Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3]N(N=O)C(N[N+]([O-])=O)=N.[Cl:13][C:14]1[CH:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]2[C:16](=[CH:17][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:19]=2)[CH:15]=1>C(OCC)C>[Cl:13][C:14]1[CH:22]=[C:21]([CH2:23][C:24]([O:26][CH3:3])=[O:25])[C:20]2[C:16](=[CH:17][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[N:19]=2)[CH:15]=1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CC(=O)O)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)Cc1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of sodium hydroxide (4M in water, 25 mL) and diethyl ether (75 mL) at 0° C. was added N-methyl-N′-nitro-N-nitrosoguanidine (2.24 g, 15.3 mmol) with swirling (no stirbar). After addition was complete, the mixture was allowed to stand at 0° C. for 15 min with occasional swirling. The ethereal was transferred in portions to a suspension of 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid (2.6 g, 7.63 mmol) in diethyl ether (50 mL) until the yellow color persisted and all of the starting material had gone into solution. The reaction was allowed to rest at room temperature for 5 min before bubbling nitrogen through the solution to remove most of the unreacted diazomethane. Column chromatography (25% ethyl acetate/n-hexane) gave 2.28 g (84%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 5.67 (s, 2H), 4.01 (s, 2H), 3.70 (s, 3H), 3.61 (t, J=8.2 Hz, 2H), 0.92 (t, J=8.3 Hz, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 171.3, 146.9, 127.7, 127.5, 126.0, 122.61, 122.57, 118.3, 82.0, 67.7, 52.1, 36.1, 17.9, −1.4.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])=[CH:5][CH:4]=1.[O:17]=[C:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1>C1COCC1.C1(C)C=CC=CC=1>[OH:17][C@:18]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:15]=[CH2:16])=[CH:5][CH:4]=2)[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1ccccc1-c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Magnesium (0.110 g, 4.58 mmol) turnings were stirred in a round bottom flask under nitrogen for 30 min. to cause scratching of the surface of the magnesium. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-2-vinylbiphenyl (Intermediate 1, 1.13 g, 4.36 mmol) in THF (30 mL), was added dropwise at reflux with vigorous stirring. The Grignard solution (40 mL) was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (Intermediate 2, 1.0 g, 3.53 mmol) in toluene (30 mL) at 0° C. and stirred for 1 hr and then quenched with a saturated NH4Cl solution. The aqueous layer was extracted with DCM. The combined organics were washed with brine and dried over MgSO4, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-33% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (0.5 g, 30% yield) as a yellow oil. LCMS: rt=1.92 min. [M+Na]+=490; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 9H) 0.88-1.14 (m, 2H) 2.38-2.50 (m, 1H) 2.74 (dd, J=13.58, 10.22 Hz, 1H) 3.89 (d, J=11.60 Hz, 2H) 3.76-3.84 (m, 1H) 3.86 (s, 3H) 4.00 (dd, 1H) 4.23 (s, 1H) 4.24-4.28 (m, 1H) 4.55-4.66 (m, 1H) 5.20 (dd, J=10.9, 1.22 Hz, 1H) 5.71 (dd, J=17.55, 1.07 Hz, 1H) 6.70 (dd, J=17.40, 10.99 Hz, 1H) 7.28 (dd, 1H) 7.34 (dd, J=7.17, 1.68 Hz, 1H) 7.37 (d, J=8.55 Hz, 2H) 7.54 (d, J=8.24 Hz, 2H) 7.65 (d, J=7.32 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][C:31]([F:34])=[C:32](I)[C:26]=2[CH:25]=1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][C:31]([F:34])=[C:32]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CCCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: CC(=O)c1cc2c(I)c(F)ccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1c(-c2c(F)ccc3sc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-butoxy phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo-5-fluorobenzo[b]thiophene and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH3:18][O:19][N:20]([CH3:24])[C:21](Cl)=[O:22].N1C=CC=CC=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:21]([N:20]([CH3:24])[O:19][CH3:18])=[O:22])=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)Cl
Reactant: Nc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Yield: 36.8 %

Procedure:
4-(3,4-Dichlorobenzyloxy)aniline (26.7 g), N-methoxy-N-methylcarbamyl chloride (13.5 g) and pyridine (8.7 g) are dissolved in toluene (200 ml), and the reaction mixture is heated under reflux for 5 hours. Water is added to the reaction mixture to dissolve the by-produced sodium chloride. The toluene layer is washed with dilute hydrochloric acid and water in that order, dried and concentrated under reduced pressure. The residual crude crystals are recrystallized from ethanol to give N-[4-(3,4-dichlorobenzyloxy)phenyl]-N'-methyl-N'-methoxyurea (Compound No. 9) (13 g) as white plates. M.P., 114° to 115° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[N+:17]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O.[H][H]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[NH2:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: COc1cccc(NC(=O)OC(C)(C)C)c1N
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of the N-tert-Butyloxycarbonyl-3-methoxy-2-nitro aniline (4 mmol) in MeOH was added catalytic amount of Raney Nickel in water, hydrogen was applied at 40 psi and the mixture was stirred overnight. The mixture was filtered over Celite and the solvent was evaporated to give the desired product in 55% yield. MS (ESI)=239 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][C:35]3[NH:39][CH:38]=[N:37][CH:36]=3)=[O:31])[C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][C:35]3[NH:39][CH:38]=[N:37][CH:36]=3)=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NCCc1cnc[nH]1)C(=O)NC3=O
Agent: BrB(Br)Br
Product: O=C(CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O)NCCc1cnc[nH]1
Reaction time: 48 h
Yield: 46 %

