Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=[NH:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[C:28](=[N:41][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=2)[CH:11]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Brc1cc2ccc(OCc3ccccc3)cc2cc1OCc1ccccc1
Agent: [Pd]
Agent: C[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc3cc(N=C(c4ccccc4)c4ccccc4)c(OCc4ccccc4)cc3c2)cc1
Temperature: 110 °C

Procedure:
3,6-Bis-benzyloxy-2-bromo-naphthalene (2.47 g, 5.89 mmol), benzophenone imine (1.19 mL, 7.07), Pd2(dba)3 (0.013 g, 0.015 mmol), BINAP (0.027 g, 0.044 mmol) and sodium methoxide (0.445 g, 8.25 mmol) are added to a dry flask over nitrogen. Toluene (10 mL) is added at ambient temperature and the reaction heated to 110° C. for 15 h. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is dried and evaporated to afford a brown oil, which is chromatographed over silica, eluting with a gradient of 100:1 to 20:1 hexanes/MTBE, to afford benzhydrylidene-(3,6-bis-benzyloxynaphthalen-2-yl)-amine.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[O:40]1CCO[CH:41]1[CH2:45][Mg]Br.C(OC)(OC)OC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.Cl>C1COCC1.O.CO>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:39])[CH2:45][CH:41]=[O:40])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: Br[Mg]CC1OCCO1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: COC(OC)OC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC(O)CC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
In a dry 200 mL round-bottomed flask was 10-(Cholest-5-en-3β-oxy)decanal (2.65 g, 4.90 mmol) dissolved in THF (10 ml), under argon to give a colorless solution. A 0.5 M THF solution of ((1,3-dioxolan-2-yl)methyl)magnesium bromide (9.80 ml, 4.90 mmol) was added dropwise, and the resulting solution was allowed to stir for 4 h at room temperature. The resultant solution was quenched by slowly adding 100 mL of NaHCO3 solution and extracting with EtOAc (3×100 mL). The combined organic phase was washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated in a 500 mL round bottomed flask. Trimethyl orthoformate (10.83 ml, 98 mmol), PPTS (0.246 g, 0.980 mmol) and methanol (10 ml) were added to the flask and the contents brought to reflux for 2 h. The solution was cooled to room temperature and evaporated to dryness. The residue was then taken up in Acetone (20 ml) and 1.0N HYDROCHLORIC ACID (4.90 ml, 4.90 mmol) and allowed to stir overnight. The reaction mixture was diluted to 200 mL with water and extracted with ethyl acetate (3×100 mL). The organic phase was combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and concentrated. The resultant wax was purified via column chromatography on a 40 g Biotage SNAP column eluting with a 0-50% gradient over 1 L. The pure fractions were combined and evaporated to dryness to give 12-(Cholest-5-en-3β-oxy)-3-hydroxydodecanal (1.97 g, 3.37 mmol, 68.7% yield) as a colorless wax. 1H NMR (300 MHz, CDCl3) δ0.69 (3H, s); 0.85-1.74 (49H, m); 1.75-2.13 (7H, m); 2.14-2.28 (1H, m); 2.33-2.44 (1H, m); 3.14 (1H, tt, J=11.2, 4.4 Hz); 3.46 (2H, t, J=6.8 Hz); 3.93-4.10 (1H, m); 5.36 (1H, d, J=5.2 Hz); 5.42-5.55 (1H, m); 9.78 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:25][OH:26])[CH2:27][CH3:28])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CC[C@H](N)CO
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (9.000 g, 26.45 mmol) and (S)-2-amino-1-butanol (12.7 ml) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 2 hr. then at 100° C. overnight. The mixture cooled to rt and poured into ice-water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 13.6 g of crude product as a light yellow oil. The oil was purified through silica gel column chromatography using chloroform to 2% MeOH in chloroform as eluent to give 6.6839 g (64%) of the title compound as a white glass foam. The glass foam was triturated with hexane to give a white solid. The solid was recrystallized from di-iso-propyl ether to give a white crystals, mp 122.5-124° C. Anal. calc. for C20H25ClN2O4: C, 61.14; H, 6.41; N, 7.13; found: C, 60.98; H, 6.43; N, 6.95.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[Br:36]Br.S([O-])(O)=O.[Na+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][C:3]=1[Br:36]
Reactant: Nc1ccc(NC(=O)c2ccccc2)c2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c(Br)cc(NC(=O)c2ccccc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 20 °C
Yield: 86.5 %

