Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=O)[C:7](OCC)=[O:8])[CH2:3][CH2:2]1.Cl[Si](C)(C)C.Cl.N>O1CCCC1.ClCCl.CO>[NH3:5].[CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)NCC1CC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: OCCNCC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 150.1 %

Procedure:
A solution of ethyl [(cyclopropylmethyl)amino](oxo)acetate (5.9 g, 34.6 mmol) in tetrahydrofuran (30 ml) was added at ambient temperature to a mixture of borane-tetrahydrofuran complex (130 ml of a 1.0 N solution in THF, 130 mmol) and chlorotrimethylsilane (34 ml, 268 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. Methanol (20 ml) was added and the reaction stirred for a further 30 minutes before dilution with dichloromethane followed by addition of a concentrated solution of hydrochloric acid (4 ml). The mixture was stirred for 30 minutes, basified with methanolic ammonia (7 N) and the resultant solid filtered and washed with dichloromethane. The organic phases were recovered, concentrated and purified by chromatography on silica gel. Elution with dichloromethane followed by increased polarity to dichloromethane:methanol (95:5), dichloromethane:methanolic ammonia (9:1) yielded 2-((cyclopropylmethyl)amino)ethanol as a pale yellow liquid (2.99 g, 75% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][O:21][CH3:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][O:21][CH3:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC[C@H]1CCCN1c1c(C(C)=O)cc(Cl)c2cccnc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC[C@H]1CCCN1c1c(C(C)N)cc(Cl)c2cccnc12
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-7-yl}ethanone (14 mg, 0.044 mmol) and ammonium acetate (33.8 mg, 0.439 mmol) in methanol (0.25 mL,) and acetonitrile (0.25 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (5.52 mg, 0.0878 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C17H23ClN3O(M+H)+: m/z=320.2; found: 302.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:10]=1[C:11](OCC)=[O:12]>>[CH3:7][O:8][C:9]1[CH:19]=[C:18]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:17]=[CH:16][C:10]=1[CH2:11][OH:12]
Reactant: CCOC(=O)c1ccc(F)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1cc(-n2ccnc2C)ccc1CO

Procedure:
Prepared from 2-methylimidazole and ethyl 2-methoxy-4-fluorobenzoate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:19])[O:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:19])[O:14][CH2:15][CH2:16][CH2:17][O:18]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)OCCCO1

Procedure:
The title compound was prepared from 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-methyl-[1,3]dioxan-2-yl)-phenyl]-amide (as prepared in the previous step, 145 mg, 0.276 mmol) and tetrabutylammonium fluoride (216 mg, 0.820 mmol) according to the procedure in Example 1, step (i) (69.4 mg, 64%). 1H-NMR (CDCl3; 400 MHz): δ 9.61 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.74 (s, 1H), 7.38 (dd, 1H, J=8.4, 1.9 Hz), 7.26 (m, 1H), 5.88 (s, 1H), 3.92-3.79 (m, 4H), 2.34-2.26 (m, 4H), 2.13 (m, 1H), 1.87-1.77 (m, 4H), 1.52 (s, 3H), 1.28 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C22H24N4O3, 393.1 (M+H). found 393.1.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].[NH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:37][CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])=[O:9])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 4, 35 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 1-amino-2-methylpropan-2-ol (12.42 mg, 0.139 mmol), 4-methylmorpholine (0.046 mL, 0.418 mmol), and BOP (61.6 mg, 0.139 mmol). This was stirred for 1 h and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=33.2 min) to give single enantiomer 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-(2-hydroxy-2-methylpropyl)propanamide (15.3 mg, 0.026 mmol, 36.8% yield): LC/MS=574.3 [M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.69 (4 H, d, J=8.14 Hz), 7.52-7.65 (3 H, m), 5.11 (1 H, s), 3.52 (2 H, t, J=6.71 Hz), 3.31 (3 H, dt, J=3.25, 1.57 Hz), 2.48 (2 H, t, J=6.71 Hz), 1.16 (6 H, d, J=1.76 Hz). HPLC Peak RT=9.0 min (Analytical Method D).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[C:12](Cl)=[N:11][C:10]([C:14]#[N:15])=[C:9]([C:16]#[N:17])[N:8]=1.O.Cl>O1CCCC1>[C:1]([NH:5][C:12]1[C:7]([Cl:6])=[N:8][C:9]([C:16]#[N:17])=[C:10]([C:14]#[N:15])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reaction time: 0.5 h

