Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Si:20]([N:27]1[CH:30]([CH2:31][CH:32]=[O:33])[CH:29]([N:34]=[N+:35]=[N-:36])[C:28]1=[O:37])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O1CCCC1>[Si:20]([N:27]1[CH:30]([CH2:31][CH:32]([OH:33])[CH2:2][C:1]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH:29]([N:34]=[N+:35]=[N-:36])[C:28]1=[O:37])([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC=O
Reactant: CC(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC(O)CC(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A solution of benzyl acetate (0.011 mol) in anhydrous tetrahydrofuran (5 ml) is added dropwise to solution of lithium diisopropylamide (0.011 mol) in anhydrous tetrahydrofuran (20 ml) at -78° C. After stirring 15 more min at -78° C. the reaction mixture is treated dropwise with a solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-oxoethyl)-azetidin-2-one (0.01 mol) in tetrahydrofuran (10 ml). The mixture is stirred at -78° an additional 15 min and then quenched with 2.5 N hydrochloric acid (10 ml). The mixture is diluted with ethyl acetate, washed with water, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, and evaporated under vacuum to afford N-(t-butyldimethylsilyl)-3-azido-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one.
Reaction SMILES: COC1C=CC(N=CC2C=CC(C#N)=CC=2)=CC=1.[CH:19](=[N:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:60])[CH2:43][CH2:44][CH2:45][C:46](N2C(C3C=CC=CC=3)COC2=O)=[O:47])=[CH:38][CH:37]=1.C1(C(O)CCCC(N2C(C3C=CC=CC=3)COC2=O)=O)C=CC=CC=1>[Ni]>[NH2:32][CH2:31][C:30]1[CH:29]=[CH:28][C:27]([N:26]2[CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:45]([CH2:44][CH2:43][CH:42]([OH:60])[C:39]3[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=3)[C:46]2=[O:47])=[CH:34][CH:33]=1
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reactant: N#Cc1ccc(N=Cc2ccccc2)cc1
Agent: [Ni]
Agent: COc1ccc(N=Cc2ccc(C#N)cc2)cc1
Agent: O=C(CCCC(O)c1ccccc1)N1C(=O)OCC1c1ccccc1
Product: NCc1ccc(N2C(=O)C(CCC(O)c3ccccc3)C2c2ccccc2)cc1

Procedure:
Compound (16) was prepared as described in example IIIa-d, the differences being that: a) instead of 4-[(4-methoxyphenylimino)methyl]benzonitrile, 4-(benzylideneamino)benzonitrile was used, b) instead of 3-[5-(4-fluorophenyl)-5-hydroxy-pentanoyl-4-phenyloxazolidin-2-one, 3-[5-(phenyl)-5-hydroxypentanoyl]-4-phenyl-oxazolidin-2-one was used, and c) the product IIId was subjected to reduction with Raney nickel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][C:33]3[CH:34]=[N:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3ccc(C(F)(F)F)nc3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3ccc(C(F)(F)F)nc3)cnc21
Temperature: 70 °C
Yield: 37.6 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(6-(trifluoromethyl)pyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.097 mmol) in HCOOH (5 mL) was added Zn dust (37.7 mg, 0.58 mmol). The reaction was heated at 70° C. for 1.5 h, cooled to RT and filtered. The filtrate was concentrated to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(6-(trifluoromethyl)pyridin-3-yloxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (20 mg, 37.7% yield) as an oil. LCMS: MH+ 549 and TR=1.799 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:12][CH2:13][C:14]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]2[C:15]=1[N:16]=[C:17]([O:29][CH3:30])[C:18]([O:27][CH3:28])=[N:19]2>COC(C)(C)C>[CH3:28][O:27][C:18]1[C:17]([O:29][CH3:30])=[N:16][C:15]2[C:20](=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:14]=2[CH2:13][NH:12][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:11])[N:19]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Reactant: COc1ccc(N=C=O)cc1
Solvent: COC(C)(C)C
Product: COc1ccc(NC(=O)NCc2cc([N+](=O)[O-])cc3nc(OC)c(OC)nc23)cc1
Reaction time: 3 h

