Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[O:11][CH3:12].[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC(OC)=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[O:11][CH3:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: COc1n[nH]c2ccc(Br)cc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(OC)c2c1

Procedure:
3-(3-Methoxy-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester CCXI was prepared from 5-bromo-3-methoxy-1H-indazole, using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:30]=2)=[O:27])[C:9]1=[O:42])=[O:6])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:51])C=1>C(Cl)Cl>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:51])[CH:30]=2)=[O:27])[C:9]1=[O:42])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CSc1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)c1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
1-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea (460 mg) obtained from Step 2 of Example 33 was dissolved in methylene chloride (20 ml), m-chloroperbenzoic acid (170mg) was added under ice-cooling, stirred for 30 minutes. The reaction mixture was washed subsequently with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodiun sulfate, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby obtain 320 mg of the title compound (Yield: 68%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]2=[CH:13][CH:14]=[CH:15][C:4]=12.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]2[CH2:13][CH2:14][CH2:15][C:4]1=2
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)C1=CC2=CC=CC2=N1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c(n1Cc1ccc(Cl)c(Cl)c1)CCC2
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Sodium hydride (25 mg, 60%), was added to a solution of ethyl cyclopenta[b]pyrrole-2-carboxylate (96 mg) (T. Aubert et al., J. Chem. Soc. Perkin Trans. 1, 1989, 1369) and the reaction stirred for 30 minutes. 3,4-Dichlorobenzyl bromide (154 mg) was added and stirring continued for a further 2 hours. The reaction was quenched by addition of water and extracted with ether. Combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the product as a white crystalline solid (0.15 g, 83%), NMR d(DMSO) 1.18 (3H, t), 2.30 (1H, m), 2.53 (2H, m), 4.10 (2H, q), 5.40 (2H, s), 6.67 (1H, s), 6.92 (1H, dd), 7.25 (1H, s), 7.57 (1H, d); M/z (+) 338 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[F:33][C:34]([F:41])([F:40])[C:35]1[CH:39]=[CH:38][NH:37][N:36]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]2[CH:38]=[CH:39][C:35]([C:34]([F:41])([F:40])[F:33])=[N:36]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)N1Cc2cccn2Cc2ccccc21

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.25 g, degreased with hexane), 3-trifluoromethylpyrazole (0.61 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m/z: 457.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[Cl:18][C:19]([CH2:21]Cl)=[CH2:20]>C1COCC1>[Cl:18][C:19](=[CH2:20])[CH2:21][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(Cl)CCl
Reactant: COC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cl)CC1(C(=O)OC)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of methyl cyclopentanecarboxylate (2.0 g, 15.60 mmol) in THF (70 mL) cooled to −78° C. was added 2 M solution of LDA in THF (10.1 mL, 20.3 mmol). The mixture was stirred at −78° C. for 1 hour. To this mixture was added 2,3-dichloroprop-1-ene (3.46 g, 31.2 mmol) and allowed to warm to room temperature. The reaction mixture was quenched with aq. NH4Cl and extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by chromatography using EtOAc/heptane gradient to give methyl 1-(2 chloroallyl)cyclopentanecarboxylate (1.82 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46-1.75 (m, 6H), 1.98-2.18 (m, 2H), 2.66 (s, 2H), 3.61 (s, 3H), 5.02 (d, J=1.3 Hz, 1H), 5.14 (d, J=1.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([O:25]CC4C=CC=CC=4)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C(Cl)(Cl)Cl.CCCCCC.N1C2C(=CC=CC=2)CC1>C(O)C.C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[CH:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)ccc1OCc1ccccc1
Agent: [Pd]
Agent: c1ccc2c(c1)CCN2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(-n2ccc3c(O)cccc32)cc1F
Yield: 67.9 %

