Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([C:40](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1>O1CCCC1.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:14][O:15][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:39]2[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:57][CH:56]=2)([CH2:16][OH:17])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
To a solution of nucleoside 1-(3-O-Benzyl-4-C-hydroxymethyl-β-D-xylofuranosyl)thymine 5 (5.38 g, 14.2 mmol) in anhydrous tetrahydrofuran (400 cm3) was added AgNO3 (2.66 g, 15.7 mmol) followed by anhydrous pyridine (5.7 cm3) and 4,4′-dimethoxytrityl chloride (5.30 g, 15.6 mmol). The mixture was stirred in the dark under nitrogen for 18 h at room temperature. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate (10 cm3) and the resulting mixture was extracted with dichloromethane. The combined organic phase was evaporated to dryness under reduced pressure and the residue was co-evaporated with toluene and was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5% methanol; 0.5% pyridine, v/v) as eluent to afford nucleoside 6 (3.13 g, 31%) as a white foam after evaporation of the solvents. δC ((CD3)2SO) 164.1 (C-4), 158.4, 145.1, 138.5, 137.0, 135.9, 135.7, 130.1, 130.1, 129.2, 128.5, 128.5, 128.2, 128.1, 127.7, 127.6, 127.0, 125.7, 113.5 (DMT, benzyl, C-6), 151.4 (C-2), 110.1 (C-5), 85.8, 85.2, 84.6, 83.5 (C-1′, C-3′, C-4′, DMT), 76.8 (C-2′), 72.3 (CH2Ph), 65.2 (C-5″), 62.1 (C-5′), 55.4 (2× CH3O), 12.6 (5-CH3).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cncc(C#N)c2Oc2ccc3[nH]ccc3c2)cc1OC
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (120 mg, 0.44 mmol), 5-hydroxyindole (71 mg, 0.53 mmol) and K2CO3 (91 mg, 0.66 mmol) in CH3CN (4.0 mL) was heated at 80° C. for 4 h. After cooling to r.t., the reaction mixture was diluted with water (20 mL) and the precipitate was collected by filtration and washed with ether containing MeOH to give 121 mg (74%) of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-yloxy)nicotinonitrile 220 as a tan solid. MS: 372.2; melting range: 192-194° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]1.C(N(CC)CC)C>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:10]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)C1CNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(N2CC(C(=O)O)C2)cc1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
To a stirred solution of 4-fluoro benzaldehyde (5 g, 40.28 mmol) in DMSO (70 mL) was added azetidine-3-carboxylic acid (8.14 g, 80.56 mmol) followed by addition of triethyl amine (20.38 g, 201.41 mmol) at room temperature. Resulting reaction mixture was heated at 100° C. for 24 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was cooled to room temperature and quenched with ice cold water (150 mL). Aqueous layer was extracted with EtOAc (3×150 mL). Combined organic layer was washed with water (2×300 mL), dried over sodium sulphate; filtered and evaporated in vacuo to afford brown colored solid (4 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ: 3.54-3.59 (m, 1H), 4.03 (t, 2H, J=6.8 Hz), 4.16 (t, 2H, J=8.36 Hz), 6.52 (d, 2H, J=8.36 Hz), 7.69 (d, 2H, J=8.6 Hz), 9.68 (s, 1H); LC-MS (M−H): =203.70
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:19])[NH:11][C:12]([CH3:18])=[C:13]2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)CCCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester (0.8 g, 2.53 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 3-Chloropropionyl chloride (0.32 g, 2.53 mmol) was dissolved in THF (15 mL) and added dropwise to the mixture over 10 min. The mixture was stirred at 0° C. for 1 h., concentrated in vacuo, and the residue extracted with CH2Cl2 /brine. The CH2Cl2 layer was dried over Na2SO4 ; filtered, and concentrated in vacuo. Silica gel chromatography (1:1 to 1:0 EtOAc:hexane gradient) gave the title compound (1.05 g, 100%) as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2ccccc2c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 81.4 %

