Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([CH3:8])[N:6](C)[CH2:5][CH2:4][N:3]1[C:10](OCC1C=CC=CC=1)=O>CO>[CH3:10][N:3]1[CH2:4][CH2:5][NH:6][C@@H:7]([CH3:8])[C@@H:2]1[CH3:1]
Reactant: C[C@H]1[C@H](C)N(C(=O)OCc2ccccc2)CCN1C
Solvent: CO
Product: C[C@@H]1NCCN(C)[C@H]1C
Yield: 156 %

Procedure:
Phenylmethyl (2S,3S)-2,3,4-trimethyl-1-piperazinecarboxylate (323 mg, 1.23 mmol) (Example 198) was dissolved in 20 mL of MeOH, degassed and placed under argon. 10% Pd/C (81 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 3 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. After 2.70 mL 1N HCl was added, the resulting filtrate was concentrated in vacuo to provide the hydrochloride salt of (2S,3S)-1,2,3-trimethylpiperazine (246 mg, 100%). LCMS: (M+H)+: 129.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:45])([F:44])[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[O:18][CH:19]=[C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]4[CH:38]=[C:37]([C:39](OCC)=[O:40])[N:36]=[N:35]4)=[CH:26][CH:25]=3)[N:21]=2)=[CH:11][CH:10]=1.C(OCC)C.O>C1COCC1>[F:45][C:8]([F:7])([F:44])[C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]2[O:18][CH:19]=[C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]4[CH:38]=[C:37]([CH2:39][OH:40])[N:36]=[N:35]4)=[CH:26][CH:25]=3)[N:21]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(CCCCc2ccc(OCc3coc(/C=C/c4ccc(C(F)(F)F)cc4)n3)cc2)nn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCc1cn(CCCCc2ccc(OCc3coc(/C=C/c4ccc(C(F)(F)F)cc4)n3)cc2)nn1
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Lithium aluminium hydride (35 mg) was added to a solution of ethyl 1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole-4-carboxylate (500 mg) in THF (10 ml) at 0° C., and the mixture was stirred for 30 min. After the reaction was completed, the reaction mixture was combined with diethyl ether and water and filtered with Celite. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give the titled compound (435 mg) as a colorless crystal powder.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)C.[CH:12]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[O:20][CH2:21][O:22][C:14]=2[CH:13]=1.O>O1CCCC1.CS(C)=O>[CH2:21]1[O:22][C:14]2[CH:13]=[CH:12][C:17]([CH:18]3[CH2:1][O:19]3)=[CH:16][C:15]=2[O:20]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: c1cc2c(cc1C1CO1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To an ice-cooled suspension of potassium tert-butoxide (0.82 g) in tetrahydrofuran (6.6 ml) was added trimethylsulfonium iodide (98% purity; 1.5 g) in dimethyl sulfoxide (6.6 ml). After the addition was complete, piperonal (1.0 g) in tetrahydrofuran (3.3 ml) was added dropwise to the mixture while the internal temperature was maintained below 5° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted once with ethyl acetate. The extract was washed twice with water and once with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 3,4-methylenedioxyphenyloxirane (1.0 g), which was used for next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7].[Br-].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccn2)c(OC)c1
Temperature: 25 °C

Procedure:
To 300 mL of degassed THF was added methyl 3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (20.95 g, 66.7 mmol), 2-pyridylzinc bromide (200 mL of 0.5M solution in THF, 100 mmol), and tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.3 mmol). The mixture was degassed with argon for an additional 30 minutes and heated at reflux under an argon atmosphere overnight. The reaction mixture was cooled to rt and concentrated in vacuo. The resultant brown residue was partitioned between EtOAc (1500 mL) and 50% saturated NaHCO3 (1000 mL). The aqueous layer was extracted with EtOAc (500 mL), and the combined organic layers washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (0–25% EtOAc/hexanes) to give methyl 3-methoxy-4-pyridin-2-ylbenzoate as a colorless solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (d, 1H), 7.92–7.83 (m, 3H), 7.70–7.65 (m, 2H), 7.40–7.36 (m, 1H), 3.91 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:17]([F:20])([F:18])[F:19])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1Sc1ccccc1
Reaction time: 17 h

