Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[CH:14][C:15]3[C:23]4[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=4[Cl:24])[NH:17][C:16]=3[C:26]([OH:28])=[O:27])[CH2:10][N:9]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:4][CH:3]=1.C[Si]([N:40]=[C:41]=[O:42])(C)C>O1CCCC1>[C:32]([O:31][C:29]([N:9]1[CH2:10][C:11](=[CH:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[NH:17][C:16]=2[C:26]([OH:28])=[O:27])[C:12](=[O:13])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH2:40])=[O:42])=[CH:3][CH:4]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2c(C(=O)O)[nH]c3cc(Cl)cc(Cl)c23)C(=O)N1c1ccc(N)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2c(C(=O)O)[nH]c3cc(Cl)cc(Cl)c23)C(=O)N1c1ccc(NC(N)=O)cc1

Procedure:
To a solution of example 16 (0.070 g) in tetrahydrofuran (4 ml) under nitrogen at room temperature was added trimethylsilylisocyanate (0.080 ml). The solution was refluxed for 4 hrs, after which time the product was seen to precipitate from the solution. The solid was filtered off and washed with tetrahydrofuran (10 ml) affording the title compound as an orange solid. (0.042 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: O=Cc1c(O)ccc2c1CCCO2
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(NCc2c(O)ccc3c2CCCO3)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5- carboxaldehyde (308 mg, 1.73 mmol) and p-aminoacetophenone (236 mg, 1.73 mmol) in methanol (8 mL) was heated at reflux for one hour. The mixture was cooled to 15° at which time the intermediate Schiff's base crystallized. After filtration and drying a light orange product (221 mg, 43.3%) was obtained. This material was suspended in methanol (8 mL) and sodium borohydride (28 mg, 0.74 mmol) was added. After stirring at room temperature for ten minutes the mixture was poured into water (75 mL) and the resulting suspension neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(4-acetylphenyl) aminomethyl-3,4-dihydrobenzopyran (170 mg, 76.6%), m.p. 213°-215° C.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[NH:45][C:46](OC1C=CC([N+]([O-])=O)=CC=1)=[O:47])[C:38]([O:40][CH3:41])=[O:39]>C1COCC1>[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[NH:45][C:46]([N:17]1[CH2:18][CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]([CH2:14][NH:13][C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[CH2:16]1)=[O:47])[C:38]([O:40][CH3:41])=[O:39]
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 217 mg of the crude product of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.175 mL of triethylamine in 4.0 mL of THF was added 243 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 214 mg of methyl 3-chloro-4-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=2[CH:9]=[N:8]1.OS(O)(=O)=O.[Cl:27]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[Cl:27][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([CH2:6][C:5]3[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)[N:8]=[CH:9][C:10]=2[C:11]=1[NH2:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)ccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine (0.056 g, 0.192 mmol) in THF (1.0 mL) was cooled to −78° C. under N2. H2SO4 (0.00512 mL, 0.0961 mmol) was added and the mixture was stirred for 5 minutes. N-chlorosuccinimide (0.0257 g, 0.192 mmol) was added in one portion and the reaction was stirred at −78° C. for 1 hour. Sodium carbonate (0.0204 g, 0.192 mmol) was added and the mixture was warmed to ambient temperature. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were then washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (40% EtOAc/hexane) in which two major bands were observed. The higher band was determined to be the title compound (0.028 g, 44%) and was isolated as a dark yellow/green solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:24].CO>C(Cl)Cl>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][Br:24])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CO
Product: BrCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a suspension of 2-phenyl-4-(4-hydroxymethylphenoxy)ethyloxazole (30 g, 102 mmol) in 300 mL of methylene chloride at 5° C under a nitrogen atmosphere was added phosphorous tribromide (10.02 mL, 107 mmol) dropwise keeping the temperature of the reaction below 20° C. The resulting solution was allowed to stir for about 2 hours at room temperature. The reaction was cooled to about 10° C and 20 mL of methanol was added. After about 5 minutes, the solvent was removed and the solid remaining was partitioned between 1.35 L of ethyl acetate and 1.05 L of cold 5% aqueous sodium bicarbonate. The organics were washed with another 1.05 L of 5% aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and removed to give 33.3 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([Mg]Br)[CH3:11]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:10][CH3:11]
Reactant: O=Cc1ccccc1Br
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1Br
Temperature: 25 °C
Yield: 102.3 %

Procedure:
A solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) in THF (30 mL) at −70° C. was treated with 3 M solution of ethylmagnesium bromide (3.5 mL, 10.5 mmol). The mixture was warmed to room temperature for 6 hours and quenched with saturated solution of NH4Cl. The mixture was extracted with ethyl ether to provide the crude alcohol (yield: 2.2 g; ˜100%).
Reaction SMILES: C([O:4][N:5]1[C:10]([NH2:11])=[CH:9][C:8](Cl)=[N:7][C:6]1=[NH:13])(=O)C.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[NH2:11][C:10]1[N:5]([OH:4])[C:6](=[NH:13])[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]=1
Reactant: CC(=O)On1c(N)cc(Cl)nc1=N
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Reaction time: 0.5 h

