Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=O)([O-])=O.C(O)(C(F)(F)F)=O>[Pd].CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2
Reactant: O=C1Cc2cc(C(=O)c3cccc([N+](=O)[O-])c3)ccc2N1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Cc2ccc3c(c2)CC(=O)N3)c1
Reaction time: 0.75 h
Yield: 69.9 %

Procedure:
The PARR apparatus was charged with was charged with 5-(3-Nitro-benzoyl)-1,3-dihydro-indol-2-one (50 g, 0.18 mol), 10% Pd/C (5 g) and DMF (500 mL). The reactor was evacuated, purged with N2(g) then filled with H2(g) (60 psi) at room temperature. After hydrogenating at 60 psi for 45 min thin layer chromatographic analysis (TLC) (Hexanes/EtOAc 1:1) indicated that the reaction had caused the reduction of the nitro group to an amine and the reduction of the keto group to the alcohol. Subsequently, TFA 926 mL, 0.35 mol) was added and the reaction was continued for 4 h. The reaction was filtered through celite and the solvent from the filtrate was removed in vacuo. The solids obtained were washed with saturated NaHCO3(aq) (500 mL), and H2O (500 mL) then triturated with Methyl-t-Butyl Ether (500 mL) and then triturated again with methanol to afford 5-(3-Amino-benzyl)-1,3-dihydro-indol-2-one (30 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccccc1Cl
Yield: 52.3 %

Procedure:
Prepared according to Procedure A using 2-amino-5-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.2 mL, 29.2 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.5 mL, 23.3 mmol) and CHCl3 (50 mL). The product was purified by recrystallization from MeOH to provide 1.72 g of a dark yellow solid (52%). 1H NMR (CDCl3) δ: 8.37 (dd, J=1.5, 8.3 Hz, 1H); 8.22 (br s, 1H); 7.48 (d, J=2.3 Hz, 1H); 7.42 (dd, J=1.5, 8.1 Hz, 1H); 7.31 (dt, J=1.4, 7.8 Hz, 1H); 7.22 (dd, J=2.4, 8.8 Hz, 1H); 7.09 (dt, J=1.5, 7.7 Hz, 1H); 6.67 (d, J=8.8 Hz, 1H); 5.56 (br s, 2H)
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:65])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:33]([O:59][CH3:60])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:57][CH3:58])[C@@H:43]([CH3:56])[C:44]([NH:46][CH2:47][CH2:48][CH:49]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=[CH:50]3)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:33]([O:59][CH3:60])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:57][CH3:58])[C@@H:43]([CH3:56])[C:44]([NH:46][CH2:47][CH2:48][CH:49]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=[CH:50]1)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:65])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of #65 (540 mg, 0.603 mmol, 1 eq.) in dichloromethane (10 mL, 0.06 M) was added triethylamine (10 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #66 (347 mg, 85%) as a colorless solid. HPLC (Protocol A at 45° C.): m/z 674.5 [M+H+], retention time=7.015 minutes. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.03 (br d, J=9 Hz) and 8.05 (br d, J=9 Hz), total 1H], [7.77 (br dd, J=5.5, 5.5 Hz) and 7.98 (br dd, J=5.5, 5.5 Hz), total 1H], 6.54-6.65 (m, 2H), 6.10-6.19 (m, 2H), 5.11-5.19 (m, 2H), [4.48 (dd, J=9, 8 Hz) and 4.54 (dd, J=9, 7.5 Hz), total 1H], 3.94-4.04 (br m, 1H), 3.26 and 3.29 (2 s, total 3H), 3.17 and 3.19 (2 s, total 3H), 2.93 and 3.06 (2 br s, total 3H), 1.20 and 1.21 (2 s, total 3H), 1.12 and 1.13 (2 s, total 3H), [1.04 (d, J=6.8 Hz) and 1.07 (d, J=6.7 Hz), total 3H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[N:18]=2)=[CH:10][CH:9]1[CH3:24])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[CH3:23][C:19]1[C:17]2[N:18]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH:9]([CH3:24])[CH:10]=3)[S:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc2sc(C3=CC(C)N(C(=O)OC(C)(C)C)CC3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2sc(C3=CC(C)NCC3)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Scheme IIA, Step B: To a mixture of 1-(t-butyloxycarbonyl)-4-(4-methylbenzothiazol-2-yl)-2-methyl-1,2,5,6-tetrahydropyridine (1.297 g, 3.77 mmol) in dichloromethane (12 mL) at 0° C. was added trifluoroacetic acid (12 mL). The mixture was stirred at 0° C. for 30 minutes, then at 20° C. for 30 minutes. The mixture was diluted with 2 N sodium hydroxide and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was chromatographed over silica gel (dichloromethane/10% methanol/1% ammonium hydroxide in dichloromethane gradient elution) to give the intermediate title compound as a yellow oil (0.738 g, 85%). FDMS m/e=245 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1.C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
4-Aminobenzonitrile (98%, 500.0 g (4.15 mol) was dissolved in a mixed solvent of pyridine (360 ml) and acetonitrile (900 ml). To this, p-toluenesulfonyl chloride (872.3 g (4.44 mol)) was added with stirring at room temperature. After stirring for 16 hours at room temperature, water (4000 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 1153 g (98%) of 4′-cyano-p-toluenesulfonanilide as pale red crude crystals.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:20][C:10]1=2)(=[O:8])[C:2]1C=CC=CC=1.S1C2NC3C(C=2C=C1C(OC)=O)=CC=CC=3.C(Cl)(=O)C.[H-].[Na+]>>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:20][C:10]1=2)(=[O:8])[CH3:2]
Reactant: COC(=O)c1cc2c3ccccc3n(C(=O)c3ccccc3)c2s1
Agent: COC(=O)c1cc2c([nH]c3ccccc32)s1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Product: COC(=O)c1cc2c3ccccc3n(C(C)=O)c2s1

