Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[O:5][C:6]=1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C([Li])(C)(C)C.CON(C)[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33].O>CCOCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:6]1[O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=2[C:2]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[CH3:10]
Reactant: CCOC(OCC)c1oc2ccccc2c1Br
Reactant: CON(C)C(=O)c1ccccc1F
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)c1oc2ccccc2c1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
To a solution of 3 g of 3-bromo-2-(diethoxymethyl)-benzo[b]furan in 80 ml of dry ether under nitrogen at −100° C. was added 17.4 ml of a 1.7 M solution of tert-butyllithium in hexanes. The solution was stirred at the low temperature for 2 h then a solution of 2.76 g of N-methoxy-N-methyl-2-fluorobenzamide in 20 ml of dry ether was added and the solution stirred at the low tempertature for 10 min. The solution was then allowed to slowly warm to 0° C., water was added and the organic layer was separated, washed with water and dried over sodium sulfate and evaporated. Gravity chromatography eluting 0 to 50% toluene in heptane afforded 0.91 g of 2-(diethoxymethyl)-3-(2-fluorobenzoyl)-benzo[b]furan as an oil, 1H-NMR (200 MHz, CDCl3) d 5.76 (CHOEt).
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:22]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CCCN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 25.2 %

Procedure:
Following the procedure of Example 3, step 4, 0.300 g (1.60 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.244 g (1.77 mmol) of anhydrous potassium carbonate and 0.243 ml (1.60 mmol) of 1-bromo-3-phenylpropane. Chromatography on flash silica, eluting with 50-100% ethyl acetate/petroleum ether and 2-10% methanol/dichloromethane, then on a Lobar column, eluting with 50% ethyl acetate/petroleum ether, gave 0.123 g (26%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate, the title product hydrochloride was obtained as a white solid, m.p. 196°-201° C. NMR δ(D2O/CD3CN) 1.54 (1H, m), 1.68 (1H, m), 1.75-1.89 (2H, m), 2.08-2.15 (2H, m), 2.61-2.77 (4H, m), 2.84 (1H, t, J=12.2 Hz), 2.92 (2H, m), 3.08-3.18 (3H, m), 3.56 (1H, m), 3.71 (1H, m), 7.19-7.26 (3H, m), 7.29-7.33 (4H, m), 7.39-7.43 (2H, m). m/z (CI+, NH3) 306 (M+H)+, 200 (M-CH2CH2Ph)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]#[N:27])[CH2:22][CH2:21]1.[F-].[K+]>CS(C)=O>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:27][CH2:26][C@H:23]4[CH2:24][CH2:25][C@H:20]([C:19]#[N:18])[CH2:21][CH2:22]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1CCC(CN)CC1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#C[C@H]1CC[C@H](CNc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1

Procedure:
A mixture of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (50 mg, 0.189 mmol), -4-(aminomethyl)cyclohexanecarbonitrile (111 mg, 0.25 mmol) and KF (47 mg, 0.82 mmol) in DMSO (0.5 mL) was heated at 130° C. overnight. LCMS showed the reaction was almost complete. The mixture was purified by prep. HPLC to give EX. 8-88 (26 mg, 38%) as an off-white solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH:20]([OH:22])[CH3:21].O.C([O-])(=O)C.[Na+]>Br>[CH3:21][CH:20]1[O:22][C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4](=[O:18])[C:3]=2[CH2:19]1
Reactant: CC(O)Cc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC1Cc2c(c3cccnc3n(-c3ccccc3)c2=O)O1
Temperature: 90 °C

Procedure:
A solution of 4-hydroxy-3-(2-hydroxypropyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (8.9 g; 0.03 mole) in 47% HBr (90 ml.) was stirred in an atmosphere of nitrogen. The solution was heated to 90° C. for 41/2 hrs. then was allowed to cool, poured into water and was adjusted to pH 4.5 with sodium acetate. The product was filtered off, washed with water, dried in air and recrystallized from CHCl3 /isopropanol to yield the product, m.p. 223°-224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](N)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1OCCOC1>[O:16]=[C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH:15]=[CH:14][C:13]=2[NH:12]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4ccccc4c3c2)cc1
Reaction time: 30 h
Yield: 93 %