Procedure:
26.9 g of 3-nitro-4-(phenylthio)-benzotrifluoride in 250 ml of ethanol are hydrogenated in the presence of 10 g of Raney-nickel at room temperature and atmospheric pressure for 17 hours. The mixture is filtered and evaporated under reduced pressure. There is obtained 3-amino-4-(phenylthio)-benzotrifluoride as a red-brown oil. The compound is distilled under greatly reduced pressure and boils at 110°-135° C/0.1 mm; orange-coloured oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)(=[O:3])[CH3:2].C(N(CC)CC)C.O.C(OCC)(=O)C>C(#N)C>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH:16]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
N′-Acetyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carbohydrazide (86.5 mg, 0.172 mmol) synthesized in Example (22a) was dissolved in acetonitrile (5 mL), (methoxycarbonysulfamoyl)triethylammonium hydroxide (60.7 mg, 0.258 mmol) and triethylamine (36 μL, 0.26 mmol) were added, and stirring was carried out at 80° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-75%) to afford the desired compound (49.1 mg, yield 59%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])(=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCc2sccc21
Reactant: O=C(Oc1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 73 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 36.25 mmol). After the addition of Benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-Benzoyl-5,6-dihydro-cyclopenta[b]thiophen-4-one (4.3 g, 17.7 mmol) as white solid in 73% yield.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>CC(C)=O>[C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:16]2[N:17]=[C:18]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14]=3[N:15]=2)[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: c1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1
Solvent: CC(C)=O
Product: CC(=O)N1CCN(c2nc(N3CCOCC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
A suspension of 2.1 gm (0.005 mol) of 8-benzylthio-4-morpholino-2-piperazino-pyrimido-[5,4-d]-pyrimidine (m.p.: 191°-193° C.) in 150 ml of acetone was refluxed for 30 minutes after addition of 0.8 gm (0.01 mol) of acetyl chloride. The solvent was then evaporated in vacuo, and the residue was taken up in approximately 200 ml of water. The reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][CH:30]=2)=[C:25]([CH3:38])[CH:24]=1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:36])=[CH:31][CH:30]=2)=[C:25]([CH3:38])[CH:24]=1)=[O:22]
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Product: COC(=O)c1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-methoxycarbonyl-2'-methyl biphenyl-4-carboxylic acid (D41) using a procedure similar to that of Example 1 (76%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH2:55]([S:57](Cl)(=[O:59])=[O:58])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and ethanesulfonyl chloride as the starting materials in 60% yield. LCMS for C25H29ClN7O4S (M+H)+: m/z=558.0.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([F:4])[F:3].C1([Si:18]2([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:22][CH:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)C=CC=CC=1>>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][Si@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:2]([F:3])([F:4])[F:1])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccccc3C(F)(F)F)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using trifluoromethylphenol and 4-(4-phenyl-4-(3methylbutyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12]O)[O:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:15][CH2:12][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[O:9]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC1CCc2ccc(O)cc2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc2c(c1)OC(CBr)CC2
Temperature: 0 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
A mixture of (7-hydroxychroman-2-yl)methanol (6.18 g, 34.3 mmol) and CBr4 (19.3 g, 58.3 mmol) in CH2Cl2 is treated with a solution of triphenylphosphine (9.0 g, 34.3 mmol) in CH2Cl2 at 0° C., stirred at 0° C. for 6 hr and concentrated in vacuo to give a residue. The residue is purified by column chromatography (silica gel, 60% CH2Cl2 in hexanes as eluent) to give the title product as an oil, 4.61 g (55% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][C:14]=1[O:26][CH3:27]>O1CCCC1>[Cl:19][C:17]1[C:16]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][C:14]([O:26][CH3:27])=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:18]=1
Reactant: COC(=O)CCCc1cc(Cl)c(C2CCCCC2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C2CCCCC2)c(Cl)cc1CCCCO
Reaction time: 24 h

Procedure:
4 g of LiAlH4 are added in portions at 0° with stirring, and in an inert gas atmosphere, to 8.6 g of 4-(5-chloro-4-cyclohexyl-2-methoxyphenyl)-butyric acid methylester in 300 ml of anhydrous tetrahydrofuran. After 24 hours at 20°, the mixture is poured onto icecold NH4CL solution. The mixture is then acidified to pH=3 and extracted three times with ethyl acetate. The organic phases are washed once with water, dried over Na2SO4 and concentrated. The residue is distilled at 170°/0.5 mm.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:15][C:16]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:12](=[O:13])[CH2:11][C:1]12[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(O)cc1Cl
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc(O)cc1Cl