Procedure:
Preparation as described for (21) from (19) (0.5 g), acetyl chloride (0.17 g) and NaH (0.06 g) resulted in (22) (0.55 g), m.p. 179°-181° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][S:20]([N:23]1[CH2:28][C@@H:27]([CH3:29])[NH:26][C@@H:25]([CH3:30])[CH2:24]1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:26]3[C@H:25]([CH3:30])[CH2:24][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:28][C@@H:27]3[CH3:29])=[CH:4][C:5]=2[N:6]=1
Reactant: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 80 °C

Procedure:
To a mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (380 mg) and (3S,5R)-1-methanesulfonyl-3,5-dimethyl-piperazine (314 mg) in acetonitrile (10 mL) was added potassium carbonate (620 mg). The reaction mixture was heated at 80° C. for 16 h and then allowed to cool to room temperature. The reaction mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>O1CCCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1C=C(c2cccnc2F)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: OC1CCC(c2cccnc2F)C1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 3-(2-fluoropyridin-3-yl)cyclopent-2-enol (1184 mg, 6.61 mmol) in tetrahydrofuran (40 mL) was treated with palladium, 10% wt. on activated carbon (703 mg, 0.661 mmol). The reaction mixture was evacuated under vacuum and backfilled with hydrogen (3×), and stirred under hydrogen at 23° C. After 4 h, the reaction was filtered through celite, the filter cake washed with 1:1 methanol:dichloromethane (50 mL), the filtrates combined and concentrated, affording the product as a yellow oil. MS (ESI, pos. ion) m/z: 182.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.Br[C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[C:16]#[N:17].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.CC(C)([O-])C.[Na+]>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]>[CH3:1][O:2][C:3]1[C:4]2[CH2:12][N:11]([C:14]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=3[C:16]#[N:17])[CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Cc1ccc(Br)c(C#N)c1
Reactant: COc1ncnc2c1CNCC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: COc1ncnc2c1CN(c1ccc(C)cc1C#N)CC2
Reaction time: 14 h