Procedure:
3-(2-Methyl-1-naphthyl)benzaldehyde (2.39 g, 9.70 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (10 mL) and tetrahydrofuran (10 mL), and sodium borohydride (0.189 g, 5.00 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (1.96 g, yield 81%) as a colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=O)[C:13](Cl)=O.CCO>C(Cl)Cl>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[I:11])[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)ccc1I
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)ccc1I
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
5-Bromo-2-iodo-benzoic acid (25.0 g, 76.47 mol) was dissolved in CH2Cl2 (75 ml) at room temperature. Oxalyl chloride (14.5 ml, 152.94 mmol) was added and the mixture was stirred at 40° C. for 30 minutes. The mixture was allowed to cool to room temperature and EtOH (6.69 ml, 114.71 mmol) was added. The mixture was concentrated under reduced pressure to give 27.2 g (quantitative) of 5-bromo-2-iodo-benzoic acid ethyl ester as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2([CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1.C(O)(=O)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>CO>[CH3:1][C@@H:2]1[C:6]2([CH2:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1
Reactant: O=Cc1ccccc1
Reactant: C[C@H]1NC(=O)OC12CNC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1NC(=O)OC12CN(Cc1ccccc1)C2
Temperature: 0 °C

Procedure:
A solution of (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one (937 mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0 mL, 9.9 mmol) in methanol (65 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) at rt for min. The mixture was then cooled to 0° C., and 3 N hydrochloric acid (100 mL) was added. The methanol was then removed in vacuo. The resulting aqueous solution was washed with ethyl acetate. The ethyl acetate wash was back extracted with 1 N hydrochloric acid, and the aqueous acidic phases were combined and basified with potassium carbonate. The organic phase was discarded. The aqueous mixture was then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired (8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one was obtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol, 87% yield). MS (EI) for C13H16N2O2: 233 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(NCc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 4-Bromo-benzylamine to produce N-(4-Bromo-benzyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:19]>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]2[Cl:19]
Reactant: O=c1[nH]c(C(F)(F)F)nc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nc(Cl)c2cc(I)ccc2n1

Procedure:
6-iodo-2-trifluoromethyl-3H-quinazolin-4-one (3.1 g, 9.1 mmole) was mixed with 20 mL of POCl3, heated to reflux for 3 h, removed most of unreacted POCl3 under vacuo. The residue was extracted with 15 mL of NaHCO3 (sat) and 200 mL of ether, ether layer was dried with MgSO4 and concentrated to give the light yellow solid 3.05 g, mp 145°-146° C., MS (CI): m/z 359 (MH)+.
Reaction SMILES: [CH2:1]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1)[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH:19](Cl)[C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH3:17][C:12]1[CH:13]=[CH:14][C:15]2[O:16][CH:19]([C:20]([OH:22])=[O:21])[O:8][C:7]3[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=3[CH2:1][C:10]=2[CH:11]=1
Reactant: Cc1ccc(O)c(Cc2cc(C)ccc2O)c1
Reactant: O=C(O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1ccc2c(c1)Cc1cc(C)ccc1OC(C(=O)O)O2

