Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.C([N:42]1[CH2:46][CH2:45][C:44](=O)[CH2:43]1)(OC(C)(C)C)=O.COC(OC)OC.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH:44]2[CH2:45][CH2:46][NH:42][CH2:43]2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: c1ccc(CNCc2ccc(CN(C3CCNC3)C3CCCc4cccnc43)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To the solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (195 mg, 0.43 mmol) and N-Boc-3-pyrrolidone (91 mg, 0.49 mmol) in methanol (3 ml) was added trimethylorthoformate (2 ml) and three drops of acetic acid, at room temperature. This mixture was allowed to stir for 30 min. at room temperature and sodium cyanoborohydride (130 mg, 2.09 mmol) was added. Stirring was continued for a further 18 hours at room temperature and then the reaction mixture was concentrated. The residue was dissolved in ethylacetate (300 mL), and washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4) and evaporated. Purification of the residue by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) gave the desired product (120 mg, 45%) as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1(C)C=CC=CC=1>[CH:22]1([CH2:21][N:20]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CC1CCCCC1
Reaction time: 10 h
Yield: 79.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 1.98 ml (0.01525 mol) of aminomethyl-cyclohexane were added thereto and the mixture was boiled for 23 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. After chromatography over silica gel with cyclohexane/ethyl acetate 3:1 the product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.82 g (80%) of rac-cis-3-cyclohexylmethyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 136°-137°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32]OS(C)(=O)=O)[C:6]=2[CH:38]=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][N:43]3[C:39](=[O:49])[C:40]4=[CH:48][CH:47]=[CH:46][CH:45]=[C:41]4[C:42]3=[O:44])[C:6]=2[CH:38]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCOS(C)(=O)=O)c3cc(Cl)ccc32)cn1
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 7-chloro-5-(2-methanesulfonyloxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.2 g), and the mixture is stirred at 110° C. for one hour. The reaction solution is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=O)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C-]#N.[Na+].Cl.[OH:22][CH:23]1[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([N:25]3[CH2:26][CH:23]([OH:22])[CH2:24]3)=[O:15])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OC1CNC1
Reactant: CCOC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(O)C1
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a suspension of ethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate—for preparation, see e.g. WO 97/05131—(0.53 g, 2.10 mmol) in dry methanol (10 mL) was added sodium cyanide (20 mg, 0.42 mmol). A solution of 3-hydroxyazetidine hydrochloride (0.38 g, 2.78 mmol) and triethylamine (0.39 mL, 2.78 mmol) in methanol (10 mL) was added at ambient temperature. The mixture was stirred for 2.5 h. Water (30 mL) was added and the mixture was extracted with dichloromethane. The organic layers were combined and evaporated to a white solid, which was treated with toluene (5 mL) and then filtered. The product was washed with toluene (5 mL) and then dried in vacuo. There was obtained 0.52 g (90%) of 2B as a solid. 1H NMR (400 MHz, CD3OD): δ 4.00 (dd, 1H), 4.46 (dd, 2H), 4.70 (m, 1H), 4.93 (dd, 1H), 7.62 (d, 2H), 8.11 (d, 2H), MS (APCI+) m/z 280 [M+H]+.
Reaction SMILES: OC(CN1CCOCC1)CN1CCCC2NC(C=O)=C(C)C=2C1=O.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:36]\[C:37]1[NH:46][C:45]2[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:40](=[O:57])[C:39]=2[C:38]=1[CH3:58].[F:59][C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1C1C(F)=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[F:59][C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1[C:27]1[C:26]([F:25])=[CH:34][CH:33]=[C:32]2[C:28]=1/[C:29](=[CH:36]/[C:37]1[NH:46][C:45]3[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]4[CH2:51][CH2:52][O:53][CH2:54][CH2:55]4)[C:40](=[O:57])[C:39]=3[C:38]=1[CH3:58])/[C:30](=[O:35])[NH:31]2
Reactant: O=C1Cc2c(ccc(F)c2-c2cccc(F)c2F)N1
Reactant: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Agent: Cc1c(C=O)[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)c(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (84 mg, 0.25 mmol) and 4-(2,3-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one 74 g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and added with 35 μl of piperidine to the solution at room temperature. Upon completion of the addition, the mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound 2-((Z)-(4-(2,3-difluorophenyl)-5-fluoro-2-oxoindolin-3-ylidene)methyl)-5-((R)-2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 75 (100 mg, yield 78%) as an orange solid.
Reaction SMILES: [Mg].O1C[CH2:5][CH2:4][CH2:3]1.C(Cl)C=C.[CH3:11][C:12]1[CH2:17][CH:16]([CH3:18])[CH:15]([CH:19]=[O:20])[CH2:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH2:17][CH:16]([CH3:18])[CH:15]([CH:19]([CH2:5][CH:4]=[CH2:3])[OH:20])[CH2:14][CH:13]=1
Reactant: C1CCOC1
Reactant: CC1=CCC(C=O)C(C)C1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C=CCCl
Product: C=CCC(O)C1CC=C(C)CC1C
Temperature: 0 °C

