Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.FC1C=CC=C(F)C=1NC(N1CCC(OC2C=CC(NC3C4C=C(F)N=CC=4N=CN=3)=CC=2C)CC1)=O>>[CH:32]1([NH:37][C:38]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:15][C:16]4[C:17]5[CH:25]=[C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)[N:23]=[CH:22][C:18]=5[N:19]=[CH:20][N:21]=4)=[CH:3][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C=NC1CCCC1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)Nc2c(F)cccc2F)CC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCN(C(=O)NC2CCCC2)CC1

Procedure:
The title compound was prepared from [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine and cyclopentyl isocyanate by a procedure analogous to the synthesis of 4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid (2,6-difluoro-phenyl)-amide above. LRMS: 532.3/421.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.57 (s, 1H), δ 8.78 (s, 1H), δ 8.32 (s, 1H), δ 7.48-7.54 (m, 3H), δ 7.12 (d, J=9.14 1H), δ 6.24 (d, J=7.30, 1H), δ 4.50-5.19 (m, 1H), δ 3.84-3.89 (m, 1H), δ 3.74-3.76 (m, 4H), δ 3.51-3.59 (m, 6H), δ 3.12-3.18 (m, 2H), δ 2.16 (s, 3H), δ 1.81-1.86 (m, 4H), δ 1.29-1.76 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([Si:15]([CH3:24])([CH3:23])[O:16][CH:17]([CH:20]1[CH2:22][CH2:21]1)[CH2:18]O)([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:11]([Si:15]([CH3:24])([CH3:23])[O:16][CH:17]([CH:20]1[CH2:22][CH2:21]1)[CH2:18][O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC(CO)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidin-5-ol (250 mg, 1.25 mmol), 2-(tert-butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethanol (407 mg, 1.88 mmol) and triphenylphosphine (493 mg, 1.88 mmol) in THF (12 mL) was added DIAD (370 μL, 1.88 mmol). The reaction mixture was stirred at RT for 18 hours before being concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-30% ethyl acetate in cyclohexane) to give 5-[2-(tert-Butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,4,6-trichloro-pyrimidine as a viscous yellow oil (411 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 4.14 (1H, dd, J=8.83, 6.02 Hz), 3.99 (1H, dd, J=8.82, 4.21 Hz), 3.60-3.53 (1H, m), 1.13-1.03 (1H, m), 0.89 (9H, s), 0.56-0.50 (2H, m), 0.46-0.28 (2H, m), 0.10 (3H, s), 0.07 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:21]S(C(C)(C)C)=O)[CH2:18][CH2:19][OH:20]>CO>[NH2:21][C:5]1([CH2:18][CH2:19][OH:20])[C:6]2[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([F:13])[C:7]=2[O:14][C:15]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=2
Reactant: CC(C)(C)S(=O)NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Solvent: CO
Product: NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 12.14 mmol) in dry MeOH (100 mL) at −20° C. was added a mixture of MeOH (80 mL)acetylchloride (20 ml). The resulting reaction mixture was stirred at −20° C. for 30 min and then quenched with 10% aqueous solution of Na2CO3. DCM was added, the organic phase was separated and dried over Na2SO4. The solution concentrated under reduced pressure and the residue was purified by chromatography (0-50% EtOAc/hexanes) to afford 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (4.0 g, 10.71 mmol, 88% yield) as a light yellow solid-foam.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:22][CH3:23].O1CCOCC1>O>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=[C:8]2[C:7]3[C:2]([Br:1])=[C:3]([O:22][CH3:23])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1ccccc1)CC3=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2oc3c(O)cc(-c4ccccc4)nc3c2c1Br
Temperature: 110 °C
Yield: 91.7 %

Procedure:
A mixture of 13B (2.0 g, 0.0053 mol), FeCl3.6H2O (6 g) and 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 13C (1.8 g, 90.4% yield).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Oc2ccccc2)c1
Yield: 99 %

Procedure:
To a solution of (3-(phenyloxy)phenyl)methanol (10 g, 49.4 mmol) in chloroform (20 ml) was added thionyl chloride (36 ml, 500 mmol) and the mixture was heated under reflux overnight. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1-(chloromethyl)-3-(phenyloxy)benzene (10.7 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: CCCCC(CC)CN
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl-n-hexylamine (0.33 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(4-(naphthalen-2-yloxy)butyl)amine, solid, m.p. 94° C., (yield 0.61 gm, 87.3%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCC2CC2)ccc1CBr
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a mixture of 4-(cyclopropylmethoxy)-1-methyl-2-nitrobenzene (66.4 g) and a solution of N-bromosuccinimide (68.4 g) in ethyl acetate (1.0 L) was added 2,2′-azobis(2-methylpropionitrile) (2.63 g) in 5 portions at 90° C. The reaction mixture was stirred at 90° C. overnight. To the reaction mixture were added N-bromosuccinimide (34.2 g) and 2,2′-azobis(2-methylpropionitrile) (1.32 g) at 90° C. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and left standing overnight. The resulting crystals were collected by filtration, washed with methanol, and dried under reduced pressure to give the title compound (49.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)=[CH:13][CH:12]=2)=[O:10])=[C:2]([OH:1])[CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1O
Yield: 119.9 %