Procedure:
With stirring, 85.5 parts of 1-amino-4-benzoylaminoanthraquinone are suspended in 200 parts of nitrobenzene. The suspension is diluted with 100 parts of water and then a solution of 50.4 parts of bromine in 60 parts of nitrobenzene is added in the course of 1 hour at 30°-35° C. The reaction is brought to completion by stirring for 3 hours at 50°-55° C. The mixture is cooled to 30°-35° C. and, after addition of 65 parts of a 40% sodium hydrogen sulfite solution, stirred for 1/2 hour and cooled to 20° C. Finally, the reaction product is collected by suction, washed with 60 parts of nitrobenzene as well as with ethanol and hot water, and dried, affording 91 parts (86.5% of theory) of 1-amino-2-bromo-4-benzoylaminoanthraquinone with a melting point of 241° C.-243° C. Br: calculated 18.97%, found 18.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5].Cl.[CH:25](OC)(OC)OC>>[CH2:13]([N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:1]=[CH:25]2)[CH2:12][CH2:11]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(OC)OC
Reactant: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=c1c2ccccc2ncn1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 200 mg 2-amino-N-(1-benzyl-piperidin-4-yl)benzamide (from Step A) in 5 mL of trimethyl orthoformate was added 0.2 mL of concentrated HCl. After stinring at 85° C. for 14 hours, the reaction was cooled to room temperature. The reaction mixture was partitioned betweem EtOAc and aqueous sodium bicarbonate. Aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded 120 mg of the title compound as a viscous oil.
Reaction SMILES: C(CC[O:5][C:6]([C:8]1[C@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]([C:16]([O:18][CH2:19][O:20][CH3:21])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#N.[OH-].[Na+].O.Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:14][C:13]1[NH:12][C:11]([CH3:15])=[C:10]([C:16]([O:18][CH2:19][O:20][CH3:21])=[O:17])[C@@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: COCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 3.6 mg of methoxymethyl (4S)-5-(2-cyanoethoxy-carbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylate in 0.25 ml of dioxane was added 0.1 ml of 1N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 5 ml of ethyl acetate, to which were added water and 0.1 ml of 1N aqueous hydrochloric acid. The resulting mixture was dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure to obtain 2.6 mg of the objective compound.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[CH2:1]([N:7]([CH2:8][CH:9]1[O:10][CH2:11][CH2:12][O:13]1)[C:28](=[O:29])[CH2:27][Cl:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Hexyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.0 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5.0 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-hexyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][CH:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]4)[N:17]3[CH3:20])=[C:13]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:12]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:86](=[NH:99])([C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:87]1([C:86](=[N:99][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([C:11]3[N:19]=[C:18]4[C:14]([N:15]=[C:16]([CH2:21][N:22]5[CH2:27][CH2:26][CH:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]5)[N:17]4[CH3:20])=[C:13]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:12]=3)[N:3]=2)[C:93]2[CH:94]=[CH:95][CH:96]=[CH:97][CH:98]=2)[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3nc(I)c4ccccc43)nc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3nc(N=C(c4ccccc4)c4ccccc4)c4ccccc43)nc21
Temperature: 120 °C

Procedure:
To a solution of 2-(1-((2-(3-iodo-1H-indazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g), tris(dibenzylideneacetone)dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.6 mg) and cesium carbonate (74 mg) in 1,4-dioxane (0.5 mL) was added benzophenone imine (40 μL). The reaction was heated at 120° C. until complete, about 90 minutes. The crude reaction mixture was loaded onto silica and purified by flash column chromatography to afford 2-(1-((2-(3-(diphenylmethyleneamino)-1H-indazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[CH2:39][N:40]1[CH2:41][CH2:42][N:43]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:44][CH2:45]1
Reactant: C1CN(CC2OCCO2)CCN1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CC2OCCO2)CC1
Yield: 43 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(1,3-dioxolan-2-ylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH2:16][CH3:17])[C:4]1=[O:18])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:32]([O-])([O-:34])=[O:33].[K+].[OH-].[Na+]>CC#N.O>[CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[C:12]([N+:32]([O-:34])=[O:33])=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH2:16][CH3:17])[C:4]1=[O:18])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCC1C(=O)N(CC)CCc2ccc(OC)cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCC1C(=O)N(CC)CCc2cc([N+](=O)[O-])c(OC)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30.8 %

