Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)=[CH:55][CH:54]=1)[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)=[CH:57][CH:58]=1)[CH3:51]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 73% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C([Sn](=O)CCCC)CCC.[CH2:28]([C@@:32]1(O)[C@H:36](OCCCC)[C@@H:35]([C:42](=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)[CH2:29]CC.BrCCCCC=C.[I-].[Na+]>>[CH:29]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])=[CH:28][CH2:32][CH2:36][CH2:35][CH3:42]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Agent: C=CCCCCBr
Agent: CCCC[Sn](=O)CCCC
Agent: [I-]
Product: CCCCC=CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (10.5 g) was treated with dibutyl tin oxide (10.5 g, 1 eq). The resulting 2',3'-O-dibutylstannyleneuridine was treated with 6-bromohexene (3.5 ml, 1.2 eq.) and sodium iodide (3.3 g, 1.o eq.) at 115° C. as per Example 50 to give the 2' and 3' isomers (3.3 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([F:31])[CH:21]=[C:22]([F:30])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH:34]1[CH2:38][CH2:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:47][CH2:46][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:35]4[NH:36][CH2:37][CH2:38][N:34]=4)=[CH:40][CH:41]=3)=[O:29])[C:24]3[C:19](=[C:20]([F:31])[CH:21]=[C:22]([F:30])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2cc(F)cc(F)c2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: O=C(CC1c2cc(F)cc(F)c2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCc1ccc(C2=NCCN2)cc1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-8,10-difluoro-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 656.1 (MH+).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>O>[C:1]([NH:9][C@@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C@@H:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCc2ccccc21
Agent: O=C(O)CC[C@@H](NC(=O)c1ccccc1)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: N[C@H]1CCCc2ccccc21
Temperature: 55 °C

Procedure:
A stirred mixture of 284 grams (1.13 moles) of (R)-(+)-N-benzoylglutamic acid, 136 grams (2.26 moles) of acetic acid, and 2 liters of water is heated to 55° C. to give a solution. To this stirred solution is added 333 grams (2.26 moles) of racemic 1,2,3,4-tetrahydro-1-naphthylamine.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[CH:24][C:23]=1[F:33])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[CH3:34][Mg]Br.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)=[CH:24][C:23]=2[F:33])[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[C:1]([OH:3])([CH3:34])[CH3:2])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: C[Mg]Br
Reactant: CC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 13 %

Procedure:
N-((1R,2R)-2-acetylcyclohexyl)-4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)benzenesulfonamide (150 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5.0 mL) and a solution of 1.4M methyl magnesiumbromide in 3:1 toluene/tetrahydrofuran (2.0 mL, 2.8 mmol) was added. After 1 h, TLC indicated conversion to a new product. The reaction mixture was quenched with methanol followed by saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give a mixture of starting material and product. The crude mixture was purified by flash chromatography on silica gel twice using a gradient of 15-50% ethyl acetate/hexanes followed by 10-35% ethyl acetate/hexanes to give 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(2-hydroxypropan-2-yl)cyclohexyl)benzenesulfonamide as a colorless oil (20 mg, 13% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.66-7.78 (m, 4H), 7.62 (dd, J=10.83, 1.51 Hz, 1H), 7.52 (t, J=7.81 Hz, 1H), 7.35-7.45 (m, 2H), 7.21-7.28 (m, 3H), 4.44-4.56 (m, 2H), 3.87 (d, J=3.02 Hz, 1H), 3.06 (s, 1H), 1.85 (d, J=8.31 Hz, 2H), 1.62-1.69 (m, 2H), 1.52-1.61 (m, 3H), 1.49 (br. s., 1H), 1.18 (s, 3H), 1.05-1.16 (m, 7H). MS [M+H+Na]+=529.19.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([S:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CC(C)CC(Sc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CC(Sc1ccc(-c2ccc(CN)cc2)cc1)C(=O)NCC#N
Reaction time: 18 h