Procedure:
A mixture of 27.4 g (0.120 mole) of 2,2'-methylene bis-p-cresol, 15.5 g (0.120 mole) of dichloroacetic acid, 66.5 g (0.480 mole) of potassium carbonate and 500 ml of isopropyl alcohol was refluxed for 24 hours with vigorous stirring after which 15.5 g. (0.120 mole) of dichloroacetic acid was added and the mixture was refluxed with stirring for 64 hours. The isopropyl alcohol was removed by distillation and replaced with 500 ml of water. The precipitate was collected, washed with 2% aqueous potassium hydroxide, suspended in 1 liter of water, and the suspension was acidified to litmus with 10% aqueous HCl. The resulting precipitate was collected and dried affording 2,10-dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid, m.p. 200°-205°C (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10](O)=[O:11])[O:9][C:5]=2[CH:4]=1.C(Cl)(=O)C([Cl:18])=O>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([Cl:18])=[O:11])[O:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)Cl)oc2c1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6.0 g (0.031 mole) of 6-methoxy-2-benzofurancarboxylic acid (A. McGookin, A. Robertson, and W. B. Whalley, J. Chem. Soc. 787 (1940)) in 100 ml of tetrahydrofuran (under a nitrogen atmosphere) was added in one portion, 3.3 ml (4.8 g; 0.038 mole) of oxalyl chloride. The mixture was stirred for 5 minutes, then treated with 3 drops of N,N-dimethylformamide. After stirring at room temperature for 2 hours, the solvent was evaporated to leave a residue of crude 6-methoxy-2-benzofurancarbonyl chloride, mp 96°-99° (a mp of 101° is given by A. McGookin, etc., cited above). The residue was re-dissolved in 100 ml of dichloromethane, and the solution was filtered. The filtrate was added dropwise over 20 minutes to an ice-cooled solution of 3.6 g (0.037 mole) of N,0-dimethylhydroxylamine hydrochloride and 9.4 ml (7.7 g; 0.077 mole) of 1-methylpiperidine in 100 ml of dichloromethane. After stirring for 2 hours, the mixture was added to 400 ml of ice-cold 5% aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with fresh dichloromethane (3× 100 ml). The combined organic layers were washed with water (1× 200 ml), 3% aqueous sodium bicarbonate (2× 200 ml), and water again. The extracts were dried (anhydrous magnesium sulfate) and evaporated. Trituration of the residue with ether yielded 5.4 g (74% yield) of the analytically pure amide product, mp 73°-77°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[N:6][CH:7]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(OCC)(=O)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[N:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cccc(Oc2ncc(Br)cn2)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(Oc2ncc(Br)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
5-Bromo-2-(3-(chloromethyl)phenoxy)pyrimidine (810 mg, 2.70 mmol) was treated with triethyl phosphite (1 mL, 2.2 mmol), and heated to 150° C. After 16 h, the reaction mixture was removed from the heat and ethyl acetate (about 3 mL) followed by heptane were added. As the reaction mixture cooled an oily precipitate formed. The mixture was made homogenous by addition of ethyl acetate. Heptane was added dropwise until a white solid precipitated. Additional heptane was added and the solid was filtered, washed with heptane and dried in vacuo to afford the title compound (0.737 g, 68% yield) as a white solid. MS (APCI) M+1=401; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=6.92 Hz, 6H) 3.18 (d, J=21.64 Hz, 2H) 3.98-4.10 (m, 4H) 7.06-7.11 (m, 1H) 7.15 (q, J=2.01 Hz, 1H) 7.20-7.26 (m, 1H) 7.35-7.42 (m, 1H) 8.56 (s, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14]I)[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14][N:1]=[N+:2]=[N-:3])[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](CN=[N+]=[N-])CCN1[C@@H](C)c1ccccc1
Reaction time: 18 h

Procedure:
Sodium azide (5.34 mmol) was added to a solution of (2S,3R)-3-iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Step 5.5) (3.56 mmol) in DMF (30 mL) at rt. After 18 h, the reaction mixture was poured onto water and extracted with MTBE (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to to afford the title compound as a brown oil. HPLC: tR=3.26 min (method A); ESI-MS: [M+H]+ 289.
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C1C=C(C)C=C(C)C=1)C1C=C(C)C=C(C)C=1)C.C(O)(=O)C.[H][H]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(=NCc1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCP(c1cc(C)cc(C)c1)c1cc(C)cc(C)c1
Agent: [I-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(NCc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
The process is carried out as in Example 6, but the reaction conditions are modified as follows: 0.636 g (3 mmol) of N-benzyl-N-(1-phenylethylidene)amine, 10.2 mg (0.0152 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 21.4 mg (0.0333 mmol) of {(R)-1-[(S)-2-diphenylphosphino)ferrocenyl]}ethyl-di(3,5-dimethylphenyl)phosphine (ligand) and 15 mg (0.04 mmol) of tetrabutylammonium iodide, 2 ml of acetic acid, 15 ml of toluene, 30 bar of hydrogen, reaction temperature: 25° C. The reaction time is 20 minutes. The conversion is complete, the ee 31%.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]([CH3:23])[C:7]([C:9]1[S:17][C:16]2[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=2[C:10]=1[O:20][CH2:21][CH3:22])=[O:8])[CH3:2].[CH2:26](Br)[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH3:23])[C:7]([C:9]1[S:17][C:16]2[CH:15]=[C:14]([CH3:18])[N:13]([CH2:26][C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12](=[O:19])[C:11]=2[C:10]=1[O:20][CH2:21][CH3:22])=[O:8])[CH3:25]
Reactant: CCOc1c(C(=O)N(C)CCN(CC)CC)sc2cc(C)[nH]c(=O)c12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(=O)N(C)CCN(CC)CC)sc2cc(C)n(CC(=O)c3ccccc3)c(=O)c12
Temperature: 60 °C
Reaction time: 15 h
Yield: 12.9 %