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.9 g) and 2-chloro-4-hydroxyaniline to give the title compound as a white solid. (0.15 g).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:3]1=[O:19].Br.O=C1C2C(=C(CC(O)=O)C=CC=2)CC1.BrBr>C(O)(=O)C.O>[Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:11][C:12]([OH:14])=[O:13])[C:3]1=[O:19]
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1CC(Br)C2=O
Agent: Br
Agent: BrBr
Agent: O=C(O)Cc1cccc2c1CCC2=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2c1CC(Br)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The (2-bromo-1-oxoindan-4-yl)acetic acid can be obtained in the following manner: 4 ml of hydrobromic acid at 47% are added to a solution of 38 g of (1-oxoindan-4-yl)acetic acid in 800 ml of acetic acid. 11 ml of bromine are added dropwise and over 10 minutes to this solution cooled to a temperature close to 15° C. and then the reaction medium is kept stirring for one hour at a temperature close to 15° C. The reaction medium is allowed to return to a temperature close to 20° C. and the reaction is continued for 2 hours. The reaction medium is poured into a mixture of 800 g of ice and 800 ml of water and then filtered on sintered glass. The filtrate is taken up in three times 800 ml of dichloromethane and the combined organic phases are washed with twice 800 ml of distilled water, dried over magnesium sulphate, filtered on paper and concentrated under reduced pressure at 50° C. The solid residue thus obtained is triturated in 240 ml of diisopropyl ether, filtered on sintered glass and air dried. 45.4 g of (2-bromo-1-oxoindan-4-yl)acetic acid are thus obtained in the form of a cream-coloured solid melting at 120° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.C1(C)C(C)=CC=CC=1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([Si:2]([CH3:13])([CH3:1])[CH3:14])=[CH:8][CH:7]=2)[C:10](=[O:12])[CH3:11])=[CH:17][CH:18]=1)#[N:21]
Reactant: CC(=O)Nc1ccc([Si](C)(C)C)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: CC(=O)N(c1ccc(C#N)cc1)c1ccc([Si](C)(C)C)cc1

Procedure:
Under a flow of argon, in a 1 L-recovery flask, 27 g of N-(4-(trimethylsilyl)phenyl)acetamide, 30 g of 4-bromobenzonitrile, 6.3 g of copper (I) iodide, 45.6 g of potassium carbonate, and 412 mL of xylene were placed. After stirring, 7.1 mL of N,N′-dimethylethylenediamine was added. The resultant was heated and stirred at reflux for 18 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:12]=1.[CH2:27]=O>C(Cl)(Cl)Cl>[C:20]1([CH2:19][N:16]2[CH2:17][CH2:18][CH:13]([N:11]3[C:12]4[CH:27]=[N:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=5[C:8]=4[NH:9][C:10]3=[O:26])[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1-c1cn(C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Reactant: C=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.67 g (7.66 mmol) of 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one in 50 ml of chloroform was mixed with 3.0 g of paraformaldehyde and refluxed for 3.5 hours. The residue remaining after evaporation of the solvent was taken up in 100 ml of methanol and acidified with methanolic hydrogen chloride solution. After stirring for one hour at room temperature the mixture was poured into 300 ml of saturated sodium hydrogen carbonate solution. The resulting mixture was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was purified by column chromatography over silica gel using FM4 as eluant. From the appropriate fractions 0.5 g (18.2% of theory) of a colourless, amorphous substance were isolated, Rf=0.24 (FM4).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: c1ccoc1
Product: O=C(c1cn(-c2cccc(-c3ccccc3)c2)cn1)c1ccco1

Procedure:
This compound was prepared by method C using compound 12a and furan. HRMS (ESI+): m/z=315.1138 [M+H]
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:25][CH2:24][CH2:23]4)=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: C1CNC1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: Fc1ccc(-c2csc3cc(OCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and azetidine were converted to yield 1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-azetidine as colorless oil, MS: 342 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OCC1CCNCC1
Product: O=C(NCCCN1CCC(CO)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (150 mg, 0.37 mmol) and 4-piperidylmethanol (51.0 mg, 0.44 mmol). The title compound was afforded as a solid (30.0 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.83 (1H, m), 8.40 (1H, s), 3.38 (1H, m), 3.21 (4H, m), 2.83 (2H, m), 2.28 (2H, m), 1.60 (4H, m), 1.30 (1H, m), 1.00 (2H, m). MS m/z: 503.33, 505.32 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:25]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=3)=[O:26])[CH:7]=[CH:6][CH:5]=2)([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cccc(N)c2)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@]1(c2cccc(NC(=O)c3ccc(Cl)cn3)c2)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(3-amino-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-4) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=381.2 [M+H]+.