Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C>[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C(N)=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C(N)=O)c1ccccc1
Yield: 65.3 %

Procedure:
2.2 g (5.3 mmoles) of H-Leu-Asp-L-Phg-NH2.HCl, prepared as described in Example 6, Step 3, are reacted with 2.32 g (5.8 mmoles) of BOC-Trp-OSu in 50 ml of DMF in the presence of 1.48 ml (10.6 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo and the residue is triturated with water. The obtained crude product, weighing 3.30 g, is crystallized from 70 ml of 80% ethanol under decolourizing. 2.30 g (65%) of BOC-Trp-Leu-Asp-L-Phg-NH2 are obtained; m.p.: 205°-207° C. (decomposition), Rf5 : 0.40, [α]D : -7.3° (c: 1.0, in dimethyl formamide).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]#[CH:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>C(Cl)Cl>[C:1]([NH:8][C@H:9]([C:12]#[CH:13])[CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of (R)-N-Boc-2-amino-but-3-yn-1-ol (150 mg, 0.81 mmol) (Example 104B) and imidazole (110 mg, 1.62 mmol) (Aldrich) in CH2Cl2 (10 mL) was added at 0° C. tert-butyldimethylsilyl chloride (146 mg, 0.97 mmol) (Fluka). After 5 min the reaction mixture was poured into H2O and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated to a residue which after silica gel column chromatography with a 0-30% Et2O in hexanes gradient afforded the product. (Yield 210 mg, 83%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>[OH-].[Na+]>[CH:12]1([NH:15][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: Clc1ccnc2ccccc12
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(NC3CC3)ccnc2c1
Temperature: 180 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
A mixture of 4-chloroquinoline (13.9 g) and cyclopropyl amine (9.7 g) was heated at 180° C. under stirring for 16 hours. After cooling, a solution of sodium hydroxide 1N (200 ml) was added. After extraction with dichloromethane (200 ml), the organic layer was separated and dried over sodium sulfate. The solvent was removed under reduce pressure to afford an oil, which was crystallized in acetonitrile (50 ml). Cyclopropyl-quinolin-4-yl-amine (6.6 g; 42% yield) was obtained after filtration.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25].C(N(CC)CC)C.[P:33]([O-:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:35]([O:34][P:33]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:36]
Reactant: CCOP([O-])OCC
Reactant: Cc1c(I)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1nc2n(c1C)N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Yield: 10.1 %

Procedure:
100 mg of 9-iodo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is stirred in 2 ml of dimethylformamide, 0.03 ml of triethylamine, 0.032 ml (30 mg) of diethyl phosphite and 15 mg of tetrakis(triphenylphosphine)-palladium(O) at 100° C. for 2 hours. Then, it is diluted with 10 ml of water and extracted with ethyl acetate. The organic phase that is concentrated by evaporation is chromatographed on silica gel with dichloromethane:ethanol=95:5 as an eluant. 10 mg of 8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine-9-phosphonic acid diethyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:13])([F:14])[F:15])[CH:4]=1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)c(C(F)(F)F)c1
Yield: 96 %

Procedure:
A solution of (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (4.90 g, 22.06 mmol) in methanol (40 mL) was treated with concentrated sulfuric acid (7 drops). The reaction mixture was heated under reflux for 2 h. The reaction was then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid methyl ester (5.02 g, 96%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14]([O-:16])=O)[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](O)[CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][O:16][C:26]3[CH:27]=[C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:30])[CH:23]=[CH:24][C:25]=3[CH3:28])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CC(=O)[O-]
Reactant: COC(=O)Cc1ccc(C)c(O)c1
Product: COC(=O)Cc1ccc(C)c(OCCc2nc(-c3ccc(Br)cc3)oc2C)c1

Procedure:
By the same procedure as Example 31 and Example 32 using [2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetate instead of the compound prepared in Example 30 and methyl(3-hydroxy-4-methylphenyl)acetate instead of methyl(2-fluoro-3-hydroxyphenyl)acetate, the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29](O)=[O:30])[C:23]=2[N:22]=[CH:21]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>ClCCl>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([N:17]3[CH2:18][CH2:19][C:14]4([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[C:6]=5[C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=5[O:13]4)[CH2:15][CH2:16]3)=[O:30])[C:23]=2[N:22]=[CH:21]1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: O=C(O)c1cccc2[nH]cnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2cccc3[nH]cnc23)CC1
Reaction time: 12 h

Procedure:
To a solution of 1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (211 mg, 0.830 mmol), 1H-benzimidazole-4-carboxylic acid (134 mg, 0.830 mmol) and triethylamine (346 μL, 2.50 mmol) in dichloromethane (2 mL) was added HATU (314 mg, 0.830 mmol) in one portion and the mixture was stirred for 12 hours. The reaction mixture was treated with 1M NaOH (1 mL) for 10 minutes. Dichloromethane (5 mL) was added. The two layers were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated to yield a residue that was purified on silica using a gradient of 0.5-30% MeOH in dichloromethane to yield (1H-benzo[d]imidazol-4-yl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 399.5. found 400.5 (M+1)+. Retention time: 1.12 minutes (4 min run).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 11.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC column; Solution A: 0.1% trifluoroacetic acid solution in acetonitrile; Solution B: 0.1% aqueous trifluoroacetic acid solution; eluted with 10% Solution A to 100% Solution A), and a saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydrous, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (32.3 mg, 11.1%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:3]=1.Cl.[NH2:21][C:22]1[C:27]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][CH:25]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[N:23]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:1].[NH2:21][C:22]1[N:23]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:3]=3)[CH2:36]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 140 °C

