Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][CH2:45][C:46]([O:48]C)=[O:47])[CH:5]=[CH:6][CH:7]=1.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][CH2:45][C:46]([OH:48])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared as a white foam (0.172 g, 47%) from {2-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}acetic acid, methyl ester using a procedure similar to step 4 of example 165; dec. >50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.16–1.32 (m, 8H), 1.44–1.53 (m, 2H), 1.67–1.76 (m, 2H), 3.17–3.42 (m, 6H), 3.61 (s, 2H), 4.12 (t, J=7 Hz, 2H), 6.37 (d, J=3.1 Hz, 1H), 6.95–6.99 (m, 2H), 7.06–7.10 (m, 2H), 7.32 (m, 1H), 7.41–7.55 (m, 6H), 7.57–7.60 (m, 2H), 7.68–7.77 (m, 2H), 7.87 (s, 2H), 8.54 (t, J=5.5 Hz, 1H), 12.50 (broad s, 1H); IR (KBr) 3410, 2940, 1625, 1560, 1540, 1460, 1220, 1130 cm−1; mass spectrum [(+)APCI], m/z 687 (M+H)+; Anal. Calcd. for C39H40Cl2N2O5.0.5H2O: C, 67.24; H, 5.93; N, 4.02. Found: C, 67.26; H, 6.02; N, 3.96.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=C[N:30]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([C:46]2[CH:54]=[C:53]3[C:49](C[N:51]([C@@H](C(C)C)C(OC)=O)[C:52]3=[O:55])=[CH:48][CH:47]=2)=CC=1.C1(C2OC(C(OCC)=O)=NN=2)C=CC=CC=1>>[CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]4[O:55][C:52]([C:53]5[CH:54]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[N:51][N:30]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: CCOC(=O)c1nnc(-c2ccccc2)o1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nnc(-c5ccccc5)o4)cc3)cc2C1=O
Yield: 44 %

Procedure:
The compound of example 625 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with commercially available ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (Enamine Ltd, Ukraine, Europe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH:22]=[CH2:23])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH:22]=[CH2:23])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@@]1(C)[C@H]2CC[C@@H]1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@]1(C)C(=O)CC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A solution of 700 mg of 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol in 30 ml of dichloromethane was mixed with 740 mg of pyridinium chlorochromate and stirred for 3 hours at room temperature. By filtration of the reaction mixture on silica gel (solvent mixture: cyclohexane/ethyl acetate=7/3) and subsequent concentration by evaporation of the filtrate in a rotary evaporator, 680 mg (98%) of 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one was obtained as almost colorless foam, which was used in the next stage without further purification.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[O:8][CH2:7][C:6]([OH:42])=[O:5])[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
A solution of tert-butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was stirred in CH2Cl2 (2 mL) and TFA (2 mL) for 1 h. The volatiles were removed in vacuo and the residue was triturated with ethyl ether. The crude product was purified using prep HPLC (method 10-35_90 mins) to afford to give 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid. (0.43 mg, 0.10 mmol)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=4[CH3:35])[CH2:24][CH2:23]3)[CH:21]=1)[CH2:10][C:9]2([CH3:37])[CH3:36])=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:35][C:29]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=1[N:25]1[CH2:24][CH2:23][N:22]([C:20]2[CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:37])([CH3:36])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=[N:18][CH:19]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
A mixture of 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 0.60 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.25 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=471.3.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>CN(C)C=O.C(OCC)(=O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: Nc1ccc(F)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Temperature: 115 °C

Procedure:
To a solution of 4-fluoroaniline (2.40 mL, 24.5 mmol) in N,N-dimethylformamide (30 mL) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give 2-amino-N-(4-fluoro-phenyl)-benzamide as white solid. Yield: 2.00 g (35%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1C(O)=O.OCCS(C1C=CC(OC2C=CC(S)=CC=2)=CC=1)(=O)=O>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(CCO)c1ccc(Oc2ccc(S)cc2)cc1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 19 was repeated, except that the compounds shown in 1st and 2nd columns of the following table were used in place of the 1-amino-2-carboxy-4-bromoanthraquinone and 4-(4'-β-hydroxyethylsulfonylphenoxy)thiophenol, respectively, thereby obtaining a corresponding anthraquinone compound. The color shade obtained by dyeing cotton with the compound is as shown in a 3rd column of the table.
Reaction SMILES: [CH3:1][C@@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:10]1=[O:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[NH4+]>>[CH3:1][C@@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)([CH2:14][CH2:15][OH:16])[C:10]1=[O:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H](c1ccccc1)N1CCC(CCO[Si](C)(C)C(C)(C)C)(Cc2ccc(F)cc2)C1=O
Agent: [F-]
Agent: [NH4+]
Product: C[C@H](c1ccccc1)N1CCC(CCO)(Cc2ccc(F)cc2)C1=O