Procedure:
To a stirred slurry of 53 grams of magnesium (2.2 mole) and 500 ml of dry tetrahydrofuran under nitrogen, is added dropwise a solution of 168 grams (2.2 moles) of allyl chloride and 276 grams (2.0 moles) of 4,6-dimethyl-3-cyclohexenecarboxaldehyde at reflux over a two-hour period. The reaction mixture is heated at reflux for 30 minutes, whereupon 400 ml of toluene is added. A distillation head is attached to the reaction flask and the toluene is distilled at atmospheric pressure to a pot temperature of 114° C. The remaining solution is cooled to 0° C., whereupon 900 ml of 18% aqueous hydrochloric acid solution is slowly added with external cooling. Two clear layers are formed. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing the second wash with caustic soda. The organic layer is quickly distilled. The distillate is fractionally redistilled through a 1"×12" Goodloe packed column to afford 250 grams of 4,6-dimethyl-alpha-allyl-3-cyclohexenemethanol (b.p. 102°, 3.2 mm Hg pressure).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1>C[C@@H](N(C)C)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.[Fe].O>[OH:15][C@@H:16]1[C:12]2[C:2](=[CH:10][CH:9]=[CH:14][CH:13]=2)[CH:3]=[CH:7][C@H:8]1[N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: C1CCOC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Fe]
Agent: C[C@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)N(C)C
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=Cc2ccccc2[C@H]1O
Temperature: 80 °C
Yield: 52 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (5.4 mg, 0.011 mmol), (R)-(S)-BPPFA (12.2 mg, 0.022 mmol), phthalimide (510 mg, 3.47 mmol) and 1 (100 mg, 0.69 mmol) were added. THF (4 mL) was then added, followed by heating to 80° C. for 3 days. The reaction mixture was then poured in to water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine dried over Na2SO4, and concentrated in vacuo. The resulting solid was purified by flash chromatography (30% ethyl acetate in hexanes) to give 2 as a white crystalline solid (103.5 mg, 52%). The ee was determined to be 74% using, HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 10% isopropanol in hexanes were 21.1 min (major)and 29.1 min. Rf=0.36 on silica gel (30% ethyl acetate:hexanes); mp 175-176° (dec); [α]25D=−6.1° (c=12.9, CHCl3); IR (KBr, cm−1) 3536 (br), 3067 (w), 2921 (w), 1772 (m), 1693 (s), 1388 (s), 1084 (m), 955 (m), 719 (s); 1H NMR (400 MHz, CDCl3) δ7.78-7.75 (2H, m), 7.68-7.64 (2H, m), 7.57-7.55 (1H, m), 7.26-7.22 (2H, m), 7.09-7.07 (1H, m), 6.51 (1H, dd, J=9.7, 2.7 Hz), 5.84 (1H, ddd, J=9.7. 2.7, 2.2 Hz), 5.48 (1H, d, J=12.8 Hz), 5.12 (1H, ddd, J=12.8, 2.5, 2.4 Hz), 2.82 (1H, s); 13C NMR (400 MHz, CDCl3) δ168.6, 137.3, 134.2, 132.6, 132.1, 128.7, 128.2, 128.1, 126.9, 126.5. 124.4, 123.5, 70.9, 55.3. HRMS calcd for C18H11NO2 (M+-H2O): 273.2939. Found: 273.0793.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH2+:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:24]Cl)=[CH:18][CH:17]=1>>[ClH:15].[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[N:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[C@@H:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[CH2:24][S:13]1)[CH3:2]
Reactant: CCc1cc(C#N)ccc1N=C=S
Reactant: CC(C)C[NH2+][C@H](CCl)Cc1ccc(Cl)cc1
Agent: [Cl-]
Product: CCc1cc(C#N)ccc1N=C1SC[C@H](Cc2ccc(Cl)cc2)N1CC(C)C
Product: Cl

Procedure:
(1S)-1-(4-Chlorophenylmethyl)-2-hydroxyethylamine was made from (L)-4-chlorophenylalanine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(4-chlorophenylmethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(4-chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-Hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(4-chlorophenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(4-chlorophenylmethyl)-2-chloroethyl)-N isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(4-chlorophenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[CH:22]([NH2:24])=[O:23]>O>[CH:22]([NH:24][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)=[O:23]
Reactant: NC=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)c1cc(CNC=O)cc(C(C)(C)C)c1O
Temperature: 170 °C
Yield: 76 %

Procedure:
A mixture of 11.09 g (47 mmol) 3,5-di-tert.butyl-4-hydroxybenzaldehyde, 40 g ammonium formate and 40 mL formamide were stirred and heated to 170° C. for 30 minutes. The mixture was allowed to cool down to room temperature and treated with 100 mL water. The crude N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine precipitated from the mixture, was isolated by filtration, washed with water and dried. The crude N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was recrystallized from toluene/heptane 1/1. 9.36 g (76%) of N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was isolated (130-1° C.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:14])C.[Cs+]>CN(C)C=O>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([OH:14])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)ccnc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
2,4-dichloro-3-nitro-pyridine (4.01 g, 20.8 mmol) and cesium acetate (8.0 g, 41.6 mmol) were dissolved in anhydrous N,N-dimethyl formamide (104 ml) under nitrogen atmosphere, and the reaction mixture was heated to 800 and stirred for 18 hours. The reaction mixture was cooled to room temperature the reaction was quenched by adding water. The organic layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain pale-yellow solid (1.69 g, 47%).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:43])[CH2:7][C:8]1[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[N:13]=1>O.C1COCC1>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=4[CH2:7][C:6]([OH:43])=[O:5])[C:17]([CH3:18])=[CH:16][N:15]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1CC(=O)O
Temperature: 40 °C

