Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][NH:26][CH3:27])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28].Br[CH2:30][CH2:31][F:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][F:32])[CH3:27])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28]
Reactant: CNCCOc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Reactant: FCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)CCF)C3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A mixture of Example 144 (100 mg; 0.23 mmol; 1 eq.), 1-bromo-2-fluoro-ethane (47 mg; 0.37 mmol; 1.6 eq.) and NaHCO3 (193 mg; 2.29 mmol; 10 eq.) in DMF was stirred at 100° C. for 30 minutes. 1-Bromo-2-fluoro-ethane (47 mg; 0.37 mmol; 1.6 eq.) was added and the resulting mixture was stirred at 100° C. for 30 minutes then concentrated in vacuo. After dilution with EA, the solution was washed with sat. aq. NaHCO3 then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 10% MeOH in EA) afforded the title compound (50 mg, 49%) as a white foam. 1H NMR (DMSO-d6) δ 7.51-7.39 (m, 1H), 7.36-7.24 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 4.80 (d, J=7.3 Hz, 2H), 4.59 (d, J=19.7 Hz, 2H), 4.37 (td, J=5.0, 3.2 Hz, 1H), 4.21 (td, J=5.1, 3.3 Hz, 1H), 4.12 (t, J=5.3 Hz, 2H), 2.84 (s, 2H), 2.81 (s, 1H), 2.71 (t, J=5.2 Hz, 2H), 2.67-2.60 (m, 2H), 2.60-2.53 (m, 2H), 2.15 (s, 3H). HPLC (max plot) 97.5%, Rt 2.65 min. UPLC/MS: (MS+) 446.2 ([M+H]+).
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=[O:15])[CH2:9][CH2:8]2>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]([CH3:1])([OH:15])[CH2:9][CH2:8]2
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C[Mg+]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC1(O)CCc2cc(Cl)ccc2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of TiCl4 (95 mL, 1M in toluene) at −45° C. is added a solution of CH3MgBr (4.2 mL 3M in THF). The solution is stirred for 20 minutes. After this time, 6-chloro-3,4-dihydro-1H-naphthalene-2-one (11.3 g, 63 mmol) in 80 mL of CH2Cl2 is added dropwise over 15 minutes. The reaction is stirred for an additional 15 min at −45° C. The solution is warmed to 0° C. After 2 h, the solution is diluted with H2O and CH2Cl2. The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as an oil (11.3 g, 57.5 mmol). 1H NMR (CDCl3, 300 MHz) δ7.10 (m, 2H), 6.97 (m, 1H), 3.02 (m, 2H), 2.80 (s, 3H), 1.85 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[S:14]([C:17]1[C:25]2[C:21](=[N:22][S:23][N:24]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].N1C=CC=CC=1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[NH:1][S:14]([C:17]1[C:25]2=[N:24][S:23][N:22]=[C:21]2[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of methyl 2-amino-4-chlorobenzoate (7.0 g, 37.7 mmol) in DCM (75 mL) at room temperature (rt) was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (9.45 g, 39.6 mmol), pyridine (9.1 mL, 112 mmol), and DMAP (0.23 g, 1.88 mmol). The mixture was stirred at rt overnight, poured into 1 N HCl (200 mL), and extracted with DCM (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (hexanes/EtOAc) to afford the title sulfonamide as a tan solid (11.65 g, 80%). MS (ESI−): mass calcd. for C14H10ClN3O4S2, 383.8; m/z found, 382 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.38 (s, 1H), 8.40 (dd, J=7.2, 1.2, 1H), 8.24 (dd, J=8.8, 1.2, 1H), 7.80 (d, J=8.4, 1H), 7.76 (d, J=2.0, 1H), 7.74 (dd, J=8.8, 7.2, 1H), 6.94 (dd, J=8.4, 2.0, 1H), 3.92 (s, 3H). Anal. calcd. for C14H10ClN3O4S2: C, 43.81; H, 2.63; N, 10.95. Found: C, 44.19; H, 3.00; N, 11.23.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[CH:18]2[Si:23]([CH:26]1[C:34]2[C:29](=[C:30](Br)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:36])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH3:37])[CH:18]3[Si:23]([CH:26]2[C:34]3[C:29](=[C:30]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[CH:31]=[CH:32][CH:33]=3)[CH:28]=[C:27]2[CH3:36])([CH3:25])[CH3:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF, 13.0 ml of 1.0 M 4-(tert-butyl) phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.37 g (5.0 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.85 g (98%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[N:19]([CH3:34])[C:20](=[O:33])[N:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[C:29]#[N:30])=[CH:24][CH:23]=4)[C:17]=3[C:16]3[CH:15]=[C:14]([C:35]4[CH:36]=[N:37][C:38]5[C:43]([CH:44]=4)=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:13]=[CH:12][C:11]=3[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[C:18]2[N:19]([CH3:34])[C:20](=[O:33])[N:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[C:29]#[N:30])=[CH:24][CH:23]=3)[C:17]=2[C:16]2[CH:15]=[C:14]([C:35]3[CH:36]=[N:37][C:38]4[C:43]([CH:44]=3)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COc1ccc(CNc2nc3ccc(-c4cnc5ccccc5c4)cc3c3c2n(C)c(=O)n3-c2ccc(C(C)(C)C#N)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3nc(N)c21
Reaction time: 5 h