Procedure:
Demethylation of (128) prepared as described in example 241 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (129) as a yellow powder (46%), mp 158–162° C. (dec). 1H NMR δ [(CD3)2SO] 11.75 (br, 1H), 11.05 (br s, 1H), 9.36 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.91 (t, J=5.3 Hz, 1H), 7.71 (s, 1H), 7.59–7.54 (m, 2H), 7.50–7.42 (m, 4H), 7.14 (dd, J=8.8, 2.4 Hz, 1H), 6.57 (br, 1H), 4.65 (t, J=6.5 Hz, 2H), 3.13 (m, 2H), 2.55 (t, J=6.5 Hz, 1H), 2.40 (t, J=6.5 Hz, 1H). FABMS found [M+H]+: 530.1431, 528.1440. C28H23ClN5O4 requires 530.1409, 528.1439.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH3:11])[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with pyrrolidine in N,N-dimethylacetamide at 50° C. for 2 hours to yield trans-methyl-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 437 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([NH2:32])[C@@H:28]([CH3:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([NH:32][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[C@@H:28]([CH3:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N
Product: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NCc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 4(R)-amino-3(S)-methyl-piperidine-1-carboxylic acid benzyl ester (prepared according to literature procedure (ref 1)) following procedure B. LC-MS showed the product had the expected M+H+ of 451.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]([CH2:19]O)([CH2:17]O)[CH3:16]>>[CH3:14][C:15]1([CH3:19])[CH2:17][O:10][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)[O:11][CH2:16]1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC1(C)COB(c2cccc(C(F)(F)F)c2)OC1
Yield: 58 %

Procedure:
The title compound (58%, crystals) was prepared from 3-trifluoromethylphenylboronic acid and neopentylglycol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][C:15](=[O:17])[C:14]([C:18](=O)[CH2:19][CH3:20])=[C:13]([OH:22])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:23]([O:25][NH2:26])[CH3:24]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][C:15](=[O:17])[C:14]([C:18](=[N:26][O:25][CH2:23][CH3:24])[CH2:19][CH3:20])=[C:13]([OH:22])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(C)=O)cc2)CC1=O
Solvent: C1CCOC1
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(C)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 2.0 g of 5-(4-acetamidophenyl)-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 1.0 g of aqueous solution containing 50% of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water and the crystal sedimented was collected with a filtering step. The crystal was dissolved in 20 ml of chloroform and the solution was washed with water and extracted with 15 ml of aqueous solution containing 5% of sodium hydroxide. To the alkaline solution was added a dilute hydrochloric acid solution and the crystal sedimented was extracted with chloroform. The solution was washed with water and dried with anhydrous magnesium sulfate and the chloroform was distilled off from it under reduced pressure. Thus 1.4 g of the desired compound was obtained. It was in the form of pale yellow crystals having a melting point of 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-Chloro-6-methyl-nicotinic acid (3.58 g, 20.86 mmol) was dissolved in DMF (34 mL). MeI (5.8 mL, 93.88 mmol) and K2CO3(7.78 g, 56.33 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reactant was distilled under reduced pressure to remove the solvent and extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex=1/2) to obtain the title compound (3.68 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1.[Br:30]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:30])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1
Reactant: CCCCNc1nc(N)c2ncn(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCNc1nc(N)c2nc(Br)n(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Yield: 63 %

Procedure:
To a solution of 66 (299.4 mg, 0.72 mmol) in CHCl3 (5 mL) was added a 10% (v) solution of Br2 in chloroform. The reaction was stopped when starting material was consumed, monitored by HPLC. Bromine was quenched with a saturated Na2SO3 solution and product extracted with DCM (2×10 mL). Organics were washed with water (2×10 mL) and brine (1×10 mL) and dried over Na2SO4. Purified by flash column eluting 10% methanol in ethyl acetate. Evaporation of solvent gave 223.6 mg (63%) of 67 as a yellow solid. LCMS: m/z for C20H28BrN6O2P++H observed 495.2 and 497.2 at 1.98 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: Fc1cccc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
6-(3-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 1-bromo-3-fluorobenzene according to the procedure of Example 4, as a light yellow solid: mp 181-182° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.62-7.44 (m, 5H), 7.16 (t, 1H, J=2.22 Hz), 6.97 (d, 1H, J=8.83 Hz), 1.67 (s, 6H); MS (EI) m/z 271 ([M+H]+, 40%); Anal. Calcd. For C16H14FNO2: C, 69.91; H, 5.3; N, 5.1. Found: C, 70.0; H, 5.32; N, 4.92.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][O:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][C:28]=1[S:29](Cl)(=[O:31])=[O:30])=[O:23].C(OCC)(=O)C>O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][C:28]=1[S:29](=[O:31])(=[O:30])[N:10]([CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12])[CH3:11])=[O:23]
Reactant: CNCC(O)c1ccc(F)cc1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methylamino-ethanol (8.4 g) and triethylamine (7 mL) in tetrahydrofuran (80 mL) was added 3-chloro sulfonyl-thiophene-2-carboxylic acid methyl ester (10 g) on an ice bath over 20 minutes. The solution was brought back to room temperature and stirred for 1 hour. Ethyl acetate was added to the reaction solution, the resulting salt was removed by filtration, and solvent was evaporated at reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate), and a pale yellow oily substance (15.6 g) was obtained.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1ccccn1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccccn1