Procedure:
To a suspension of (2,4-dihydroxy-phenyl)-(4-hydroxy-phenyl)-methanone (9.2 g, 40 mmol) and oven dried potassium carbonate (11.6 g, 84 mmol) in acetone refluxing at 60° C., was added benzyl bromide (10 mL, 83 mmol) in two portions of 5 mL each, dropwise. The reaction was refluxed for 12 hours and solids were filtered and washed with 100 ml of CH7Cl2. The solvents combined and evaporated to give yellow product along with some tribenzylated side product, which was recrystallized from CH2Cl2:hexane (1:5) to get (9.84 g, 60%) of pure product T1. 1H NMR (400 MHz, DMSO-d6) δ, 7.4 (m, 12H, Ar—H2′/6′, 2×C6H5), 6.97 (m, 3H, Ar—H3′/5′, Ar—H6), 5.84 (d, 1H, Ar—H3), 5.6 (dd, 1H, Ar—H5), 5.14 (s, 2H, PhCH2), 4.94 (s, 2H, PhCH2).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCCc3ccc(-c4ccccc4)cc3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(1,1′-biphenyl-4-yl)ethylamine gave the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:38]([BH3-])#N.[Na+].[OH-].[Na+].Cl>CCOCC.C(O)(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH3:38])[CH:16]2[C:19]2([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=3)[CH2:20][CH2:21][CH2:22]2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccc(OC(F)(F)F)cc3)CCC1)NCC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccc(OC(F)(F)F)cc3)CCC1)N(C)CC2
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-benzyloxy-6-methoxy-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline (4.1 g, prepared in a similar manner to that described in Example RC18), 37-40% aqueous formaldehyde solution (4.4 ml), acetonitrile (90 ml) and sodium cyanoborohydride (2.32 g) was stirred at 5° C. for 15 minutes, then neutralised with glacial acetic acid and stirred for a further 16 hours. The mixture was poured into dilute aqueous sodium hydroxide solution and extracted with ethyl acetate. The extracts yielded a gum which was dissolved in ether and treated with hydrogen chloride to give 7-benzyloxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.
Reaction SMILES: O[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]c(O)nc2c1
Product: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Yield: 40 %

Procedure:
According to the procedure of A. T. James, et al., J. Chem. Soc., 1515 (1950), a mixture of 2-hydroxy-5-nitro-1H-benzimidazole (10.0 g, 0.0558 mol) and phosphoryl chloride (100 mL) was heated under reflux for 3 hours. The mixture was cooled, concentrated, and ice water was added. The resulting precipitate was collected by filtration. NMR analysis showed the material to be a 1:1 mixture of starting material and product. (Note: Longer heating does not improve the conversion.) Purification by flash chromatography (material preadsorbed onto silica; eluent 40% EtOAc/hexane) gave 4.4 g (40%) of the off-white solid product m.p. 215°-217° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(OCc2ccccn2)cc1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a suspension of sodium hydride (60% active, 125 mg) in dimethylformamide (2 ml) at ambient temperature was added ethyl 4-hydroxycinnamate (250 mg) under nitrogen atmosphere, and the mixture was stirred for 1 hour. 2-Picolyl chloride hydrochloride (256 mg) was added to the mixture at the same temperature, and allowed to stand for 16 hours. The reaction mixture was poured into water, extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give ethyl 4-(2-pyridylmethoxy)cinnamate (188 mg) as colorless powder. mp 95° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][N:14]3[CH2:18][CH2:17][C:16]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]3=[O:33])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:40][N:41](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:17][CH2:18][N:14]([CH2:13][C:11]3[O:10][N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:40]#[N:41])=[CH:3][CH:4]=4)[N:12]=3)[C:15]2=[O:33])=[CH:20][CH:21]=1
Reactant: CC(=O)N(C)C
Reactant: O=C1N(Cc2nc(-c3ccc(Br)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: N#Cc1ccc(-c2noc(CN3CCC(c4ccc(F)cc4)(c4ccc(F)cc4)C3=O)n2)cc1
Temperature: 120 °C

