Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 464 (M+H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH:20][NH2:21])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.C1(C)C=CC=CC=1>CO>[CH3:6][N:4]([CH:3]=[N:21][NH:20][C:18]([C:16]1[CH:15]=[CH:14][C:13]2[NH:9][CH:10]=[N:11][C:12]=2[CH:17]=1)=[O:19])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: NNC(=O)c1ccc2[nH]cnc2c1
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)C=NNC(=O)c1ccc2[nH]cnc2c1
Yield: 87 %

Procedure:
Dimethylformamide dimethyl acetal (19 g, 15.90 mmol) was added to a suspension of 1H-benzo[d]imidazole-5-carbohydrazide (3.50 g, 19.88 mmol) in 1:1 toluene; methanol (60 mL) and refluxed overnight. The volatiles were evaporated in vacuo to afford crude compound which was triturated with 6% methanol in chloroform (10 mL), precipitated solid was filtered and dried under reduced pressure to afford 3.20 g (69.56%%) 1H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide as brown solid.
Reaction SMILES: [NH:1]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:2]([C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:35]([N:37]1[CH2:80][CH2:79][CH2:78][C@H:38]1[C:39]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:68](OCC1C=CC=CC=1)=[O:69])[C@@H:58]([CH3:67])[O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:88][NH2:89]>CN(C=O)C.CO>[NH:1]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:2]([C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:35]([N:37]1[CH2:80][CH2:79][CH2:78][C@H:38]1[C:39]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:68]([NH:88][NH2:89])=[O:69])[C@@H:58]([CH3:67])[O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)NN)[C@@H](C)OCc1ccccc1)C(C)C

Procedure:
Compound XIV (1.6 g, 1.32 mmol) was dissolved in DMF/MeOH (5:3; 16 ml) and treated with H2NNH2 (0.78 ml) for 72 hrs at 25° C. The white solid was filtered and washed with MeOH and water, yield 1.05 g (70.5%); mp 210°-210.5° C; [α]D25 -22.5° (c 1, DMF). Anal. Calcd for C58H84N10O13 (1129.37): C, 61.68; H, 7.50; N, 12.40. Found: C, 61.72; H, 7.26; N, 12.30.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=O.[CH2:9]([NH2:12])[CH:10]=[CH2:11]>C1C=CC=CC=1>[CH2:9]([N:12]=[CH:3][C:2]([CH3:1])([CH3:8])[CH2:5][CH:6]=[CH2:7])[CH:10]=[CH2:11]
Reactant: C=CCN
Reactant: C=CCC(C)(C)C=O
Solvent: c1ccccc1
Product: C=CCN=CC(C)(C)CC=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
2,2-Dimethyl-4-pentenal (2.8 g, 25 mmol) was dissolved in 15 mL benzene. To this solution allylamine (2.85 g, 50 mmol) was added. A few molecular sieves were used to absorb water generated during the reaction. The mixture was stirred at room temperature overnight. Removal of the solvent and excess amount of allylamine on rotavapor provided 3.76 g of the title compound as clear liquid (yield 100%). 1H-NMR (400 MHz, CDCl3): •7.52(s, 1H), 5.99-5.90(m, 1H), 5.80-5.70(m, 1H), 5.15-4.99(m, 4H), 4.01-3.99(m, 2H), 2.17(d, 2H), 1.06(s, 6H).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].[NH2:13][C:14]1[C:15]([C:22](OC(C)=CC(=O)NC(C)(C)C)=[O:23])=[N:16][C:17]([Cl:21])=[C:18]([NH2:20])[N:19]=1>C(Cl)Cl.O1CCCC1>[NH2:13][C:14]1[C:15]([C:22]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:23])=[N:16][C:17]([Cl:21])=[C:18]([NH2:20])[N:19]=1
Reactant: CSC(=N)N
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Yield: 83.6 %

