Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11]C)[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Br.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:11])[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c1CC(C)(C)C2N1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2c(O)cccc2C1N1CCCCC1

Procedure:
A mixture of the 4-methoxy compound from Step 3 above (5 g) and 48% aq. HBr (50 ml) in glacial acetic acid (50 ml) is refluxed for three hours. The mixture is poured into H2O, the pH added to 8-10 and extracted with methylene chloride. The organic extract is washed with sat'd NaCl, dried, filtered, evaporated and the residue chromatographed (silica gel, hexane/ether) affording the desired product as a green solid.
Reaction SMILES: [Br:1]Br.[S:3]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:4]1[S:3][C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=1
Reactant: BrBr
Reactant: CN1CCC(=C2c3ccccc3CCc3sccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(=C2c3ccccc3CCc3sc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Bromine (1.0 mL, 19.5 mmol) was added dropwise to a chloroform (50 mL) solution of 4-(9,10-dihydro-1-thiabenzo[f]azulen-4-ylidene)-1-methylpiperidine (5.76 g, 19.5 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and an organic layer was separated. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform-methanol=9:1), to give 5.6 g (91%) of the captioned compound in the form of white crystals.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.O>ClCCl>[Br:1][CH2:2][C:3]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)CBr
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N1CCc2ccccc2C1
Reaction time: 0.75 h

Procedure:
Bromoacetyl chloride (0.25 mL) was added slowly to a cold (5° C.) solution of 1,2,3,4-tetrahydroisoquinoline (0.8 g) in dichloromethane (25 mL) and the mixture was stirred in an ice bath for 45 minutes, then at room temperature overnight. Water (20 mL) was added, the layers were separated and the organic layer was washed in turn with 0.5N hydrochloric acid and sodium bicarbonate solution. The dried extract (MgSO4) was evaporated to provide 0.762 g of 2-(2-bromo-1-oxoethyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][CH2:35][CH2:36]N>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH2:35][O:34][CH3:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Product: COCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-methoxyethylamine, afforded the crude title compound as an orange foam (109 mg); LCMS (method B): RT=3.69 min, M+H+=504. This crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[NH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1/[CH:5]=[N:13]/[CH:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1cccc(OC)c1C=O
Reactant: CC(C)C(N)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1/C=N/C(C(C)C)C(C)C

Procedure:
A mixture of 25.0 g (150 mmol) 2,6-dimethoxybenzaldehyde, 19.1 g (165 mmol) 3-amino-2,4-dimethylpentane and 0.500 g p-toluenesulfonic acid in 100 ml toluene was heated in a Dean-Stark apparatus to reflux for 2 hours. Then the cooled reaction mixture was washed with aqueous NaHCO3 solution, brine dried over Na2SO4, filtered and evaporated. The crude product was filtered through a silica pad with heptane/ethyl acetate 2:1 as eluent: 22.0 g [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine as slightly yellow crystals: MS (EI): 264.3 ((M+H)+.), 262.3 ((M-H)+.), 248.3 ((M−CH3)+.), 220.2 ((M−(CH3)2CH)+.), 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22](OC)=[O:23])[C:9]=2[C:26](OC)=[O:27])[N:3]=1.[BH4-].[Li+].CO>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:26][OH:27])[N:3]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2cccc(Br)n2)c1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2cc(CO)c(CO)c(-c3cccc(Br)n3)c2cc1OC
Yield: 80.4 %

Procedure:
To a suspension of 1-(2-bromo-6-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (715 mg) in tetrahydrofuran (20 ml) is added lithium borohydride (174 mg), and the mixture is refluxed. To the mixture is added dropwise a mixture of methanol (2.2 ml) and tetrahydrofuran (10 ml) under reflux over a period of two hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and ethyl acetate and water are added to the residue. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) to give 1-(2-bromo-6-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (505 mg).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH2:34][CH2:33]3)=[CH:26][CH:25]=2)=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])[CH:9]=1.Cl>C(O)C>[F:3][C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@H:32]3[CH2:33][CH2:34][C@H:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH2:36][CH2:37]3)=[CH:26][CH:25]=2)=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Aqueous lithium hydroxide (2.0 M, 5.8 mL, 2.3 mmol) was added to a solution of ethyl (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (1.4 g, 2.3 mmol) in ethanol (40 mL). The reaction was heated to 50° C. for 3 h. The reaction was allowed to cool to ambient temperature and then acidified to a pH of ˜3 with 1.0 N aq. HCl. The mixture was extracted with EtOAc (3×150 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound as a white solid (1.28 g, 98%). MS (LCMS) m/z 580.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:36]([O:35][C:33]([NH:32][C@@H:28]([CH2:27][CH2:26][NH:25][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[C:29]([OH:31])=[O:30])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (15 mg, 0.05 mmol), (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (crude, 0.28 mmol) and sodium methoxide (15 mg, 0.28 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 20 mg. 1H NMR (CD3OD, 200 MHz): δ=8.37 (d, 1H, J=9.0 Hz), 7.64-7.46 (m, 3H), 7.38-7.18 (m, 4H), 4.27-4.14 (m, 1H), 3.56 (t, 2H, J=6.6 Hz), 2.32-1.82 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[C:16]1[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:30](=[O:37])[NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>O>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][NH:31][C:30]([C:25]1[C:24]2[O:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[C:11]3[CH2:10][CH:9]4[NH:8][CH:13]([CH2:14][CH2:15]4)[CH2:12]3)[C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:37].[C:40]([OH:42])([C:39]([F:44])([F:43])[F:38])=[O:41]
Reactant: CN(C)CCNC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2