Procedure:
Tert-butyl {4′-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)thio]-1,1′-biphenyl-4-yl}methylcarbamate (1.75 g, 3.74 mmol) was dissolved in dioxane (15 mL). Methanesulfonic acid (485 μL, 7.5 mmol) was added and the reaction mixture was stirred for 18 h. Aqueous sat. NaHCO3 was added and the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (95:3:2 dichloromethane/methanol/triethylamine) to yield 2-{[4′-(aminomethyl)-1,1′-biphenyl-4-yl]thio}-N-(cyanomethyl)-4-methylpentanamide.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:18][CH3:19])[C:15](O)=[O:16].N1C=CC=CC=1>CCOCC>[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:18][CH3:19])[C:15]([Cl:3])=[O:16]
Reactant: CC=C(C(=O)O)c1ccccc1COC
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC=C(C(=O)Cl)c1ccccc1COC
Temperature: 20 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
At 0° to 5° C., 3.7 g of thionyl chloride was dripped into 4.9 g (24 mmol) of α-(2-methoxymethylphenyl)-β-methylacrylic acid and 2.5 g of pyridine in 40 ml of ether. The mixture was stirred for 3 hours at about 20° C. After filtration, the residue was washed with diethyl ether. The filtrate was combined with the ether phase. After removal of the solvent, there was obtained 5.2 g (96.5%) of the title compound as a colorless oil. The crude product can be used for further reactions without any additional purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH3:6])=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:15]([NH:1][C@@H:2]([CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC1CCCCCC1)NCc1ccccc1

Procedure:
1.04 g (5.22 mmol) methyl (S)-2-amino-3-cycloheptyl-propionate were stirred with 0.62 ml (5.22 mmol) benzylbromide, 1.44 g (10.4 mmol) potassium carbonate and 20 ml DMF at 100° C. for 3.5 h. Then water was added and the mixture was extracted with ethyl acetate. The organic phase was evaporated down and the residue was purified by flash chromatography.
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]([NH:11][C:3]2[C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=3)=[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1

Procedure:
The product from Example 140A and 4-trifluoromethoxyphenylboronic acid were processed using the method analogous to that described in example 110C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.29-10.76 (bs, 1H), 9.11 (dd, J=6.9, 1.7 Hz, 1H), 8.63 (dd, J=4.1, 1.7 Hz, 1H), 7.75-7.78 (m, 2H), 7.32-7.39 (m, 2H), 7.24-7.29 (m, 2H), 7.14-7.19 (m, 3H), 3.67 (s, 2H); MS (APCI) m/z 431 (M+H)+. Anal. calculated for C21H14F4N4O2: C, 58.61; H, 3.28; N, 13.02. Found C, 58.37; H, 2.91; N, 12.81.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15].[O-:17][C:18]#[N:19].[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:18]([NH2:19])=[O:17]
Reactant: CC(=O)NCCc1c[nH]c2ccc(N)cc12
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NCCc1c[nH]c2ccc(NC(N)=O)cc12

Procedure:
The product from Example 3 is dissolved in acetic acid-water (1:2, 3 mL) and sodium cyanate (2 mmol) added. This is stirred until a brownish gum is precipitated. The mixture is extracted with chloroform (3×30 mL), and the organic extracts washed with saturated sodium bicarbonate, dried with magnesium sulfate and the solvent evaporated in vacuo. The resulting product is purified by reverse-phase HPLC as above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[C:9]#[C:10][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:9]([C:8]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[CH:4][C:3]=1[O:2][CH3:1])#[CH:10]
Reactant: COc1cc(N2CCN(C)CC2)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N2CCN(C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A solution of 1-{3-methoxy-4-[(trimethylsilyl)ethynyl]phenyl-4-methylpiperazine (583 mg, 1.927 mmol) in anhydrous methanol (12 mL) is treated with powdered anhydrous potassium carbonate under stirring at room temperature for 1.5 h. After removing the solvent under vacuum the residue was taken up with EtOAc (80 mL) and water (5 mL). The phases were separated, the organic phase was washed with brine (3×10 mL), water (10 mL), dried over sodium sulfate and the solvent removed under vacuum. The dark oil obtained was purified by chromatography on silica gel (DCM/MeOH/TEA 90/10/0.1) to give the title compound as brownish solid (374 mg, 84.2%).
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=[O:11])([O:5]C)=[O:4].Br>>[P:3]([CH2:7][NH:8][C@@H:9]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][CH:26]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=[O:11])([OH:4])([OH:5])=[O:2]
Reactant: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCc1nnn[nH]1)OC
Agent: Br
Product: O=C(NCCc1nnn[nH]1)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O