Procedure:
Prepared from 2-amino-6(5H)-phenanthridinone 3 and 4-methyl benzenesulfonamide according to General Procedure A. P-dioxane was used as solvent and the reaction was run at 40° C. for 30 hours. Purification of compound by crystallization in dioxane gave a brown solid (93% yield). mp 199-203° C. 1H-NMR (400 MHz, DMSO-d6), 10.20 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 7.95 (s, 1H), 7.88 (t, J=7.6, 1H), 7.65 (m, 3H), 7.33 (d, J=8.2 Hz, 2H), 7.19 (m, 2H). Anal. (C20H16N2O3S), C H N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCN(CC)CC.Cl[C:24]1[C:25]2[C:30]([N:31]=[C:32]3[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:29][CH:28]=[CH:27][CH:26]=2>CO>[CH:26]1[C:25]2[C:30](=[N:31][C:32]3[C:37]([C:24]=2[NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:15][CH:14]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(CCCCCCCO)cc1
Reactant: Clc1c2ccccc2nc2ccccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: OCCCCCCCc1ccc(Nc2c3ccccc3nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.4 %

Procedure:
To a solution of 636.9 mg (3.07 mmol) of 4-(7-hydroxyheptyl)-aniline 30 and 428 μL (3.07 mmol) of Et3N in 20 mL of MeOH were added 656.4 mg (3.07 mmol) of 9-chloroacridine. After stirring for 7 hr at room temperature, the solvent was evaporated. Purification by column chromatography on silica gel with 5% MeOH in CH2Cl2 gave 1.079 g (91%) of N-(9-acridinyl)-4-(7-hydroxyheptyl)-aniline 31: 1H NMR (300 MHz, CDCl3, TMS) δ 8.0-7.9 (m, 4H), 7.63 (t, J=7 Hz, 2H), 7.3-7.2 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.7-1.5 (m, 4H), 1.4-1.3 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(C#N)cc1-c1nc(-c2ccccn2)no1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), zinc cyanide (3.5.1 mg, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 23.1 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was heated under an argon atmosphere at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 30% ethyl acetate in hexane afforded 6.9 mg (12%) of 3-(2-pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[NH:15][C:16]([C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:17])[CH2:12]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH:6]1[NH:15][C:16]([C:18]1[C:19]([S:4][CH2:1][CH2:2][CH3:3])=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:17])[CH2:14]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Propanethiol (1.45 mL, 16 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.2 g, 16 mmol), and sodium carbonate (5.09 g, 48 mmol) in DMF (50 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (400 mL) and washed with water (3×50 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was recrystallised from 15% ethyl acetate/hexane to give N-(2-adamantyl)-6-chloro-2-propylsulfanyl-pyridine-3-carboxamide (4.9 g, 84%)
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]3)[C:8]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:7]2[CH2:11][CH2:10][C:9]3([CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:8]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CCN(C1CCCCC1)C2=O
Agent: [Pd]
Solvent: CO
Product: O=C1N(C2CCCCC2)CCC12CCNCC2
Reaction time: 2 h

Procedure:
Pd/C (100 mg) was added into a solution of benzyl 2-cyclohexyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.0 g, 0.0027 mol) in methanol (10 mL) under N2. The reaction mixture was stirred under an atmosphere of hydrogen for 2 hrs. The mixture was filtered. The filtrate was concentrated to give 2-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one which was directly used in next step reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](=[O:22])[CH2:20]Br>CN(C)C=O>[CH3:17][N:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](=[O:22])[CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CN(C(=O)CBr)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 67.5 °C
Reaction time: 3 h