Procedure:
Compound 2m was treated with a 95:5 mixture of trifluoroacetic acid:water at rt, and the mixture was lyophilized, yielding the title compound 15 as a TFA salt.
Reaction SMILES: [O:1]([CH3:21])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][CH:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH2:11]3)[N:6]([CH3:7])[CH2:5]1)=[O:3].B(F)(F)F.CCOCC.S(Cl)([Cl:34])(=O)=O>C(Cl)Cl>[Cl:34][CH:11]1[NH:12][C:13]2[C:20]3[CH:10]1[CH2:9][C@@H:8]1[C:18]([C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:19][C@@H:4]([C:2](=[O:3])[O:1][CH3:21])[CH2:5][N:6]1[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)[C@@H]1C=C2c3cccc4c3C(CN4)C[C@H]2N(C)C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C=C2c3cccc4c3C(C[C@H]2N(C)C1)C(Cl)N4

Procedure:
885 mg. of methyl dihydrolysergate were dissolved in 50 ml. of methylene dichloride. 0.95 ml. of boron trifluoride etherate were added and the reaction mixture cooled to a temperature in the range 0°-5° C. A solution of 0.27 ml. sulfuryl chloride in 20 ml. of methylene dichloride was added in dropwise fashion. The reaction mixture was stirred and cooled for about 15 minutes and then quenched by pouring into an ice-dilute ammonium hydroxide mixture. D-2-chloro-6-methyl-8-carboxyergoline, methyl ester or methyl 2-chlorodihydrolysergate formed in the above reaction was isolated and purified by the procedure of Example 1. Chromatography over fluorosil using 2 percent methanol in chloroform yielded 730 mg. (74 percent yield) of crystalline material melting at 206°-8° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:5](F)=[N:6][CH:7]=1.C(O)C.[NH2:24][NH2:25]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[N:25][NH:24][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: CN(C)c1ccc(CC(=O)c2cc(Br)cnc2F)cc1
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(Cc2n[nH]c3ncc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
1-(5-Bromo-2-fluoro-pyridin-3-yl)-2-(4-dimethylamino-phenyl)-ethanone (890 mg, 2.64 mmol), ethanol (100 ml), and anhydrous hydrazine (0.4 ml, 12.74 mmol) were combined and stirred for 18 hours at room temperature. The reaction was diluted with water and the precipitate filtered and dried to obtain 500 mg (57%) of [4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-phenyl]-dimethyl-amine. MS m/z 331.1+333.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (60 mg, 0.17 mmol) and phenethyl amine (78 mg, 0.68 mmol). The title compound was obtained as a yellow solid (70 mg, 91% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (3H, m), 8.39 (1H, s), 7.27 (2H, m), 7.19 (3H, m), 3.42 (2H, m), 2.80 (2H, m). MS m/z: 452.24, 454.26 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[Mg].II.[CH2:28]([O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:13]1([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH:39]([OH:40])[C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:37]=3)[O:9][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1-c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1cccc(OCc2ccccc2)c1)c1ccccc1-c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 2-(2-bromophenyl)-4,5-diphenyloxazole (3.0 g) in tetrahydrofuran (15 ml) was added dropwise to a stirred mixture of magnesium (213 mg) and a slight amount of iodine in tetrahydrofuran (15 ml) at room temperature under a nitrogen atmosphere and the resulting mixture was stirred at 70° C. for 3 hours. The reaction mixture was added slowly to a solution of 3-benzyloxybenzaldehyde (1.69 g) in tetrahydrofuran (6 ml) under dry ice-acetone cooling and a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 3 hours and at room temperature overnight, treated with ammonium chloride aqueous solution, and partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was washed with sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane - ethyl acetate) over silica gel to afford 2-(4,5-diphenyl-2-oxazolyl)-3'-benzyloxybenzhydrol (2.21 g) as paste.
Reaction SMILES: [Br:1]C1C=C(C2C(C(Cl)=O)=CC=CC=2)[ClH]C=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[C:24]1[C:29]([C:30]2[NH:31][CH:32]=[C:33]([CH3:35])[N:34]=2)=[CH:28][N:27]=[C:26]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[N:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:25]=1>>[Br:1][C:21]1[CH:20]=[CH:19][C:18]([C:24]2[C:29]([C:30]3[NH:31][CH:32]=[C:33]([CH3:35])[N:34]=3)=[CH:28][N:27]=[C:26]([NH:36][CH2:37][CH2:38][NH:39][C:40]3[N:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)[N:25]=2)=[C:17]([Cl:16])[CH:22]=1
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Br)cc2Cl)n1