Procedure:
1-((3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)-3,3-bis(4-fluorophenyl)pyrrolidin-2-one (233 mg, 0.457 mmol; Example 235A), palladium(II) acetate (1.025 mg, 4.57 μmol), sodium carbonate (48.4 mg, 0.457 mmol) and potassium hexacyanoferrate(II) trihydrate (42.4 mg, 0.100 mmol) in N,N-dimethylacetamide (2 mL) was placed under nitrogen and heated to 120° C. The reaction was cooled, loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=8.4, 2H), 7.78 (d, J=8.4, 2H), 7.38-7.30 (m, 4H), 7.07-6.98 (m, 4H), 4.89 (s, 2H), 3.57 (t, J=6.5, 2H), 2.84 (t, J=6.4, 2H); MS (ESI−) m/z 455.1 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C@@:3]([O:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1>CC#N>[F:1][C:2]([F:15])([F:16])[C@@:3]([O:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([O:6][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:5]
Reactant: CO[C@@](C(=O)O)(c1ccccc1)C(F)(F)F
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CO[C@@](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)(c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
(R)-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (Mosher Acid) (936 mg, 3.9 mmol) and pentafluorophenol (1.10 g, 6.0 mmol) were stirred in anhydrous MeCN (6 mL) and cooled to 0° C. DCC (803 mg, 3.9 mmol) was added at one portion and the reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to rt and stirred for additions 16 h. The suspension was filtered and washed with cold MeCN. The filtrated were evaporated and dried on high vacuum. The crude product was purified by column chromatography (20:1=PE: EtOAc) to yield 4 as a colourless oil (1.52 g, 97%; Campbell et al., J. Org. Chem., 1995, 60, 4602).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[K+].[Br-]>>[C:12]1([C:10]2[N:11]=[C:4]3[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=[CH:6][N:5]3[CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccn2cc(-c3ccccc3)nc12
Agent: [Br-]
Agent: [K+]
Product: O=Cc1cccn2cc(-c3ccccc3)nc12
Yield: 29 %

Procedure:
From 3c, reaction time 18 h (yield: 29%); mp 98-100° C. (in Straub A. and al. U.S. Pat. No. 5,545,646, 1996: 96-99° C.); IR (KBr) 1699, 1542 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.90 (t, 1H, J=7 Hz), 7.36 (t, 1H, J=7 Hz), 7.46 (t, 2H, J=7 Hz), 7.79 (d, 1H, J=7 Hz), 7.95 (s, 1H), 8.00 (d, 2H, J=7 Hz), 8.33 (d, 1H, J=7 Hz), 10.88 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 108.5, 111.9, 123.8, 125.6, 126.4, 128.6, 128.9, 130.2, 133.2, 144.7, 147.3, 189.2; MS m/z 222 (M+, 45), 194 (100), 193 (84), 77 (30), 51 (31).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:47]([NH:54][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]1)=[O:11])=[CH:20][CH:19]=2)=[O:23])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCc4ccccc4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), benzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CCCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[(4-pentyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 15 mg of the title compound. 1H NMR (DMSO) 0.90 (t, 3H, J=6.79 Hz), 1.31-1.46 (m, 4H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.49 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 382 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([Br:16])[N:15]=[C:10]3[N:9]([CH:17]3[CH2:19][CH2:18]3)[C:8]2=[O:20])[CH2:4]1.Cl[C:22]1[N:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([F:32])=[CH:27][CH:28]=2)[N:23]=1.CS(C)=O.C(N(CC)C(C)C)(C)C>O.Cl.O1CCOCC1>[Br:16][C:14]1[N:15]=[C:10]2[N:9]([CH:17]3[CH2:18][CH2:19]3)[C:8](=[O:20])[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:22]4[N:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([F:32])=[CH:27][CH:28]=5)[N:23]=4)[CH2:4]3)[C:11]2=[N:12][CH:13]=1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nc(Br)cnc32)C1
Reactant: Fc1ccc2cnc(Cl)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nc(Br)cnc2n1[C@H]1C[C@H](Nc2ncc3ccc(F)cc3n2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-5-bromo-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 82, 0.143 g, 0.397 mmol) and 2-chloro-7-fluoroquinazoline (0.118 g, 0.646 mmol). DMSO (2 mL) was added followed by N,N-diisopropylethylamine (0.300 mL, 1.725 mmol) and the reaction mixture was sealed under argon and heated at 100° C. overnight. The reaction was cooled room temperature and diluted with water. The precipitate was filtered to give an off-white solid. The material was dissolved in 4M HCl in dioxane and purified by reverse-phase HPLC (Gilson; Gemini-NX 10 m C18 110A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA CH3CN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an Si-Carbonate (Silicycle) cartridge eluting with DCM/MeOH to give 50 mg (27%) of a white crystalline solid. ESI MS 469.9, 471.8 [M+1].
Reaction SMILES: [CH3:1][S-:2].[Li+].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.[NH4+].[Cl-]>C(O)C.C1COCC1>[CH3:1][S:2][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[Br:4]
Reactant: BrCc1ccccc1Br
Reactant: C[S-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CSCc1ccccc1Br
Yield: 90.7 %

Procedure:
To a stirred solution of lithium thiomethoxide (82.19 mmol, generated from n-BuLi and methylmercaptan) in 130 ml of ethanol/THF (2:3) 2-bromobenzylbromide (12.54 g, 50.17 mmol) was added. After 1 h of reflux 30 ml of a saturated aqueous NH4Cl solution was added. The mixture was concentrated and extracted with ether The organic phase was washed with water and dried with MgSO4. After evaporation the crude product was distilled to give a clear liquid of o-bromobenzyl methyl sulfide 9.88 g (89%).