Procedure:
1.01 g (5 mmoles) of 1-acetoxy-6-amino-4-chloro-1,2-dihydro-2-iminopyrimidine are added under stirring to a mixture containing 10 ml of ethanol and 3 ml of piperidine. The mixture is refluxed while stirring for 30 minutes, then 5 ml of 1N aqueous sodium hydroxide solution are added and the boiling is continued for additional 30 minutes. Thereafter, the mixture is evaporated under reduced pressure and the residue is mixed with 10 ml of water. The crystalline precipitate is filtered, washed with water and dried to give the aimed compound in a yield of 0.85 g (82%), m.p.: 262°-266° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][O:22][C:23](=[O:31])[CH2:24][CH:25]1[CH2:29][CH2:28][C:27](=O)[CH2:26]1.[B][B][B][B][B][B][B][B][B][B]>>[CH3:21][O:22][C:23](=[O:31])[CH2:24][CH:25]1[CH2:29][CH2:28][CH:27]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@:4]3([CH3:12])[C:5]([CH3:10])([CH3:11])[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH2:1])=[N:3]3)[CH:18]=2)[CH2:26]1
Reactant: COC(=O)CC1CCC(=O)C1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: COC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and (3-oxo-cyclopentyl)-acetic acid methyl ester using decaborane yielded a mixture of isomers of the title compound as a white foam. MS (ESI): m/z=419.3 [M+H]+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([C:33]#[N:34])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(#N)C>[C:33]([C:25]1[CH:24]=[C:23]([C@@H:16]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:30])=[O:31])#[N:34]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (102 mg, 0.19 mmol), ethanol (2 mL), and concentrated hydrochloric acid (3 drops). It was stirred at 25° C. for 1 h. The reaction was then diluted with some acetonitrile and concentrated with silica gel (2 g) in vacuo and purified on a Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate to 10% methanol/ethyl acetate) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide (63 mg, 77%) as a light yellow solid: [α]30589=−40.0° (c=0.10, methanol); ES-HRMS m/e calcd for C21H26N4O4S (M+H)+ 431.1748, observed 431.1749; 1H NMR (400 MHz, DMSO-d6) δ 1.12 (m, 2H, CH2), 1.38-1.78 (m, 8H, 4×CH2), 2.12 (m, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.67 (m, 2H, OCH2), 3.86 (m, 3H, ArCHCO and NCH2), 4.83 (t, J=5.3 Hz, 1 H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.95 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.11 (d, Jm=1.6 Hz, 1H, Ar), 8.11 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C(C)C>[CH2:4]([O:5][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH:3]([CH3:7])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CC(C)CO
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to example 2.2(b) from from 2-chloro-5-methanesulfonyl-benzoic acid and isobutanol.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@:16]([NH:38][C:39]([NH2:41])=[S:40])([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:14][CH:15]=1>CCO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@:16]([NH:38][C:39]2[S:40][C:1]3[CH2:5][CH2:4][CH2:3][C:2]=3[N:41]=2)([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:35])([F:36])[CH:32]([F:33])[F:34])[CH:27]=[C:26]([F:37])[CH:25]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:14][CH:15]=1
Reactant: NC(=S)N[C@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: O=C1CCCC1
Agent: BrBr
Solvent: CCO
Product: Fc1cc(OC(F)(F)C(F)F)cc([C@@](Cc2ccccc2)(Nc2nc3c(s2)CCC3)c2ccc(Cl)cn2)c1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 26.5 %

