Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)=[N:7][C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:6]2[C:5]3[C:10](=[CH:11][C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3cc(Br)ccc23)cc1Cl
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc3c(Nc4ccc(F)c(Cl)c4)nc(-c4cccnc4)nc3c2)cn1
Temperature: 120 °C
Yield: 6.6 %

Procedure:
A microwave vial was charged with 7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv), Pd(PPh3)2Cl2 (8.1 mg, 5 mol %) and potassium carbonate (160.1 mg, 1.16 mmol, 5.0 equiv). The mixture was suspended in DME/water/ethanol (7:3:2, 4 mL), and the reaction was heated under microwave irradiation conditions at 120° C. for 10 minutes. The crude reaction mixture was diluted with water (10 mL) and then filtered. The solid residue was dissolved in methanol/THF (1:1, 5 mL) with heating and then filtered through Celite to remove the catalyst. The resulting filtrate was concentrated to afford the desired product as a tan solid (7.0 mg, 6.5%). LCMS m/z=458.1 (M+1) (Method C) (retention time=2.51 min). 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.72-8.65 (m, 2H), 8.62 (d, J=8.6 Hz, 1H), 8.34-8.26 (m, 2H), 8.15 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.97-7.88 (m, 1H), 7.61-7.49 (m, 2H), 6.99 (d, J=8.7 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(F)c1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-3-fluoro-phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[CH:14]=1.C[O-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]([C:18]([O:19][CH3:20])=[O:21])[C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)CCCO2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCOc2ccc(OC)cc2C1=O

Procedure:
A mixture of 7-methoxy-3,4-dihydro-1-benzoxepin-5(2H)-one (1.9 g), sodium methoxide (2.8 g) and dimethyl carbonate (40 ml) is heated under reflux for 8 hours with stirring. The reaction mixture is treated in a manner as that in Reference Example 11 to give methyl 7-methoxy-5-oxo2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate as a colorless oily product (1.7 g). This product (1.6 g) is dissolved in a mixture of methylene chloride (20 ml) and methanol (20 ml). To the solution is added sodium borohydride (0.15 g) in limited amounts. The mixture is stirred. After addition of water, the reaction mixture is extracted with methylene chloride. The organic layers are combined, washed with water, and evaporated to dryness. To the residue are added methanol (5 ml) and 1N aqueous solution of sodium hydroxide (8 ml). The mixture is stirred at 60° C. for 30 minutes. To the reaction mixture are added water and ether, and the mixture is shaken, followed by separating the aqueous layer. The aqueous layer is acidified with dilute hydrochloric acid, and extracted with methylene chloride. The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. To the residue are added dioxane (5 ml) and concentrated hydrochloric acid (1.5 ml), and the mixture is stirred at 100° C. for 30 minutes. After addition of water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to afford 7-methoxy2,3-dihydro-1-benzoxepin-4-carboxylic acid as colorless scales (0.41 g), m.p. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[S:13][CH3:14])=[CH:4][N:3]=1.[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CO>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[S:13]([CH3:14])=[N:17][C:16]#[N:15])=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: CS[C@H]1CCC[C@H]1c1ccc(Cl)nc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CS(=NC#N)[C@@H]1CCC[C@@H]1c1ccc(Cl)nc1
Reaction time: 2 h
Yield: 84.6 %

Procedure:
cis-2-Chloro-5-(2-methylthiocyclopentyl)pyridine (0.15 g, 0.64 mmol) was dissolved in CH2Cl2 (3 mL) in a 50 mL round bottom flask and treated with cyanamide (0.035 g, 0.83 mmol). The mixture was cooled in an ice bath under nitrogen and treated with iodobenzene diacetate (0.28 g, 0.86 mmol) and allowed to stir for 2 h by which time the reaction was judged complete by TLC (CH2Cl2:MeOH/20:1). The reaction mixture was concentrated to low volume and purified by flash silica gel chromatography (CH2Cl2:MeOH/20:1) to give cis-[2-(6-chloropyridin-3-yl)cyclopentyl](methyl)-λ4-sulfanylidenecyanamide (0.145 g, 85%) as an oily 1:1 mixture of diastereomers: LC/MS (ESI) m/z 267, 1H NMR (300 MHz, CDCl3) δ 8.31 (d, 2H, J=2.7 Hz), 7.70 (dd, 1H, J=8.4, 2.7 Hz), 7.63 (dd, 1H, J=8.4, 2.7 Hz), 7.40 (d, 1H, J=8.4 Hz), 7.32 (d, 1H, J=8.4 Hz), 3.96 (m, 1H), 3.81 (m, 1H), 3.67-3.51 (m, 2H), 2.73 (s, 3H), 2.59 (m, 1H), 2.45 (s, 3H), 2.40-1.95 (m, 9H), 1.85 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[C:17]2[CH:25]=[C:24]([Cl:26])[N:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(N(CC)CC)C.CNC>CC(O)C>[Cl:26][C:24]1[N:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:12][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)[C:17]=2[CH:25]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CNC
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Clc1cc2c(Nc3ccc(Oc4ccccc4)cc3)ncnc2cn1