Procedure:
LiOH.H2O (442 mg, 10.5 mmol) was added to a stirred solution of tert-butyl 4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A18) (115 mg, 0.211 mmol) in water (4 mL) and THF (40 mL) and the resulting mixture heated at 40° C. for 18 hours. On cooling the volatiles were removed in vacuo and the residue taken up in EtOAc (100 mL). The resulting solution was washed with water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to give the title compound A19 as a clear oil (96 mg, 86%); LCMS-A: rt 5.137 min; m/z 532 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[Na+].[O:15]1[CH2:18][CH:17](O)[CH2:16]1>CN(C=O)C>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH:17]1[CH2:18][O:15][CH2:16]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2COC2)c(C)c1
Temperature: 80 °C

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (498 mg, 3 mmol) was added DMF (3 mL) and sodium hydride (240 mg, 6.0 mmol) followed by oxetan-3-ol (445 mg, 6 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled and quenched with brine solution and extracted with EtOAc (3×10 mL). The organic layer was separated and dried over sodium sulfate and evaporated to give methyl 3-methyl-4-(oxetan-3-yloxy)benzoate. To methyl 3-methyl-4-(oxetan-3-yloxy)benzoate was added sodium hydroxide (3 mL of 1 M NaOH, 3 mmol) solution and the reaction mixture was stirred for 1 hour. The reaction was acidified with 1 M HCl solution to pH 3 and extracted with EtOAc. The organics were separated and dried and concentrated in vacuo to give 3-methyl-4-(oxetan-3-yloxy)benzoic acid. ESI-MS m/z calc. 208.1. found 209.3 (M+1)+; Retention time: 1.04 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH3:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)[CH3:16])=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)[CH3:28]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1ccc2ccccc2c1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4ccc5ccccc5c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-naphthalen-2-yl-ethyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: CON(C)[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(OCC)C>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: CCCCCC[Mg]Br
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Solvent: CCOCC
Product: CCCCCCC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21

Procedure:
The general method described in Step 5 of Example 17 was used to react N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (6.10 g, 17.9 mmol) with n-hexylmagnesium bromide (13.5 mL of a 2 M solution in diethyl ether, 27 mmol) to provide 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one (6.10 g) as a yellow oil that was used directly in the next step without further purification.
Reaction SMILES: [Zn](CC)[CH2:2][CH3:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[OH:13][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)c1ccccc1
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
(+)-Me-IAN amine (19.0 mg, 66.8 μmol) was dissolved in toluene (0.85 mL) in a 10 mL flask. Et2Zn (1.22 mL, 1.1 M in toluene, 1.34 mmol) was added in one portion via syringe. Immediately, a clear red-orange solution formed. After stirring for 30 min., benzaldehyde (0.068 mL, 0.669 mmol) was added. This addition immediately lightened the solution to a pale orange-yellow. After 19 h, the solution returned to its red-orange color. Water was added and the mixture was extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and concentrated iii vacuo. Purification of the crude product via flash column chromatography on silica gel gave 1-hydroxy-1-phenylpropane as a light yellow liquid (28.6 mg, 31.4%). HPLC analysis of the product (OD column, 1.0 mL/min, 2% iPrOH in hexanes) gave 85.2% ee (retention time of major peak=13.7 min, retention time of minor peak=16.3 min) and a decrease in the ee of (+)-Me-IAN amine (from 99% to 93.2% ee).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[N-:15]=[N+]=[N-].[Na+].Cl[Sn]Cl.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1cc(Br)ccc1F)C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 7, step a) in DMSO (6.2 mL) was treated with NaN3 (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl2.dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 seconds followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 minutes. The reddish solution with heavy off-white particulates was then treated with anhydrous Na2SO4 (˜6 g) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:13]([O:14][CH3:15])[CH3:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 16.7 g (108.4 mmol) (4-fluorophenyl)acetic acid in dry methylene chloride under nitrogen atmosphere was added 13.8 g (141.5 mmol) N,O-dimethyl-hydroxylamine, 20 mL triethylamine, 14.2 g (119.3 mmol) 4-dimethylaminopyridine (DMAP) and 27 g (140.6 mmol) EDC. The reaction mixture was stirred at RT for 2 hr then transferred to a separatory funnel. The mixture was washed consecutively with 2 N aq. HCl, brine, saturated aq. NaHCO3 and brine. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum to give 21 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.26 (2H, m), 7.02 (2H, m), 3.77 (2H, s), 3.65 (3H, s), 3.21 (3H, s).