Procedure:
A mixture of the compound of Example 145 (300 mg, 0.821 mmol), phenacyl bromide (196 mg, 0.985 mmol), potassium carbonate (272 mg, 1.97 mmol) and DMF (5 mL) was stirred at 60° C. for 15 hr. After cooling, the mixture was diluted with water (10 mL), and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=1/9 to 10/0) to give the title compound (51.2 mg, 13%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(O)=[O:33].O>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][NH:27][C:26](=[O:33])[CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccnc(F)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: CC(=O)O
Solvent: O
Product: O=C1C(n2cc(-c3cc[nH]c(=O)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Temperature: 25 °C

Procedure:
In a sealed tube, 6-fluoro-3-[4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 mg, 0.236 mmol) in 1.2 mL of 5:1 AcOH/H2O was heated at 120° C. overnight. After cooled to ambient temperature and solvent reduced under reduced pressure, the residue was purified by column chromatography on silica gel (0-20% MeOH in EtOAc) to afford 98 mg title compound.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:4](=[O:5])[CH2:3][C:2]([F:1])=[C:7]([F:9])[F:8])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=C(Cl)CC(F)=C(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCNC(=O)CC(F)=C(F)F
Temperature: 0 °C
Yield: 92.4 %

Procedure:
2.5 g (0.0158 mole) 3,4,4-trifluoro-3-butenoyl chloride is added to a mixture of water (15 mL), dichloromethane (15 mL) and n-butyl amine (2.34 g, 0.032 mole) with stirring at 0° C. After stirring for 30 min, the organic layer is successively washed with 2N HCl, water, 5% sodium bicarbonate and brine, and dried. Evaporation of the solvent gave 2.85 g of title compound as a white solid, a 92% yield. m.p. 34°-36° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][CH3:34])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:34])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:23])=[CH:4][C:5]=4[Cl:22])[C:9](=[O:21])[N:10]3[CH2:19][CH3:20])=[CH:15][N:14]=2)=[CH:28][CH:27]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 200 °C
Yield: 73 %

Procedure:
A mixture of Example A3 (3 g, 8.5 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (20 mL) was charged in a sealed vessel, and then the mixture was heated at 200° C. overnight. Volatiles were removed and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (3 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 7.70 (s, 1H), 7.18-7.17 (m, 3H), 6.86 (d, J=8.4 Hz, 2H), 6.73 (d, J=9.6 Hz, 1H), 6.30 (s, 1H), 5.31 (s, 2H), 4.84 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 1.11 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 467.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:16]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:45]([O:47][C:48](C1CCC(=O)CC1)=[O:49])[CH3:46]>>[CH2:45]([O:47][C:48]([CH:25]1[CH2:26][CH2:22][CH:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]3[CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:15]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:33])([F:34])[F:35])=[CH:27][C:16]2=3)[CH2:23][CH2:24]1)=[O:49])[CH3:46]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Product: CCOC(=O)C1CCC(N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1

Procedure:
Prepare the title compound by essentially following the procedures described in the synthesis of (S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)amine (Example 3 step 19) by replacing cyclopentanecarboxaldehyde with 4-oxo-cyclohexanecarboxylic acid ethyl ester. Isolate the title compound by chromatography over silica gel, eluting with ethyl acetate/hexane. MS (ES+): 707 (M+H).