Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 85.1 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (2.965 g, 10.5 mmol) was treated with 4-fluorophenyl isocyanate (1.601 g, 1.31 mL, 11.6 mmol, 1.1 equiv.) in CH2Cl2 (20 mL), in a similar manner as described in Example 1.2 to afford Compound 2 (3.755 g, 8.94 mmol, 85%) as a white solid. LCMS m/z (%)=419 (M+H79Br, 99), 421 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.49 (broad s, 2H), 7.77 (d, J=9.0 Hz, 1H), 7.50-7.58 (m, 2H), 7.50 (s, 1H), 7.43 (s, 1H), 7.12 (d, J=8.9 Hz, 1H), 6.98-7.06 (m, 2H), 3.81 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24]>>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCBr
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCOc1cccc(F)c1F

Procedure:
Quantities: 1-bromooctane (34.9 g, 0.18 mol), potassium carbonate (50 g, 0.36 mol) and compound from Example 37 (21.7 g, 0.17 mol). The experimental procedure was as described in Example 38.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCCCCC>ClCCl.[H-].C([Al+]CC(C)C)C(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CCCCc1ccc([N+](=O)[O-])cc1
Temperature: 21 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a stirred solution of methyl 4-(4-nitrophenyl)butanoate (63) (0.45 g, 2.02 mmol) in dichloromethane (30 mL), 1M diisobutylaluminum hydride (DIBAL) solution in hexane (2.62 mL, 2.62 mmol) was added at −78° C. After 30 min, the reaction mixture was quenched with saturated Rochelle's salt solution. The resulting mixture was stirred at 21° C. until both phases were clearly separated and the organic layer was clear. After extraction, the separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude 4-(4-Nitrophenyl)butanal (64) was purified by flash column chromatography (hexane:ethyl acetate, 8:1) to give 4-(4-Nitrophenyl)butanal (64) (0.28 g, 72%): 1H NMR δ 9.79 (s, 1H), 8.16 (d, 2H, J=8.7 Hz) 7.34 (d, 2H, J=8.7 Hz) 2.77 (t, 2H, J=7.7 Hz) 2.51 (t, 2H, J=7.1 Hz), 1.95-2.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.FC(F)(F)[CH2:17][O-:18].[Na+]>FC(F)(F)CO>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[O:18][CH3:17]
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Reactant: [O-]CC(F)(F)F
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: COc1nc(-n2cccn2)nc(N)c1Br

Procedure:
The following example was synthesized using the procedure described for Example 43 from Intermediate 5 using a solution of sodium 2,2,2-trifluoroethanolate in 2,2,2-trifluoroethanol:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:26][C:27](Br)=[O:28].[CH:30]1([NH2:40])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:26][C:27]([NH:40][CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:28]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1Br
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCCc3ccccc32)cc1Br

Procedure:
prepared by reaction of 1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: C(N(CC)[C:4]([C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])C.[CH2:17]([Li])[CH2:18][CH2:19][CH3:20].[OH2:22].C(Cl)(Cl)Cl>C(OCC)C>[CH:17]1[C:6]2[C:7]3[C:14](=[O:22])[C:10]4[S:9][C:8]5[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=5[C:6]=4[C:4](=[O:5])[C:8]=3[S:9][C:10]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)C(=O)c1csc2ccccc12
Reactant: O
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C1c2sc3ccccc3c2C(=O)c2sc3ccccc3c21
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
To a solution of benzo[b]thiophene-3-carboxylic acid diethylamide (14.0 g, 60 mmol) in diethyl ether (120 ml) is cooled to −78° C. Under an inert atmosphere a solution of n-butyllithium in hexanes (41.3 ml 1.6 N solution, 66 mmol) is then added within 15 minutes. There is a slight increase of the temperature by 3° C., and the mixture is allowed to stir for another 10 minutes at −78 . . . −75° C. Then the mixture is allowed to warm to ambient temperature. After ca. 1.5 hours a reddish brown suspension is formed which is stirred for another 17 hours. Then water (150 ml) is carefully added to the mixture and also chloroform (50 ml). The mixture is stirred rapidly for 15 minutes, and the solid is filtered off, washed with water, dried and recrystallized from DMSO (50 ml) to give the product as orange brown needles mp=315° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].C(OC(=O)C)(=O)C>>[C:11]1([N:8]2[CH2:9][CH2:10][C:6]([NH:5][C:3](=[O:4])[CH3:2])=[N:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1=NN(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
A 10.0 g. amount of 3-amino-1-phenyl-2-pyrazoline (prepared in Example 8) and 10.0 ml. of acetic anhydride are mixed together and allowed to stand at room temperature for one hour. The resulting solid is collected, dissolved in dichloromethane and passed through a short column of a hydrous magnesium silicate. The effluent is heated and hexane is added to crystallize 1.2 g. of the desired product as yellow prisms, m.p. 190°-191° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)CCC.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]2[CH:11]=[CH:10][NH:9][C:4]2=[N:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Fc1cnc2[nH]ccc2c1N1CCCCC1
Temperature: 180 °C
Yield: 25.9 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and piperidine (50 mg) in 1-butanol (0.4 mL) was heated in the microwave reactor (120° C., 0.5 hour, 180° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (10 mL) two times and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 5-fluoro-4-(1-piperidinyl)-1H-pyrrolo[2,3-b]pyridine (10 mg) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[Cl:42][C:43]1[C:44]([C:53]([F:56])([F:55])[F:54])=[N:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=1[CH3:48]>>[Cl:42][C:43]1[C:44]([C:53]([F:55])([F:54])[F:56])=[N:45][N:46]([CH2:49][C:50]([N:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:40])[F:41])=[CH:29][CH:30]=3)[CH2:39][CH2:38]2)=[O:51])[C:47]=1[CH3:48]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Trifluoromethoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.20 (d, 2H), 7.04 (d, 2H), 5.38 (s, 2H), 3.60 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=471.1, found=471.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[C:27]([S:31](Cl)=[O:32])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:32]
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Reactant: CC(C)(C)S(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (80 mg, 0.17 mmol) in DCM (3 mL) was added t-butylsulfinyl chloride (28 uL, 0.25 mmol) and triethylamine (30 uL, 0.25 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS60 as a white solid (45 mg, 46%). 1H NMR (500 MHz, CDCl3): δ 7.28 (s, 1H), 6.62 (s, 1H), 6.04 (brs, 2H), 5.97 (s, 2H), 4.60 (t, J=6.5 Hz, 1H), 4.24 (s, 2H), 4.20 (m, 1H), 4.09 (m, 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.27 (s, 9H). HRMS (ESI) m/z [M+H]+ calcd. for C20H25IFN6O3S, 575.0725. found 575.0738.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:9]=[CH:8][N:7]=[C:6]2[O:21]C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:9]=[CH:8][NH:7][C:6]2=[O:21]
Reactant: COCCNCCOc1cc2ncnc(Oc3ccccc3)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCNCCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 90 °C
Yield: 102.3 %

