Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:43][C@H:44]1[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]1[OH:50].C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[C:3]([C:13]([NH:43][C@H:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]2[OH:50])=[O:15])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1c(C(=O)O)cc(Br)c2cccnc12
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Br)c2cccnc12
Reaction time: 3 h

Procedure:
To a solution of 8-amino-5-bromoquinoline-7-carboxylic acid (1.00 g, 3.74 mmol) in 20 mL of dichloromethane was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.99 g, 4.49 mmol), (1S,2S)-2-aminocyclohexanol (0.517 g, 4.49 mmol), and triethylamine (1.04 mL, 7.49 mmol). After 3 h, a brown solid was collected and washed with dichloromethane and water to provide 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-7-carboxamide that gave a mass ion (ES+) of 365.9 (81Br) for [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][N:9]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:6]2=[N:7][CH:8]=1)#[N:2].CC(C)[C@@H](NC1C=NC=C(C2C3C(=NC=C(COCCN4CCCC4)C=3)N(COCC[Si](C)(C)C)C=2)C=1)C(NCC(F)(F)F)=O>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][N:9]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:6]2=[N:7][CH:8]=1
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(C#N)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Ni]
Agent: CC(C)[C@@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(COCCN4CCCC4)cc23)c1)C(=O)NCC(F)(F)F
Solvent: CCO
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(CN)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of the 2-(5-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide, (9-1a) (110 mg, 187 mmol) 10-1a in ethanol (5.0 ml) was added Raney Nickel (2.197 mg, 0.037 mmol) Ammonium hydroxide (0.260 μl, 1.871 μmol) was added and the flask evacuated and backfilled with hydrogen gas 3 times. The mixture was stirred under hydrogen for 17 hrs. The reaction was purged with nitrogen, diluted with ethanol and filtered through a pad of celite. The filtrate was concentrated and oil purified by Reverse phase HPLC (Water:ACN w/0.1% TFA, C-18, 35-65% gradient). The pure fractions concentrated to remove acetonitrile and mixture neutralized with saturated sodium bicarbonate. The product was extracted with ethyl acetate (3×20 mL). The organics were dried with sodium sulfate, filtered and concentrated to afford the product 10-1b as a solid (50 mg, 47%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:13]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19](Cl)[C:14]=3[N:15]=[C:16]([Cl:18])[N:17]=2)[CH:7]=[CH:8][C:9]=1[F:10]>O.[OH-].[Na+].C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:13]3[N:22]=[C:21]([Cl:23])[NH:20][CH2:19][C:14]=3[N:15]=[C:16]([Cl:18])[N:17]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc(Nc2nc(Cl)nc3c(Cl)nc(Cl)nc23)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2nc(Cl)nc3c2N=C(Cl)NC3)cc1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
At 2° C. a solution of 191.99 g (5.079 mol) of sodium borohydride in 520 ml of water and 22 ml of 2N sodium hydroxide solution is added dropwise to a suspension of 1100 g (2.902 mol) of (1) in 22 l of ethyl acetate. The mixture is stirred for 2 hours at 10° C. and then heated to 71° C. The suspension is filtered through Celite and cooled to 0° C. The product that crystallises out is filtered off and dried at 40° C. until a constant weight is attained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[N:19]=[CH:18][CH:17]=[CH:16][C:9]=2[C:10]([NH:12][CH2:13][C:14]#[CH:15])=[O:11])=[CH:4][CH:3]=1.[N:22]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=1)=[N+:23]=[N-:24].