Procedure:
A suspension of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D1) (2.32 g, 5.48 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was hydrogenated in the presence of 10% Pd on charcoal (500 mg) at atmospheric pressure and room temperature overnight. The mixture was filtered and concentrated and then purified by chromatography on silica gel (elution with 0-50% ethyl acetate in hexane) to give a pink gum, which was solidified by the addition of chloroform (˜0.5 mL) and hexane. The product was collected by filtration and washed with hexane to give an off white powder. This product was dissolved in methanol and passed through an SCX cartridge (to trap a trace of indoline formed in the reaction) and the cartridge was eluted with methanol. The product containing fractions were concentrated and then triturated with hexane and dried to give the title compound (E1) as an off-white solid (905 mg).
Reaction SMILES: [ClH:1].N[C:3]1[S:4][C:5]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[S:4][C:5]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cl
Reactant: N#Cc1ccc2nc(N)sc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2nc(Cl)sc2c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-aminobenzonitrile (23.6 g, 0.2 mol) and ammonium rhodanate (30.4 g, 0.4 mol) was added glacial acetic acid (600 mL) and the resulting solution was cooled to 13.5° C. on an ice-bath. A mixture of bromine and glacial acetic acid was added drop-wise and slowly. The resulting mixture was stirred for 1 hour at 13.5° C. and filtered. The filter cake was washed with glacial acetic (6×100 mL) and placed in hot water (1000 mL) with stirring. The mixture was filtered and pH of the filtrate was adjusted to 7 with a saturated sodium carbonate solution. The precipitate was isolated and dried to give 19.5 g (56%) of 2-aminobenzothiazole-6-carbonitrile. A mixture of concentrated hydrochloric acid (113 mL) and water (52 mL) was heated at 90° C. while 2-aminobenzothiazole-6-carbonitrile (19 g, 0.108 mol) was added. The mixture was cooled to −5° C. on an ice-bath and a solution of sodium nitrite (7.72 g, 0.112 mol) in water (20 mL) was added drop-wise, keeping the temperature below than 0° C. When addition was complete the mixture was stirred for 0.5 hour and a solution of CuCl2 (16 g) in water (108 mL) was added drop-wise. When addition was complete the mixture was stirred for 10 min, and the ice-bath was removed. Stirring was continued for 2 h and the mixture was cooled to room temperature. The mixture was filtered and the solid was washed to neutrality with water and dried. This afforded 12.8 g (61%) of 2-chlorobenzothiazole-6-carbonitrile. 1H-NMR δ 8.14 (s, 1H), 8.03 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: [CH:1]1([N:8]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[CH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[Na+]>[CH:1]1([N:8]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccn(C2CCCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccn(C2CCCCCC2)c1

Procedure:
A solution of 38 g of the ester in 400 ml ethanol and 200 ml of 1.5N aqueous sodium hydroxide is stirred at room temperature for 16 hours. The ethanol is evaporated at 50° and reduced pressure and the basic solution is washed with ethyl acetate, made acidic with ice cold 5N aqueous hydrochloric acid and extracted into ethyl acetate; the extract is washed with brine, dried over MgSO4, treated with charcoal and filtered. The solvent is evaporated at 50° and reduced pressure and the residue is crystallized from ether to yield (E)-3-(1-cycloheptyl-1H-pyrrol-3-yl)-2-propenoic acid, m.p. 138°-140°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](N)=[O:5].CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a solution of Example 12 (0.130 g, 0.314 mmol) in THF (1.3 ml) cooled to 0° C., DIBAL-H (25% in toluene, 0.84 ml, 1.25 mmol) was added stirred at RT for 3 h. The reaction mixture was poured in ice-cold water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale yellow solid (0.030 g, 25%), M.P.: 202-204° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.12 (dd, J=8.0, 1.5 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 5.41 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H). MS (m/z): 386.01 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CCN=C=NCCCN(C)C.[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40]([C:45](O)=[O:46])=[CH:39]2.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][NH:21][C:45]([C:40]3[NH:41][C:42]4[C:38]([CH:39]=3)=[CH:37][C:36]([Cl:35])=[CH:44][CH:43]=4)=[O:46])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2)CC1
Reaction time: 24 h

