Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)c(-c2n[nH]c3ncccc23)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(F)c(-c3n[nH]c4ncccc34)n2)CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.430 mmol) and 1-methylpiperazine (100 uL, 0.901 mmol) and DIPEA (75 uL, 0.434 mmol) in NMP (1 ml) was allowed to stir at 140° C. overnight. The reaction mixture was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (35 mg, 15% Yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[F-].[K+]>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Temperature: 220 °C
Yield: 53.6 %

Procedure:
A mixture of 2-fluoronitrobenzene (3.5 g, 24.8 mmol), 4-chlorobenzenamine (3.05 g, 24.0 mmol), K2CO3 (3.45 g, 25.0 mmol) and KF (1.5 g, 25.8 mmol) was heated at 220° C. for 28 min under microwave condition. The solid was dissolved in DCM (150 mL), washed with water (50 mL×3), dried over Na2SO4. The solvent was evaporated in vacuo, and then the mixture was purified by Combi-flash (PE:EA=20:1) to give N-(4-chlorophenyl)-2-nitrobenzenamine (3.2 g, 52%) as a scarlet solid. 1H NMR (300 MHz, CD3OD): δ 6.82-6.87 (m, 1H), 7.27-7.31 (m, 2H), 7.41-7.45 (m, 3H), 7.70-7.73 (m, 1H), 8.15-8.18 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:32])[CH2:19][C:18](=[O:20])[CH:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:15]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:18](=[O:20])[CH2:19][C:14]([CH3:32])([CH3:13])[CH2:15][C:16]=3[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)C=C(Nc2cccc(C(F)(F)F)c2)C1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC1(C)CC(=O)C2=C(C1)N(c1cccc(C(F)(F)F)c1)C(=O)NC2c1ccc(Br)cc1

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (435 mg, 1.77 mmol) in dichloromethane (5 mL) is added to a solution of 5,5-dimethyl-3-(3-(trifluoromethyl)-phenylamino)cyclohex-2-enone (intermediate 8, 500 mg, 1.77 mmol) in dichloromethane (15 mL) and the mixture is heated at reflux over night. All volatiles are evaporated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 389 mg; ESI mass spectrum: [(79Br)-M+H]+=493, [(81Br)-M+H]+=495; Retention time HPLC: 1.38 min (Z002—002).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)(Cl)Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccnc(Cl)c2)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccnc(Cl)c2)n1
Temperature: 160 °C
Yield: 40.8 %

Procedure:
In a 5 ml microwave reaction vessel were dissolved 80 mg (0.31 mmol) 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide and 60 mg (0.38 mmol, 1.25 equiv.) of 3-Bromopyridine in 4 ml of dioxane. Cesium carbonate (139 mg, 0.43 mmol, 1.4 equiv.) were added and argon was bubbled through the suspension for 3 min. Then Xanthphos (58 mg, 0.10 mmol, 0.33 equiv.) and Pd2(dba)3.CHCl3 (32 mg, 0.03 mmol, 0.1 equiv.) were added and the mixture was heated for 2 h at 160° C. under microwave irradiation. To the mixture was added silica gel (5 g) and the mixture was evaporated to dryness in vaccuo. The powder was charged onto a flash chromatography column and eluted (heptane/ethyl acetate 2:1) to yield the title compound as a yellow solid (total 43 mg, 41%), MS (ISP): m/e=340.1, 342.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:45][CH2:44][C:42]3[CH:41]=[CH:40][N:39]=[C:38]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:30])[F:46])=[CH:33][CH:34]=4)[CH:43]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
Acid 18 (0.3 g, 1.09 mmol) was dissolved in 15 ml of THF and at rt DEPC (1.3 equiv, 0.21 mL) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 mol equiv., 0.37 g) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 mL) and washed with water (1×20 mL) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 3/petroleum ether 7) afforded 100 mg of a white solid. Yield=18% 1HNMR (DMSO, 200 MHz) δ 1.24 (m, 5H), 1.35 (m, 2H), 3.45 (m, 2H), 4.44 (d, 2H, J=6.2), 7.26 (m, 3H), 6.61 (d, 1H, J=2.1), 7.88 (d, 2H, J=7.8), 7.94 (s, 1H), 8.31 (d, 3H, J=8), 8.64 (d, 1H, J=4.1). [M+1] 543.95 (C23H21ClF3N3O3S2 requires 544.01).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nsc(-c2ccc(N3CCC4(CCc5ccccc54)CC3)nn2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
3-Chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), 2,3-dihydrospiro[indene-1,4′-piperidine] hydrochloride (78 mg) and potassium carbonate (70 mg) were suspended in N,N-dimethylformamide (3 mL), and the suspension was stirred at 80° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed twice with aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane to 50% ethyl acetate/hexane) and recrystallized from hexane/ethyl acetate to give the object product (53 mg, 60%).
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][NH:16][C:17]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]3[C:32](=[O:53])[CH2:33][C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])=[O:18])[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][NH:16][C:17]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C:29](=[O:31])[CH2:28][N:27]3[C:32](=[O:53])[CH2:33][C:34]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])=[O:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NC[C@H]1CCCN(CC2CCCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 72.2 %