Procedure:
A mixture of 6-methoxy-4-phenoxy-7-(2-(2-methoxyethylamino)ethoxy)quinazoline (760 mg, 2 mmol) in 2M hydrochloric acid (5 ml) was heated at 90° C. for 1.5 hours. The mixture was allowed to cool and adjusted to pH7 with solid sodium hydrogen carbonate. The water was removed by evaporation and the residue extracted with methylene chloride/methanol/aqueous ammonia (100/8/1). The volatiles were removed from the extract by evaporation, the residue dissolved in methylene chloride, passed through phase separating paper and the solvent removed by evaporation to give 6-methoxy-7-(2-(2-methoxyethylamino)ethoxy)-3,4-dihydroquinazolin-4-one (600 mg, 99%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:28]=[C:9]2[N:10]=[C:11]([N:15](C)[CH2:16][CH2:17]N(C)CC3C=C(C)ON=3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.N[CH2:30][CH:31]1CC[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1.NCC1CCCN1C(OC(C)(C)C)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:28]=[C:9]2[N:10]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:30][CH2:31][CH2:32][NH:33][CH2:34]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: Cc1cc(CN(C)CCN(C)c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Agent: CC(C)(C)OC(=O)N1CCCC1CN
Product: Nc1nc(NCC2CCCNC2)nc2nc(-c3ccco3)nn12

