Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:33]([CH3:34])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:35].[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[NH2:1][C:2]1[C:33]([CH3:34])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:17][CH2:18]2)=[O:31])[C:8]([N:45]2[CH2:46][CH2:47][N:42]([CH:39]3[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[CH2:43][CH2:44]2)=[O:9])=[CH:4][C:3]=1[Cl:35]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1N
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1N

Procedure:
Prepared analogously to Example 7i from 70 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 27 mg (0.16 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(#N)C>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.230 mmol) in 5 mL of dichloromethane. Added 0.5 mL of acetic anhydride. After 10 min, reaction is complete and trituration with acetonitrile gave 2-[5-(4-acetyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 91%). MS(ESI) m/z 477.3 (M+H)+
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[C:29]1([CH2:28][N:11]2[CH2:12][CH2:13][N:8]([CH2:14][C:15]3[N:16]=[N:17][C:18]4[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=4)[N:20]=3)[CH2:9][CH2:10]2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1cccc2ccccc12
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(N)c2nc(CN3CCN(Cc4cccc5ccccc45)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (70 mg; 0.12 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added 1-chloromethylnaphthalene (0.023 mL; 0.18 mmol) followed by potassium carbonate (65 mg; 0.470 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 35 mg of yellow colored 3-(4-Naphthalen-1-ylmethyl-piperazin-1-ylmethyl)-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>CC(C)=O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccnc3)c3cc(Br)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: Brc1cnc2[nH]cc(-c3cccnc3)c2c1
Temperature: 65 °C

Procedure:
To a solution of 5-bromo-3-(pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (662 mg, 1.55 mmol) in acetone (30 mL) and methanol (20 mL) was added 2N NaOH (1.8 mL). The reaction was heated in a 65° C. oil bath for 1 h and then evaporated to near dryness. The crude reaction product was partitioned between EtOAc and 1N NaOH and extracted. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give product that was used for the next step without any further purification. LCMS-ESI+: calc'd for C12H8BrN3: 274.0 (M+H+); found: 274.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])=[C:4]([O:17][CH2:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][NH:24]C(=O)C(F)(F)F)=[CH:21][CH:20]=2)[N:3]=1.CN>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])=[C:4]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][NH2:24])=[CH:31][CH:32]=2)[N:3]=1
Reactant: [N-]=[N+]=NCCCn1cnc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc21
Agent: CN
Solvent: CO
Product: [N-]=[N+]=NCCCn1cnc2c(OCc3ccc(CN)cc3)nc(N)nc21
Temperature: 50 °C