Procedure:
To NaOH (1 M in water; 18.7 mL; 18.7 mmol) is added S-methylisothiourea sulphate (4.25 g; 15.3 mmol). The mixture is stirred until complete dissolution is achieved. CH2Cl2: tetrahydrofuran (1:1; 30 mL) and then 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (Intermediate 2; 2.00 g; 6.10 mmol) are added and the mixture is stirred at room temperature over night. The organic solvents are evaporated, then water (50 mL) is added. The precipitate formed is collected by filtration while applying suction, washed successively with water, methanol and then with diethyl ether and then dried at 50° C. to yield the title compound (1.33 g, 84% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[C:21]([CH3:23])[C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:28][C@@H:29]1[CH2:33][O:32][N:31]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:30]1=[O:39].FC(F)(F)CN1C(=O)[C@H](C2C=CC=CC=2C(N)=O)CO1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[C:21]([CH3:23])[C:17]([C:18]([NH:28][C@@H:29]4[CH2:33][O:32][N:31]([CH2:34][C:35]([F:37])([F:36])[F:38])[C:30]4=[O:39])=[O:20])=[CH:16][N:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ncc1C(=O)O
Reactant: N[C@@H]1CON(CC(F)(F)F)C1=O
Agent: NC(=O)c1ccccc1[C@@H]1CON(CC(F)(F)F)C1=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ncc1C(=O)N[C@@H]1CON(CC(F)(F)F)C1=O

Procedure:
The title compound was obtained by coupling the carboxylic acid obtained in Step E (0.15 g) with (R)-4-Amino-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-3-one (0.10 g, obtained as described in Example 3 for the preparation of compound B5) as described in Example 12, Step C. The title product was obtained as a white solid (48 mg). M.p. 53-55° C. LCMS (Method F) 2.13 min, M+H 583/585.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[O:15]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[OH:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1O
Reaction time: 48 h
Yield: 94.6 %

Procedure:
A solution of 3.0 g of (1R,2R)-N-tert-butoxycarbonyl-2-benzyloxycyclohexylamine in 100 mL of methanol was combined with 300 mg of 5% palladium on carbon, and hydrogenated at room temperature under atmospheric pressure. After 48 hours, palladium on carbon was filtered off, and the filtrate was concentrated. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate 2:1) to obtain 2.0 g of the desirable compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCN1CCCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)piperidine
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12]C=2)=CC=1.[NH:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[O:15]1[CH2:14][CH2:9][CH:10]([N:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17]2)[CH2:11][CH2:12]1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C2CCOCC2)C1

Procedure:
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl piperidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate on EXAMPLE 1A.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH3:31])[CH2:16]1)(=O)=O.C>C(O)C.CN(C)C=O>[CH3:31][N:17]1[C@H:18]2[C@@H:28]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:30]=3[C:20]([CH2:19]2)=[CH:21][NH:22]4)[CH2:29][C@@H:15]([CH2:14][N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C:3]2=[O:9])[CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: O=C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1C[C@H](CN2C(=O)CCC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
0.8 g of 50% sodium hydride in an oil was added in small portions to a mixture of 3.4 g of succinimide and 50 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 30 minutes. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration, and washed with water. The crystals thus obtained were treated with charcoal in ethanol and recrystallized from ethanol to obtain 0.9 g of the titled compound as colorless needles having a melting point of 233°-238° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.Cl.O1CCOCC1.[Na]>O>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(CCOC)C2)ncc1Cl
Temperature: 120 °C
Yield: 46.5 %

Procedure:
10-(2-Methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (45 mg, 0.19 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (58 mg, 0.19 mmol) and 4N HCl in dioxane (53 μl, 0.21 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-15% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (43.6 mg, 43%) as a yellow foam. MP: 104.5-105.5° C.; 1H-NMR (CDCl3) δ 9.68 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.42 (m, 2H), 7.21 (s, 1H), 7.08 (d, J=8.1 Hz, 2H), 6.91 (s, 1H), 6.20 (br s, 1H), 3.33 (t, J=5.8 Hz, 2H), 3.20 (s, 3H), 3.11-2.98 (m, 6H), 2.86 (br s, 2H), 2.59-2.46 (m, 4H), 2.39 (m, 1H), 1.73 (d, J=10.36, 1H); LC/MS (ESI+): 493 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)Cl.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.C(OCC)C>[C:12]1([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[NH:8][C:5]3=[N:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1Cc2cc(-c3ccccc3)cnc2N1
Temperature: 95 °C
Yield: 51.4 %