Procedure:
Prepare by the method of Example 18.2 using 1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (1.7 g, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4 mmol) to give, after chromatography on silica gel eluted with 1/1 ethyl acetate/hexane, the title compound as diastereomers: Rf=0.51 and 0.25 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: Cl[Si:2]([CH3:20])([CH3:19])[CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:18].[CH3:21][C:22]1[CH-:26][C:25]([CH3:27])=[C:24]([CH3:28])[C:23]=1[CH3:29].[Na+]>O1CCCC1>[CH3:19][Si:2]([CH3:20])([CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:18])[CH:26]1[C:25]([CH3:27])=[C:24]([CH3:28])[C:23]([CH3:29])=[C:22]1[CH3:21]
Reactant: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Reactant: Cc1[cH-]c(C)c(C)c1C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C)=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a light yellow solution of chlorodimethyl(2-methyl-4-phenyl-1H-indenyl)silane (9.40 g, 31.4 mmol, 1.00 eq.) in tetrahydrofuran (40 ml) at −30° C. was added sodium (tetramethylcyclopentadienide) (4.76 g, 33.0 mmol, 1.05 equiv.) in portions to give a cloudy orange solution. The reaction was allowed to warm to room temperature and stirred for 23 hours. The mixture was evaporated under vacuum, leaving an orange residue. The residue was extracted with pentane (50 ml) and the extract was filtered to give a bright yellow solution and yellow solid. The solution was evaporated under vacuum to yield thick, orange oil. Yield 10.16 g (84%). 1H NMR(C6D6): δ7.61 (d, 2H), 7.41 (m, 1H), 7.31 (m, 4H), 7.19 (m, 1H), 6.85 (s, 1H), 3.60, (s, 1H), 3.16 (br s, 1H), 2.00 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H), 1.82 (s, 6H), −0.23 (s, 3H), −0.24 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:19].[Na+:20]>>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:19])=[O:1].[Na+:20]
Reactant: O=C1Cc2cccc(Oc3ccccc3Cl)c2N1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1c(CC(=O)[O-])cccc1Oc1ccccc1Cl

Procedure:
Thus obtained 2-oxo-7-(2-chlorophenoxy)indoline was treated successively with sodium hydroxide in a similar manner to that of Example 29 to give sodium 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate, which was identified with the crop obtained in Example 5-(2) by I.R. and N.M.R. spectra.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:30](=O)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5csc(C(C)C)n5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 24 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.066 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), p-anisaldehyde (0.023 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.019 g, 24%); 1H-NMR (500 Mz, DMSO-d6): δ 1.33 (d, J=7.0 Hz, 6H, iPr—CH3), 2.68 (m, 4H, piperazine N(CH2)2), 3.22-3.34 (m, 1H), 3.62-3.70 (m, 6H, piperazine N(CH2)2 and NCH2), 3.84 (s, 3H, OMe), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 7.35 (s, 1H, thiazole 5-H), 8.14 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.33 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.71 min—527/529 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 527.1232, calculated for C24H28BrN6OS (M+H)+: 527.1229.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: NCc1cccc(F)c1F
Product: CN1CCCn2c1cc(NCc1cccc(F)c1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (2,3-difluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[Cl-].[NH4+].C([N:15]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:15])=[O:10])=[N:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(C(=O)O)nc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-aminopyridine-2-carboxylic acid (2.0 g) in N,N-dimethylformamide (50 mL) were added ammonium chloride (3.9 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.1 mL) and 1-hydroxybenzotriazole (4.4 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (260 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:34]=[C:35]=[S:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:35](=[S:36])[NH:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Reactant: S=C=Nc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1cccc2ccccc12

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (476 mg, 2.0 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.31 ml, 2.2 mmol) and 1-naphthyl isothiocyanate (407 mg, 2.2 mmol). The mixture was heated to reflux for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:19 tert-butyl methyl ether/dichloromethane). The product was obtained in a yield of 87 mg (9%).
Reaction SMILES: [C:1]1([C:11](OC)=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:10][O:9][C:7]([C:1]1([CH:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:8]
Reactant: COC(=O)C1(C(=O)OC)CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COC(=O)C1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of dimethyl cyclohexane-1,1-dicarboxylate (2.8 g, 14.0 mmol) in dichloromethane(55 mL) at −78° C. under a nitrogen atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 19 mL, 28 mmol) dropwise. After 3 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (11 mL), then 1N HCl (14 mL) and allowed to warm to room temperature. The mixture was filtered through Celite@ and the organic phase was separated, was dried (MgSO4) and was evaporated in vacuo to yield the title compound which was used without further purification (1.23 g, 52%). MH+171.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]([NH2:21])=[S:20])[N:15]=[CH:14]1>CC(O)C>[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]2[S:20][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:21]=2)[N:15]=[CH:14]1
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc2c(c1)Cc1sc(Cc3c[nH]cn3)nc1-2
Yield: 32.4 %