Procedure:
Azide 23 (Example 10, 50 mg, 0.11 mmol) is dissolved in 1 mL methanol, and 2 mL methylamine (33% in ethanol) are added. The reaction mixture is stirred at 50° C. over night and all volatiles are removed in vacuo. The product is purified by flash column chromatography (CH2Cl2/MeOH 10:1) to yield 33.5 mg. 1H-NMR (400 MHz, DMSO-d6): δ=7.85 (s, 1H, H-8), 7.41, (d, J=8.1, 2H, ArH), 7.35 (d, J=8.1, 2H, ArH), 6.44 (s br, 2H, NH2), 5.44 (s, 2H, OCH2), 4.05 (t, J=, 2H, CH2), 3.72 (s, 2H, CH2), 3.35 (t, J=6.5, 2H, CH2), 1.99 (m, 2H, CH2) ppm. MS (ESI) m/z 354.1 [M+H]+.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:19][C:14]=2[CH:13]=[CH:12][CH2:11][N:10]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C)(C)C>CO.[C].[Pd]>[CH3:24][N:22]([CH3:23])[C:21]([O:20][C:18]1[CH:17]=[CH:16][C:15]2[CH:9]([CH2:8][CH2:7][OH:6])[N:10]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11][CH2:12][CH2:13][C:14]=2[CH:19]=1)=[O:25]
Reactant: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)Oc1ccc2c(c1)CCCN(C(=O)OC(C)(C)C)C2CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of t-butyl 7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylate (207 mg, 0.550 mmol) synthesized in step (k) of Example 192 in methanol (10 ml) was added 10% palladium carbon (27 mg), and the resulting mixture was stirred for 1 hour at room temperature. After stirring, the reaction mixture was filtered through celite and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1:1-0:1) as the eluent to afford the title compound (189 mg, yield: 91%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:14][C:10]1[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C=NCCCCl
Reactant: Nc1cccnc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(NCCCCl)Nc1cccnc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1-Chloro-3-isocyanato-propane (1.897 g, 15.873 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (1 g, 10.582 mmol) in toluene (15 mL) over a period of 30 minutes at 0° C. The reaction temperature was maintained at room temperature for 6 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 2.1 g (95.45% yield) of 1-(3-chloro-propyl)-3-pyridin-3-yl-urea.
Reaction SMILES: N[C:2]1C=CC2CCCCC(=O)C=2C=1.[CH3:14][S:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][CH2:23][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:21][C:20]=2[CH:30]=1.CSC1C=CC2CCCCC(=O)C=2C=1>>[CH3:14][S:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][CH2:23][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:21][C:20]=2[CH:30]=1.[CH3:2][CH:24]1[CH2:23][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:21][C:20]2[CH:30]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:25]1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Agent: COC(=O)C1=Cc2cc(SC)ccc2CCC1
Agent: CSc1ccc2c(c1)C(=O)CCCC2
Product: COC(=O)C1=Cc2ccccc2CC(C)C1

Procedure:
Methyl 2-methylthio-6,7-dihydro-5H-benzocycloheptene-8-carboxylate was synthesized by carrying out reactions according to the methods described in Reference Example 1, (a) to (c), except for using the 3-methylthio-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one obtained in the above item (b).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[C:29]([O:30][CH3:31])=[CH:28][C:18]2[CH2:19][C@H:20]([C:25]([OH:27])=O)[S:21][CH2:22][C:23](=[O:24])[C:17]=2[CH:16]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]([C@H:20]2[CH2:19][C:18]3[CH:28]=[C:29]([O:30][CH3:31])[C:15]([O:14][CH3:13])=[CH:16][C:17]=3[C:23](=[O:24])[CH2:22][S:21]2)=[O:27])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: COc1cc2c(cc1OC)C(=O)CS[C@@H](C(=O)O)C2
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc(OC)c(OC)cc3C(=O)CS2)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 41.3 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.149 g) in dichloromethane (3 ml) was added to a solution of (R)-(−)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.183 g) and diethyl 4-aminobenzylphosphonate (0.158 g) in N,N-dimethylformamide (DMF) (3 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.109 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residue was treated with ethanolisopropyl ether and the solid was removed by filtration. The filtrate was concentrated and the residual oil was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform-methanol (15:15:1, v/v), (2R)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxamide (0.136 g, 41%) was obtained. Colorless amorphous solid. Melting point 96-98° C. Optical rotation [α]D (23° C.) −155.00 (c=0.50, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:18][CH:19]([Cl:21])[Cl:20])[C:15]([OH:17])=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl-].[C:23]([C@@H:25]([NH3+:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[F:35])#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:18][CH:19]([Cl:21])[Cl:20])[C:15]([NH:36][C@H:25]([C:23]#[N:24])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=2[F:35])=[O:17])[C:9]([F:10])([F:11])[F:12])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C[C@H]([NH3+])C#N)c(F)c1
Reactant: O=C(O)[C@H](CC(Cl)Cl)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C[C@@H](C#N)NC(=O)[C@H](CC(Cl)Cl)N[C@@H](c2ccc(Br)cc2)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]amino}-4,4-dichlorobutanoic acid (120 mg) and (1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethanaminium chloride (66 mg) were dissolved in DMF (1.5 ml) and HATU (223 mg) was added. The reaction mixture was stirred at room temperature for 5 min and Hunig's base (204 μL) was added. The solution was stirred for 18 hours. The mixture was poured onto an aqueous sodium hydrogen carbonate (saturated, 20 ml) and water (20 ml). The mixture was stirred in an erlenmeyer flask for 10 min. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried on MgSO4. It was concentrated under reduced pressure. The crude product was purified by flash (eluted with 20:80 to 55:45 EtOAc/hexanes).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:26])[NH:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O.O>[CH3:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:26])=[CH:12][CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A solution of methyl-[4-(quinolin-3-ylcarbamoyl)-phenyl]-carbamic acid tert-butyl ester (8.5 g, 22.5 mmol) in dichloromethane (100 ml), trifluoroacetic acid (100 mL) and water (10 mL) was stirred at room temperature for 6 hours. The solvent was evaporated in vacuo, and the residue was suspended in 1 N aqueous sodium hydroxide (200 mL). The product was collected by filtration, washed with water and dried in vacuo, to give a colorless solid, 5.4 g (87%). MS: m/z 278 (MH+). 1H NMR (DMSO-d6): 2.77 (d, 3 H), 6.44 (br d, 1 H), 6.63 (d, 2 H), 7.54-7.67 (m, 2 H), 7.89 (d, 2 H) superimposed on 7.95 (t, 2 H), 8.82 (d, 1 H), 9.16 (d, 1 H) and 10.26 (s, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7](=[N:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCN=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNCc1ccccc1