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[N:19]=[CH:18][CH:17]=[CH:16][C:9]=2[C:10]([NH:12][CH2:13][C:14]2[N:24]=[N:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:27]=3)[CH:15]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)c1cccnc1NCc1ccc(Cl)cc1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(NCc1cn(Cc2cccc(Oc3ccccc3)c2)nn1)c1cccnc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-(4-chlorobenzyl)aniline (9k, 217 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-chlorobenzylamino)-N-(prop-2-ynyl)nicotinamide 10k as pure product. To a solution of 2-(4-chlorobenzylamino)-N-(prop-2-ynyl)nicotinamide (10k, 150 mg, 0.50 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 124 mg, 0.55 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1k (184 mg, 60%); mp: 209-211° C.; 1H NMR (300 MHz, CDCl3) δ 8.45 (t, J=5.2 Hz, 1H), 8.14-8.11 (m, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.50 (brs, 1H), 7.45 (s, 1H), 7.27-7.13 (m, 7H), 7.02 (t, J=7.5 Hz, 1H), 6.90-6.80 (m, 5H), 6.36-6.32 (m, 1H), 5.33 (s, 2H), 4.60 (d, J=5.2 Hz, 2H), 4.49 ppm (d, J=6.0 Hz, 2H); MS (ESI m/z): 525 [M+H]+. Yield: 60%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19](O)=[O:20])[CH:2]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([NH:22][C:19](=[O:20])/[CH:18]=[CH:17]/[C:8]3[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:31]=2)[CH:27]=[CH:28]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1)Nc1ccc2cc[nH]c2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 6-aminoindole (59 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-50% EtOAc in hexane), the title compound as an amorphous orange solid. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[CH:13][C:12]2=[O:26])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[CH:13][C:12]2=[O:26]
Reactant: Cc1ccccc1-c1cc(=O)c2cc(OCc3ccccc3)ccc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(=O)c2cc(O)ccc2o1

Procedure:
6-Benzyloxy-2-(2-methylphenyl)-4H-chromen-4-one (mp 115°) is hydrogenated in ethyl acetate over palladium (10% on charcoal) at atmospheric pressure and room temperature for 1 hour. The mixture is filtered over celite, and the filtrate is evaporated in vacuo. The title compound is obtained (colourless crystals; mp 180°).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:26]([O-])=O)=[C:19]([CH2:20][C:21](OCC)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP(O)(O)=O>[Pt].C(O)C>[CH2:1]([NH:8][CH2:9][C@@H:10]1[O:11][C:12]2=[C:19]3[C:18](=[CH:17][CH:16]=[C:13]2[O:14][CH2:15]1)[NH:26][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])ccc2c1O[C@@H](CNCc1ccccc1)CO2
Agent: [Pt]
Agent: O=P(O)(O)O
Solvent: CCO
Product: O=C1Cc2c(ccc3c2O[C@@H](CNCc2ccccc2)CO3)N1
Temperature: 40 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
In a 500 mL Parr shake flask is charged crude ethyl {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetate (6.02 g, 14.5 mmol), ethanol (50 mL) and Pt—C (5% on carbon, 50% w/w water, 1.0 g). The flask is pressurized to 30 psig and shaken for 18 h. The pressure is released, the catalyst is removed by filtration through celite, and ethanol (20 mL) is used to rinse the filter cake. To the solution is added 85% H3PO4 (1.21 mL, 17.4 mmol) and the mixture is heated to 40° C. for 36 h. The solution is filtered through celite and the volatiles are removed. The residue is suspended in isopropyl acetate (50 mL), THF (25 mL) and 1 N NaOH is added until pH 10 is obtained. The organic extracts are washed with water and then with brine treated with Darco 12-20Li (0.5 g), filtered through celite and evaporated giving crude title compound (2.50 g, 55%) as a red-orange syrup. LCMS (Basic Method): 1.84 min, 311 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.4 (br s, 1H), 7.35-7.27 (m, 5H), 6.73 (d, J=8.3 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 4.37-4.35 (m, 1H), 4.25 (dd, J=2.2, 11.5 Hz, 1H), 4.03 (dd, J=7.3, 11.5 Hz, 1H), 3.88 (s, 2H), 3.44 (s, 2H), 2.97-2.88 (m, 2H), 8.9 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.C(OCC)(=O)C>CN(C)C=O.O1CCCC1>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:37])[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1NC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 1.75 g (3.43 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2′-methyl-4-nitro-biphenyl-2-yl)-isobutyramide in 11 ml N,N-dimethylformamide under argon 4.1 ml (4.1 mmol) of 1 M potassium hexamethyldisilazide solution in tetrahydrofuran were added dropwise at 0°. Stirring was continued for 1 h at room temperature and the reaction mixture was cooled to 0° again. At this temperature, 0.32 ml (5.14 mmol) methyl iodide were added. After stirring for 3 hrs at room temperature, ethyl acetate was added and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/hexane 1:1) to give 1.0 g (56%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2′-methyl-4-nitro-biphenyl-2-yl)-isobutyramide as yellow crystals, MS (EI):524(M+).