Procedure:
t-Butylamine, 7.3 g (.1 mole), in 50 ml of dry tetrahydrofuran was added dropwise under nitrogen to a solution of 10 g (0.05 mole) of 2,3-dichloro-5,6-dicyanopyrazine in 100 ml of tetrahydrofuran. The rate of addition was controlled so that the reactants did not exotherm to greater than 35° C. When the addition was complete, the reactants were stirred an additional half hour and then poured into 1 l. of water. After adjusting the pH to 1-2 with 10% HCl, the precipitated product was filtered and washed thoroughly with water. Crude product after drying was twice recrystallized from 1-chlorobutane to give light yellow crystals having a mp of 169°-173° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(=O)([O-])O.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxy-2-methylbenzoic acid (300 mg) in dimethylformamide (3 ml) was added with potassium hydrogencarbonate (236.9 mg), the mixture was stirred for 10 minutes, and then added with benzyl bromide (0.35 ml), and the mixture was stirred at 40° C. for 2 hours. The mixture was added with distilled water, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane to hexane ethyl acetate=50:1 to 20:1 to 2:1) to obtain the title compound (351.8 mg).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].[CH3:17][C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>O.C(#N)C>[CH3:17][C:18]([C:20]1[O:21][C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)=[CH:23][CH:24]=1)=[O:19]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
A mixture of 322 g (2.0 moles) of 3-aminobenzotrifluoride, 690 ml of concentrated hydrochloric acid and 260 ml of water was heated with steam for 20 minutes at 80° and then cooled to 0°. An additional 200 ml of water was added to aid in stirring. A solution of 138 g (2.0 moles) of sodium nitrite in 500 ml of water was added dropwise while maintaining the temperature between 0°-5° by means of an ice bath. The reaction mixture was stirred for 30 minutes and then filtered to remove a small amount of solid which was discarded. The pH of the solution was adjusted to ca. 4 by the addition of 900 ml of saturated sodium acetate solution. A solution of 220 g (2.0 moles) of methyl-2-furyl ketone in 200 ml of acetonitrile was added followed by a solution of 40 g of CuCl2 . 2H2O in 100 ml of water. The reaction was stirred at 5°-15° for 1 hour and then warmed to room temperature becoming slightly exothermic. The reaction mixture was controlled below 33° by means of an ice bath. After 11/4 hour the reaction was no longer exothermic and was stirred at room temperature overnight. The oil mixture was extracted with 2 × 750 ml and 1 × 500 ml portions of ether. The ethereal extracts were combined and washed with 2000 ml of 5% sodium carbonate solution, with 1500 ml of water and then dried over magnesium sulfate. The ether was removed on the calab evaporator and the residue refrigerated for 72 hours. The solid which was formed was filtered, washed with pet ether and air-dried to yield 174 g. The crude product was recrystallized from 2500 ml of hexane/charcoal to yield 112 g (24%) of 5-(m-trifluoromethylphenyl)-2-furyl methyl ketone. An analytical sample was prepared by recrystallizing a sample of crude product twice from hexane/charcoal, m.p. 105°-109°.
Reaction SMILES: [Cl:1][C:2]([Cl:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](OC)=[O:4].[NH3:17]>ClCCl.O>[Cl:1][C:2]([Cl:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([NH2:17])=[O:4]
Reactant: COC(=O)C(Cl)(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N
Solvent: ClCCl
Solvent: O
Product: NC(=O)C(Cl)(Cl)c1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
A solution of methyl 2,2-dichloro-2-(4-nitrophenyl)acetate (1.36 parts) in dichloromethane (13.6 parts) was stirred with concentrated ammonia solution (10 parts) at 25° C. for 24 hours before diluting the reaction mixture with water (50 parts) and extracting with dichloromethane. The dichloromethane extracts were washed with water and evaporated to give 2,2-dichloro-2-(4-nitrophenyl)acetamide (0.86 parts, 63,4%) (1Hnmr in D6 dimethylsulphoxide 87.95 medium (2H), 88,23 broad (2H), δ8.35 medium (2H)).
Reaction SMILES: [NH2:1][C@@H:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])OC(C)(C)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]=O)=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH3:22][O:21][C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:1]2[C:5](=[O:11])[CH2:4][CH2:3][C@@H:2]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:25][CH:24]=1)=[O:20]
Reactant: COC(=O)c1ccc(CC=O)cc1
Reactant: CC(C)(C)OC(=O)CC[C@@H](N)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCN2C(=O)CC[C@@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of H-D-Glu(OtBu)-OtBu (0.5 g, 2.23 mmol) in MeOH (15 mL) were added 4-carbomethoxyphenylacetaldehyde (obtained from methyl 4-formyl benzoate as described in J. Med. Chem. 1989, 32, 1277-1283) (0.4 g, 2.23 mmol), acetic acid (0.15 mL, 2.67 mmol), and NaCNBH3 (3.3 mL, 1.0 M THF solution, 3.3 mmol). The resulting solution was stirred at RT for 3 h then was diluted with EtOAc (100 mL) and washed with water (50 mL), and brine (50 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo. The crude oil was diluted with xylene and the solution refluxed for 5 h. This solution was concentrated under reduced pressure and purified by silica gel column chromatography using EtOAc/hexane as eluent to afford the title compound (0.75 g, 75%) as a white solid. Rf0.45 (EtOAc/hexane 1/1); 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.95-2.05 (m, 1H), 2.10-2.20 (m, 1H), 2.25-2.35 (m, 1H), 2.40-2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.10-3.20 (m, 1H), 3.82 (dd, 1H), 3.91 (s, 3H), 3.90-4.01 (m, 1H), 7.25 (d, 2H), 7.96 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].Cl>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:2]2[CH:10]=[CH:6][C:5]([O:15][CH3:12])=[CH:4][CH:3]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COc1ccc(-c2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 193.7 %