Procedure:
1.9 g (0.05 mol.) of lithium aluminum hydride was dissolved in 80 ml of anhydrous tetrahydrofuran. N-benzylidene-n-dodecylamine was gradually added to the mixture at room temperature and heated at 50°~60° C. for an hour to yield N-benzyl-n-dodecylamine (III). The product was purified by distillation. b.p. 150°~157° C./0.6 mmHg.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([CH3:14])=[CH2:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[C:19](=[O:21])=[O:20]>C(OCC)C>[CH3:14][C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]2[C:19]([OH:21])=[O:20])=[CH2:13]
Reactant: C=C(C)c1cccc2c(Br)cccc12
Reactant: O=C=O
Agent: CC[Mg]Br
Solvent: CCOCC
Product: C=C(C)c1cccc2c(C(=O)O)cccc12
Temperature: 20 °C
Reaction time: 18 h

Procedure:
In a nitrogen atmosphere, a solution of 1-bromo-5-(1-methylethenyl)-naphthalene [14.21 g, described by W. F. Short and H. Wang, J. Chem. Soc., 991 (1950)] in diethyl ether (140 ml) was added dropwise to a mixture of ethyl magnesium bromide (prepared from 2.94 g of magnesium and 4.29 ml of ethyl bromide) in diethyl ether (30 ml) at 0° C. The mixture was stirred at 20° C. for 18 hr and then heated at reflux for 1 hr. The cooled solution was poured onto an excess of solid carbon dioxide. The mixture was dissolved in diethyl ether. The resulting solution was washed with a 2N aqueous solution of H2SO4, brine and 10% aqueous NaHCO3 (4x). The basic washes were combined and made acidic (pH 3) with 6N aqueous HCl. The resulting solid was collected, washed with water and dried to give 9.7 g of the title compound; mp 138°-140° C.; NMR(CDCl3) δ 2.15 (s, 3H), 5.0 & 5.38 (2s, 2H), 8.0 (m, 6H), 10.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:16][CH:15]([O:17][Si](C(C)(C)C)(C)C)[CH:14]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C:13]1=[CH2:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:16][CH:15]([OH:17])[CH:14]([CH2:25][OH:26])[C:13]1=[CH2:34]
Reactant: C=C1C(CO[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1C(CO)C(O)CC1n1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 57 (180 mg, 0.344 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (2 mL of 1 M solution in THF). The reaction mixture was stirred at room temperature for 1 hour. It was poured into DCM (50 mL), washed with water (3×10 mL), dried over sodium sulfate, and concentrated in vacuo to give the title compound (55 mg, 54%).
Reaction SMILES: Br.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].Cl.NO>O.[O-2].[O-2].[Mn+4]>[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9]
Reactant: Nc1ccccc1C1=NCCN1
Agent: [Mn+4]
Agent: Br
Agent: Cl
Solvent: O
Product: Nc1ccccc1-c1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A mixture of 2-(4,5-dihydro-1H-imidazol-2-yl)aniline hydrobromide (50.0 mg, 0.207 mmol) and manganese dioxide (170 mg, 1.96 mmol) in N,N′-dimethylpropylenurea (2.0 mL) was heated at 150. (bath temp.). After 1 hour, the reaction mixture was cooled to room temperature, poured into a solution of hydroxylamine hydrochloride (0.5 g) in water (50 mL), and the resulting mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure. The crude residue was triturated with isopropylether, and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica-gel, ethyl acetate as the eluent) to give 2-(1H-imidazol-2-yl)aniline (20 mg, 61% yield).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.BrC[CH2:11][CH2:12][OH:13].COCCN1CCNCC1>>[OH:13][CH2:12][CH2:11][CH2:1][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: O=CN1CCNCC1
Reactant: OCCCBr
Agent: COCCN1CCNCC1
Product: OCCCN1CCNCC1