Procedure:
255 mg (0.533 mmol) of methyl 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carboxylate (Example 16A), 259 mg (0.799 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.56 ml (3.2 mmol) of N,N-diisopropylethylamine were initially charged in 4.5 ml of DMSO. The mixture was heated at 140° C. in a microwave for 45 min. The crude product was purified by means of preparative HPLC (method 10). 28 mg (8% of theory) of the product were obtained in solid form.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[O:8][C:7]2([CH3:16])[CH3:15])([O-])=O>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[O:8][C:7]2([CH3:16])[CH3:15]
Reactant: CC1(C)OC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OC(C)(C)c2cc(N)ccc21
Reaction time: 48 h
Yield: 94.8 %

Procedure:
A solution of 5-nitro-1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran (Compound 77, 3.8 g, 16 mmol) in 40 mL of ethanol and 10 mL of ethyl acetate was treated with 5% Pd-C (0.38 g) and the resulting reaction mixture was stirred under an atmosphere of hydrogen for 2 days. The reaction mixture was filtered over a bed of Celite™ and the filtrate was evaporated to afford the title compound (2.9 g, 95%) with trace amount of starting material. 1H NMR (300 MHz, CDCl3): δ 6.86 (d, 1H, J=8.1 Hz), 6.59 (dd, 1H J=2.0, 8.1 Hz), 7.03 (d, 1H, J=8.0 Hz), 3.73 (br s, 2H), 1.48 (s, 6H), 1.47 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].ClCCl.C(=O)(O)[O-].[Na+].C[N+](C)(C)C.Cl[I-:24]Cl>O.CO>[I:24][C:7]1[C:6]([CH3:9])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cl[I-]Cl
Reactant: Cc1ccc(C)c(N)c1
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(I)c(C)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 2,5-dimethylaniline (20 g, 165 mmol) in a 1:1 mixture of dichloromethane and methanol (400 mL) was added sodium bicarbonate (20.8 g, 250 mmol) and tetramethylammonium dichloroiodate(I) (44.7 g, 165 mmol). The resulting mixture was stirred at room temperature for 1 hour and then water was added (500 mL). The organic layer was removed and washed with 5% aqueous sodium thiosulfate (500 mL) and brine (500 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 4-iodo-2,5-dimethylphenylamine (39.6 g, 98% yield). The product was used without further purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.S(Cl)(Cl)=O.ClCCCl.C1COCC1.[CH2:26]([C:28]1[C:36]2[C:35]([NH2:37])=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=2)[N:29]=1)[CH3:27]>C(Cl)Cl>[CH2:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[NH:37][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=2)[N:29]=1)[CH3:27]
Reactant: CCc1nn(Cc2cccc(OC)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CCc1nn(Cc2cccc(OC)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To imidazo[1,2-a]pyridine-3-carboxylic acid (194 mg, 1.20 mmol) in DCM (5 mL) was added thionyl chloride (2 mL). The reaction mixture was stirred for 2 hours and concentrated to give crude acylchloride HCl salt, to which DCE/THF (2 mL/2 mL) and 3-ethyl-1-((6-methoxypyridin-2-yl)methyl)-1H-indazol-4-amine (211 mg, 0.747 mmol) was added. The reaction mixture was heated to 70° C. and stirred for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 aqueous solution. The organic solution was dried over Na2SO4, filtered and concentrated. Silica gel chromatography (DCM/MeOH 10:1) provided the desired product (226 mg). MS (ES+APCI) m/z=427 (M+H).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li][CH2:12]CCC.CI>C1COCC1>[CH3:12][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [Li]CCCC
Reactant: Brc1cc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 2-bromoindole derivative 19-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. MeI (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0-15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 20-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 20-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 20-2 in 96% yield: MS-ES m/z 258.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>C1(C)C=CC=CC=1.C(OCC)(=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>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: O=C1Cc2ccc(Br)cc2N1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(-c3cccs3)cc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and thiophene-2-boronic acid (4.38 g, 34.2 mmol) in three portions over 1.5 hours. The mixture was stirred at 100° C. in an oil bath for 12 hours. The mixture was then diluted with ethyl acetate (400 mL) and washed with saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give 2.53 g (42%) of 6-thiophen-2-yl-1,3-dihydro-indol-2-one a tan solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO>[CH3:18][O:19][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)cnn2)c1
Agent: [Na+]
Solvent: CO
Product: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1
Yield: 74 %