Procedure:
62 mg (0.416 mmol) of 4-methoxyphenyl isocyanate are added at room temperature to a suspension of 100 mg (0.379 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of tert-butyl methyl ether, and the mixture is stirred for 3 hours. The suspension is then filtered off, and the filter residue is washed with tert-butyl methyl ether and dried under a high vacuum. The title compound is obtained in the form of a beige solid.
Reaction SMILES: ClCCl.[NH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH2:39][CH3:40])[N:17]=[C:16]2[CH3:41])=[N:13][CH:14]=1.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49]>O>[CH2:37]([C:18]1[N:17]=[C:16]([CH3:41])[N:15]([C:12]2[N:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][NH:4][C:48](=[O:50])[CH3:49])=[CH:10][N:11]=2)[C:20](=[O:21])[C:19]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[CH:25][CH:24]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nc(C)n(-c2ncc(OCCCN)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OCCCNC(C)=O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Process 3: To the dichloromethane (1 mL) solution of the crude product of 4′-{{1-[5-(3-aminopropoxy)pyrimidin-2-yl]-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl}biphenyl-2-carbonitrile (45 mg), pyridine (9.7 mg, 0.123 mmol) and acetyl chloride (8.3 mg, 0.106 mmol) were added and stirred at room temperature overnight. The reaction mixture was added water, and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain N-{3-{2-{4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1 (6H)-yl}pyrimidin-5-yl oxy}propyl}acetamide (35 mg) as a crude product.
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:45]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[CH3:56])=[O:46]>>[NH2:53][C:51]1[CH:50]=[CH:49][C:48]([CH3:56])=[C:47]([C:45]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)=[CH:35][C:30]=2[Cl:29])=[O:46])[CH:52]=1
Reactant: COc1cccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)c1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: COc1cccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 466 (2.32 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][CH2:44][C:43](=[O:47])[CH2:42]2)=[CH:37][CH:36]=1.[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54]O>O1CCCC1>[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]2[CH2:46][CH2:45][CH2:44][C:43](=[O:47])[CH2:42]2)=[CH:39][CH:40]=1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C1CCCC(c2ccc(O)cc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCC(c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)C1
Reaction time: 0.5 h

Procedure:
0.39 ml of azodicarboxylic acid diisopropyl ester is added at 0° C. to 0.52 g of triphenylphosphine in 20 ml of tetrahydrofuran. After 30 minutes, 289 mg of 3-(4-hydroxyphenyl)cyclohexanone and 554 mg of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propan-1-ol in 10 ml of tetrahydrofuran are added dropwise thereto. After 24 hours at room temperature, the reaction mixture is concentrated and the residue is purified over silica gel. 3-(4-{3-[2,6-Dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-cyclohexanone is obtained in the form of a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:14]([OH:18])[CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH2:26].C(Cl)CCl>ClCCl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH:26][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:14]([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Reactant: NOC1CCCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Temperature: 23 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoic acid (1.53 g, 6.12 mmol) in dichloromethane (6 mL) is added 2-tetrahydropyranyloxyamine (0.93 g, 7.96 mmol) and EDC (1.29 g, 6.73 mmol). The resulting solution is stirred at 23° C. for 3 h, concentrated in vacuo, and diluted with 50 mL of EtOAc. The organic layer is washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, and is dried over anhydrous magnesium sulfate. Concentration under reduced pressure and purification by silica gel chromatography (elution with 2:1 EtOAc-hexanes) provides (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as a solid (1.62 g, 76% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[I-].[Mg].I[CH3:19].[Cl-].[NH4+]>C(OCC)C>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]([CH3:19])([OH:13])[CH2:7]1
Reactant: CI
Reactant: COC(C)(C)CCC1CC(=O)CC(C)C1
Agent: [Cl-]
Agent: [I-]
Agent: [Mg]
Solvent: CCOCC
Product: COC(C)(C)CCC1CC(C)CC(C)(O)C1
Reaction time: 16 h