Procedure:
2-Nitrophenol S7 (2.8 g), anhydrous potassium carbonate (4.1 g), and N-methyl-N-phenyl-2-bromoacetamide (4.5 g) were suspended in N,N-dimethylformamide (50 ml), and the resulting suspension was stirred at 65-70° C. for 3 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off, obtaining 5.4 g of the compound S8.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH:35][C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH:3]=4)=[O:12])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc5ccccc5s4)cc3s2)C1
Yield: 31.1 %

Procedure:
Prepare according to Method C (Example 9), using benzothiophene-2-carboxylic acid (123 mg, 0.685 mmol), oxalyl chloride (300 μL, 3.44 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (100 mg, 0.381 mmol) to afford the title compound (50 mg, 31%). mass spectrum (m/e): 423.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.35 (s, 1H), 8.25 (d, 1H, J=2.2 Hz), 8.06 (dd, 1H, J=6.5, 1.9 Hz), 8.01 (dd, 1H, J=6.2, 2.7 Hz), 7.55 (dd, 1H, J=8.8, 2.2 Hz), 7.50-7.43 (m, 3H), 3.72 (m, 1H), 3.63 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 2.90 (m, 1H), 2.22-2.17 (m, 7H), 1.92 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([NH:16][C:17]([N:19]([CH2:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:18])[S:14][CH:15]=2)[O:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>CCO>[C:37]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][CH2:28][N:19]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:17](=[O:18])[NH:16][C:13]2[S:14][CH:15]=[C:11]([C:9]3[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=3)[N:12]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1cc(-c2csc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)CCN3CCOCC3)n2)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2csc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)CCN3CCOCC3)n2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18 mg (0.03 mmoles, 1 eq) of 5-{2-[3-(3,3-diphenyl-propyl)-3-(2-morpholin-4-yl-ethyl)-ureido]-thiazol-4-yl}-isoxazole-3-carboxylic acid ethyl ester (obtained in example 30) are dissolved in 1.5 mL of EtOH then 2 eq of 1 N NaOH are added to the solution. The mixture is stirred at room temperature for 3 hours prior to neutralisation at pH 5-6 with a 2 N HCl solution. The aqueous phase is extracted with AcOEt then the organic substances collected are washed with brine, dried over MgSO4 prior to evaporation to give 5-{2-[3-(3,3-diphenyl-propyl)-3-(2-morpholin-4-yl-ethyl)-ureido]-thiazol-4-yl}-isoxazole-3-carboxylic acid (obtained in example 32) (quantitative yield) in the form of a white solid.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10]C)[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([OH:10])[C:3]=1[OH:12])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(I)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(I)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
37.2 g of 5-iodo vanillin (commercial) and 360 ml of dichloromethane were mixed together under nitrogen and the mixture was cooled to 0° C. 135 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for 16 hours at ambient temperature and was then concentrated, cooled to 0° C. and acidified. The crystallized product was separated out, washed with water, dried and crystallized from an isopropanol-water mixture (1-2 by volume) to obtain 23.4 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19](OB(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:22]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cccc(OB(O)O)c1
Reactant: COc1ccc2cc(Br)ccc2c1Br
Product: COc1cccc(-c2ccc3c(Br)c(OC)ccc3c2)c1
Yield: 81 %

Procedure:
The compound is prepared by the reaction of 1,6-dibromo-2-methoxy-naphthalene (5.75 g, 18.20 mmol, 1 eq) with 3-methoxyphenylboric acid (2.77 g, 18.20 mmol, 1 eq) according to method A. Purification by column chromatography with hexane as the eluent yielded the desired compound in a yield of 81%, 5.1 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([CH2:46]O)=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.[CH3:48][NH:49][CH3:50]>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[CH3:48][N:49]([CH3:50])[CH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[CH:8][N:9]=4)[CH:12]=3)=[CH:20][N:19]([C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:18]=2)=[CH:41][CH:42]=1
Reactant: OCc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reactant: CNC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1