Procedure:
To a stirred mixture of 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (213 mg, 1 mmol) and phenylboronic acid (183 mg, 1.5 mmol) in toluene (6 ml) and ethanol (6 ml) were added 1 M sodium carbonate solution (2.5 ml, 2.5 mmol), lithium chloride (127 mg, 3 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (35 mg, 0.05 mmol) under N2 atmosphere. The reaction mixture was heated to reflux at 95° C. for 18 hours. The reaction mixture was diluted with chloroform (50 ml) and washed with brine (20 ml). The aqueous layer was thoroughly extracted with chloroform. The combined organic layers were dried over anhydrous MgSO1, filtered and evaporated under vacuum to give crude product. Trituation of the crude product with diethyl ether yielded 5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one as a yellow solid (108 mg, 51.4%). 1H NMR (d6-DMSO): δ 11.04 (s, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 7.60 (d, 2H, J=7.4 Hz), 7.44 (t, 2H, J=7.4 Hz), 7.32 (t, 1H, J=7.4 Hz), 3.58 (s, 2H). MS (−ve APCI): 210 (48, M+), 209 (100, M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][O:22]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)([OH:22])[CH3:23])[C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)(Cn1c2c(c3cc(Cl)ccc31)C1CCCN1CC2)c1cccnc1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (1.0 g, 4.06 mmol) in DMF (50 mL) was added sodium hydride (60%, 406 mg, 10.15 mmol). After stirring for 10 min., 3-(2-methyloxiran-2-yl)pyridine (823 mg, 6.09 mmol) was added to the reaction mixture, which was stirred at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc (2×100 mL). The organic layer was washed with water (5×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue that was crystallized with ethanol-hexane to yield the 1.2 g of 1-(10-chloro-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.70 (s, 1H), 8.49 (d, 1H), 7.62 (d, 1H), 7.36 (s, 1H), 7.12 (m, 2H), 7.02 (d, 1H), 4.17 (q, 2H), 3.86 (t, 1H), 3.19 (m, 1H), 2.86 (m, 1H), 2.74 (m, 3H), 2.41 (m, 2H), 1.85 (m, 3H), 1.7 (s, 3H). Separation by chiral HPLC provides diastereomers II-130a-d.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=O)[CH2:3][CH2:2]1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[N:23][N:24]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:25]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH:7]([NH:32][C:29]2[CH:30]=[N:31][C:26]([N:24]3[CH:25]=[C:21]([C:20]([F:34])([F:33])[F:19])[CH:22]=[N:23]3)=[CH:27][CH:28]=2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1
Reactant: COC(=O)c1ccc(C(=O)C2CCOCC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C2CCOCC2)cc1
Yield: 0.1 %

Procedure:
A round bottom flask was charged with methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (150 mg, 572 mmol), 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (130 mg, 572 mmol) and MeOH (1.2 mL). Decaborane reagent (26.4 mg, 229 mmol) was added in one portion and the reaction stirred over the week-end. The reaction mixture was quenched with HCl solution (1N, aq.) and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide (±)-methyl 4-((tetrahydro-2H-pyran-4-yl)((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)methyl)benzoate (206 mg, 78%) as a colorless gum. MS (M+1): 461.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:17]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCOc2cc(O)ccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)OCCC2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Hydroxy-2,3-dihydro-4H-chromen-4-one (900 mg) was dissolved in DMF (10 mL), and tert-butyl(chloro)diphenylsilane (1.711 mL) and 1H-imidazole (448 mg) were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=90:10 to 80:20) to obtain 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-one (2.08 g) as a colorless transparent syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:13]=1[N+:24]([O-])=O.Cl[Sn]Cl.O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:13]=1[NH2:24]
Reactant: COCC(C)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: COCC(C)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1N
Yield: 99 %

Procedure:
[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (318 mg, 0.83 mmol) and SnCl2.H2O (472 mg, 2.5 mmol) were treated substantially as described in Part D of Example 74a to yield 290 mg of crude 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (EI) m/z 353.23 [(M+H)+, 100].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:18])[NH:11][NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1.[C@@H:37]1([O:18][C:10]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([F:17])([F:16])[F:15])[NH:12][N:11]=2)[O:54][C@H:53]([CH2:55][OH:56])[C@@H:48]([OH:49])[C@H:43]([OH:44])[C@H:38]1[OH:39]
Reactant: Cc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1

Procedure:
4-[(4-Methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Example 26 using 1,2-dihydro-4-[(4-methylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Example 35 using 4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[N:5]1[C:3](=[O:4])[CH2:2][N:6]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:19]2
Reactant: O=C(NN(C(=O)CCl)C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(=O)N1C1C2CC3CC(C2)CC1C3
Reaction time: 1 h
Yield: 70.5 %

Procedure:
Under an argon atmosphere, a solution of benzyl 2-(2-chloroacetyl)-2-(adamantan-2-yl)hydrazinecarboxylate (726 mg, 1.93 mmol) in tetrahydrofuran (20 mL) was added at 0° C. with potassium-t-butoxide (238 mg, 2.12 mmol), and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=3:1), and benzyl 2-(adamantan-2-yl)-3-oxo-1,2-diazetidine-1-carboxylate (463 mg, 70.4%) was obtained as a colorless oil.