Procedure:
A mixture of trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester (50 mg, 0.16 mmol), EDCI (75.26 mg, 0.39 mmol), 5-chloro-1H-indole-2-carboxylic acid (36.86 mg, 0.19 mmol), HOBt (31.8 mg, 0.24 mmol) and ethyldiisopropylamine (71.2 mg, 0.6 mmol) dissolved in dichloromethane solvent (10 mL) was stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified with silica gel column chromatography to obtain the desired compound (75 mg, 96%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([F:8])[C:5]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH2:16][CH:17]4[CH2:19][CH2:18]4)[N:14]=[N:15][C:11]=3[C:10]=2[C:22]([F:25])([F:24])[F:23])=[CH:4][CH:3]=1.[B-](F)(F)(F)[CH:27]=[CH2:28].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:17]1([CH2:16][N:13]2[C:12]3[CH:20]=[CH:21][C:9]([C:5]4[C:6]([F:8])=[N:7][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=4)=[C:10]([C:22]([F:25])([F:24])[F:23])[C:11]=3[N:15]=[N:14]2)[CH2:19][CH2:18]1
Reactant: C=C[B-](F)(F)F
Reactant: Fc1nc(Cl)ccc1-c1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-(6-Chloro-2-fluoropyridin-3-yl)-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (135 mg, 0.37 mmol) was dissolved in degassed tetrahydrofuran (3.3 mL) and treated with potassium trifluoro(vinyl)borate (174 mg, 1.3 mmol, 4 equiv), cesium carbonate (154 mg, 0.47 mmol, 1.3 equiv) and bis(tri-tert-butylphosphine)palladium(0) (56 mg, 0.11 mmol, 0.3 equiv). The mixture was placed into a preheated oil bath at 65° C. for 1.5 hours, cooled to ambient temperature, diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100% dichloromethane), providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCN)cc1F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene (1.5 g, Intermediate (2)] in THF (50 mL) is treated dropwise with a solution of lithium aluminum hydride in ether (23 mL, 1M). The mixture is heated at 40° C. for 3 hours, cooled to room temperature, diluted with ether and quenched with Na2SO4.10 H2O (104 g). After standing at room temperature overnight the reaction mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 2-(3-fluoro-4-methoxy-phenyl)-ethylamine [0.81 g, Intermediate (3)] as an oil. MS: 170 (M+H); 1H NMR (CDCl3): δ 6.9-7 (3H, m); 3.85 (3H, s); 2.95 (2H, t); 2.7 (2H, t).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[Br:18]Br>CO>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][Br:18])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
4-Benzyloxyacetophenone (56.57 g, 250 mmol) was dissoved in 1350 ml of methanol, with warming, and bromine (15.5 ml, 300 mmol) was added dropwise as a solution in 150 ml of methanol. After stirring for 3 hours the methanol was evaporated and the residue was suspended in 200 ml of 1 M hydrochloric acid and stirred for 10 minutes. The organic material was extracted into dichloromethane (1×500 ml, and 1×200 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to an off-white solid, which was recrystalized from hot ethanol and water, to afford 69.39 g (91%) of 4-benzyloxyphenacylbromide. M.p. 85-88° C. MS(GC): m/z 306 (M+1). 1H-NMR (CDCl3, 200 MHz) δ: 4.39 (s, 2H); 5.13 (s, 2H); 7.03 (d, 2H); 7.32-7.46 (m, 5H); 7.98 (d, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][NH:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])=[CH:19]2)=[N:2]1
Reactant: CN(C)CCN
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: CN(C)CCNCc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with N,N-dimethylethylenediamine (62 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 186 (0.01 g, 14%).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CCCCCCC>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[O:1]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(OCc2ccccc2)c1C=O
Reactant: CC(C)(O)C(N)=O
Solvent: CCCCCCC
Solvent: O
Product: COc1cccc(OCc2ccccc2)c1C1NC(=O)C(C)(C)O1
Temperature: 240 °C
Yield: 60.7 %

Procedure:
A mixture of commercially available 2-hydroxyisobutyramide (638.5 mg, 3 eq), 2-benzyloxy-6-methoxy-benzaldehyde (500 mg) (Katritzky A. R. et al ARKIVOC 2001, 2, 3, 3-12) is heated at 240° C. for 5 min using microwave irradiation (Lecolier S. et al Chimica Therapeutica 1969, 4,6, 437-445). The crude oil is poured into water and extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 1/1 to 1/0) gives the title compound as a yellow solid (0.41 g, 61%); LC-MS: tR=0.65 min; [M+H]+=328.22.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C@@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: O=C1COc2ccccc2N1
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Yield: 77.9 %

Procedure:
4H-Benzo[1,4]oxazin-3-one (2.47 g, 16.5 mmol), (R)-(3-bromo-2-methyl-propoxy)-tert-butyldimethylsilane (95MF94) (4.01 g, 15.0 mmol) and Cs2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM24-21) (3.92 g, 78%). 1H NMR (CDCl3) δ 7.15-7.11 (m, 1H), 6.99-6.91 (m, 3H), 4.60-4.50 (m, 2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz, 1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz, 1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz, 1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz, 1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27]C(=O)C2C=CN=C(OCC)C=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:10](=[O:12])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[N:9][CH:8]=2)[CH:18]=[CH:19][C:20]=1[C@@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Reactant: CCOc1ccc(C(=O)O)cn1
Agent: Cl
Product: CCOc1ccc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cn1

Procedure:
In analogy to Example 83, step a) using 6-ethoxy-3-pyridinecarboxylic acid (CAS 97455-65-7) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 362.0 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Br:37])[CH:33]=2)[CH:28]=1)=[O:26]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Br:37])[CH:33]=2)[CH:28]=1)=[O:26])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Reaction time: 72 h
Yield: 84.3 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (24.0 g) was dissolved in acetonitrile (330 mL), and triethylamine (15.6 mL) was added. A solution of 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g) in acetonitrile (170 mL) were added. Reaction mixture was stirred over 3 days and evaporated under vacuum. Oil was dissolved in dichloromethane (100 mL), extracted with water (50 mL) and with NaHCO3 solution (50 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-30% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (39.2 g, 84%) as a tan solid.