Procedure:
A 100 mL flask was charged with 4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.78 g, 16 mmol), 2-bromo-5-methylbenzonitrile (4.18 g, 19.2 mmol), bis(dibenzylideneacetone)palladium(0) (372 mg, 0.64 mmol), xantphos (529 mg, 0.896 mmol), and sodium tert-butoxide (2.33 g, 24 mmol), capped with a septum and purged with nitrogen. Dry argon-sparged toluene (50 mL) was added. The heterogeneous mixture was placed in an oil bath at 100° C., and heated under argon overnight. After 14 hours, TLC showed the reaction was complete. The mixture was removed from the heat, diluted with ethyl acetate (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column (0-100% EtOAc/hexane) to afford a light orange solid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:25][NH:24][C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[O:12][CH2:13][C:14]=2[CH:20]=1)=[NH:22]
Reactant: N#Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 81.2 %

Procedure:
A stirred suspension of 2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazine-6-carbonitrile (example 117) (310 mg, 1.07 mmol), hydroxylamine hydrochloride (275 mg, 3.96 mmol), sodium carbonate (227 mg, 2.14 mmol) in ethanol (4 ml) and water (4 ml) was heated under reflux conditions for 17 h, water (10 ml) was added, the precipitate was collected by filtration, washed with water and hexane. The crude product was further purified by crystallization (diethyl ether/methanol 10:1) to yield the title compound as white solid (280 mg, 81%). MS (ISP): m/e=323.3 (M+H+); m.p. 206° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=O)[CH2:5][CH2:6][CH3:7].O.[OH-].[Li+].[ClH:22].Cl.[NH2:24][C@@H:25]([CH2:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)[C@H:26]([OH:37])[CH2:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([I:36])[CH:31]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.CO.O>[ClH:22].[ClH:22].[F:45][C:43]1[CH:44]=[C:39]([CH:40]=[C:41]([F:46])[CH:42]=1)[CH2:38][C@H:25]([NH:24][C:12](=[O:14])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([CH2:8][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][CH3:7])[CH:10]=1)[C@H:26]([OH:37])[CH2:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([I:36])[CH:31]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(I)c1
Reactant: CCCN(CCO)Cc1cccc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCO)Cc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(I)c2)c1

Procedure:
Methyl 3-{[(2-hydroxyethyl)(propyl)amino]methyl}benzoate (500 mg, 2 mmol) and lithium hydroxide monohydrate (170 mg, 4 mmol) are stirred in 2:1:1 tetrahydrofuran/methanol/water (4 mL) at room temperature for 16 h. The reaction is concentrated under reduced pressure and redissolved in DMF (15 mL). To this solution is added (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-iodobenzyl)amino]butan-2-ol dihydrochloride (1 g, 2 mmol), diisopropylethylamine (1.4 mL, 8 mmol), then HATU (1.1 g, 3 mmol), and the reaction stirred 2 h. Purification by flash column chromatography (silica, 10% methanol/chloroform) provides the title compound as the free base. The residue is dissolved in diethyl ether (5 mL) and 1N hydrochloric acid in diethyl ether (3 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 652.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ncccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 4-nitrobenzylamine (6.09 g, 40.0 mmol), 2-chloropyrimidine (4.82 g, 42.1 mmol), triethylamine (11.2 ml, 80.4 mmol) and ethanol (120 ml) was stirred at 110° C. for 24 hours, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate-THF. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give N-(4-nitrobenzyl)-N-(2-pyrimidinyl)amine (0.99 g, 4.3 mmol, 11%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(OCC)C>[NH:20]1[C:16]2=[N:17][CH:18]=[N:19][C:14]([N:11]3[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]3)=[C:15]2[CH:22]=[N:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ncc23)CC1
Agent: Cl
Solvent: CCOCC
Product: NC1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 177 %