Procedure:
0.34 g of 2-bromo-1-indanone and 0.26 g of 4-imidazolyl thioacetamide hydrochloride were dissolved in 7 ml of 2-propanol with heating, and the solution was heated for 30 minutes under reflux. After cooling the reaction solution, the precipitated crystals were collected by filtration and washed with ethyl acetate. The collected crystals were partitioned between chloroform and a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with chloroform several times. The combined chloroform layers were washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. By evaporation of the solvent, 0.12 g (32%) of 2-(4-imidazolylmethyl)-8H-indeno[1,2-d]thiazole was obtained. This free base was dissolved in methanol and mixed with 0.055 g of fumaric acid to effect crystallization. The resulting crude crystals were recrystallized from methanol-diethyl ether to obtain 0.10 g of fumarate.
Reaction SMILES: [NH2:1][C:2](=[O:12])[CH2:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>>[NH2:18][C:17]1[N:10]([C:6]2[CH:5]=[C:4]([CH2:3][C:2]([NH2:1])=[O:12])[CH:9]=[CH:8][CH:7]=2)[N:11]=[C:15]([C:14]([CH3:21])([CH3:20])[CH3:13])[CH:16]=1
Reactant: NNc1cccc(CC(N)=O)c1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2cccc(CC(N)=O)c2)n1

Procedure:
3-(2-amino-2-oxoethyl)phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl)acetamide. See WO 2006/071940.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:5][CH:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:3]1.FC(F)(F)C(O)=O.ClC1[N:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]2[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=2)[CH:29]=1.C(N(CC)CC)C>C(O)CCC>[O:19]=[S:2]1(=[O:1])[CH2:3][CH:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[N:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]4[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=4)[CH:29]=3)[CH2:10][CH2:11]2)[CH2:5]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CS(=O)(=O)C2)CC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc(N3CCN(C4CS(=O)(=O)C4)CC3)ncn2)s1
Temperature: 150 °C

Procedure:
50-2 (0.20 g, 0.68 mmol) was first treated with trifluoroacetic acid (4 mL) for 30 minutes and then concentrated under reduced pressure. The residue was then dissolved in n-butanol (4 mL) to which 35-1 (0.16 g, 0.68 mmol) and triethylamine (0.34 g, 3.41 mmol) were added and then heated at 150° C. for 18 hours. Upon cooling the solid was filtered off, washed with n-butanol, ethyl ether and then purified on a silica column to yield 50-3. Hi-Res MS: calc: 392.0958 found: 392.0949. 1H-NMR (DMSO-d6): 12.10(s, 1H); 8.43(s, 1H); 8.26(s, 1H); 6.24(s, 1H); 4.28(m, 2H); 4.15(m, 2H); 3.57(br s, 4H); 3.22(m, 1H); 2.46(t, 4H).
Reaction SMILES: COC1C=C(C=CC=1OC)C[C@@H](C)N.Cl.COC1C=C(C=CC=1OC)C[C@@H](C)N.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:35]=O.[N+:42]([CH2:45][CH3:46])([O-:44])=[O:43]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:35]=[C:45]([N+:42]([O-:44])=[O:43])[CH3:46])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC[N+](=O)[O-]
Agent: COc1ccc(C[C@@H](C)N)cc1OC
Agent: Cl
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC

Procedure:
A process according to Claim 1, wherein said (R)-3,4-dimethoxy-amphetamine hydrodchloride of Formula (3) is prepared by condensing 3,4-dimethoxybenzaldehyde (10) with nitroethane (Henry's reaction) to form 3,4-dimethoxy-phenyl-2-nitro-propene (11), wherein said 3,4-dimethoxy-phenyl-2-nitro-propene is then reduced to 3,4-dimethoxy-phenyl-acetone (12) by means of a catalytic hydrogenation, wherein said 3,4-dimethoxy-phenyl-acetone (12) is then reacted with (R)-α-methyl-benzyl-amine (13) to form the corresponding chiral imine (14), wherein said chiral imine (14) is then diastereoselectively reduced to (R,R)-N-phenyl-ethyl-3,4-dimethoxy-amphetamine (15) hydrochloride intermediate by means of a catalytic hydrogenation with Raney nickel with the intermediate (15) being then debenzylated by a further hydrogenation, thus yielding (R)-3,4-dimethoxy-amphetamine hydrochloride, according to the following reaction scheme: ##STR25##
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:29](=[CH:30][CH:31]=1)[O:28][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:32].[OH-].[Na+]>>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:32])[C:8]4[C:29](=[CH:30][CH:31]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:33])=[O:2])[CH:7]=4)[O:28]3)[CH2:12][CH2:13]2)=[CH:20]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3c[nH]c4ccccc34)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3c[nH]c4ccccc34)CC1)O2
Yield: 87.3 %

Procedure:
(E)-3-{1′-[2-(1H-indol-3-yl)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (129 mg, 0.29 mmol) was hydrolyzed with 4 M NaOH following the procedure described in Example 40, Step B, giving (E)-3-{1′-[2-(1H-indol-3-yl)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (109 mg, 87%). The product was treated with NH2OTHP according to the procedure described in Example 40, Step C, giving (E)-3-{1′-[2-(1H-indol-3-yl)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Removal of the THP protecting group following the procedure described in Example 40, Step C gave (E)-3-{1′-[2-(1H-indol-3-yl)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide, which was purified by preparative LC-MS and obtained as its trifluoroacetate salt (37 mg, white solid).