph), 80.9 (C Boc), 110.9 (C), 112.4, 115.9, 116.0, 119.4, 119.9, 122.5, 124.8, 128.0, 128.5, 128.6, 128.8, 129.4, 129.5, 130.6 (C), 131.4 (CH), 138.0, 138.8, 139.5 (aromatic C), 157.9, 159.1 (aromatic C and CO Boc), 172.7, 173.6, 174.4, 174.9 (CO amide).
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(F)(F)F)=[CH:18][C:17]=2[CH2:29][C:30]([O:32]C)=[O:31])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:18]=1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a stirred solution of methyl 2-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (250 mg, 0.51 mmol) in 10 mL of MeOH and water (1:1, v/v) was added NaOH (1N solution, 2 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. After MeOH was removed in vacuo, the residue was dissolved in water and acidified with 0.5N HCl. The mixture was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white powder (142 mg, yield 75%). MS calcd for (C15H14BFN2O6S): 380.1. MS found (ESI negative): (M−H)−=379.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.58 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.17 (d, J=10.4 Hz, 1H), 6.44 (d, J=2 Hz, 2H), 6.36 (dd, J=8.8, 2 Hz, 1H), 4.88 (s, 2H), 3.89 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2ccc(O)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2ccc(O)cc2)c1
Yield: 45.9 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (190 mg, 0.28 mmol) in ethyl acetate (8.1 mL) and methanol (1.34 mL) was stirred for 4.45 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 19 mg). The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and purified by preparative HPLC to yield 89 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[2-(4-hydroxyphenyl)ethyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[O:24])[NH:20][C:21](=[S:23])[S:22]/1.[CH3:25]CN(C(C)C)C(C)C.IC>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[O:24])[N:20]=[C:21]([S:23][CH3:25])[S:22]/1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl
Solvent: CCO
Solvent: CI
Product: CSC1=NC(=O)/C(=C/c2ccccc2Nc2c(Cl)ccc(C)c2Cl)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To room temperature suspension of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone (3.177 g, 8.04 mmols) in 125 mL of ethanol is added Hunig's base (1.57 mL, 9.03 mmols) followed by iodomethane (600 μL, 9.63 mmols). After stirring at room temperature overnight the yellow solid is collected by filtration to give 2.861 g (87%) of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-(methylthio)-4(5 H)-thiazolone. An analytical sample is obtained by recrystallization from hexane-ethyl acetate; mp 233°-236° C. Calc'd for C18H14Cl2N2OS2:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[C:23](O)=[O:24])[CH3:12].Cl.[NH2:27][CH:28]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[O:30]=[C:29]1[CH:28]([N:27]2[C:23](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][C:14]=3[O:13][CH:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH3:12])[C:17]2=[O:18])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(Oc1cccc(C(=O)O)c1C(=O)O)c1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)c1ccc2ccccc2c1
Yield: 64 %

Procedure:
A mixture of 3-(1-naphthalen-2-yl-ethoxy)-phthalic acid (0.36 g, 1.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.16 g, 1.0 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (100 mL), and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the product at 95:5 CH2Cl2-methanol, 0.27 g, in 64% yield; mp 174-176° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.69 (99.65%); 1H NMR (DMSO-d6) δ 1.71 (d, J=6.0 Hz, 3H), 1.99-2.09 (m, 1H), 2.51-2.65 (m, 2H), 2.84-2.97 (m, 1H), 5.13 (dd, J=12.5 Hz, J=5.3 Hz, 1H), 6.00 (q, J=6.0 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.44-7.53 (m, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.87-7.96 (m, 3H), 8.00 (s, 1H), 11.15 (s, 1H): 13C NMR (DMSO-d6) δ 22.0, 23.7, 31.0, 48.8, 76.5, 115.5, 117.2, 121.5, 123.6, 124.5, 126.2, 126.4, 127.6, 127.8, 128.5, 132.5, 132.7, 133.4, 136.7, 139.4, 154.8, 165.3, 166.7, 170.0, 172.8; Anal. Calcd for C25H20N2O5: C, 70.08; H, 4.71; N, 6.54. Found: C, 69.71; H, 4.51; N, 6.28.
Reaction SMILES: C(O)[C@@H](O)C(O)=[O:4].NC=CC1C=CC=CC=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:4])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)[C@H](O)CO
Agent: NC=Cc1ccccc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To a solution (cooled to 0° C) of 5.3 g (0.05 mole) D-glyceric acid in 150 ml of acetonitrile, there was added 8.9 g (0,075 mole) β - aminostyrene and 10.3 g (0.05 mole) N.N' - dicyclohexylcarbodiimide. A precipitate of N.N' - dicyclohexylurea is formed immediately, but the reaction was allowed to proceed for 15 hours at room temperature. After filtration and removal of the acetonitrile by distillation under reduced pressure, the residue was taken up in ethyl acetate and extracted with HCl, bicarbonate and water. After drying and removal of the solvent the residue was crystallized from chloroform, yielding 7.5 g (73%), m.p. 135°-136° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[C:24]([N:26](C(OCC2C=CC=CC=2)=O)[CH3:27])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6]>CO.[Pd]>[CH3:27][NH:26][C:24]1[CH:23]=[CH:22][C:4]([C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[O:6])=[C:3]([Cl:2])[CH:25]=1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
The 1-[2-chloro-4-(N-benzyloxycarbonyl-N-methylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride obtained in accordance with Example 18 is dissolved in 15 ml of methanol and debenzylated in the presence of 0.2 g of 10% palladium-on-carbon, yielding 1-[4-(N-methylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 200°.
Reaction SMILES: C1(C([NH:20][CH2:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)=[CH:30][CH:29]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:44].Cl>CCO>[ClH:44].[NH2:20][CH2:21][C@@H:22]1[CH2:24][C@H:23]1[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1
Reactant: ClCCl
Reactant: c1ccc(C(NC[C@@H]2C[C@H]2COCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: NC[C@@H]1C[C@H]1COCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 8 h