Procedure:
To [1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (28 mg, 0.088 mmol) was added HCl (1 ml, 4M solution in dioxane, 4 mmol). The suspension was stirred at room temperature for 1 hour, and then diluted with diethyl ether (4 ml). The ethereal layer was discarded and the solid washed with a further portion of diethyl ether (2 ml). The ethereal layer was again discarded, and the resultant solid dried under high vacuum to yield the desired product (34 mg). The free base was liberated by dissolution of this material in methanol, loading onto an acidic resin SCX-2 cartridge, and elution from the cartridge with ammonia in methanol. LC/MS Rt 0.86 [M+H]+ 219
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([Cl:45])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([Cl:45])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1Cl
Yield: 36.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.86 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(3-chloro-4-methoxyphenyl)-1-hexanone (0.82 g) were reacted and treated in the same manner as in Example 172 to give 0.45 g of 4-amino-5-chloro-N-((1-(6-(3-chloro-4-methoxyphenyl)-6-oxohexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.C(N=C=N[CH2:33][CH2:34][CH2:35][N:36](C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:36][CH:35]3[CH2:34][CH2:33][CH:5]([C:4]4[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=4)[CH2:6][CH2:7]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccccc5)CC4)cc3)c(Cl)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.0899 g, 0.238 mmol), N,N-dimethylpyridin-4-amine (0.00291 g, 0.0238 mmol), and (1R,4R)-4-phenylcyclohexanamine (0.0627 g, 0.358 mmol) in DMF (1.25 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0549 g, 0.286 mmol), and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5% to 50% EtOAc in hexanes to yield two isomers of the product. The first eluting isomer was collected and called isomer 1 (27 mg). The second eluting isomer was called isomer 2 (32 mg). The relative configurations of each of these isomers were not determined.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]([CH2:8][CH3:9])[C:5](Cl)=[O:6])#[N:2].[CH3:22][NH:23][CH3:24]>C(Cl)Cl>[C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]([CH2:8][CH3:9])[C:5]([N:23]([CH3:24])[CH3:22])=[O:6])#[N:2]
Reactant: CCC(C(=O)Cl)C(C#N)(c1ccccc1)c1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: CCC(C(=O)N(C)C)C(C#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyano-3,3-diphenyl-2-ethylpropionyl chloride (0.1 mol prepared from 0.1 mol of the acid as described above) in 100 ml of methylen chloride was added dropwise while stirring to a mixture of 65 ml of 33% aqueous dimethylamine (ca. 0.5 mol) and 100 g of crushed ice. The mixture was stirred for 1 hour at room temperature, whereupon the organic phase was separated and washed with dilute hydrochloric acid. After drying over magnesium sulphate, filtration and evaporation, the residue was crystallized from a mixture of methylene chloride and ether. Yield: 28 g (88%) of the amide as a white crystalline substance melting at 170°-172° C.
Reaction SMILES: C(O)(=O)C.[N:5]([O-:7])=[O:6].[Na+].[F:9][C:10]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[N+]([O-])(O)=O>O>[F:9][C:10]1[CH:25]=[C:24]([N+:5]([O-:7])=[O:6])[C:23]([F:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=N[O-]
Reactant: O=S(=O)(Nc1cc(F)ccc1F)c1ccccc1
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(NS(=O)(=O)c2ccccc2)cc1F
Temperature: 96 °C

Procedure:
To 310 ml of acetic acid diluted with 160 ml of water are added: 1.5 g of sodium nitrite, 0.16 mole (42 g) of 2,5-difluoro-N-benzenesulphonylaniline prepared in the previous stage and 0.94 mole (39 ml) of nitric acid (d=1.52). The reaction mixture is heated to 96° C. for 1 hour. After cooling it is poured onto 1 kg of ice and water. The expected product precipitates. After being filtered off and washed to neutrality it is recrystallized from 250 ml of acetic acid; it melts at 176° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH2:11]([NH:18][CH2:19][CH2:20][NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH2:11]([NH:18][CH2:19][CH2:20][NH:21][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=1[CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCNCc1ccccc1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1c(Cl)nnc(NCCNCc2ccccc2)c1C

Procedure:
Heat a mixture of 3,6-dichloro-4,5-dimethylpyridazine (6.90 g, 39.0 mmol), N-benzylethylenediamine (8.78 g, 58.5 mmol), and diisopropylethylamine (25.2 g, 195 mmol) in DMSO (78 mL) at 120° C. for 3 d. Cool the reaction mixture, pour into H2O, and extract the mixture with Et2O. Wash the organic layer with H2O, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue using flash silica gel chromatography (gradient of 0 to 5% 2 M NH3/MeOH in CH2Cl2) to obtain the title compound as a waxy solid (6.41 g, 57%). ES/MS m/z 291.2 (M+1).