Procedure:
2-Furan-2-yl-N5-piperidin-3-ylmethyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine was prepared in the same manner as described in Example 6(a) and (b) above, except that 3-aminomethyl-1-Boc-piperidine was used as the starting material instead of 2-aminomethyl-1-Boc-pyrrolidine (both starting materials are commercially available from Astatech, Monmouth Junction, N.J.).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].C([O:14][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=O)C>CO.O>[CH3:9][O:10][NH:11][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:14]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CONC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (0.5 mL) was added to a mixture of O-methylhydroxylamine hydrochloride (220 mg) and 2-(3-imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 3 Step A, 3.0 mg, 0.006 mmol) in 0.5 mL of methanol. The reaction mixture was kept in a sealed tube at 110° C. for 2 days with stirring. After cooling to room temperature the solution was diluted with water and extracted with dichloromethane. The crude product, after concentration, was loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 2-(3-Imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methoxy-amide was obtained as a white solid (1.9 mg, 65%). 1H NMR (400 MHz, CDCl3) δ (ppm): 11.98 (br, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.03 (br, 2), 6.74 (s, 1H), 5.80 (br, 1H), 3.89 (s, 3H), 3.00 (m, 8H), 2.17 (m, 2H), 1.92 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H25N7O3: 460.20 (M+H). Found. 460.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[OH:40][C@@H:41]([C:45](C)([S:47]([CH3:50])(=[O:49])=[O:48])[CH3:46])[C:42](O)=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:42](=[O:43])[C@@H:41]([OH:40])[CH:45]([S:47]([CH3:50])(=[O:49])=[O:48])[CH3:46])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)([C@H](O)C(=O)O)S(C)(=O)=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](O)C(C)S(C)(=O)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution containing the product from Example 2C (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) were added the product from Example 156C (0.008 g, 0.041 mmol), DEPBT (0.015 g, 0.050 mmol), and N,N-diisopropylethylamine (0.020 mL, 0.115 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the product (0.015 g, 56% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.97 (s, 3 H), 1.01 (s, 3 H), 1.49-1.53 (m, 2 H), 2.53-2.60 (m, 1 H), 2.76-2.81 (m, 3 H), 2.93 (s, 3 H), 3.49 (s, 3 H), 3.64-3.70 (m, 1 H), 3.83 (d, J=9.9 Hz, 1 H), 4.21 (d, J=6.3 Hz, 1 H), 4.17-4.30 (m, 2 H), 4.98 (d, J=5.5 Hz, 1 H), 6.28 (d, J=6.3 Hz, 1 H), 6.67 (d, J=9.92 Hz, 1 H), 7.12-7.33 (m, 9 H), 7.52 (d, J=9.6 Hz, 1 H), 7.80-7.91 (m, 5 H), 8.64 (d, J=4.8 Hz, 1 H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@@H:21]1[CH2:24][C@H:23]([CH2:25][OH:26])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][C@@H:21]1[CH2:24][C@H:23]([CH2:25][O:26][N:28]2[C:32](=[O:33])[C:31]3[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]2=[O:38])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CON2C(=O)c3ccccc3C2=O)C1

Procedure:
A solution of 6.54 ml (0.0391 mol) of diethyl azodicarboxylate (93%) in 30 ml of benzene is added dropwise to a mixture of 7.5 g (0.03726 mol) of cis-3-(N-BOC-amino)-cyclobutanemethanol, 6.08 g (0.03726 mol) of N-hydroxyphthalimide, 9.774 g (0.03726 mol) of triphenylphosphine and 120 ml of benzene at 20°-30° C., while stirring. The reaction mixture is stirred at room temperature for 2 hours and filtered, the crystalline residue (diethyl 1,2-hydrazinedicarboxylate) is washed with benzene and the filtrate is evaporated in vacuo. The residue is purified by means of flash chromatography on silica gel using ethyl acetate/hexane mixtures (1:3 and 1:2). After evaporation of the product-containing fractions and recrystallization of the residue from ethyl acetate/hexane, the title compound is obtained, m.p. 131.5°-132.5° C.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:7]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1ccsc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccsc1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
6.2 g of 1-phenyl-l-(3-thienyl)methanol was dissolved in 50 ml of chloroform. To the mixture was added 30 g of manganese dioxide, followed by stirring overnight. Manganese dioxide was filtered off, and the filtrate was evaporated, to give 6.08 g of the target compound.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(CC)CC>CCO>[CH3:37][C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][NH:24][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22])=[O:32])([CH3:35])[CH3:36]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (157 mg, 0.450 mmol) and (R)-2-aminomethyl-1-Boc-pyrrolidine (100 mg, 0.495 mmol) in 3 mL of EtOH containing Et3N (0.095 mL, 0.559 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 232 mg (98%); 1H NMR (CDCl3) 1.47 (brs, 9H), 1.83 (m, 1H), 1.90 (m, 2H), 2.03 (m, 1H), 3.31 (m, 1H), 3.37 (m, 2H), 3.62 (m, 1H), 4.09 (m, 2H), 4.24 (m, 6H), 7.26 (m, 1H), 7.50 (m, 1H), 8.27 (s, 1H), 8.55 (brs, 1H); MS (ESI) 529.38 (MH+).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17](C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][N:17]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:16][CH2:15]3)[CH:10]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
The title compound, MS: m/e=578.1 (M+H+), [α]58920=−19.14 (c=0.4545, chloroform), was prepared in accordance with the general method of example 102 (part1) and example 38 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and methane sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[C:4]([CH3:26])[N:3]=[C:2]([NH:1][C:31]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[O:32])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)nc(N)n1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)nc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-methylpyrimidine-4-carboxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and cyclobutanecarbonyl chloride (27 mg, 0.26 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.Cl.[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1.C(N(CC)CC)C>CN(C=O)C>[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][N:29]([C:5]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=4)=[O:6])[CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-Methylbenzoyl chloride (14 mg, 0.09 mmol) was added to a mixture of 1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (30 mg, 0.09 mmol), triethylamine (64 μL, 0.46 mmol), and DMF (0.7 mL) at 25° C. The mixture was allowed to stir at 50° C. overnight before it was cooled to 25° C. The mixture was filtered and then purified by reverse phase-HPLC to give (1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(m-tolyl)methanone. ESI-MS m/z calc. 373.2. found 374.2 (M+1)+. Retention time: 2.04 minutes (4 min run).