Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[CH2:11]([O:18][C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:22]2[CH2:23][C@H:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)Cn1cncn1
Yield: 30 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 252, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (36 mg, 30%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.14 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.58 (d, 2H), 7.41-7.28 (m, 5H), 7.19 (t, 2H), 7.06-6.92 (m, 4H), 5.27 (q, 2H), 4.58 (d, 2H), 4.49 (t, 1H), 4.40-4.34 (m, 1H), 3.90-3.75 (m, 2H) 2.42-2.22 (m, 1H), 2.11-2.01 (ml H). MS (EI) for C28H26FN5O4. found 516.0 (MH+).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[CH3:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([C:10]1[N:6]([N:5]2[C:4](=[O:12])[C:3]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]3[C:1]2=[O:17])[C:7]([CH3:11])=[CH:8][CH:9]=1)=[O:22]
Reactant: Cc1cccn1N1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2Cl)n1N1C(=O)c2ccccc2C1=O
Yield: 75.1 %

Procedure:
To a suspension of 1-phthalimido-2-methylpyrrole (105 g, 0.46 mol) and o-chlorobenzoyl chloride (162.5 g, 0.93 mol) in 1.5 liters of dichloromethane at 0° was added tin (IV) chloride (243 g, 0.94 mol) over 15 minutes. The resultant mixture was warmed to room temperature over 30 minutes and then quenched with 2 liters of H2O. The organic layer was washed with H2O and brine, dried (MgSO4), charcoaled and filtered. Evaporation of the volatiles left an oil which was purified by flash chromatography (silica, dichloromethane) to give 126 g of powder. This powder was recrystallized from ether-petroleum ether to give 82 g (48%) of powder, m.p. 260°-262°.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][N:3]=1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[F:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[C:6]=1[CH3:9]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnc(Cl)c1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1c(F)cncc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
A mixture of 2-chloro-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (212 mg; 0.7808 mmol), zinc powder (155.3 mg; 2.37 mmol), and acetic acid (3.0 mL; 47 mmol) was heated at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL) filtered through celite, and evaporated under vacuum to yield the title compound in quantitative yield. LCMS (ESI): [M-pinacol]+H=156.4; 1H NMR (400 MHz, DMSO) δ 8.55-8.47 (m, 2H), 2.42 (d, J=2.0 Hz, 3H), 1.33 (s, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]4[N:28]([CH3:31])[CH:29]=[N:30][C:21]=4[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]3[CH:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]4[N:28]([CH3:31])[CH:29]=[N:30][C:21]=4[CH2:20]3)(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Cn1cnc2c1CC(C(=O)O)N(S(=O)(=O)c1ccc(-c3ccc([N+](=O)[O-])cc3)cc1)C2
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cn1cnc2c1CC(C(=O)O)N(S(=O)(=O)c1ccc(-c3ccc(N)cc3)cc1)C2
Reaction time: 2 h