Procedure:
To a solution of 0.0037 ml of oxaryl chloride in 0.3 ml of dichloromethane, 0.0065 ml of dimethyl sulfoxide was added at −78° C., followed by 20 minutes' stirring at the same temperature. Then a solution of 25 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.9 ml of dichloromethane was added at the same temperature, followed by 30 minutes' stirring, addition of 0.0024 ml of triethylamine at the same temperature, and 20 minutes' stirring at room temperature. The reaction liquid was diluted with chloroforom, washed with saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck); chloroform/methanol=9/1), to provide 18 mg of the title compound as a pale pink solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:5]1([C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(N)c(OC)c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCC2)c(OC)c1
Temperature: 150 °C
Yield: 62.8 %

Procedure:
Ex-38A: Method A: A mixture of 2,4-dimethoxyaniline (1.0 g, 6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was heated at 150° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. After the mixture was partitioned, the aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography. Elution with ethyl acetate and hexane (1:2, v/v) gave 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (0.85 g, 63%). 1H-NMR (300 MHz, CDCl3) δ 6.76 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.41 (dd, J=2.7, 8.9 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.18–3.14 (m, 4H), 1.95–1.90 (m, 4H). Method B: Sodium tert-butoxide was charged to a mixture of 1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75 mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.26 g, 0.28 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.35 g, 0.56 mmol) in degassed toluene (60 mL). The reaction mixture was heated at 100° C. under N2 for 17 h. After cooling to room temperature, the reaction mixture was diluted with water (60 mL) and partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate and toluene was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography with ethyl acetate and hexane (1:2, v/v) to give 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (1.82 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH2:21][C:22]([O:24][C@H:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]4[CH2:50][CH2:51]4)[CH:38]=3)[CH2:34][C:33]3[C:32]([Cl:52])=[CH:31][N+:30]([O-:53])=[CH:29][C:28]=3[Cl:27])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (0.234 g, 0.606 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.212 g, 0.505 mmol), EDC (0.290 g, 1.514 mmol) and DMAP (0.031 g, 0.252 mmol) in DCM (15 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 1N NaHCO3 and brine. The organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1) affording (S)-4-(2-(2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.200 g, 0.254 mmol, 50% yield). MS/ESI+ 787.8 [MH]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: CC(C)CI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CC(C)C)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(=O)C2C(=CC=CC=2)C(O)=O)[CH2:9][CH2:8]1)([OH:3])=[O:2].[ClH:29]>>[ClH:29].[ClH:29].[ClH:29].[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[CH2:8][CH2:9]1
Reactant: O=C(O)CCCN1CCN(CCCCNC(=O)c2ccccc2C(=O)O)CC1
Agent: Cl
Product: NCCCCN1CCN(CCCC(=O)O)CC1
Temperature: 100 °C
Yield: 95 %