Procedure:
6-Chloro-4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidine was prepared by the reaction of 4-phenoxyaniline and 4,6-dichloropyrido[3,4-d]pyrimidine in 2-propanol according to Procedure A, with triethylamine present to give the free base of the product directly. Reaction of this product with dimethylamine (33% aqueous solution) according to Procedure C gave the title compound: δH (CDCl3) 9.00 (1H,s), 8.54 (1H,s), 7.70 (2H, d), 7.00-7.44 (5H,m), 7.13 (2H,d), 6.38 (1H,s), 3.22 (6H,s); m/z (M+1)+358.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:31]2[CH2:35][CH2:34][NH:33][C:32]2=[O:36])=[N:28][C:27]=1[CH3:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:32]2=[O:36])=[N:28][C:27]=1[CH3:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: BrCc1ccccc1
Product: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Yield: 38 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with ethyl bromoacetate to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 38% yield: 1H NMR (300 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 5.87 (t, J=5.4 Hz, 1H), 4.57 (d, J=5.4 Hz, 2H), 4.27-4.13 (m, 4H), 4.08 (s, 2H), 3.76-3.68 (m, 2H), 2.63 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[C:20]([Br:21])=[CH:19][C:6]2[N:7](C(C)C)[C:8]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:9][C:5]=2[C:4]=1[N+:22]([O-:24])=[O:23].[C:25](N1CCNCC1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CCO>[Br:2][C:3]1[C:20]([Br:21])=[CH:19][C:6]2[NH:7][C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15]3)=[N:9][C:5]=2[C:4]=1[N+:22]([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)n1c(N2CCNCC2)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c([N+](=O)[O-])c(Br)c(Br)cc3[nH]2)CC1
Temperature: 120 °C
Yield: 67.9 %

Procedure:
2,5,6-tribromo-4-nitro-1H-1,3-benzodiazole (Method 2A) (17.5 mmol, 7 g) was dissolved in EtOH (30 ml) with N-Boc-piperazine (52.5 mmol, 9.78 g). The resulting mixture was stirred at 120° C. until the reaction was complete (8 h) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was purified on silica gel using DCM/MeOH (99:1) to afford tert-butyl 4-(5,6-dibromo-4-nitro-1H-1,3-benzodiazol-2-yl)piperazine-1-carboxylate (6 g). m/z 405.8; rt 2.4 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[C:10]([O:14][C:15]([N:17]1[C@@H:21]([C@H:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][C@H:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:30]([O:29][C@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:21]1[CH2:20][CH2:19][C@@H:18]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:42](=[O:43])[NH:9][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:8])=[CH:45][CH:46]=2)[N:17]1[C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
1-Pyridin-2-yl-ethylamine (77 mg, 0.628 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (300 mg, 0.571 mmol), HATU (260 mg, 0.685 mmol, 1.2 equivalents) and DIPEA (470 μL, 2.69 mmol, 4.7 equivalents) in DMF (1.2 mL). The reaction was stirred at room temperature for 16 hours before being loaded directly onto a silica column and purified by normal phase flash chromatography using silica gel (20-100% hexanes/ethyl acetate). The product fractions were collected and concentrated in vacuo to afford the title compound as a colorless gum (350 mg, 97%). LC-MS=630.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)#[N:31].O>O1CCOCC1>[Cl:23][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[N:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([OH:14])([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C#N)nc3)cc2Cl)C(F)(F)F)ccn1

Procedure:
A mixture of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 40 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palldadium(II) (7 mg), Cs2CO3 (96 mg) and 2-cyanopyridine-5-boronic acid pinacol ester (CAS Reg. No. 741709-63-7, 45 mg) in dioxane (2 ml) and water (0.2 ml) was heated at 100° C. for 10 min in a sealed tube. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (32 mg) as a yellow solid. MS (m/e)=432.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[K].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=1>O1CCOCC1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:3]2[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]2([CH3:10])[CH3:1])[N:23]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K]
Solvent: C1COCCO1
Product: CC1(C)CCCC(C)(C)N1c1cccc(N2C(C)(C)CCCC2(C)C)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a 1,4-dioxane solution (30 ml) of 2,2,6,6-tetramethylpiperidine (3.11 g, 22.0 mmol) and potassium-bis(trimethylsilyl)amide (4.39 g, 22.0 mmol)2 was added 2,6-dibromopyridine (2.37 g, 10.0 mmol). The reaction mixture was stirred vigorously at 100° C. overnight. After cooling down to room temperature, the reaction was quenched with water and extracted with diethyl ether/THF (1:1) mixtures. The combined extracts were washed with 1 M Na2CO3, dried over MgSO4, filtrated, and evaporated to dryness. The product was purified by flash chromatography on silica gel leading to colorless oil (Rf=0.5 in Ethylacetate:hexane=1:20, Yield=1.13 g (31.6%))
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:19][CH:20]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25].[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:23]([CH2:22][CH2:21][CH:20]([CH3:19])[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)[C:24]2=[O:25])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCC(C)c1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(CCc1cc2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O)c1ccncc1
Yield: 37 %