Procedure:
1 g (2.3 mmol) of 5-(4′-nitrobiphenyl-4-sulfonyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid was dissolved in 15 ml of dimethylformamide (DMF) and, after addition of 0.1 g of hydrogenation catalyst (10% Pd on activated carbon), quantitatively hydrogenated within 2 h. After removal of the solvent, the crude product was purified by chromatography.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([C@H:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([C@H:42]4[CH2:46][CH2:45][O:44][CH2:43]4)[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1cnn([C@H]2CCOC2)c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnn([C@H]3CCOC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 37 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(S)-tetrahydro-furan-3-yl]-1H-pyrazole following a procedure analogous to that described in Example 1. Yield: 37% of theory; LC (method 3): tR=3.16 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[CH:18].Br[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.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.O>[Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1Br
Reactant: Brc1ccc2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 18a (0.74 g, 2.4 mmol) and 2-bromoquinoline (2.0 g, 9.6 mmol) in a vial was evacuated and back-flushed with Argon. Dry DMF (10 mL) and DIEA (1.7 mL, 9.7 mmol) were added via syringe and the mixture was deoxygenated by bubbling Argon through the stirred solution for 5 min. To the mixture was added CuI (46 mg, 0.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.17 g, 0.24 mmol). The reaction mixture was stirred at rt overnight, and was poured into water (50 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain a residue which was purified by flash column chromatography on silica gel (30-70% EtOAc/heptane) to obtain compound 18b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H16BrN5O: 434.1 (M+H). found: 434.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.[C:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)#[N:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:27][C:23]1([C:21]#[N:22])[CH2:26][N:25]([C:4](=[O:6])[C@H:3]([N:7]2[C:16](=[O:17])[C:15]3=[CH:18][NH:19][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[CH2:8]2)[CH:2]([CH3:20])[CH3:1])[CH2:24]1
Reactant: CC1(C#N)CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N1CC(C)(C#N)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 30.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.293 mmol). DMF (0.5 mL), 3-cyano-3-methylazetidine (85 mg, 0.439 mmol), HOBt (67.2 mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) and N,N-dimethylpyridin-4-amine (53.6 mg, 0.439 mmol) were added and the solution was stirred at 25° C. for 4 h. The fractions were collected and lyophilized to afford the title compound as a white solid (31.5 mg, 30.6%). 1H NMR (400 MHz, DMSO-d6) δ 0.78 (dd, J=6.82, 3.28 Hz, 3 H) 0.96 (dd, J=8.59, 6.32 Hz, 3 H) 1.44-1.68 (m, 3 H) 2.26-2.44 (m, 1 H) 3.84 (dd, J=9.47, 5.18 Hz, 1 H) 3.99-4.14 (m, 1 H) 4.21 (dd, J=9.47, 5.68 Hz, 1 H) 4.34-4.65 (m, 1 H) 4.85 (dd, J=19.45, 5.56 Hz, 1 H) 4.96-5.11 (m, 2 H) 7.08 (d, J=5.05 Hz, 1 H) 7.86 (d, J=4.04 Hz, 1 H) 8.26 (dd, J=4.80, 3.28 Hz, 1 H) 12.22 (br. s., 1 H). [M+H] calc'd for C19H21N5O2, 352; found, 352.5.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:10][CH2:9][C@@H:8]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate (3.02 g, 11.7 mmole) in CH2Cl2 (50 mL) and triethylamine (4.0 mL, 28.6 mmol) was cooled to −20° C. (internal temperature). Neat methanesulfonyl chloride (2.0 mL, 25.7 mmol) was added dropwise, maintaining the internal temperature at −20° C. (+/−5° C.). The reaction mixture was stirred at −20° C. for an additional 30 min and at 0° C. for 1 h. Reaction progress was followed by TLC and LC-MS. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×20 mL), washed with water (3×10 mL), dried (Na2SO4), decanted, and stripped to give 4.13 g (quant) of product. 1H NMR (CDCl3) δ 0.80-1.40 (10H), 1.40 (s, 9H), 1.65 (t, 2H), 1.75 (d, 1H), 2.95 (s, 3H), 3.94 (m, 1H), 4.10 (m, 1H), 4.24 (m, 1H), 4.60 (m, 1H). MS ESI+ve m/z 236 (M(−BOC)+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH3:37])[N:23]4[N:22]=3)=[C:16]([O:42][CH3:43])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[CH3:43][O:42][C:16]1[CH:15]=[C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:37])[S:38]([CH3:41])(=[O:40])=[O:39])[N:23]2[N:22]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2=CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxy-4-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (41 mg) was dissolved in dichloromethane (1 ml), and trifluoroacetic acid (1 ml) was added. The solution was stirred 2 hours at room temperature, and then concentrated. Purification on Gilson reverse phase chromatograph (15% to 45% acetonitrile/water gradient) and lyophilization afforded N-(2-{2-[2-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide, compound with trifluoroacetic acid as an orange solid, 16 mg. mp 204-205° C. LCMS (E/I+) 505 (M+H). NMR 1H (DMSO-d6) 9.01 (s, 1H), 8.85 (br s, 1H), 7.98-8.05 (m, 2H), 7.80 (s, 1H), 7.64-7.70 (m, 1H), 7.51-7.62 (m, 2H), 7.24-7.48 (m, 1H), 7.11 (s, 1H), 6.98-7.05 (m, 2H), 6.91-6.96 (d, J=4.56, 1H), 6.21 (s, 1H), 3.88 (s, 3H), 3.65-3.82 (m, 2H), 3.39-3.48 (m, 2H), 3.12 (s, 3H), 2.87 (s, 3H), 2.55-2.64 (m, 2H), 2.32 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]C[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1CC[O:46]CC1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][O:46][CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCOCC1
Yield: 22.3 %