Procedure:
3-(3-Methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one 5.0 gm 0.025 mol) dissolved in diethyl ether (5.0 mL) was added to a cooled (5~C.) solution of methylmagensium iodide formed by treating magnesium turnings (0.70 g, 0.028 mol) in diethyl ether (20 mL) with iodomethane (1.6 mL, 0.026 mol). After stirring 16 hours at 25~C., a saturated aqueous ammonium chloride solution (ca. 2 mL) was added and subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-1,5-dimethylcyclohexan-1-ol as a mixture of diastereoisomers in a ratio of 2.9:65.6:1.9:29.6, bp0.5 147-149~C. This compound was determined to possess a warm woody note. NMR(CDCl3)δ 0.5(m,1H), 0.9(d,3H), 1.0-1.1(m,1H), 1.2(s,6H), 1.3(s,3H), 1.3-1.9(m,10H), 1.9-2.0(brs,1H), 3.2(s,3H); IR(neat) 3400, 2925, 1460, 1370, 1220, 1080 cm- 1 ; MS(m/e) 43, 55, 73, 107, 122, 163, 181, 213, 214.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:17][O:18][CH3:19].C([Li])CCC.CN([CH:28]=[O:29])C.Cl>C1COCC1>[C:12]([C:4]1[C:3]([O:16][CH2:17][O:18][CH3:19])=[C:2]([CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1)[CH:28]=[O:29])([CH3:15])([CH3:14])[CH3:13]
Reactant: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.5 h

Procedure:
46.00 g (140.0 mmol) of the compound obtained in Example 13 (a) and 500 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 61.5 ml (154.00 mmol) of an n-butyllithium solution (2.5M in hexane) are added dropwise at −78° C. and the mixture is stirred for 30 minutes at this same temperature. 13.0 ml (168.0 mmol) of DMF are then added dropwise and the mixture is allowed to return to room temperature. The reaction mixture is acidified with hydrochloric acid (1N) and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 46.00 g (100%) of the expected compound are collected in the form of an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]12([C:23]3[CH:32]=[C:31]4[C:26]([CH:27]=[CH:28][C:29](B(O)O)=[CH:30]4)=[CH:25][C:24]=3[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][C:23]([C:13]45[CH2:14][CH:15]6[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]6)[CH2:22]4)[CH2:20]5)=[C:24]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:25]=3)[CH:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
300 mg (8.8 mmol) of tetrakis(triphenyl-phosphine)palladium(0), 50 ml of toluene and 2.46 g (8.8 mmol) of methyl 2-hydroxy-4-iodobenzoate were introduced into a three-necked flask under a stream of nitrogen and stirring was carried out at room temperature for 20 minutes. 5.52 g (13.4 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid and 8.8 ml of an aqueous potassium carbonate solution (2N) were then added and the reaction mixture was heated at reflux for 8 hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). 1.65 g (36%) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate were obtained.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClC(Cl)C>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1cccnc1
Temperature: 120 °C

