Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13])=O.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:21][OH:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13]
Reactant: Cc1cccc(C(=O)c2ccc(O)c(Cl)c2Cl)c1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(C(=NO)c2ccc(O)c(Cl)c2Cl)c1C

Procedure:
A mixture of 31 g of 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone and 30.5 g of hydroxylamine hydrochloride in 250 ml of pyridine is refluxed for about one week. The pyridine is evaporated in vacuo and the residue is partitioned between ethyl acetate and 5% HCl. The ethylacetate extract is washed, dried over Na2SO4 and evaporated. Trituration with hexane gives 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]=[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]2[C:34]=1[C:35](O)=[O:36]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]3=[N:26][C:25]=2[CH3:24])=[O:36])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc2c(C)cccn2c1C(=O)O
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3c(C)cccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,8-Dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[N:15]1([CH2:14][CH2:13][N:8]2[C:7]3[CH:20]=[CH:21][C:4]([NH2:1])=[CH:5][C:6]=3[O:12][CH2:11][CH2:10][CH2:9]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCCN2CCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)OCCCN2CCN1CCCC1

Procedure:
10% Palladium on Carbon (50% Wet) (174 mg) and 3-Nitro-9-(2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (270 mg, 0.93 mmol) in Ethanol (15 mL) was shaken under an atmosphere of Hydrogen (40 psi) overnight. The mixture was filtered over Celite, washing with 60 mL ethanol. After conc., 9-(2-Pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine was obtained as an oil (224 mg, 92%). 1H-NMR (CDCl3): 6.80 (d, 1H, J=8.0 Hz), 6.34 (m, 2H), 4.05 (m, 2H), 3.44 (br s, 2H), 3.27 (m, 2H), 3.14 (t, 2H, J=5.6 Hz), 2.65 (t, 2H, J=7.2 Hz), 2.56 (m, 4H), 1.98 (m, 2H), 1.78 (m, 4H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:13].[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][C@H:15]([OH:16])[CH3:17])=[CH:6][C:5]=1[F:13]
Reactant: Fc1cc2cc[nH]c2cc1Cl
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)Cn1ccc2cc(F)c(Cl)cc21
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.42 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 85 hours and subsequently treated with is water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene/ethyl acetate (19:1). There was obtained 0.51 g (74.6%) of (R)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as white crystals (m.p. 104°-105°.)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:18]=1[CH2:19]Cl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(Cl)Cl.CC(C)=O>[CH3:14][C:12]1[N:13]=[C:3]2[C:2]([NH:1][CH2:19][C:18]3[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:17]=3[CH3:16])=[CH:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][N:4]2[C:11]=1[CH3:15]
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 83.4 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (0.6 g, 2.9 mmol), 2,6-dimethylbenzylchloride (0.45 g, 2.9 mmol), sodium carbonate (1.0 g, 9.4 mmol) and potassium iodide (0.2 g, 1.3 mmol) were added to acetone (25 ml) and refluxed for 19 h. Methylene chloride was added and inorganic salts were filtered off. The solution was washed with a bicarbonate solution, the organic layer was separated, dried and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent and the product was washed with diethyl ether to give 0.78 g (82%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(F)(F)C1C=CC=CC=1>[Br:19][CH2:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1cc(F)cc(CBr)c1
Temperature: 105 °C
Yield: 6.3 %

Procedure:
A solution of 3-fluoro-5-nitrotoluene (1.0 g, 6.45 mmol) in trifluorotoluene (15 ml) was treated with NBS (1.721 g, 9.67 mmol) and AIBN (0.212 g, 1.289 mmol) and heated at 105° C. overnight. The mixture was cooled to RT, the solids removed via filtration and the filtrate concentrated to dryness to afford 1-(bromomethyl)-3-fluoro-5-nitrobenzene (95 mg, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C(O)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2cn(-c3ccncc3)c3cc(Cl)ccc23)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Fc1ccc(-c2cn(C3CCNCC3)c3cc(Cl)ccc23)cc1
Yield: 81.8 %

Procedure:
6-Chloro-3-(4-fluorophenyl)-1-(4-pyridyl)-lH-indole 2e (1.8 g) was dissolved in acetic acid (100 ml) and PtO2 (0.2 g) was added. After hydrogenation for 30 h at 3 ato the catalyst was filtered off, the acetic acid was evaporated in vacuo and water (50 ml) was added. The acidic solution was made alkaline (pH>9) with concentrated sodium hydroxide and extracted with ethyl acetate (2×50 ml). The combined organic phases were successively washed with diluted sodium hydroxide (50 ml), washed with brine, and dried (Na2SO4). Evaporation of the solvent gave 1.5 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH3:32][O:33][C:34]1[N:39]=[C:38]([O:40][CH3:41])[C:37](B(O)O)=[CH:36][N:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:37]5[C:38]([O:40][CH3:41])=[N:39][C:34]([O:33][CH3:32])=[N:35][CH:36]=5)=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(Br)cc4)oc3C)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(-c5cnc(OC)nc5OC)cc4)oc3C)ccc21
Temperature: 85 °C
Yield: 45 %