Procedure:
In the manner described in Example 21C 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) was reacted with morpholine (96 μL, 1.11 mmol), diisopropylethyl amine (193 μL, 1.11 mmol), and tetrabutyl ammonium iodide (136 mg, 0.37 mmol). The purification and isolation steps afforded 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylthio)phenyl)urea (49 mg, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.48 (s, 1H), 7.55-7.25 (m, 5H), 6.47 (s, 1H), 4.25 (m, 2H), 3.99 (s, 3H), 3.59 (m, 4H), 2.5-2.35 (m, 6H), 2.01 (m, 2H), 1.37 (s, 9H); LCMS (ESI) m/z 593 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[CH:15]2[CH2:14][C:13](=[O:29])[NH:12][CH:11]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:38])[CH2:24][CH2:25]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 1 h
Yield: 31.1 %

Procedure:
At room temperature, to a solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(piperazin-1-yl)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.054 mmol) in THF was added acetic anhydride (6 mg, 0.06 mmol). After stirred for 1 h, the mixture was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>CO.N1CCCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccc(F)c1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cccc(F)c1
Temperature: 75 °C

Procedure:
6-Chloro-1,3-dihydro-indol-2-one (Aldrich, 7.5 g, 44.92 mmol) was treated with 3-fluoro-benzaldehyde (Aldrich, 5.57 g, 44.92 mmol) in methanol (50 mL) and piperdine (0.2 mL). The mixture was heated at 75° C. overnight and then cooled to room temperature. The solid was filtered and dried to give a yellow solid. 8.8 g.
Reaction SMILES: [C:1]([S-:4])(=[S:3])[CH3:2].[Na+].Cl[CH:7]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[C:1]([S:4][CH:7]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[S:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)c1ccc2cc(OC)ccc2c1
Reactant: CC(=S)[S-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(SC(C)=S)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 0.2 moles of sodium dithioacetate and 0.12 moles of ethyl α-chloro-6-methoxy-2-naphthylacetate in 300 ml. of absolute ethanol is stirred at room temperature for 15 hours. The reaction mixture is filtered, washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to dryness to obtain ethyl α-thioacetylthio-6-methoxy-2-naphthylacetate.
Reaction SMILES: [C:1]1([C:7]([O:9]C)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1=CC=CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=CC=CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Methyl 1,3-cyclohexadiene-1-carboxylate (914 mg, 6.62 mmol) was dissolved in methanol (10 ml) and a 2N aqueous sodium hydroxide solution (4 ml) was added thereto and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated, made acidic with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1,3-cyclohexadiene-1-carboxylic acid (761 mg, 92.7%) as white solid. This compound has the following NMR spectrum.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]1[CH2:8][CH:7]([NH:9]C(=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4]1.[ClH:19]>C(OCC)C>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH:3]1[CH2:8][CH:7]([NH2:9])[CH2:6][CH2:5][NH:4]1
Reactant: CC(C)(C)OC(=O)NC1CCNC(C(F)(F)F)C1
Agent: Cl
Solvent: CCOCC
Product: NC1CCNC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
115 mg (0.43 mmol) of tert-butyl [2-(trifluoromethyl)piperidin-4-yl]carbamate were initially charged in 2.2 ml of diethyl ether, 2.14 ml (4.28 mmol) of 2 N hydrochloric acid in diethyl ether were added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was dried under high vacuum. 89 mg of the target compound were obtained (101% of theory).
Reaction SMILES: [CH2:1]([O:9][P:10](=[O:13])([OH:12])[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)C.[OH-].[Na+:18].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:31]>O>[CH2:1]([O:9][P:10]([O-:13])([O-:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Zn+2:31].[Na+:18]
Reactant: CCCCCCCCOP(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOP(=O)([O-])[O-]
Reaction time: 0.5 h