Procedure:
110 mg (0.182 mmol) of 2-{4-[4-(4-methoxy-benzylamino)-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-phenyl}-2-methyl-propionitrile (Example 109a) in 1.1 ml TFA are stirred at rt for 24 h and then at 35° C. for 5 h. The reaction mixture is purified by preparative HPLC to provide the title compound as an off-white solid. ES-MS: 485 (M+H)+; analytical HPLC: tret=2.86 minutes (Grad 1).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.39 g. sodium in 200 ml. dry acetone, 20 g. valeramidine hydrochloride, and 27.6 g. 3,4-dichlorophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetone 10.5 g. of the hydrochloride of 1-(3,4-dichlorophenyl)-3-(pentanimidoyl)urea; m.p. 177°-179°C.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)=[CH:3]C=1.Cl.C(Cl)(=O)C1C=CC=[N:20][CH:19]=1>>[N:20]1[CH:19]=[CH:6][CH:5]=[C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)[CH:3]=1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: c1cncc(-c2nnc3n2CCCN3)c1

Procedure:
The title compound is prepared according to the procedure for 3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (example 17a) from nicotinoyl chloride hydrochloride.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([CH:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[N:29]=5)[N:26]=4)[CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3]N=1.N[C:35]1C=C(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)C=CC=1.C1(S(Cl)(=O)=O)C2C(=CC=CC=2)C=CC=1>>[C:6]1([S:11]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[N:29]=4)[N:26]=3)[CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:13])[C:5]2[C:10](=[CH:1][CH:35]=[CH:3][CH:4]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(N)c3)ccc2n1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5cnccc45)c3)ccc2n1
Agent: O=S(=O)(Cl)c1cccc2ccccc12
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5ccccc45)c3)ccc2n1

Procedure:
Following the procedure for compound N-(6-(3-(isoquinoline-5-sulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 6), N-(6-(3-aminophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 5) (0.032 g, 0.12 mmol) was reacted with 1-naphthalenesulfonyl chloride (0.034 g, 0.15 mmol, Aldrich, St. Louis, Mo.) to afford the title compound as a white solid. MS (ESI positive ion) m/z: 458 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.92 (s, 1H), 10.91 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.4 Hz, 1H), 8.21-8.24 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 8.02 (d, J=9.4 Hz, 1H), 7.74-7.78 (m, 1H), 7.62-7.70 (m, 3H), 7.58 (d, J=7.8 Hz, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8.0 Hz, 1.6 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C@H:24]([CH2:36][OH:37])[CH2:25][CH2:26][N:27]2[CH2:34][CH2:33][C:30]3([CH2:32][CH2:31]3)[C@H:29]([OH:35])[CH2:28]2)[C:20](=[O:38])[C@@H:19]1[CH3:39])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(NCC)C>>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C@H:24]([CH2:36][O:37][C:1](=[O:3])[CH3:2])[CH2:25][CH2:26][N:27]2[CH2:34][CH2:33][C:30]3([CH2:32][CH2:31]3)[C@H:29]([OH:35])[CH2:28]2)[C:20](=[O:38])[C@@H:19]1[CH3:39])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCNCC
Product: CC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 71.5 %