Procedure:
To a solution containing (1S)-(5-{2-[2-(4-bromo-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}-indan-1-yl)-acetic acid ethyl ester (0.100 g, 0.21 mmol), 1,1′-phosphino)ferrocene]dichloro palladium(II) (16.9 mg, 0.02 mmol), and 2,4-dimethoxy-pyrimidin-5-boronic acid (0.076 g, 0.41 mmol) in degassed toluene and dioxane (4:1, 2 mL) was added aqueous 2 M sodium carbonate (0.5 mL). The mixture was heated at 85° C. for 16 hours. The reaction mixture was cool to rt and concentrated under vacuum and the residue was dissolved in methanol and acetonitrile and filtered through a C8 reverse phase extraction cartridge. The filtrated concentrated and the residue was purified by preparative HPLC to obtain [(1S)-5-(2-{2-[4-(2,4-dimethoxy-pyrimidin-5-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-indan-1-yl]-acetic acid ethyl ester in 45% yield, (50 mg, 0.09 mmol). 1H NMR (CD3Cl) δ 1.3 (t, 3H), 1.8 (m, 1H), 2.4 (m, 5H), 2.9 (m, 3H) 3.1 (t, 2H), 3.5 (m, 1H), 4.1 (s, 6H), 4.2 (m, 4H), 6.7 (m, 2H), 7.1 (d, 1H) 7.8 (d, 2H), 8.4 (s, 1H); MS (ES) 544 (M+1)+.
Reaction SMILES: O.COC1C=C[N+]([O-])=CC=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.[C:23]([CH:28]1[CH2:32][C:31]2([CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[O:30][C:29]1=[O:38])(=[O:27])[CH:24]([CH3:26])[CH3:25]>CS(C)=O.C(=O)(O)[O-].[Na+].O>[C:23]([C:28]1[C:29](=[O:38])[O:30][C:31]2([CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:32]=1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)C1CC2(CCOCC2)OC1=O
Agent: COc1cc[n+]([O-])cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(=O)C1=CC2(CCOCC2)OC1=O
Reaction time: 0.33 h

Procedure:
2.16 g 4-Methoxypyridine-1-oxide hydrate and 5.57 g 2-iodoxybenzoic acid (45 wt-%) are suspended in 20 ml dimethylsulfoxide and stirred for 20 minutes until all material has dissolved. Then 3.0 g 3-isobutyryl-1,8-dioxaspiro[4.5]decan-2-one are added and the mixture is stirred for 24 hours. The mixture is diluted with saturated solution of sodium bicarbonate in water and the formed precipitate is filtered off. The mother liquour is extracted for three times with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 40:60).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([OH:23])CCC.[OH-].[K+]>Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:23])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(CC#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(CC(N)=O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 75 %

Procedure:
To a solution of 3-(2-fluoro-biphenyl-4-yl)butyronitrile in tent-butyl alcohol was added 1.87 g of finely powdered potassium hydroxide. The resulting suspension was stirred and heated to 70° C. for 2.5 hours and cooled to room temperature. The reaction suspension was diluted with 1.0 N HCl solution (100 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were combined and washed with 5% bicarbonate solution (100 mL) and then with H2O (100 mL). The organics were then dried over MgSO4, and concentrated to a white solid which was re-crystallized several times with EtOAc/Hex to give white flaky prisms (1.62 g, 75% yield).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[F:23][C:24]([F:36])([F:35])[C:25]1[NH:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:34][C:32]4[CH:31]=[CH:30][C:28]5[N:29]=[C:25]([C:24]([F:36])([F:35])[F:23])[NH:26][C:27]=5[CH:33]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)cc1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 2-trifluoromethyl-3H-benzimidazol-5-ylamine (78 mg, 0.38 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 34 mg (26%) of brown powder; LC/MS: 473 (M+H); HPLC: 95% pure, RT=2.99 min; 1H NMR: (DMSO, δ) 9.73 (s, 1H), 9.09 (s, 1H), 8.51 (d, J=8.4, 2H), 8.40 (s, 1H), 8.13 (br s, 1H), 8.04 (d, J=8.4, 2H), 7.71 (m, 2H), 7.38 (d, J=4.9, 1H), 7.03 (d, J=4.9, 1H), 3.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[CH3:35])[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[CH3:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
Example 52 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.53 (t, 1H, J=4.8 Hz), 7.28–7.22 (m, 8H), 7.12 (dd, 1H, J=2.0, 8.4 Hz), 7.03 (d, 1H, J=8.0 Hz), 4.80 (s, 1H), 3.36 (dd, 2H, J=6.0, 11.6 Hz), 2.91 (d, 2H, J=14.0 Hz), 2.64 (m, 1H), 2.47 (m, 1H), 2.38 (t, 2H, J=5.6 Hz), 2.24 (s, 3H), 2.00–1.93 (m, 2H), 1.70–1.56 (m, 6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 580.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:30]([OH:32])[CH3:31])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CC=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetaldehyde was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.06(s,2H), 4.84(m,1H), 6.08(s,1H), 3.73(d,1H), 3.35(m,1H), 2.14(s,3H), 2.12(s,3H), 2.11(s,6H), 1.4–1.7(m,4H), 1.51(d,3H), 0.96(t,6H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([CH3:25])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.[I-].[Na+]>[CH3:25][C:17]1[CH:16]=[C:15]([CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(CC(=O)O)cc2)c2ccccc2n1
Yield: 75.7 %