Procedure:
(S)-5-[N-[2-(Dimethylphosphonomethylamino)-3-(4-biphenylyl)propionyl]-2-aminoethyl]tetrazole is treated with 30% HBr/glacial HOAc under conditions similar to those of example 1 to yield (S)-5-[N-[2-(phosphonomethylamino)-3-(4-biphenylyl)propionyl]-2-aminoethyl]tetrazole.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14].Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>CC(N(C)C)=O>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14]
Reactant: CC(C)CCBr
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
A suspension of sodium hydride (95%, 0.048 g, 2.0 mmol) in dimethylacetamide (2 mL) at 20° C. under nitrogen was reacted with the product of Example 1A (0.3 g, 1.83 mmol). The reaction mixture was stirred for ½ hour then treated with 1-bromo-3-methylbutane (0.3 g, 2.0 mmol) and stirred for an additional 16 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel eluting with hexanes and ethyl acetate (3:1) to give the title compound as a white solid (0.218 g, 51%). MS (ESI−) m/z 233 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.93 (s, 3H), 0.96 (s, 3H), 1.55 (m, 2H), 1.66 (m, 1H), 4.14 (t, J=7.72 Hz, 2H), 7.37 (dd, J=7.91, 4.96 Hz, 1H), 8.38 (dd, J=7.72, 1.84 Hz, 1H), 8.78 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: Cl[C:2]([Cl:12])=[CH:3][C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:13]1([O-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:12][CH:2]=[C:3]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(C)(C=C(Cl)Cl)CC
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC(C)(CC)C(=CCl)Oc1ccccc1
Yield: 65.3 %

Procedure:
626 g (3 moles) of 1,1-dichloro-3-ethyl-3-methyl-1-heptene and 696 g (6 moles) of sodium phenolate are heated under reflux in 3 L of dimethylformamide for 16 hours. The mixture is diluted with methylene chloride and extracted by shaking several times with 2 N aqueous sodium hydroxide solution. After drying and evaporating on a rotary evaporator, 666 g of crude product remain. Distillation at boiling point0.1 100°-110° C. gives 523 g (65% of theory) of 1-chloro-3-ethyl-3-methyl-2-phenoxy-hept-1-ene. NMR (CDCl3): δ 0.7-1.6 (m, 17 H), 5.8 and 5.85 (2 s, 1 H) and 6.8-7.4 (m, 5 H). ##STR60##
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:32][C:31]=2[C:39](O)=[O:40])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[O:34][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:32][C:31]=2[C:39]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]([CH3:20])[C:13]4=[O:21])[CH:8]=2)=[O:40])=[CH:28][CH:29]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: CS(=O)(=O)c1nc(C(=O)O)c(-c2ccc(F)cc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2nc(S(C)(=O)=O)oc2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 20 h
Yield: 53.5 %

Procedure:
6-(5-amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (110 mg, 0.28 mmol) was dissolved in DMF (5 mL) with 5-(4-fluoro-phenyl)-2-methanesulfonyl-oxazole-4-carboxylic acid (142 mg, 0.5 mmol) at RT. HATU (150 mg, 0.39 mmol) was added, followed by DIEA (0.5 mL, 2.87 mmol). The mixture was stirred for 20 h. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 82 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 548.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH2:12])[CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1cccc2cnc(Cl)cc12
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc2cnc(Cl)cc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-chloro-5-nitro-isoquinoline (20.9 g., 0.1170 mole, prepared according to the method of Example 1 hereinabove) was suspended in glacial acetic acid (160 ml), and water (160 ml) was then added while the temperature of the mixture was being raised to 60°C. Keeping the temperature between 60° and 70°C, powdered iron (15.2 g) was added slowly to the stirred mixture, and stirring was continued for 2 hours after addition of the iron was completed. The reaction mixture was allowed to stand overnight, and was then made alkaline with 20% w/v aqueous sodium hydroxide solution, and filtered. The residue was dried overnight, over silica gel in a vacuum oven at 50°C. The dried cake was then broken up and extracted -- three times with ether under reflux. The ether extract was boiled with charcoal, dried over anhydrous sodium sulphate, filtered, and the ether evaporated off to yield 9.25 g of 3-chloro-5-amino-isoquinoline of m.p. 176° - 177°C. Further ether extraction of the filter cake yielded another 4.2 g of 3-chloro-5-amino-isoquinoline of m.p. 175° - 177°C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[NH:7][CH:8]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:9]32)=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:23]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:8]2[NH:7]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Br)ccc3C(=O)NC2C1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN2c3cc(-c4ccccc4)ccc3C(=O)NC2C1
Yield: 45.6 %

