Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[N+:4]([C:7]1[CH:48]=[CH:47][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH2:45])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].[CH3:49][C:50]([CH3:52])=O>>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH:45][CH:50]([CH3:52])[CH3:49])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:47][CH:48]=1)([O-:6])=[O:5]
Reactant: CC(C)=O
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Agent: Cl
Product: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(5R,7R)-4-(1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate was prepared by the procedures described in Example 18, substituting (5R,7R)-4-(5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride with (5R,7R)-4-(4-(aminomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate trihydrochloride, and substituting formaldehyde with acetone. LCMS (APCI+) m/z 647 [M+H]+; Rt=3.32 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=1[CH2:31][CH2:32][CH3:33].[H-].[Na+].[I-].[Na+]>CN(C)C=O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=3[CH:15]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CC1(C(=O)O)CCc2cc(O)ccc2O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)CCC(C)(C(=O)O)O3)ccc(C(C)=O)c1O
Yield: 68.9 %

Procedure:
The procedure of Example 7 was employed to alkylate 0.9 g of the ethyl ester of racemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid with 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone (1.5 g), using sodium hydride (12.16 mmole), and sodium iodide (10 mmoles), in N,N-dimethylformamide. After saponification with lithium hydroxide monohydrate (1.5 g), the crude acid product was purified by chromatography on silica gel. There was obtained 1.16 g (68.9%) of racemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid as an off-white solid mp 108°-110.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Si](C)(C)C)=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25].[I:26]Cl>ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([I:26])=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)nc(N)c1OC
Reactant: ClI
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(I)c(F)c2F)nc(N)c1OC
Temperature: 70 °C
Yield: 66 %

Procedure:
Methyl 6-amino-2-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-methoxypyrimidine-4-carboxylate (330 mg, 0.90 mmol) was stirred in 1,2-dichloroethane (5 mL), treated with iodine monochloride (1.0 g, 6.9 mmol), and heated to 70° C. for 21 h. After cooling, the mixture was diluted with ethyl acetate, washed with 15% sodium bisulfite, washed with saturated NaCl, dried (Na2SO4), and evaporated. The material was purified by RP-HPLC using 70% acetonitrile to provide the title compound as a white solid (250 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:20])[C:10]([CH2:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Si]([O:42][NH2:43])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:20])[C:10](=[O:11])[CH2:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([NH:43][OH:42])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: CC(C)C(CC(=O)N(C)CCOc1ccc(Cl)cc1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(CC(=O)N(C)CCOc1ccc(Cl)cc1)C(=O)NO
Temperature: 0 °C
Reaction time: 18 h
Yield: 7.1 %

Procedure:
A solution of Intermediate 25 (0.31 g) in dichloromethane (15 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g) and O-tert-butyldimethylsilylhydroxylamine (0.17 g) and the mixture was stirred for 18 h, then washed with water (40 ml), and the aqueous extracted with dichloromethane (20 ml). The combined organic extracts were dried over magnesium sulphate (1 g) and evaporated to give a yellow gum. This was taken up in tetrahydrofuran (20 ml), cooled to 0° C. and tetrabutylammonium fluoride (1M, 1.08 ml) added and the reaction stirred for 8 min, before acetic acid (2 drops) was added. The solvent was removed in vacua, water (10 ml) was added, and the slurry extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (30 ml), dried over magnesium sulphate (0.5 g) and the solvent removed in vacua. Purification by flash chromatography (silica, eluent 5% methanol/dichloromethane) yielded the title compound as a gummy solid (0.023g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13]([OH:15])=[O:14])=[O:4].[O:16]=[C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[C:13]([C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([N:21]2[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[NH:18][C:17]2=[O:16])[CH2:27][CH2:26]1)([OH:15])=[O:14]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.94 g (32 mmol) of the compound from Example II and 8.26 g (40 mmol) of 4-(2-oxo-1-benzimidazolinyl)piperidine (Aldrich) are initially introduced in 120 ml of DMF. The mixture is treated with 5.52 g (40 mmol) of potassium carbonate and 0.45 g (3 mmol) of sodium iodide and stirred overnight at room temperature. The batch is diluted with 600 ml of H2O and the product is precipitated at pH 5 by dropwise addition of 33 ml of 1N hydrochloric acid. The precipitate is filtered off with suction, stirred with 300 ml of diethyl ether and dried in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[N:49][CH:50]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:47]4[CH:48]=[N:49][CH:50]=[C:45]([Cl:44])[CH:46]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cncc(Cl)c4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 86 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross-coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 5-chloropyridin-3-ylboronic acid yielded the title compound (86% yield) as a white solid. MS (ISP): m/z=686.3 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:21])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[C:5]([Cl:3])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC(=O)Cl
Reaction time: 8 h