Procedure:
The title compound was prepared from formylpiperazine and 3-bromo-1-propanol in the same manner as in Preparation Example 1(5) to (7).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:32]3[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=3[O:30][CH:29]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:32]3[CH:33]=[CH:34][C:35]([O:37][CH2:16][CH2:15][CH2:14][O:13][C:10]4[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=4)=[CH:36][C:31]=3[O:30][CH:29]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc2c(-c3ccc(F)cc3)coc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(-c4ccc(F)cc4)coc3c2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3-(4-Fluoro-phenyl)-benzofuran-6-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H25FO6 [M+NH4]+: 482, [M+Na]+: 487, [M+H]+: 464.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]3)[C:9]([CH2:15][S:16][CH2:17][CH3:18])([C:11]([F:14])([F:13])[F:12])[OH:10])=[CH:4][C:3]=1[O:31]C.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]3)[C:9]([CH2:15][S:16][CH2:17][CH3:18])([C:11]([F:13])([F:12])[F:14])[OH:10])=[CH:4][C:3]=1[OH:31]
Reactant: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(F)c(OC)c1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(F)c(O)c1)C(F)(F)F
Reaction time: 22 h

Procedure:
Analogously to example 10 42 mg (0.09 mmol) 4-fluoro-α-[(ethylsulfanyl)methyl]-3-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)benzeneethanol in 1.7 ml dichloromethane are treated with 0.9 ml of a 1 M solution of boron tribromide in dichloromethane at −20° C. The typical work up after 22 hours at room temperature and chromatography on silica gel (acetone in hexane 50%) yields 28 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: COC[C@H](C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-phenoxy benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH:28]([CH3:30])[CH3:29])[N:24]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:27]=[CH:26][N:25]([CH:28]([CH3:30])[CH3:29])[N:24]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: CC(C)n1ccc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a solution of 3-bromo-4-nitro-1H-indazole (Preparation B; 2.2 g, 9.1 mmol) in DMF (18 mL) was added potassium carbonate (2.5 g, 18 mmol) at ambient temperature. After 15 minutes, at ambient temperature, 3-(chloromethyl)-1-isopropyl-1H-pyrazole hydrochloride (1.8 g, 9.1 mmol) was added. The mixture was allowed to stir for 18 hours. The mixture was concentrated, diluted with ice-water and stirred for one hour. The resulting fine solids were collected by filtration and dried under vacuum to give 3-bromo-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (3 g, 91% yield).