Procedure:
A mixture of the part A compound from Example 3 (100 mg, 0.26 mmol), phenyl boronic acid (48 mg, 0.39 mmol), a solution of aqueous 2.0 M sodium bicarbonate (380 μl, 0.76 mmol) and tetrakis(triphenylphosphine) palladium(0) (1 mg, 0.86 μmol) in degassed DME (1.5 mL) was heated at 90° C. for 18 h under nitrogen. The mixture was diluted with ethyl acetate (20 mL), washed with a solution of aqueous saturated sodium bicarbonate (3×20 mL), dried over sodium sulfate and concentrated. The crude product was purified by ISCO flash chromatography (silica gel/hexane-ethyl acetate 100:0 to 0:100 gradient) to afford the title compound as a white solid (45 mg, 45% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:19]1([CH2:18][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH2:5][CH2:4][O:3][C:2]([CH3:15])([CH3:1])[C:7]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OCCc2c1[nH]c1ccccc21
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCCc2c1n(Cc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3,4,9-Tetrahydro-1,1-dimethylpyrano[3,4-b]indole (5 g, 25 mmole, described by C. A. Demerson et al., cited above) was added portionwise to a suspension of sodium hydride (3 g, 58% dispersion in mineral oil) in 25 ml of dry dimethylformamide. This was stirred at room temperature for one hour. Benzyl chloride (3.8 g, 30 mmole) was added dropwise with ice cooling. The temperature was raised to 40° C. for 30 min. The reaction was poured into ice-water and the mixture was extracted with diethyl ether, washed twice with water, dried and evaporated. The solid residue (10 g) was chromatographed on silica gel using 10% ethyl acetate in benzene to afford 4.5 of white solid which was crystallized from butanol to give 9-phenylmethyl-1,3,4,9-tetrahydro-1,1-dimethylpyrano[3,4-b]indole, mp 132°-134° C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([OH:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:19]([O:23]C(=O)CBr)(C)(C)[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH:1]1[C:11]2[CH:10]([O:12][CH2:20][CH2:19][OH:23])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1c2ccccc2CSc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCOC1c2ccccc2CSc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
6,11-Dihydrodibenzo[b,e]thiepin-11-ol (1.14 g, 5 mmol) was dissolved in dry THF (25 mL) at 0° C. Sodium hydride (0.24 g of 50% mineral oil dispersion, 5 mmol) was added portionwise at 0° C. and then refluxed for 30 min. tert-Butylbromoacetate (980 mg, 5.0 mmol) in dry THF (10 mL) was added over a period of 20 min followed by a 30 min reflux. The reaction mixture was quenched with water at 0° C. and the product extracted with ether. The combined ex-extracts were dried (MgSO4), and concentrated in vacuo. The product was redissolved in ether and added dropwise to an ether (15 mL) suspension of lithium aluminium hydride (190 mg, 5.0 mmol). The reaction was stirred 16 h at room temperature, quenched with water, cooled, and filtered through Decalit. The ether solution was washed with saturated NaCl, dried, and purified by chromatography eluting with ethyl acetate/dichloromethan (1:10) to give 850 mg (63%) of 2-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxy)-ethanol. 1H NMR (300 MHz, CDCl3) δ 3.55-3.70 (m, 2H), 3.75-3.85 (m, 2H), 4.00 (bs,1H), 4.85 (bs, 1H), 5.55 (bs, 1H), 7.03-7.13 (m, 3H), 7.13-7.48 (m, 5H).