Procedure:
C 18 resin: Pentadecanoyl chloride was synthesized by reacting 10 ml of 2 M thionyl chloride in 10 ml of toluene with 1.5 gm pentadecanoic acid. After 40 minutes of refluxing, the remaining thionyl chloride and toluene were removed by distillation. 4 gm of the 3-amino-propyl resin was then incubated overnight with the freshly prepared pentadecanoyl chloride in pyridine. The next day, the resin was twice washed with methylene chloride and then three times more with methanol and dried.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[N+]([O-])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO.ClCCl>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(O)cc1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The same procedure as that used for saponification of (S)-4-(1-methylheptyloxy)-3-nitro-phenol was used except the reaction was carried out in a methanol/dichloromethane [4:1]mixture at 60° C. Flash chromatography with hexanes/ethyl acetate [93/7] afforded (S)-4'-(1-methylheptyloxy)-4-hydroxybiphenyl (Compound 40, Scheme VIII, R2 =(S)--OCH(CH3)C6H13) as a white solid (mp 100.5° C.); Rf [hexanes/ethyl acetate 90/10]: 0.2; 1H NMR (300 MHz, CDCl3): δ0.88(t, 3H, J=6.6 Hz), 1.20-1.64(m, 9H), 1.33(d, 3H, J=6.1 Hz), 1.74(m, 1H), 4.38(m, 1H), 5.07(s, 1H), 6.87(d,2H, J=8.5 Hz), 6.93(d, 2H, J=8.5 Hz), 7.42(d, 2H, J =8.5 Hz), 7.44(d, 2H, J=8.5 Hz); 13C NMR (300 MHz, CDCl3): δ14.02, 19.73, 22.54, 25.51, 29.22, 31.74, 36.45, 74.17, 115.59, 116.16, 127.74, 127.94, 133.22, 133.77, 154.55, 157.31; IR (CHCl3): 3560, 3350(broad), 3020, 2920, 2840, 1610, 1500, 1250, 1220, 1175, 825 cm-1. Mass spectrum, m/z(rel.intensity): 298(M+ 11), 186(100), 185(4), 157(4).
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:8][CH2:7][CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[Cl:35])=[CH:19][CH:18]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1)=[O:36]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3ccnc4ccccc34)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)C(=O)N(Cc3ccnc4ccccc34)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.05 M) of tert-butyl (3-[cyclopropyl(quinolin-4-ylmethyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 95:5 (v/v) CH2Cl2: 2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+): 578.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:16]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:2].Cl>CCOCC>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH2:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(N)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of crude 2-(benzhydrylidene-amino)-3-(3-nitro-phenyl)-propionic acid ethyl ester (4.1 g, ≈10.2 mmol) in ether (100 mL) was added 1M aqueous hydrochloric acid and the mixture stirred vigorously at ambient temperature for 4 hours. The layers were separated and the organic layer extracted with 1M aqueous hydrochloric acid (3×50 mL). The combined aqueous layers were cautiously adjusted to pH=8 with solid potassium carbonate and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo to give crude 2-amino-3-(3-nitro-phenyl)-propionic acid ethyl ester. The crude amine was dissolved in acetonitrile (100 mL), di-tert-butyldicarbonate (2.4 g, mmol) added and the mixture stirred at ambient temperature for 16 hours. The reaction mixture was poured into water (500 mL), extracted with ether (3×100 mL), the combined organic extracts were washed with 0.1M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give crude 2-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propionic acid ethyl ester as an orange/yellow viscous oil (3.35 g, ≈97%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].O.[CH2:18](OCC)C>CN(C)P(N(C)C)(N(C)C)=O.C[Sn](C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(COC(C)=O)c(Br)c1
Reactant: CCOCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)c1ccc(COC(C)=O)c(C)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
5.30 g of methyl 4-[(acetyloxy)methyl]-3-bromobenzoate was dissolved in 50 mL of hexamethylphosphoramide, to which 6.6 mL of tetramethyltin and 0.26 g of bis(triphenylphosphine)-palladium(II) dichloride were added at room temperature in a stream of nitrogen, and this solution was stirred for 3 hours at 70° C. The reaction mixture was cooled to room temperature, and was added to a mixture of water and diethyl ether, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 4.17 g of methyl 4-[(acetyloxy)methyl]-3-methylbenzoate as brown oil.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CCOC(=O)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ester 16 (1.05 g, 3.281 mmol) in ethanol (4 ml) was treated at room temperature with 5% NaOH aqueous solution (2.6 ml). The resulting mixture was stirred at room temperature for 3 h. The ethanol was removed in vacuo and aqueous 5% HCl solution (2.6 ml) was added. The aqueous mixture was extracted with chloroform and the organic extracts dried (Na2SO4), filtered and the solvent removed under reduced pressure. The remaining white solid was recrystallized from hexane/ethyl acetate as a white powder (806 mg, 84%). δH (400 MHz, MeOD) 4.66 (2H, s, CH2), 7.41-7.51 (3H, m, ArH), 7.69 (2H, d, J=7.2 Hz, ArH), 7.87 (2H, d, J=8.4 Hz, ArH), 8.01 (2H, d, J=8.4 Hz, ArH); δc (100.6 MHz, MeOD) 64.9, 127.2, 127.7, 128.6, 128.7, 129.0, 134.5, 139.1, 147.2, 168.2.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].O[C:8]1[CH:17]=[CH:16]C=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12]C2=O>CCOCC>[CH2:14]=[C:9]1[CH2:10][CH2:11][CH2:12][C:3]2[C:2]([OH:5])=[CH:1][CH:16]=[CH:17][C:8]1=2
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CCCc2c(O)cccc21
Reaction time: 0.25 h