Procedure:
In a sealable vessel, the acid-amide 12 (0.22 g, 0.55 mmol) was dissolved in concentrated hydrochloric acid (5 mL). The reaction vessel was sealed and heated to 100° C. for 9 hours, and then cooled to 0° C. The precipitate was collected by vacuum filtration. The collected solids were dried under vacuum to give 13 (0.19 g, 95%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 1.78-2.15 (m, 8H), 2.45-2.56 (m, 3H), 3.01 (t, J=7.30 Hz, 2H), 3.31-3.42 (m, 6H), 3.57-4.51 (m, 6H). Compound 13 was employed in the next reaction without further purification
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=1[C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[CH:46][C:45]([S:49](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:51])=[O:50])=[CH:44]2.C(O)(C(F)(F)F)=O>C1COCC1.C(O)(=O)C.C(Cl)Cl.CO.O>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=1[C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[CH:46][C:45]([S:49]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)(=[O:51])=[O:50])=[CH:44]2
Reactant: COc1ccc(CNc2ccncn2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cnc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)cnc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 5118.1 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)pyrimidin-4-amine (Intermediate OO; 28.7 mg, 0.134 mmol) was added THF (509 μl) and the resulting clear solution cooled in an ice water bath prior to the drop wise addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (26.0 μl, 0.134 mmol). The mixture was stirred for 20 min at 0° C. prior to the addition, faster than drop wise, of a solution of perfluorophenyl 8-(2-methoxy-4-(trifluoromethyl)phenyl)-1,7-naphthyridine-3-sulfonate (see EXAMPLE 322, STEP 3) (70 mg, 0.127 mmol) in THF (0.5 ml, 0.1 ml rinse). The resulting mixture was allowed to stir and warm slowly to room temp (ice melt) for 1 hr. To the mixture was added acetic acid (about 10 drops) and the resulting solution dried under reduced pressure. The crude residue was purified with a 25 g HP Silicycle column (SiliCycle, Inc. Quebec City, Canada) (0-100% EtOAc in heptane). The crude oil obtained (52 mg) was dissolved in DCM (3 ml) and TFA (0.5 ml) was added and the mixture stirred overnight at room temperature. The material was purified with a 25 g HP spherical silica column (15 μm spherical, Interchim, Mouintlucon, France) ramping DCM:MeOH (90:10) in DCM (0 to 50%) providing product, obtained as a film which was lyophilized from MeOH/H2O to afford 8-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-1,7-naphthyridine-3-sulfonamide (3 mg, 6.50 mmol, 5.11% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.69 (s, 3H) 6.77 (d, J=6.41 Hz, 1H) 7.39-7.47 (m, 2H) 7.54 (d, J=7.91 Hz, 1H) 8.08 (d, J=6.30 Hz, 1H) 8.16 (d, J=5.56 Hz, 1H) 8.44 (s, 1H) 8.75 (d, J=5.56 Hz, 1H) 8.97 (s, 1H) 9.23 (d, J=1.82 Hz, 1H). m/z (ESI) 462.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CCCCCC>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccccc1C=O
Yield: 97.3 %

Procedure:
2-Hydroxybenzaldehyde (110 g), was alkylated by mixing this compound with 1-bromononane (180 g), anhydrous potassium carbonate and dimethylformamide (800 mL). This mixture was heated at 80oC for 14 hours. Hexane and water were then added and the hexane extract was concentrated and the residue was distilled to yield the 2-nonyloxybenzaldehyde (210 g), bp 121° C (0.3mm Hg). A solution of 2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at 10 C was reduced by treating with an excess of sodium borohydride (6 g) and after stirring the mixture for a further 15-20 min. at room temperature, the compound 2-nonyloxybenzylalcohol was isolated by extraction into hexane. Removal of the hexane in vacuo yielded the crude 2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile (500 mL) and the resultant solution was heated at reflux for 14 hours. Removal of the solvents in vacuo and crystallization of the residue from a tetrahydrofuran/ethyl ether mixture gave the pure [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (208 g).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[OH-].[Na+].Br[CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>C(N(CC)CC)C>[CH2:2]([NH:4][CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)[CH3:3]
Reactant: CCN
Reactant: CC(=O)c1cccc(CBr)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCNCc1cccc(C(C)=O)c1
Yield: 66.6 %

Procedure:
The procedure described in Referential Example 4 was repeated, except that ethylamine hydrochloride (16.31 g; 200 mmol), sodium hydroxide (instead of triethylamine) (8 g; 200 mmol), and 3′-bromomethylacetophenone (4.26 g; 20 mmol) were used, to thereby yield 2.36 g of the target compound (yield: 66.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([O:34]CC)=[O:33])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Li+].CO.Cl>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=[O:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-n3ccccc3=O)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Yield: 78.7 %

Procedure:
Ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.5 g, 1.03 mmol) was hydrolyzed with lithium hydroxide (0.13 g, 3 mmol) and a mixture of methyl alcohol(5 mL), THF (25 mL) and water (25 mL) for 24 h. The reaction was acidified with conc. HCl and the resulting solid filtered off. The product was suspended in 1:1 CH2Cl2/hexanes, filtered, and dried to afford 0.37 g (79%) white solid; Mass Spec (M+H)+457.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.Cl>CO>[Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(-n2cc(Cl)c(OC3CCNCC3)cc2=O)cc1F
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A suspension of tert-butyl 4-(5-chloro-1-(4-cyano-3-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (2.2 g, 4.18 mmol) in MeOH (15 mL) was added hydrogen chloride (4M in 1,4-dioxane) (0.609 g, 16.70 mmol) and stirred at rt. After 6 h stirring, solvent MeOH was evaporated and the resulting crude was diluted with EtOAc (50 mL). After saturated aqueous NaHCO3 was added to adjust PH>7, the resulting mixture was vigorously stirred for 2 h. The organic layers was collected and the aqueous layer was back-extracted with EtOAc 2×. The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give a brown solid as a crude product (1 g, 2.88 mmol). MS (ESI) 348 (M+H).