Procedure:
To a mixture of trans-2-triphenylmethylaminomethyl-[4-(benzoxazol-2-yl)benzyloxymethyl]cyclopropane (0.252 g; 0.458 mmol) in 40 ml EtOH:CH2Cl2 ; 10:1 is added ethanolic HCl until pH≅2. This is stirred overnight, further ethanolic HCl is added and stirring continued another 24 hrs. The reaction mixture is then heated to reflux for 5 hrs., concentrated in vacuo and flash chromatographed using CH2Cl2 : EtCH; 3:1 to obtain trans-2-aminomethyl-[4-(benzoxazol-2-yl)benzyloxy-methyl]cyclopropane hydrochloride as a white solid (m.p. >250° C.).
Reaction SMILES: [Br:1][C:2]1[S:15][C:5]2[S:6][CH2:7][CH:8]([CH2:11][C:12]([OH:14])=O)[C:9](=O)[C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Br:1][C:2]1[S:15][C:5]2[S:6][CH2:7][CH:8]3[CH2:11][C:12](=[O:14])[N:23]([C:20]4[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=4)[N:24]=[C:9]3[C:4]=2[CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CSc2sc(Br)cc2C1=O
Solvent: CCO
Product: O=C1CC2CSc3sc(Br)cc3C2=NN1c1ccc(Cl)cc1
Yield: 40.2 %