Procedure:
To a solution of cyclopentanone (68 mg, 0.8 mmol) in EtOH (1 ml) was added Br2 (15 mg, 0.09 mmol) at r.t., sealed and stirred for 5 mins. The yellow solution became clear colorless. (R)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)thiourea (20 mg, 0.04 mmol) was added to the reaction mixture and the mixture was heated at 75° C. for 16 hrs, then heated at 160° C. under microwave for 30 mins. The reaction mixture was purified by prep HPLC, desired fraction condensed under vacuum to give (R)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine (6 mg, 27% yield). LCMS: 3.67 min [M+1] 566.40 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CD3OD) δ ppm 2.32-2.42 (m, 2H), 2.55-2.66 (m, 2H), 2.69-2.80 (m, 2H), 3.88 (d, J=13.14 Hz, 1H), 4.28 (d, J=13.39 Hz, 1H), 6.27 (t, J=50.0 Hz, 1H), 6.61 (d, J=6.82 Hz, 2H), 6.97-7.09 (m, 4H), 7.24 (s, 1H) 7.34 (ddd, J=9.98, 2.02, 1.89 Hz, 1H), 7.41 (d, J=8.59 Hz, 1H) 7.79 (dd, J=8.59, 2.53 Hz, 1H), 8.38 (d, J=2.02 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:26][CH2:27][CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)([Cl:38])=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:20]3[C:21]([O:26][CH2:27][CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-1H-imidazole (475 mg, 1.152 mmol) and triethylamine (321 uL, 2.304 mmol) in methylene chloride (6 mL) cooled to 0° C. was added phosgene (895 uL, 1.728 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0° C. for 30 min then concentrated to dryness. The residue was taken in ethyl acetate, and the solids were filtered off. The filtrate was concentrated to give crude 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride as yellow solids (450 mg).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2NN=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)cc1
Yield: 92 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (1.17 g), 5-(4-t-butylphenyl)-1H-tetrazole (1.00 g) and pyridine (10 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with cold hexane to give methyl 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1.51, yield 92%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 210–211° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][CH2:35][CH2:34][NH:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNc1ccc(Cl)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: O=C(O)/C=C\C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc(Cl)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(p-chlorophenyl)ethylenediamine maleate and DBU in DME. ES-MS m/e (%): 357 (M{37Cl}+H+, 40), 355 (M{35Cl}+H+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH2:24][CH2:23]1
Reactant: ClCCCOc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(CCCOc2ccc(-c3cc4ccccc4[nH]3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of (2-(4-(3-chloropropoxy)phenyl)indole (1 mmol, 285 mg) and 4-methylpiperazine (2 mL) was heated at 80° C. for 5 h. After concentration, the residue was purified by column chromatography (MeOH/CH2Cl2) afforded the title compound (285 mg): 1H NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.53 (m, 3H), 7.32 (bd, 1H, J=8.1 Hz), 7.1 (td, 1H, J=1.1, 7.0 Hz), 7.05 (td, 1H, J=1.1, 7.0 Hz), 6.90 (m, 2H), 6.64 (m, 1H), 3.99 (t, 2H, J=6.3 Hz), 2.48 (m, 10H, J=6.4 Hz), 2.25 (s, 3H), 1.93 (quintet, 2H, J=6.3 Hz); EIMS m/z 350 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=C.[O:10]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:10]
Reactant: O=[O+][O-]
Reactant: C=CCCCCCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCCCCCCCBr
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A solution of 8-bromo-1-octene (5.0 g, 26 mmol) in a mixture of 25 mL of MeOH and 5 mL of CH2Cl2 was cooled to -50° C. and treated with O3 until a blue color persisted (45 min) and then for an additional 10 min. The mixture, at -40° C., was purged with N2 for 10 min, allowed to warm to -20° C., under N2, and kept at -20° C. while 1.3 g (34 mmol) of sodium borohydride was added in portions over 30 min (evolution of H2 was evident at each addition). The mixture was stirred 30 min more at -20° C. and quenched with the dropwise addition of 20 mL of H2O. This mixture was stirred for 10 min, and extracted with hexane; the organic extracts were washed with water, then brine, dried (Na2SO4) and concentrated to give 3.65 g (72%) of 7-bromo-1-heptanol: NMR (CDCl3) δ1.44 (m, 9H), 1.85 (m, 2H), 3.41 (t, 2H), 3.65 (t, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH:4]=1.Cl.[CH3:21]O>>[CH3:21][O:1][CH2:2][C:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH:4]=1
Reactant: CO
Reactant: Cc1c(C)c2c(c(C)c1O)C=C(CO)C1(CCC1)O2
Agent: Cl
Product: COCC1=Cc2c(C)c(O)c(C)c(C)c2OC12CCC2

Procedure:
3-(Methoxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol was prepared by treating 3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol with methanol in the presence of conc. hydrochloric acid:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:18]2[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=2)[N:12]=1.O>CN(C)C=O>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:19]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=3)[N:12]=[C:11]([CH2:10][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Oily sodium hydride (60%, 0.27 g) was added to a solution of morpholine (0.537 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (2.5 g) was added. The resulting mixture was stirred at 100° C. for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The crystals were collected by filtration and then recrystallized from ethanol to give ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate (1.9 g, 68%). Colorless prisms. mp. 146°-147° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][OH:15])[CH:6]=[CH:5]2.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(Cl)Cl>>[C:19]([O:15][CH2:14][CH2:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:16]([O-:18])=[O:17])[C:8]1=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 6-chloro-2-(2-hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (400.0 mg, 0.00149 mol), acetic anhydride (0.21 mL, 0.0022 mol), pyridine (0.18 mL, 0.0022 mol) and methylene chloride (20 mL, 0.2 mol) and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure to afford the product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:16]([Al](CC(C)C)CC(C)C)C(C)C.C(I)I.[OH-].[Na+]>C(Cl)Cl>[CH:13]1([CH2:12][C:11]2[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][C:10]=2[OH:15])[C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:14]1
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ICI
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(CC2CC2)c1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The compound of Example 5 (1.0 g, 4.8 mMol) was dissolved in methylene chloride (20cm3) and transferred to a 100 ml three-neck round bottom flask under an argon atmosphere at 0° C. Triisobutylaluminum (2.95 g, 3.76 ml, 14.9 mmol) was added dropwise via a dropping funnel. The reaction mixture was stirred for about 20 minutes while maintaining the temperature at 0° C., then methylene iodide (1.67 g, 0.5 ml, 6.2 mmol) was added via syringe, and the reaction mixture was stirred at room temperature for about four hours then slowly poured into an ice cold solution of 10% sodium hydroxide. The aqueous layer was extracted twice with about 25 ml of methylene chloride, and all of the organic fractions were combined, dried over magnesium sulfate and concentrated in vacuo to give the product.