Procedure:
Palladium(II)acetate (55 mg; 0.23 mmol) was added under argon to a mixture of 5-bromosalicylic acid (5.4 g; 22.4 mmol), sodium carbonate (7.2 g; 68.1 mmol) and 4-methoxyboronic acid (3.8 g; 25 mmol) in water (125 ml). The reaction mixture was stirred at room temperature for 1 h. The resulting slurry was dissolved in hot water (1300 ml) and filtered to give a filtrate and a precipitate. The filtrate was acidified with hydrochloric acid. The precipitate was washed with water and dried in vacuo to give 5.3 g (95%) of 4-hydroxy-4′-methoxy-3-biphenylcarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[O:8][C:7]([CH3:17])([CH3:16])[CH2:6][C:5]2=[O:18].S(Cl)([Cl:22])(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][CH:13]([CH3:14])[CH3:15])[O:8][C:7]([CH3:16])([CH3:17])[CH2:6][C:5]2=[O:18]
Reactant: CC(C)Oc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O

Procedure:
Following General Procedure B, 6-bromo-7-isopropoxy-2,2-dimethyl-chroman-4-one, (Compound 6, 2.2 g, 7.0 mmol) and sulfuryl chloride (0.84 mL, 10.5 mmol) in dichloromethane were reacted to yield the title compound as white trapezoidal plates after recrystallization from hexanes.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:8](=S)[C:6]2([CH3:10])[CH2:7][CH:3]1[CH2:4][CH2:5]2.C[O:13]C1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>>[CH3:1][C:2]1([CH3:11])[C:8](=[O:13])[C:6]2([CH3:10])[CH2:7][CH:3]1[CH2:4][CH2:5]2
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: CC12CCC(C1)C(C)(C)C2=S
Product: CC12CCC(C1)C(C)(C)C2=O
Yield: 23 %

Procedure:
Thiofenchone (23 mg, 0.14 mmol) was reacted with bis-(p-methoxyphenyl)telluroxide for 42 h. Fenchone (5 mg, 23%) νmax 1965,1930,1875,1742,1465,1385 and 1025 cm-1 was obtained after p.l.c. (petroleum ether-ethyl acetate 20:1). A low yield was obtained due to volatility of the product. Sulphur and bis-(p-methoxyphenyl)telluride were, however, isolated in 75 and 81% yields respectively.
Reaction SMILES: [Br:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:21]=O>C(O)=O>[Br:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][N:8]([CH3:21])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Br)CCNCC2c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: COc1cc2c(cc1Br)CCN(C)CC2c1ccccc1