Procedure:
To a suspension of CH3PPh3I (897 mg, 2.22 mmol) in Et2O (10 mL) was added t-BuOK (249 mg, 2.22 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (300 mg, 1.85 mmol). The mixture was stirred at room temperature overnight, diluted with diethylether, and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The crude residue was purified by short column chromatography and was concentrated under reduced pressure to give 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol. A mixture of 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 5-methyl-5,6,7,8-tetrahydro-naphthalen-1-ol (110 mg, 36%).
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([F:35])[CH:29]=1>C(O)(C)C.CCOCC>[ClH:5].[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[C:13]([O:16][CH3:17])[CH:14]=3)[N:9]=[CH:8][N:7]=2)=[C:30]([F:35])[CH:29]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 50 °C
Yield: 89.9 %

Procedure:
3.5M Hydrogen chloride in ethanol (75 μl, 0.26 mmol) was added to a suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (80 mg, 0.25 mmol), (prepared as described for the starting material in Example 2c), in isopropanol (3 ml), the mixture was heated to 50° C. and 4-chloro-2-fluoroaniline (44 mg, 0.3 mmol) was added. The mixture was heated at reflux for 30 minutes. After cooling, the mixture was diluted with ether (3 ml). The precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (105 mg, 82%).
Reaction SMILES: Cl[C:2](=[O:20])[CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.S1C=CC=C1.O(C(C)C)C(C)C.[H][H]>[Pd].CN(C)C(=O)C>[O:20]=[CH:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH2:9]1
Reactant: O=C(Cl)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CC(=O)N(C)C
Solvent: CC(C)OC(C)C
Product: O=CCC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.7 %

Procedure:
A mixture of 90 parts of (phenylmethyl) 4-(2- chloro-2-oxoethyl)-1-piperidinecarboxylate, 90 parts of N,N-dimethylacetamide 6 parts of a thiophene solution and 438 parts of 2,2'-oxybispropane was hydrogenated at normal pressure and at room temperature in the presence of 5 parts of palladium-on-charcoal 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was taken up in water. The separated organic layer was dried, filtered and evaporated, yielding 75 parts (95.7%) of (phenylmethyl) 4-(2-oxoethyl)-1-piperidinecarboxylate as a residue (interm. 7).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[NH2+:4][S:5][S:6][C:7]=1[Cl:8].[Cl:9][C:10]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:11]=1[NH2:12]>>[Cl-:2].[Cl:2][C:3]1[NH2+:4][S:5][S:6][C:7]=1[Cl:8].[Cl:2][C:3]1[C:7](=[N:12][C:11]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=2[Cl:9])[S:6][S:5][N:4]=1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: ClC1=C(Cl)SS[NH2+]1
Agent: [Cl-]
Product: Clc1ccc(N=c2ssnc2Cl)c(Cl)c1
Yield: 216.3 %

Procedure:
4,5-Dichloro-1,2,3-dithiazolium chloride was synthesized by the method described in the literature (Appel, R. et al., Chem. Ber., Vol. 118, 1632 (1985)). By reacting 13.40 g of the obtained 4,5-dichloro-1,2,3-dithiazolium chloride with 10.43 g of 2,4-dichloroaniline with the method described in the above literature, 13.66 g of 4-chloro-5-[(2,4-dichlorophenyl)imino]-5H-1,2,3-dithiazol was obtained (yield 71%).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[O:17])=[CH:14][N:13]=2)=[C:8]([CH3:26])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[O:17])=[CH:14][N:13]=2)=[C:8]([CH3:26])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC2CCOC2)cn1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1noc(C)c1CCc1ccc(C(=O)NC2CCOC2)cn1
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A stirred mixture of 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-N-(tetrahydro-furan-3-yl)-nicotinamide (31 mg, 0.087 mmol) and 10% Palladium on charcoal (5 mg) in ethanol (5 mL) was shaken under an atmosphere of hydrogen for 3 h. The reaction mixture was filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 100:0 to 9:1) afforded the title compound (17 mg, 55%) as a colorless oil. MS: m/e=328.4 [M+H]+.