Reaction SMILES: [C:1]([C:5]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([C:5]1[C:12]2[S:11][C:10]([NH:13][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])=[N:9][C:8]=2[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1n[nH]c2nc(N)sc12
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1n[nH]c2nc(NC(=O)c3ccco3)sc12
Temperature: 70 °C
Reaction time: 23 h
Yield: 81 %

Procedure:
To a stirring solution of 3-tert-Butyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.153 mmol) and pyridine (74 μL, 0.92 mmol), or alternatively PS-DMAP (Argonaut resin, 6 equiv.), in THF (0.75 mL) was added furan-2-carbonyl chloride (75 μL, 0.76 mmol). The reaction mixture was stirred at 70° C. for 23 h, then cooled to room temperature and treated with THF (1 mL) and PS-trisamine (Argonaut resin, 20 equiv.) for 2 h. The resin was filtered, washed with DMF and the solvent was evaporated. The residue was treated with MeOH (1 mL) and a 4N aqueous solution of NaOH (0.25 mL) and the solution was stirred at room temperature for 2 h. The reaction mixture was neutralized to pH 7 with a 1N aqueous solution of HCl and extracted with ethyl acetate (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 36 mg (82%) of furan-2-carboxylic acid (3-tert-butyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as an off-white solid. 1H-NMR (d6-DMSO) δ: 12.8 (broad s, 1H, NH), 12.7 (broad s, 1H, NH), 8.03 (d, 1H), 7.69 (broad s, 1H), 6.74 (dd, 1H), 1.36 (s, 9H); HPLC/MS m/z: 291 [MH]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([C:1](=[O:3])[CH3:2])[CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2cc3c(n2C2CC2)CCCNC3)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2c(cc(-c3ccccc3)n2C2CC2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.9 g. of acetyl chloride in 25 ml. of chloroform is added to a cooled solution of 11.0 g. of 1-cyclopropyl-2-phenyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine and 5.0 g. of triethylamine in 50 ml. of dry chloroform. The mixture is stirred at ambient temperature for 20 hours, washed with water, dried, and concentrated to provide 1-cyclopropyl-2-phenyl-5-acetyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine as an oil. The oil is treated according to the manipulative procedure described above in Example 2, to give crystals, m.p. 85°C. dec., of 1-cyclopropyl-2-phenyl-5-ethyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine oxalate.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@H:7]([CH2:10][NH2:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@H:7]([CH2:10][NH:11][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: NC[C@@H]1COc2cc(O)ccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNC[C@@H]3COc4cc(O)ccc4O3)cc2o1
Temperature: 94 °C

Procedure:
(R)-2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (2.58 g, 14.2 mmole), 7-(3-chloropropoxy)coumarin (3.08 g, 12.9 mmole), diisopropylethylamine (10 ml, 57 mmole) and sodium iodide (1.98 g, 13.2 mmole) were combined in 175 ml of DMF and heated at 94° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum. The residue was twice column chromatographed on silica gel using 1% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.45 on silica gel with 5% methanol/dichloromethane) were combined and concentrated in vacuum and the pure free base redissolved in methanol and boiled on a hot plate, the methanol gradually being replaced with isopropanol. 4N HCL/isopropanol was added and the title compound was collected by filtration. After two additional recrystallizations from isopropanol, 0.35 g of white solid, monohydrochloride, m.p. 236°-242° C., was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[OH:16].[CH3:17][CH:18]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:19].N1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[O:16][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:19])[CH3:17]
Reactant: COc1cc2c(cc1O)CC(C)(C)NC2C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2C
Yield: 105.9 %

Procedure:
239 (183 mg, 0.83 mmol), TIPS-Cl (237 mg, 3.5 mmol) and imidazole (237 mg, 3.5 mmol) in DCM (10 ml) were stirred at rt for 24 h. The reaction mixture was quenched with water (5 ml) and extracted with DCM (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (personal flashmaster: 20 g, EtOAc:MeOH:TEA; 100:10:1) afforded the title compound (332 mg) as a yellow oily solid. 1H NMR (270 MHz; CDCl3) 1.07 (18H, d, J=6.4 Hz, 6×CH3CH), 1.08 (3H, s, CH3), 1.15-1.28 (3H, m, 3×CHCH3), 1.25 (3H, s, CH3), 1.21 (3H, d, J=6.4 Hz, CH3CH), 2.44 (1H, d, J=15.8 Hz, CHH), 2.65 (1H, d, J=15.8 Hz, CHH), 3.74 (3H, s, OCH3), 4.0 (1H, q, J=6.4 Hz, CHCH3), 6.46 (1H, s, CH), 6.67 (1H, s, CH). LC/MS (ES+) tr=1.8 min, m/z 378.24 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(F)c(Cl)c2)cc1
Yield: 89.3 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 6.43 g (20.6 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 5.37 g (30.9 mmol) of 3-chloro-4-fluorophenylboronic acid. Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) gave 6.64 g (89%) of 2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 179.5-181.1° C.; NMR (CDCl3) δ 3.06 (s, 3H), 6.86-6.93 (m, 1H), 6.98 (t, J=8 Hz, 1H), 7.19 (dd, J=2, 7 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.38-7.53 (m, 4H), 7.84 (d, J=9 Hz, 2H). MS (FAB): m/e 367 (M+Li); HRMS Calc'd for C19H14ClFO2S: 360.0387. Found: 360.0401. Anal. Calc'd for C19H14ClFO2S: C, 63.25; H, 3.91; F, 5.27. Found: C, 62.92; H, 4.02; F, 5.19.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:14])=[C:9](/[CH2:12][CH3:13])\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:15]([O:17][C@@H:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:14])=[C:9](/[CH2:12][CH3:13])\[CH2:10][O:11][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:18]([O:17][CH2:15][CH3:16])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC/C(CO)=C(\C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(CC)=C(/C)c2ccc(Br)cc2)cc1)OCC
Yield: 81 %

Procedure:
The title compound (535 mg, 81%) was prepared from (Z)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (prepared as described in example 96b) (355 mg, 1.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (348 mg, 1.46 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]CC=C)=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].CN(C)[C:25]1[CH:30]=CC=C[CH:26]=1>>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[C:7]([CH2:30][CH:25]=[CH2:26])[C:6]=1[C:19]([CH3:22])([CH3:20])[CH3:21])(=[O:3])[CH3:2]
Reactant: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Reactant: CN(C)c1ccccc1
Product: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-1-(2-propenyloxy)benzene (11.0 g) was dissolved in N,N-dimethylaniline (50 ml) and the solution was refluxed for 18 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (15% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol [8.84 g (yield, 77%)] as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10](=O)[NH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]2=[N:8][CH:9]=1
Reactant: O=c1cnc2c(Cl)nccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnc2c(Cl)nccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A suspension of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one (0.57 g, 3.14 mmol) in phosphorus oxychloride (10.24 mL, 110 mmol) was stirred at 110° C. for two hours, and then concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (580 mg, 2.90 mmol). MS m/z=200 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:29][CH2:30][CH2:31][NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[C:35]([NH2:45])[N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>COCCOC>[NH2:45][C:35]1[N:34]=[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:15]2[N:14]3[N:13]=[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:46])=[O:3])[CH2:7][CH2:8]4)[N:20]=[C:19]3[CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:16]=2)[CH:38]=[CH:37][C:36]=1[C:39](=[O:44])[C:40]([F:41])([F:43])[F:42]
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC(=O)O)CC4)nn23)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
130 mg (0.19 mmol) of ethyl(4-{5-[(2-{[6-amino-5-(trifluoroacetyl)pyridin-2-yl]amino}ethyl)-amino]-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}piperidin-1-yl)acetate (Example 56A) were dissolved in 1,2-dimethoxyethane (7.5 ml), water (5 ml) and 31 mg (0.76 mmol) of sodium hydroxide were added and the reaction mixture was stirred at RT for 16 h. The mixture was then concentrated by lyophilization. This gave, after purification of the residue by preparative HPLC (Method 11), 60 mg (48% of theory) of the product as a solid.