Procedure:
Acetic anhydride (42 mg, 0.41 mmol) was added at 0° C. to a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (intermediate 39; 182 mg, 0.41 mmol) and pyridine (32 mg, 0.41 mmol). The ice bath was removed, then after 16 h excess reagent was destroyed by addition of diethylamine (15 mg, 0.21 mmol). After evaporation of volatile material, chromatography (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (143 mg, 72%). Colorless gum, MS (ISP)=488.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](I)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CC(C)([O-])C.[Na+].COC(C)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
6-Chloro-3-iodo-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1C; 2 g, 3.73 mmol), morpholine (0.488 mL, 5.60 mmol), sodium tert-butoxide (0.538 g, 5.60 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (0.152 g, 0.187 mmol) was dissolved in dioxane (10 mL) and degassed under argon for five minutes. The reaction mixture was heated to 60° C. for 30 min under microwave irradation. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-30% EtOAc/Hexanes) gave 4-(6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine. MS ESI calc'd. For C30H28ClN4O [M+H]+ 495. found 495.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[CH:18]=[C:17]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:30]=4)[CH:25]=3)[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:35]([O:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:17]1[N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=3)[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[CH:18]=1)[CH:33]=[CH:32]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of {4-[5-(6-benzyloxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-ylamino]-phenyl}-carbamic acid tert-butyl ester (compound C2)(450 mg), TFA (2 ml) and dichloromethane (10 ml) is stirred 4 h at ambient temperature. The reaction mixture is evaporated and coevaporated with toluene. The residue is partitioned between a aqueous saturated solution of sodium bicarbonate and ethyl acetate. After drying the organic phase is evaporated and the residue is dried in vacuum. A solid in quantitative yield is obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[OH:21])=[O:13])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[OH:21])=[O:13])[N+:5]([O-:30])=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2ccccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (0.20 g, 0.57 mmol) in 3.0 mL CH2Cl2 at room temperature was added 3-chloroperbenzoic acid (0.20 g, 1.15 mmol). The reaction mixture was stirred at room temperature for 18 h. Additional 3-chloroperbenzoic acid (0.20 g, 1.15 mmol) was added to reaction mixture and was stirred at room temperature for an additional 18 h. The reaction mixture was concentrated, and the resultant residue was subjected to silica gel chromatography eluting with 0-75% ethyl acetate in hexanes to afford 4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide 1-oxide that gave a mass ion (ES+) of 367.1 for (81Br) for M+H+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([Cl:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 99.2 %

Procedure:
193.2 g (1 mole) of 4-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixture, the reaction mixture was refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and then poured into hexane. The precipitated solid was separated by filtration and dried. 210 g of 4-nitrocinnamoyl chloride was yielded. 63.5 g (0.3 mole) of 4-nitrocinnamoyl chloride and 400 g of methylethylketone were placed in a reaction vessel and the reaction mixtures were stirred by heating at 50° C. under a nitrogen current. 15.42 g (0.14 mole) of resorcinol, 32 g of pyridine, and 100 g of methylethylketone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction solution was refluxed with stirring under a nitrogen current for 2 hours. After the reaction, the precipitate was separated by filtration and the filtrated solid was washed by water and dried. 64 g of white colored crystals (1,3-bis (4-nitrocinnamic acid) benzene) was yielded.
Reaction SMILES: [NH2:1]CCCCCCCCCCCCN.[C:15]([OH:30])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C(O)=O>>[CH2:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:1]
Reactant: NCCCCCCCCCCCCN
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Product: NCCCCCCCCCCC(=O)O