Procedure:
1,3-Diethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (564 mg, 2.28 mmol) was dissolved in 1 ml of anhydrous MeCN. The reaction was cooled to 0° C. and trifluoroacetic anhydride (3.00 mL, 21.2 mmol) and Potassium nitrate (230 mg, 2.28 mmol) were charged. The reaction was stirred for 1.5 h and then the reaction was basified with 1-2 ml of 30% NaOH solution and allowed to stir for 1 h. Pour reaction into 75 ml water and extract with 3×30 ml portions of methylene chloride. Dry the combined organic over magnesium sulfate and evaporate. Product is a yellow brown oil (625 mg). Crude material was chromatographed on a 40 g Isco column using 30-50% EtOAc in hexanes as the eluent to yield 1,3-diethyl-8-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (205 mg, 31%) as a tan waxy solid as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:18]1[C:24](Cl)=[O:25]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([CH3:22])[CH3:23])[C@H:18]1[C:24]([O:9][CH:6]1[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:25]
Reactant: C=CCC1=CCC(O)C1
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=CCC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C1
Yield: 65.6 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-3-cyclopenten-1-ol (115 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (5 mg) and toluene (5 ml), (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarbonyl chloride (171 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 165 mg of (RS)-3-(2-propenyl)-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (Compound No. 41). Yield 65% DD27 1.4895
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>>[OH:32][CH2:31][CH:30]([CH2:33][OH:34])[NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1)=[O:28]
Reactant: NC(CO)CO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(CO)CO)cc2)CC1
Yield: 79 %

Procedure:
By the same procedure as described in the example 31, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using 2-amino-1,3-propanediol. Then, the product was recrystallized using ethyl acetate and ether to give the desired compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)(=[O:14])[CH3:13]
Reactant: NC1CCc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CCc2ccccc2C1
Yield: 65 %

Procedure:
Using a procedure similar to that described in Example 1, 1.50 g of 2-amino-tetralin yielded 1.01 g (65%) of 2-acetamido-tetralin following treatment with acetic anhydride.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH:20][C:21]([C:23]1[C:24]([CH3:36])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:27][CH:28]=1)=[O:22])[CH:15]=[CH:14]2.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH:20][C:21]([C:23]1[C:24]([CH3:36])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:27][CH:28]=1)=[O:22])[CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A solution of benzoyl chloride (0.85 mmol) in anhydrous DCM (2 mL) is added drop-wise to a solution of 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-amino-indol-1-yl)-amide (0.47 mmol) and triethylamine (1.41 mmol) in anhydrous DCM (16 mL) and the mixture is stirred at rt overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc (25 mL), and washed with water (2×20 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered and concentrated. The residue is triturated with EtOAc to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-benzoylamino-indol-1-yl)-amide (95 mg, 43%) as a solid. MS: 466 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.99(s, 3H), 6.72(d, H), 7.38-7.48(m, H), 7.48-7.80(m, 6H), 7.83-8.016(m, 3H), 8.07-8.20(m, H), 8.23-8.35(m, 2H), 9.24(s, H), 10.25(br, H).
Reaction SMILES: Br[CH:2]1[C:6]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].C([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.Cl>C1COCC1>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2([CH:2]([B:27]([OH:28])[OH:26])[CH2:3][CH2:4][CH2:5]2)[C:7]1=[O:15]
Reactant: O=C1Nc2ccccc2C12CCCC2Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCCC2B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a solution of 5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (13.1 g, 53 mmol) in anhydrous THF (300 cm3) under N2, was added sodium hydride (60% in mineral oil, 2.1 g, 53 mmol). After 30 minutes, the reaction mixture was cooled to −78° C. and butyl lithium (2.5 M in hexanes, 22 cm3, 53 mmol) was added slowly. After 30 minutes, tris-iso-propylborate (34 cm3, 146 mmol) was added, and the reaction mixture was slowly brought to room temperature, and stirred for 14 hours. The reaction mixture was poured into 1N HCl and extracted with EtOAc (×3). The organic layers were collected and washed with 1N HCl, water, dried (MgSO4) and evaporated to give the subtitled compound (7.8 g, 64%) as a tan solid which was used without further purification. 1H NMR (DMSO-d6) δ10.3 (s, 1H), 7.9 (s, 1H), 7.7-7.6 (m, 2H), 6.8 (d, 1H, J=7.7 Hz), 3.4 (s, 1H), 2.0-1.7 (m, 8H); MS (FI-POS) m/z @231.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C@@H:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]1[C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (3.54 g, 16.6 mmol) was dissolved in dry dichloromethane (80 mL), triethylamine (5.8 mL, 41.5 mmol) was added followed by benzylchloroformate (3.5 mL, 24.9 mmol) and the reaction is stirred at room temperature for 2 h under nitrogen. The reaction was diluted with dichloromethane, washed with 0.2 N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil. The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes to afford the title compound as a clear oil (1.66 g, 29% yield).