Procedure:
To a solution of methyl (4-hydroxyphenyl)acetate (10.0 g, 60.2 mmol) in 400 mL THF was added 4-chloromethyl-2-methylquinoline (11.5 g, 60.2 mmol), cesium carbonate (29.4 g, 90.3 mmol), and sodium iodide (451 mg, 3 mmol). The reaction was heated to reflux for 72 hr, after which the reaction was extracted from sat KH2PO4 with EtOAc×3. The combined organic layers were dried with MgSO4, filtered, and concentrated. This residue was taken up in 200 mL MeOH and treated with 1 M NaOH (100 mL) for 16 hr. The reaction was treated with dilute KH2PO4 and EtOAc. A solid formed between the layers that was filtered through a sintered glass funnel and recrystallized from EtOH/water to give 14 g (76%) of the product acid. MS found: (M+H)=308.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][C:22]([N:1]2[CH2:10][CH2:9][CH2:8][C:7]3[N:6]=[CH:5][C:4]4[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=4[C:2]2=3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c3c(ncc2c1)CCCN3
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CCCc2ncc3ccccc3c21

Procedure:
1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine (3.22 g) was treated with cold phenylacetyl chloride (35 ml). Most of the material dissolved and then a precipitate separated. The mixture was diluted with ether (50 ml), and the precipitate was isolated by vacuum filtration and washed twice with ether. The filter cake was dissolved in water (100 ml), and the solution was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×100 ml). The combined and dried (Na2SO4) organic phase was filtered and concentrated to an oil (5.4 g), which was purified by HPLC (silica gel, eluted with ethyl acetate). The appropriate fractions were combined and concentrated to an oil (4.76 g). Trituration with ether and seeding (seed crystals formed on the neck of the flask which contained the oil) gave 2.68 g of crystals, m.p. 88.5°-89.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:36][C:33]1[CH:32]=[N:31][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH2:25][CH2:26]2)=[N:35][CH:34]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CS(=O)(=O)OCC1CCN(c2ncc(F)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc(OCC3CCN(c4ncc(F)cn4)CC3)cn2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 0.15 g, 0.60 mmol), [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methyl methanesulfonate (0.234 g, 0.81 mmol) and K2CO3 (0.17 g, 1.20 mmol) in DMF (6 mL) was stirred at 100° C. in a preheated oil bath for 2.5 h. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a light brown solid. The crude product was purified by chromatography on a silica gel column eluted with 1:30 acetone/CH2Cl2 then 1:20 acetone/CH2Cl2 to give 0.132 g (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.30 (s, 1H), 8.18 (s, 2H), 8.11 (d, 2H, J=8.0 Hz), 8.02 (d, 2H, J=8.1 Hz), 4.80-4.65 (m, 2H), 4.25 (d, 2H, J=6.6 Hz), 3.07 (s, 3H), 3.00-2.85 (m, 2H), 2.10-2.05 (m, 1H), 2.00-1.85 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[C:10]1([S:16]([OH:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Cl-].[Ca+2]>C(Cl)Cl>[C:10]1([S:16]([CH:5]2[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[O:4]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1CCC(OC)O1
Reactant: O=S(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COC1CCC(S(=O)(=O)c2ccccc2)O1
Reaction time: 4 h
Yield: 55 %

Procedure:
2,5-Dimethoxytetrahydrofuran (17.1 ml, 0.13 M) was added dropwise to a stirred solution of benzenesulphinic acid (17.0 g, 0.12 M) in dry DCM (100ml) containing a suspension of powdered CaCl2 (1.0 g) at room temperature under argon. After 4 h, the solution was washed with water (2×50 ml), dried (Na2SO4) and evaporated. The product was crystallised (diethyl ether/hexane) to give 2-benzenesulphonyl-5-methoxytetrahydrofuran (15 9 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C([O:40][C:41](=O)[C:42]1[C:47]([CH2:48]Br)=[CH:46][CH:45]=[CH:44][C:43]=1[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][N:27]3[CH2:48][C:47]4[C:42](=[C:43]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:52])[CH3:53])[CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:40])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN2Cc3cccc(O[Si](C)(C)C(C)(C)C)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
To a solution of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (80 mg, 0.20 mmol) and diisopropyl ethylamine (35 μl, 0.40 mmol) in acetonitrile (10 ml) at room temperature was added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (69 mg, 0.20 mmol). The solution was stirred for 12 hours at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with 20% ethyl acetate/hexane to yield 42 mg (33%) of 2-amino-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.