Procedure:
7-Bromo-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9.6 g, 0.03 m), 37% formalin (27 ml) and 95% formic acid (38 ml) were mixed and heated to reflux for 16 hours. The mixture was concentrated in vacuo, treated with 10% hydrochloric acid (70 ml) and concentrated in vacuo. The residue was partitioned between ethyl acetate and ammonium hydroxide to give 7-bromo8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([N:19]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:13]1([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCN(c2ccccc2)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(NC1CCN(c2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 6.9 g (0.037 mole) of 4-nitrobenzoyl chloride in 30 ml. of chloroform was added dropwise at room temperature to a stirred mixture of 6 g. (0.037 mole) of 1-phenyl-3-aminopyrrolidine and 10 g. of potassium carbonate in 30 ml. of water and 30 ml. of chloroform. The mixture was stirred 30 minutes, the chloroform layer separated, dried over magnesium sulfate and evaporated. Recrystallization of the crude solid residue from alcohol-water gave 10.6 g. (92%) of an orange solid which melted at 153-155° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[Cu][C:15]#[N:16].C(Cl)Cl>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:15]([C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13])#[N:16]
Reactant: Cc1cc(Br)c2c(c1C)C(=O)CC2
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c2c(c1C)C(=O)CC2
Reaction time: 6 h

Procedure:
A mixture of 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J. Het. Chem. 24, 677 (1987)] and 7.3 g (82 mmol) of copper(I) cyanide in 18 ml of DMF is stirred for 6 hours at 170°. The reaction mixture is then cooled to 100° and 200 ml of toluene and a solution of 31.2 g of iron(III) chloride hexahydrate in 47 ml of water and 8.2 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is crystallised from ethyl acetate and ether and corresponds to starting compound (a). Beige crystals having a melting point of 160°-163° are obtained; IR (CH2Cl2): 2220, 1710 cm-1.
Reaction SMILES: [CH2:1]([N:4]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH3:16])=[C:10]([CH3:17])[C:9]=1Br)[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:5]([N:4]1[C:8]2[C:13](=[C:12]([CH3:14])[C:11]([O:15][CH3:16])=[C:10]([CH3:17])[CH:9]=2)[CH:2]([CH3:3])[CH2:1]1)(=[O:7])[CH3:6]
Reactant: C=CCN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1c(C)cc2c(c1C)C(C)CN2C(C)=O
Temperature: 60 °C
Reaction time: 15 h
Yield: 94.1 %

Procedure:
A solution of N-allyl-4-acetamido-3-bromo-2,6-dimethylanisole (8, 1.1 g, 3.6 mmol) in dry toluene (237 mL) and tri-n-butylstannane (1.9 mL, 7.1 mmol) was placed in a round-bottom flask fitted with a reflux condenser and slowly warmed to 60° C. under a nitrogen atmosphere. A catalytic amount of azobisisobutyronitrile was added, and the resulting mixture was heated and stirred at 85° C. for 15 h. The cooled reaction mixture was washed sequentially with 1% aq. ammonia and brine, and dried (MgSO4). Removal of solvents gave a liquid which was further purified by flash column chromatography using sequentially hexane and 1:3 ethyl acetate:hexanes as eluents to yield the indoline 9 (790 mg, 95% yield) as a colorless liquid. Spectral data: 13C NMR: δ 11.9, 16.4, 20.5, 23.9, 33.9, 57.3, 59.8, 116.5, 126.3, 129.7, 133.9, 137.6, 153.1, 168.2; HRMS: calcd. for C14H20NO2 (M+H+) 234.1494, fnd. 234.1487.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.CC(=C)C[N:15]1[C:20]2C=CC=[CH:24][C:19]=2[CH2:18][O:17][C:16]1=[O:25].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:24][C:19]1([CH2:20][N:15]2[C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[CH2:8][O:10][C:16]2=[O:25])[CH2:18][O:17]1
Reactant: C=C(C)CN1C(=O)OCc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CN2C(=O)OCc3ccccc32)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
m-Chloroperbenzoic acid (13.76 g, 55.81 mmol) was added to a solution of 1-(2-methyl-2-propenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (7.09 g, 34.88 mmol) in methylene chloride (150 ml), and the mixture was stirred at room temperature for 24 hours. To the mixture, sodium thiosulfate aqueous solution and sodium hydrogencarbonate aqueous solution were added, and the resulting mixture was filtered. The organic layer was separated, washed with sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford 1-(2-methyl-2-oxiranylmethyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (5.13 g, 67%) as a pale yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20])=O)(C)(C)C>Cl.CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoate (3.0 g, 6.8 mmol), as described in Example 18 Step D, in 4 N HCl/MeOH (20 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in ethyl acetate (80 mL), pH value adjusted to 9-10 with saturated sodium bicarbonate solution, dried over sodium sulfate, then filtered. After removing the organic solvent, the residue was used for the next step without purification. LC/MS m/z=344.1 [M+H]+.