Procedure:
A suspension of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, mg; mmol), nicotinoyl chloride hydrochloride (92 mg; 0.50 mmol) and diisopropylethylamine (0.50 mL; 2.77 mmol) in dichloroethane was heated in a sealed tube to 120° C. in a microwave oven for 10 minutes. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up into 2 M sodium carbonate solution and extracted with ethyl acetate. The extracts were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (eluent=50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes gradient) to provide 43 mg of N-(8H-Indeno[1,2-d]thiazol-2-yl)-nicotinamide 7. EI-HRMS m/e calcd for C16H11N4OS (M+) 293.0623, found 293.0620.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[NH:28]1[C:24]([C:20]2[CH:19]=[C:18]([NH:17][S:13]([C:9]3[CH:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=[CH:11][CH:10]=3)(=[O:15])=[O:14])[CH:23]=[CH:22][CH:21]=2)=[N:25][N:26]=[N:27]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccccc2)c1
Yield: 30.2 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 3-phenylbenzenesulfonylchloride (14 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 5.7 mg (30%) of the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 5.46-5.50 (m, 1 H) 7.24-7.43 (m, 5 H) 7.44-7.56 (m, 3 H) 7.70-7.79 (m, 4 H) 7.95-8.00 (m, 1 H). MS (ESI+) calcd for C19 H15N5O2S 377.0946, found 377.0946.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([O:18]C)=[O:17])[CH:8]=1.O1CCOCC1.[OH-].[Na+]>O>[CH3:1][NH:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[CH:8]=1
Reactant: CNC(=O)CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)CNC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
443.0 g. (1.5 moles) of N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine methylamide in 5.5 l. of dioxane is agitated for 2 hours at room temperature with the addition of 3.3 l. of 0.5N sodium hydroxide solution. Thereafter, 400 ml. of water is added to the reaction mixture, the dioxane is distilled off under vacuum, and the acid is precipitated with concentrated hydrochloric acid, vacuum-filtered, washed free of salt with water, and dried under vacuum at 70° C. Yield: 408 g. M.P. 256- 257°C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[SH:27]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1cc(Cl)c(Cl)cc1Cl
Product: O=C1CCc2cc(OCCCCSc3cc(Cl)c(Cl)cc3Cl)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 2,4,5-trichloro-thiophenol.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[K+].[Br-]>>[C:1]([C:5]1[N:6]=[C:7]2[C:12]([CH:13]=[O:14])=[CH:11][CH:10]=[CH:9][N:8]2[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn2cccc(CO)c2n1
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)c1cn2cccc(C=O)c2n1
Yield: 77 %

Procedure:
From 3g: reaction time 4 h (yield: 77%); mp 60-62° C.; IR (KBr) 1685, 1541, 1499 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 6.86 (t, 1H, J=7 Hz), 7.46 (s, 1H), 7.76 (d, 1H, J=7 Hz), 8.28 (d, 1H, J=7 Hz), 10.85 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 30.2, 32.7, 107.3, 111.1, 123.5, 124.5, 130.2, 144.2, 159.0, 189.6; MS m/z 202 (M+, 46), 187 (100), 174 (70), 78 (13).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]Cl)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].[OH-].[Na+]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CSc1ccc(CCCl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCN(CCc2ccc(SC)cc2)CC1
Yield: 91.4 %

Procedure:
Under nitrogen, 59.6 g of 4-methylmercaptophenylethyl chloride are heated with 75.7 g of 1-ethoxycarbonylpiperazine for 1.5 hours at 130°. A further 25.2 g of 1-ethoxycarbonylpiperazine are added thereto, and after 1.5 hours a further 25.2 g of 1-ethoxycarbonylpiperazine are added. After a total of 4.5 hours, the solution is poured onto ice-water, rendered strongly alkaline with concentrated NaOH and extracted with ether. Concentration by evaporation yields a mobile oil, which is purified by chromatography over silica gel (eluant: dichloromethane and dichloromethane/acetone 8:2). 90 g of the 1-[(4-methylmercaptophenyl)ethyl]-4-ethoxycarbonylpiperazine so obtained are boiled under reflux for 17 hours with 700 ml of concentrated HCl. The solution is diluted with ice-water, rendered alkaline with concentrated NaOH, extracted with ethyl acetate, concentrated by evaporation and recrystallised from ether/petroleum ether. The 1-[2-(4-methylmercaptophenyl)ethyl]piperazine melts at 52°-54°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Cl:15])=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc(C)cs1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C)c(Cl)s1
Reaction time: 0.5 h

Procedure:
4-Methyl-2-thiophenecarboxylic acid ethyl ester (3.4 g) synthesized in accordance with the method of Reference Example 140 was dissolved in acetonitrile (30 ml), and sulfuryl chloride (2.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room-temperature for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g). 5-Chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g) was dissolved in a mixture of ethanol (20 ml) and tetrahydrofuran (20 ml), and 1N aqueous sodium hydroxide (40 ml) was added. The mixture was stirred at 60° C for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid (2.37 g) as crystals.