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2-picolinic acid. δH (DMSO-d6) 8.8-8.6 (2H, m), 8.0 (2H, m), 7.7-7.4 (4H, m), 7.14 (2H, d, J 8.7 Hz), 6.92 (2H, d, J 8.7 Hz), 5.15 (2H, s), 4.72 (1H, m), 3.17 (2H, m); m/z (ESI, 60V) 445 (MH+).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[O:11][CH2:10]1)C1C=CC=CC=1>[Pd]>[CH3:24][C:22]1([CH3:25])[C:21]([CH3:26])([CH3:27])[O:20][B:19]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][C@H:9]([NH2:8])[CH2:10][O:11]3)[O:23]1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Agent: [Pd]
Product: CC1(C)OB(c2cccc3c2C[C@H](N)CO3)OC1(C)C
Temperature: 55 °C
Yield: 67 %

Procedure:
The title compound was synthesized as described for Intermediate example I-3 in 67% yield, starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine using 47 w % of 10% palladium on charcoal. The reaction mixture was heated to 55° C. for 1.5 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.19 (dd, 1 H), 7.04 (t, 1 H), 6.83 (dd, 1 H), 4.00-4.06 (m, 1 H), 3.50-3.59 (m, 1 H), 3.14-3.23 (m, 1 H), 2.98-3.12 (m, 1 H), 2.52-2.60 (m, 1 H), 1.29 (s, 12 H), 1.06 (s, 2 H); MS (APPI/APCI) m/z 276[M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:35]=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[O-:37]Cl=O.[Na+]>CC(O)(C)C.O.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: [O-][Cl+][O-]
Reactant: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C=O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 23 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
To 750 mg (1.6 mmol) of 8-[4-[(cis)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarbaldehyde in 60 mL of t-BuOH and 8 mL of CH3CHC(CH3)2 at 23° C. was added a solution of 1.3 mg (14.4 mmol) NaClO2, 1.3 g (10.8 mmol) NaH2PO4 in 3 ml water. After stirring at 23° C. for 12 hours, the volatiles were removed by rotary evaporation. The reaction mixture was transferred to a separatory funnel and partitioned between water and CH2Cl2. The organics were washed with brine, dried over MsSO4, and chromatographed on silica gel eluting with 20:1 CH2Cl2:MeOH containing 5% glacial HOAc. The product fractions were pooled, stripped, and treated with 75 mg (0.83 mmol) of (CO2H)2 in absolute EtOH to give 390 mg (0.6 mmol, a 38% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 230° C.; MS (ES) m/z: 494 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 3 h

Procedure:
In a 100-ml, three-necked, round-bottomed flask equipped with a magnetic stirrer, an oil bath, and a condenser topped with a drying tube were placed 1.69 g of 4-benzyloxy-4'-biphenylcarboxylic acid, 34 ml of thionyl chloride, and one drop of dimethylformamide. After stirring the solution for three hours under reflux, the thionyl chloride was distilled off, then 75 ml tetrachloromethane was added and distilled. The brown solid was dissolved in 500 ml hot dichloromethane, and the solution was treated with charcoal and filtered through Celite. The solids were washed with hot dichloromethane, and the filtrate was evaporated, to yield the following compound. ##STR36##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][NH:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCNCC(O)c2ccccc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Temperature: 25 °C

Procedure:
A solution of 30.1 g. (0.1 mol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine in 120 ml. of trifluoroacetic acid and 8.2 ml. of concentrated sulfuric acid is heated at reflux for two hours. After cooling to room temperature, the trifluoroacetic acid is removed under reduced pressure and 100 ml. of ice-water is added. This mixture is basified to pH 9-10 with 10% sodium hydroxide solution and thoroughly extracted with ethyl acetate. The extract is dried and evaporated to give 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil. Various salts can readily be prepared from the free base. For example, 5 g. (0.0176 mol) dissolved in dry ether is treated with methanesulfonic acid dropwise until no further precipitate is formed. The solid is filtered and washed with dry ether to give 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine methanesulfonate, m.p. 133°-136° C.