Procedure:
50 g of monooctylphosphoric acid and 100 g of ethanol were placed in a 500 ml reaction vessel. Further, a solution of 9.52 g of 96% sodium hydroxide (purity was taken into consideration by calculating it from the degree of neutralization determined by titration) dissolved in 200 g of ion-exchanged water was added thereto. After the temperature was elevated to 80° C., it was confirmed that they were dissolved. The solution was continuously stirred for 30 minutes. A solution of 34.2 g of zinc sulfate heptahydrate dissolved in 100 g of ion-exchanged water was added dropwise thereto. After the completion of the addition, the mixture was stirred for 30 minutes. 14.26 g of an aqueous solution of 33.33% sodium hydroxide was added dropwise thereto, to thereby adjust the pH of the reaction mixture to 5. Further, the mixture was stirred for one hour. After the completion of the reaction, the reaction mixture was cooled, and the product was collected by filtration, washed with water and dried to obtain 49.6 g of the particles of sodium zinc monooctylphosphate.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][NH2:17])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:18]=1.[CH2:19]([O:21][C:22](=[O:30])[C:23](=[CH:26]OCC)[C:24]#[N:25])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:26]=[N:17][N:16]([C:13]2[N:12]=[CH:11][C:10]3[CH2:9][CH2:8][C:7]4[CH:18]=[CH:3][CH:4]=[CH:5][C:6]=4[C:15]=3[N:14]=2)[C:24]=1[NH2:25])=[O:30])[CH3:20]
Reactant: COc1ccc2c(c1)CCc1cnc(NN)nc1-2
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ncc3c(n2)-c2ccccc2CC3)c1N
Yield: 45.5 %

Procedure:
A mixture of (8-Methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-hydrazine (100 mg, 0.41 mM), ethyl(ethoxymethylene)cyanoacetate (76 mg, 0.44 mM) in acetic acid (1 ml) was heated for 16 hr then evaporated. The residue was partitioned between dichloromethane and sodium bicarbonate (sat., 50 ml), the organic phase dried with sodium sulfate, filtered and evaporated to a solid. The solid was triturated with ethyl acetate and isolated via filtration and dried under reduced pressure to afford 5-Amino-1-(5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (63 mg, 42% yield) as a tan solid. ES-MS MH+ 366.3. 1H NMR (300 MHz, ppm, DMSO-d6): 8.65 (s, 1H), 8.17 (d, 1H), 7.78 (s, 1H), 7.55 (br s, 2H), 7.02 (d, 1H), 6.98 (s, 1H), 4.25 (q, 2H), 3.86 (s, 3H), 2.95 (m, 4H), 1.30 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([CH3:18])([N+:15]([O-])=O)[CH3:14])[CH2:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni].O>[NH2:15][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:19])[CH2:9]1)([CH3:18])[CH3:14]
Reactant: CC(C)(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CC(C)(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(1-methyl-1-nitroethyl)piperidin-2-one (1.05 g, 3.57 mmol) in degassed ethanol (75 mL) was added Raney Nickel (2 g of a 50% by weight slurry in water). The reaction mixture was shaken under 55 psi of hydrogen fro 4 hours. The reaction mixture was filtered through a bed a celite, then concentrated under vacuum to give an oil that solidified on standing. The solid was triturated in ether and collected by filtration to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 4.65 (d, J=14.5 Hz, 1H), 4.44 (d, J=14.6 Hz, 1H), 3.26 (m, 2H), 2.60 (d, J=5 Hz, 1H), 2.25 (m, 1H), 1.97 (d, J=11.5 Hz, 1H), 1.75 (m, 1H), 1.44 (m, 1H), 1.11 (d, J=9 Hz, 6H) ppm. ES MS M+1=265.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Product: O=c1[nH]c2nccc(Nc3ccc(Cl)cc3)c2c2ccccc12
Yield: 98.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-chloroaniline (83 mg, 0.65 mmol) to provide 192 (136 mg, 97% yield) as a white solid. LC-MS (M+H=322, obsd.=322).