Procedure:
5-Chloro-3-[3-(trifluoromethyl)phenyl]pyridazine (4 g, 0.015 mole, Compound No. 5) and NaOMe in MeOH (16.71 g of a 25% by weight solution, 0.077 mole) were stirred at RT under N2 in MeOH (100 mL) for 4 h. The mixture was then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude solid was recrystallized from ethyl acetate/cyclohexane to give 5-methoxy -3-[3-(trifluoromethyl)phenyl]pyridazine (2.92 g, 74% yield, Compound No. 8) as a brown solid.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.[Cl-].[NH4+]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a solution of methyl 2-hydroxyisobutyrate (1 g, 4.0 mmol) in THF (20 ml) was added sodium hydride (60% in parafin liquid) (115 mg, 4.8 mmol) at 0° C., and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 3-bromobenzyl bromide (567 mg, 4.8 mmol), and the mixture was stirred at 50° C. for 12 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (520 mg, 52%).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH:8](N)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([F:13])[CH:2]=1.[Br-:14].[K+].N([O-])=O.[Na+]>S(=O)(=O)(O)O.O>[Br:14][CH:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([F:13])=[CH:2][CH:1]=1)[C:9]([OH:11])=[O:10]
Reactant: [Br-]
Reactant: NC(Cc1ccc(F)cc1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)C(Br)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C., ice/salt bath) solution of DL-4-fluorophenylalanine (5.0 g, 27.0 mmol) and potassium bromide (10.65 g, 90.0 mmol) in 3M sulphuric acid (45 ml) was added sodium nitrite (2.64 g, 38.0 mmol) portionwise over a 0.5 h period. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The mixture was diluted with water (50 ml) and extracted with ether (2×75 ml). The combined extracts were washed with water (2×75 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (95:5:1) to give the title-acid (3.77 g, 56%), δ(250 MHz, CDCl3) 3.22 (1H, dd, J=14.3 and 7.2 Hz, CH of CH2), 3.43 (1H, dd, J=14.3 and 8.1 Hz, CH of CH2), 4.38 (1H, dd, J=7.2 and 8.1 Hz, CH), 6.98-7.31 (4H, m, Ar--H).
Reaction SMILES: C(OC([N:7]1[CH2:11][C:10](=[CH2:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=O)C=C.O.CCCC[SnH](CCCC)CCCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:15]([O:14][CH2:13][C@@H:8]1[CH2:9][C:10](=[CH2:12])[CH2:11][NH:7]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: C=CCOC(=O)N1CC(=C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: C=C1CN[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A catalytic amount of PdCl2(PPh3)2 (92 mg, 0.131 mmol) was added to a solution of the allyl carbamate 57 (1.0 g, 3.22 mmol) and H2O (0.34 mL, 18.9 mmol) in CH2Cl2 (30 mL). After 5 minutes stirring at room temperature, Bu3SnH (0.96 mL, 1.04 g, 3.57 mmol) was added rapidly in one portion. A slightly exothermic reaction with vigorous gas evolution immediately ensued. The mixture was stirred for 16 hours at room temperature under nitrogen at which point TLC (50% EtOAc/Petroleum Ether) revealed the formation of amine. After diluting with CH2Cl2 (30 mL), the organic solution was dried (MgSO4), filtered and evaporated in vacuo to give an orange oil which was purified by flash chromatography (50-100% EtOAc/Petroleum Ether) to afford the amine 58 as a slightly orange oil (0.56 g, 77%): [α]21D=−3.9° (c=5.0, CHCl3); 1H NMR (270 MHz, CDCl3) δ4.93 (t, 1H, J=2.02 Hz, NCH2C═CH2), 4.90 (t, 1H, J=2.02 Hz, NCH2C═CH2), 3.68-3.46 (m, 4H, NCHCH2OTBDMS and NCH2C═CH2), 3.30-3.21 (m, 1H, NCHCH2OTBDMS), 2.53-2.41 (m, 2H, NCH2C═CH2CH2 and NH), 2.26-2.17 (m, 1H, NCH2C═CH2CH2), 0.90 (s, 9H, SiC(CH3)3), 0.06 (s, 6H, Si(CH3)2); 13C NMR (67.8 MHz, CDCl3) δ150.0 (NCH2C═CH2), 104.7 (NCH2C═CH2), 64.7 (NCHCH2OTBDMS), 60.5 (NCHCH2OTBDMS), 51.3 (NCH2C═CH2), 34.9 (NCH2C═CH2CH2), 25.9 (SiC(CH3)3), 18.3 (SiC(CH3)3), −5.4 (Si(CH3)2); MS (EI), m/z (relative intensity) 227 (M+., 8), 212 (6), 170 (M—tBu, 36), 96 (8), 82 (M—CH2OTBDMS, 100), 75 (11); IR (Neat) 3550-3100 (br, NH), 3074 (C═CH12), 2929, 2857, 1664 (C═C), 1472, 1424, 1391, 1380, 1361, 1255, 1190, 1101, 1006, 939, 880, 838, 777, 723, 668 cm−1.