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-methyl-5-(pyridin-4-yl)pentanoate (1.5 eq.; prepared in Synthetic Example 8) and LDA(1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-methyl-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 37%). The product was purified through flash column chromatography and recrystallization (mp 154–155° C./DMF).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1

Procedure:
trans-Methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexanecarboxylate (29.00 g, 93.02 mmol) was dissolved in anhydrous acetonitrile (930 mL) and anhydrous DMF (9 mL) and heated at 55° C. under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, then, the solid residue was taken up in DCM, then, basified to pH 10 with 2M ammonia in isopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM, then, loaded onto TEA-basified silica gel. The crude product was purified by a silica gel column chromatography (eluted with 2:3 EtOAc/DCM) to obtain the title compound as a yellow powder; 1H NMR (CDCl3, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85 (ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H), 2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt, J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86) [MH+]. HPLC: tR=2.85 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1)(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>ClCCl>[C:1]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1)#[N:2]
Reactant: NC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of 3-[2-(2-carbamoylmethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.15 g) and pyridine (2.1 ml) in dichloromethane (25 ml) was added dropwise trifluoroacetic anhydride (1.1 ml) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The resultant was poured into ethyl acetate (500 ml), washed in turn with water (100 ml×2), saturated sodium hydrogen carbonate in water (50 ml×2), 1N-aqueous hydrochloric acid (50 ml×2), brine (100 ml), saturated sodium hydrogen carbonate in water (50 ml×2) and brine (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting in turn with 3% and 5% ethyl acetate in dichloromethane. Fractions containing desired product were collected. Evaporation of the solvent gave a residue, which was recrystallized from a mixture of dichloromethane and n-hexane to give 3-[2-(2-cyanomethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.28 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:21][C:28](=[O:29])[C:27]4[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=4[F:35])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.31 g) in THF (10 mL) was added 2,6-difluorobenzoyl chloride (0.18 g). The reaction was kept stirring at rt for 0.5 h and worked up with sat. NaHCO3 solution (8 mL). After extraction with EtOAc (2×10 mL), drying with Na2SO4, and concentration, the crude mixture was purified through silica gel column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide as a yellow solid (0.42 g, 95%). ESIMS (M+H)+=480.
Reaction SMILES: [OH-:1].[Ca+2].[OH-].[CH:4]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:7]([CH3:8])[C:5]=1O>>[C:7]1([CH3:8])[CH2:9][CH2:10][CH:11]([C:12]([CH2:14][OH:1])=[CH2:13])[CH2:4][CH:5]=1
Reactant: [OH-]
Reactant: Cc1ccc(C(C)C)cc1O
Agent: [Ca+2]
Product: C=C(CO)C1CC=C(C)CC1
Temperature: 222.5 °C

Procedure:
A mixture of 300 parts of 8,9-limonene oxide, 6 parts of calcium hydroxide and 6 parts of carvacrol was refluxed at 215-230° C. for 2 hours in a three-necked flask equipped agitator, Dean-Stark trap, and temperature probe. After cooling and filtration 290 parts of the mixture containing 30% of unreacted epoxide and 43% 1,8-p-menthadien-10-ol (61% selectivity) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][C:22]#[N:23])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#CCCl
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A mixture of (+) 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (3.29 g, 11 mmole), chloroacetonitrile (1.25 g, 16.5 mmole), and potassium carbonate (3.04 g) in dimethylformamide (30 ml) was stirred at 60°-65° for three hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as an oil (3.8 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1>CCOCC>[C:5]([NH:8][CH:9]1[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CCOCC
Product: CC(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (70 g, 0.686 mol) was added dropwis to an ice cooled solution of 4-Amino-2,2,6,6-Tetramethyl-piperidin (34.6 g. 0.221 mol) in ether (100 ml). After the addition was complete (about 1 h), the reaction mixture was stirred for 30 minutes at room temperature. The precipitated white product, 4-acetylamino-2,2,6,6-Tetramethyl-piperidin (55.6 g, 98%) was filtered off and washed with ether and air dried. m.p. 175° C. subl.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Br[C:16]1C2C(=CC=CC=2)C=CC=1.C(Cl)(=O)C>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:14])[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: Brc1cccc2ccccc12
Solvent: CC(=O)Cl
Product: CC(=O)c1ccc(Br)c2ccccc12

Procedure:
The 4-bromo-1-naphthoic acid required as starting material according to the process according to the invention has already been described in the literature. It can, for example, be prepared in a simple manner by reacting 1-bromonaphthalene with acetyl chloride in a Friedel-Crafts reaction to give 4-bromo-1-acetylnaphthalene (see K. Dziewouski and L. Sternback, Bull. acad. polonaise A, 1931, 59 to 68, or T. L. Jacobs, S. Winstein, J. W. Ralls and J. H. Robson Journ. org. chem. 11 (1946), 27-33) and by oxidation of the latter compound with hypochlorite [see T. L. Jacobs et. al, see above, or N. J. Leonard and A. M. Hyson, J. Am. chem. soc. 71 (1949), 1963].