Procedure:
A mixture of 296 mg {4-[4-(3-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]phenyl}methanol (compound in Example 359), 844 mg manganese (IV) oxide and 20 mL chloroform was heated for 1 hour under reflux. The reaction solution was cooled to remove insolubles, and the filtrate was evaporated. 264 mg crude product of 4-[4-(3-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]benzaldehyde was obtained as a pale brown amorphous. From 100 mg of this aldehyde derivative and 35 μL dimethylamine (50% aqueous solution), 81 mg of the title compound was obtained as a colorless amorphous under the same conditions as in Production Example 153.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])[CH:7]=1.[Sn](Cl)Cl>C(O)C.Cl.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:14]([NH2:15])[C:13]3[CH:12]=[C:11]([CH3:16])[S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(C#N)c(Nc2cc(Cl)ccc2[N+](=O)[O-])s1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1cc(Cl)ccc1N=C2N
Yield: 180.7 %

Procedure:
Suspend 2-(5-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (0.58 g, 1.98 mmol) in ethanol (20 ml), add anhydrous tin(II)chloride(1.5 g, 6.66 mmol) in concentrated hydrochloric acid (6 ml) and heat the mixture under reflux for 75 minutes. Dilute the mixture with water and allow to cool. Collect the precipitate by filtration and dry under high vacuum to give 6-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride as a yellow solid (0.537 g, 90%): Mass Spectrum (FIA) 300/302 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(=O)([O-])[O-].[K+].[K+]>[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1cccc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.28 g (5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 2.6 ml (25 mmol) 3-chloroaniline is stirred for 45 min at 90° C. under a nitrogen atmosphere. Excess 3-chloroaniline is then distlled off under HV at 60° C. and the residue distributed between 30 mldichloromethane and 20 ml of 20% aqueous potassium carbonate solution. The organic solution dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate and acetate/methanol (20:1). The product-containing fractions are dissolved in 3 ml of methanol, and acidified with 2.3 ml 3N methanolic HCl, then ether is added while stirring until slight turbidity occurs, and the mixture is cooled to 0° C., resulting in the formation of a crystalline precipitate. After filtration, washing of the filter residue with ether, drying under HV (8 h, 110° C.) and equilibration for 65 h at 20° C. and in room atmosphere, the title compound is obtained with a water content of 7.3%; Smp. 233-236° C.; ESI-MS: (M+H)+=347.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:21][C:22]1[C:23]([NH2:29])=[N:24][CH:25]=[N:26][C:27]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:29][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:22]=1[Br:21]
Reactant: Nc1ncnc(Cl)c1Br
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Yield: 52.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (300 mg, 1.12 mmol) was treated 5-bromo-6-chloropyrimidin-4-amine (373 mg, 1.79 mmol), cesium fluoride (340 mg, 2.24 mmol), N,N-diisopropylethylamine (0.974 mL, 5.59 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 10%, dichloromethane-methanol) to give 0.26 g (60% yield) of the title compound as a solid. Purity 98%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[OH:17])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@@H:23]1[O:25][CH2:24]1)(=O)=O>>[CH2:22]([O:17][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[C@@H:23]1[O:25][CH2:24]1
Reactant: CCOC(=O)CCCc1ccc(C#N)c(O)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: CCOC(=O)CCCc1ccc(C#N)c(OC[C@H]2CO2)c1
Yield: 89 %

Procedure:
Using the method of example 30(b), vide supra, ethyl 4-(4-cyano-3-hydroxyphenyl)butanoate (1.4 g, 6 mmol) and (R)-glycidyl nosylate (1.48 g, 5.71 mmol) were used to prepare 1.47 g (88%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]([F:18])([F:17])[F:19])[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 133, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 85:15). Light yellow foam (43%). MS (ESI): m/z=551.087 [M+H]+.