Procedure:
6-[(2-{[4-(4-bromo-2-chlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 4-bromo-2-chlorolbenzoyl chloride using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:24]1[C:37]2[C:36](=[O:38])[CH2:35][C:34]([CH3:40])([CH3:39])[CH2:33][C:32]=2[O:31][C:30]2[CH2:29][C:28]([CH3:42])([CH3:41])[CH2:27][C:26](=[O:43])[C:25]1=2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:22])[N:20]=2)=[CH:11][C:10]=1[CH:24]1[C:25]2[C:26](=[O:43])[CH2:27][C:28]([CH3:41])([CH3:42])[CH2:29][C:30]=2[O:31][C:32]2[CH2:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](=[O:38])[C:37]1=2
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3CCOCC3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 24.5 h
Yield: 78.4 %

Procedure:
Morpholine (0.0625 ml, 0.72 mmol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 1-2 (180 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol), and 1-hydroxybenzotriazole monohydrate (55.0 mg, 0.36 mmol) in DMF (4 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 24.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (161 mg, yield: 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COCCN1CCN(c2ccc(N)c(OC)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCN(CCOC)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 67.8 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (47 mg, 0.18 mmol), and p-toluenesulfonicacid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (90 mg, 0.122 mmol, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.19 (d, J=5.13 Hz, 1H), 8.04 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.80, 2.20 Hz, 1H), 7.69 (d, J=9.17 Hz, 1H), 7.34-7.46 (m, 3H), 7.26 (d, J=8.43 Hz, 1H), 7.19 (t, J=8.07 Hz, 2H), 6.94 (t, J=6.78 Hz, 1H), 6.67 (d, J=2.20 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 6.43-6.50 (m, 1H), 4.26 (q, J=6.97 Hz, 2H), 3.79 (s, 3H), 3.42-3.48 (m, 2H), 3.24 (s, 3H), 3.08-3.17 (m, 4H), 2.53-2.58 (m, 4H), 2.49-2.53 (m, 2H), 1.43 (t, J=6.97 Hz, 3H); MS (ESI): 735 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[C:9]([C:11]2(O)[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:8]=[N:7][CH:6]=1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:7]1[CH:8]=[C:9]([C:11]2[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH:12]=2)[CH:10]=[N:5][CH:6]=1
Reactant: OC1(c2cncnc2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C1=C(c2cncnc2)C2CCN1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
Thionyl chloride (0.35 ml. 4.8 mmol) was added to a rapidly stirred solution of 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2] octan-3-ol (0.5 g, 2.4 mmol) in dichloromethane (15 ml), at 0° C. The solution was warmed to room temperature and stirred for 1 h before adding a second portion of thionyl chloride (0.2 ml) and refluxing for 0.25 h. The mixture was cooled to 10° C., water (10 ml) added and basified to pH >10 with potassium carbonate. Extraction into dichloromethane (3×50 ml). drying (Na2SO4) and evaporation of solvents under reduced pressure gave 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2]oct-2-ene (0.16 g) as a yellow oil which crystallised on standing at 0° C., m/e 188 (M+H)+ ; δ (360 MHz,D2O) 1.86-1.98 (2H, m,CH2); 2.15-2.26(2H,m,CH2): 3.18-3.30 (2H,m,0.5×CH2 and CH); 3.62-3.72(3H,m,CH2 and 0.5×CH2) 7.23(1H,s,vinyl-H): 9.00(2H,s,pyrimidine-H); 9.15(1H,s,pyrimidine H). A solution of 3-(5-pyrmidinyl)-1-azabicyclo[2.2.2]oct-2-ene (0.31 g 1.66 mmol) in ethanol (40 ml) was hydrogenated over 10% pd/C (0.12 g) in a Parr apparatus. After 4 h the suspension was filtered through hyflo, the solvent removed under vacuum and, the residue chromatographed on alumina using dichloromethane/methanol (95:5) as eluant, to give 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2]octane (0.17 g) as a yellow oil. The hydrochloride salt was made. m.p. 267°-270° C. (dec.); (Found C,56.00; H,6.88, N,17.74. C11H15N3.HCl.0.75H2O requires C,55.69; H,6.58; N,17.71%) m/e 189 (M+ for free base); δ (360 MHz,D2O) 1.89-1.94(2H,m,CH2); 2.13-2.24 (2H,m,CH2); 2.38-2.46 (1H, m, CH-bridgehead); 3.34-3.90(7H,m,3×CH2 --N and CH); 8.85(2H,s,pyrimidine-H); 9.09 (1H,s,pyrimidine-H).