Procedure:
A mixture of 2.4 g of 2-bromo-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetic acid and 1.3 g of 4-chlorophenylhydrazine in 40 ml of ethanol is refluxed under heating for 14 hours. After cooling, the precipitated crystals are collected by filtration, washed with ethanol and then recrystallized from a mixed solvent of chloroform and ethanol to give 1.3 g of 8-bromo-2-(4-chlorophenyl)-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one as pale brown crystals, melting at 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.C(OC([N:25]1[C:33]2[N:28]([C:29](=[O:35])[N:30]=[C:31](Cl)[CH:32]=2)[CH2:27][C:26]1([CH3:37])[CH3:36])=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:31]3[CH:32]=[C:33]4[NH:25][C:26]([CH3:37])([CH3:36])[CH2:27][N:28]4[C:29](=[O:35])[N:30]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccnc(Cl)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)methanol and tert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:10])[CH2:6][CH:7]([Cl:9])[CH3:8].[CH3:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:23])[C:14]2=[CH:24][S:25][CH:26]=[C:13]12.Cl>C(O)C.CCOCC.CN(C)C=O>[ClH:9].[CH3:4][N:5]([CH3:10])[CH2:6][CH:7]([N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([CH3:11])[C:13]2=[CH:26][S:25][CH:24]=[C:14]2[C:15]1=[O:23])[CH3:8]
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CC(Cl)CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(CN(C)C)N1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.47 g. of 55% sodium hydride-mineral oil dispersion and 0.83 g. of 2-dimethylamino-1-methylethylchloride hydrochloride in 30 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.6 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates using 10:1 benzene:methanol to give a yellow oil. The oil is dissolved in ethanol and treated with anhydrous hydrogen chloride followed by dilution with ether to give a solid, which is recrystallized from ethanol to give white crystals, m.p. 280°-282°C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[C:13]([Cl:20])[C:14]4[N:15]([CH:17]=[CH:18][N:19]=4)[CH:16]=[C:11]3[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:33]1([S:36](N)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[C:13]([Cl:20])[C:14]4[N:15]([CH:17]=[CH:18][N:19]=4)[CH:16]=[C:11]3[N:10]([S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=c1[nH]c2cn3ccnc3c(Cl)c2n1-c1ccc(Br)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(Cl)c3nccn3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the crude product (Step J) in 3 ml anhydrous THF was added LHMDS (0.4 ml, 0.4 mmol, 1M/THF) at 0° C. and the mixture was stirred for 5 min. The cyclopropyl sulfonamide (83 mg, 0.59 mol) was added neat and the mixture was warmed to room temperature and stirred for 15 h. The mixture was quenched with brine, diluted with H2O and extracted using a mixture of EtOAc/THF (3:1). The organic phase was washed with brine and dried with Na2SO4. Subsequent column chromatography (100% EtOAc) gave the title product as a brown oil (36 mg, 20% over the 2 last steps). Rf (100% EtOAc)=0.35. 1H-NMR (500 MHz, MeOH-D3): δ=8.80 (s, 1H), 7.89 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (dd, 1H), 7.60-7.58 (d, 1H), 7.46 (s, 1H), 1.51-1.37 (m, 2H), 1.23-1.15 (m, 2H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]3[NH:12][CH:13]=[CH:14][N:15]=3)[O:10][C:6]=2[CH:5]=1.[CH2:18](Br)[CH3:19]>>[ClH:1].[CH2:18]([N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[O:10][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[CH:17]=[CH:16][C:7]=2[CH:8]=1)[CH3:19]
Reactant: COc1ccc2cc(-c3ncc[nH]3)oc2c1
Reactant: CCBr
Agent: Cl
Product: CCn1ccnc1-c1cc2ccc(OC)cc2o1

Procedure:
This was prepared from 2-(6-methoxybenzofuran-2-yl) imidazole hydrochloride and ethyl bromide according to the procedure of example 2; m.p.=259°-261 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH:14]1(Br)[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCC1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OC2CCC2)c(Br)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
2-Bromo-4-(trifluoromethoxy)phenol (Description 11; 1.5 g, 5.83 mmol) and cyclobutyl bromide (3.0 g, 17.5 mmol) were dissolved in dimethylformamide (10 ml). Potassium carbonate (4.85 g, 35 mmol) was added and the solution was stirred at 50° C. for 16 h. The solution was allowed to cool to ambient temperature, poured into a 10% citric acid solution (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water and dried over sodium sulphate. Removal of the solvent in vacuo gave an oil which was chromatographed on silica in 10% ethyl acetate/hexane to give the title compound as an oil (1.65 g, 91%). 1H NMR (250 MHz, CDCl3) δ7.44-7.42 (1H, m), 7.12-7.07 (1H, m), 6.73-6.70 (1H, d, J 9.0 Hz), 4.71-4.60 (1H, m), 2.52-2.41 (2H, m), 2.30-2.18 (2H, m), and 1.92-1.55 (2H, m).
Reaction SMILES: C1(C2C(=CC=CC=2)CO1)=O.[OH:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:28]>C(OCC)C>[ClH:28].[OH:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][NH2:17]
Reactant: NC(=O)c1ccccc1CO
Agent: Cl
Agent: O=C1OCc2ccccc21
Agent: [Al+3]
Solvent: CCOCC
Product: NCc1ccccc1CO

Procedure:
4.92 g of phthalide are transformed according to C. Y. Belke, S. C. K. Su, J. A. Shafer (J. Am. Chem. Soc., 93, 4552 (1971)), into 2-hydroxymethylbenzamide (melting point 147°-149° C.) which by treatment with lithium-aluminium hydride according to R. M. Laird, R. E. Parker (J. Chem. Soc., 4784 (1965)), and then with gaseous hydrogen chloride dissolved in ethyl ether, gives 2-hydroxymethylbenzylamine hydrochloride which after crystallization from an ethanol/ethyl ether mixture shows melting point of 177°-179° C. (G. Pifferi, L. Fontanella, E. Decelli, R. Monguzzi, J. Heterocyclic Chem., 9, 1209 (1972), melting point 177°-178° C.). I.R. (KBr) 3260 cm-1 (OH), 2595 cm-1 (NH3+), 1020 cm-1 (C--O), 760 cm-1 (phenyl).