Procedure:
polyamide of dodecamethylenediamine and n-dodecanedioic acid (nylon 12:12)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[CH3:35].Cl.[C:37]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:45][CH2:44][CH2:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:46])=[O:32])=[CH:28][C:27]=1[CH3:35]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C

Procedure:
Solid HATU (2.1 g, 5.6 mmol) was added to a DMF solution (25 mL) of 4-bromo-3-methylbenzoic acid (1.0 g, 4.7 mmol), i-Pr2Net (2.4 mL, 14.0 mmol), and β-alanine tert-butyl ester hydrochloride (845 mg, 4.7 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated, diluted with EtOAc, washed with water, 1N KHSO4, water, saturated aqueous NaHCO3, and brine. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:10]=1[OH:11])[CH:6]=O.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[C:19]1([C:16](=[O:18])[CH:17]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Product: COc1cc(C=CC(=O)c2ccccc2)cc(C(F)(F)F)c1O

Procedure:
The procedure described in Example 8 was repeated using 1.7 g of 3-methoxy-4-hydroxy-5-trifluoromethylbenzaldehyde and 1.0 g of acetophenone. Yield 1.1 g (45%), m.p. 166°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1>C(O)(=O)C.[Rh]>[NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:3]1
Reactant: Nc1cccc(Cc2ccccc2)n1
Agent: [Rh]
Solvent: CC(=O)O
Product: N=C1CCCC(Cc2ccccc2)N1

Procedure:
Example 298) A sample of the 2-amino-6-benzylpyridine product of Example 298 A was reduced in acetic acid under hydrogen atmosphere utilizing 5% Rh/C catalyst to afford 2-imino-6-benzylpiperidine as an oil. The oil was purified by C-18 reverse phase chromatography to give a white solid. The solid was dissolved in 1N HCl, lyophilized, and recrystallized from EtOH/EtOAc to give the title product as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([CH2:12][CH3:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:16])=O>C(O)=O>[CH2:12]([CH:10]([NH2:16])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: NC=O
Reactant: CCC(=O)CCCc1ccccc1
Solvent: O=CO
Product: CCC(N)CCCc1ccccc1

Procedure:
Ethyl magnesium bromide was reacted with 4-phenylbutylnitrile to provide ethyl 3-phenylpropyl ketone. The ketone was reacted with formamide and formic acid to afford 1-ethyl-4-phenylbutylamine. Methylation of the amine by reaction with formaldehyde and formic acid provided N,N-dimethyl-1-ethyl-4-phenylbutylamine. Quaternization of 6.2 g. of the dimethylamine according to the procedure of Example 62 afforded 6.56 g. of N,N,N-Trimethyl-1-ethyl-4-phenylbutylammonium bromide. M.P. 183°-185° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:18]([O:17][C:16]([NH:15][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A mixture of (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)carbamate (I8, 3.20 g, 10.7 mmol), methyl 4-(bromomethyl)benzoate (2.70 g, 11.8 mmol) and potassium carbonate (2.20 g, 16.1 mmol) in acetonitrile (54 mL) was stirred at RT for 16 h. The reaction mixture was removed in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts were dried with anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was re-crystallised from ethyl acetate and iso-hexane to afford (S)-Methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate as a white solid (3.25 g, 68%). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J=8.2 Hz, 2 H), 7.46 (d, J=8.2 Hz, 2 H), 7.34-7.20 (m, 6 H), 6.90-6.81 (m, 3 H), 5.87 (s, 1 H), 5.13 (s, 1 H), 5.07 (s, 2 H), 3.92 (s, 3 H), 1.44 (s, 9 H).