Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1C[C@@H](O)C[C@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3S,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp, S234-S237 (1996), 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.O.[Si:9]([O:16][C@@H:17]1[C@@H:22]([O:23][CH3:24])[C@@H:21]([CH3:25])[CH2:20][O:19][C@H:18]1[CH2:26][O:27][Si](C(C)(C)C)(C)C)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C1COCC1>[C:12]([Si:9]([CH3:11])([CH3:10])[O:16][C@@H:17]1[C@@H:22]([O:23][CH3:24])[C@@H:21]([CH3:25])[CH2:20][O:19][C@H:18]1[CH2:26][OH:27])([CH3:13])([CH3:15])[CH3:14]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@@H]1C
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)OC[C@@H]1C
Temperature: 5 °C
Reaction time: 0.42 h
Yield: 82.6 %

Procedure:
A mixture of trifluoroacetic acid (3.28 ml) and water (6.43 ml) was added to a vigorously stirred solution of (2S,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-2-[(tert-butyldimethylsilyloxy)methyl]-4-methoxy-5-methyltetrahydro-2H-pyran (1.0 g, 2.48 mmole) in dry THF (6.43 ml) at 5° C. After vigorous stirring for 25 min at 5° C., the reaction mixture was carefully quenched by the addition of cold saturated aqueous sodium bicarbonate (30 ml). The resulting emulsion was partitioned between ether (50 ml) and water (50 ml). The ether layer was washed with water (20 ml×2), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt:n-hexane (2:8) as an eluent to give (2S,3R,4S,5S)-[3-(tert-butyldimethyl-silyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol (0.595 g, 83% yield) as a colorless oil; EI-MS: m/z 290 (M+ ); 1H-NMR (CDCl3)d: 0.87 (9H,s), 0.97 (3H,d,J=7 Hz), 1.92 (1H, br.s), 2.2 (1H, m), 3.14 (2H,m), 3.28 (3H,s), 3.56 (1H,t,J=9 Hz), 3.57 (1H,dd,J=3 & 11.5 Hz), 3.65 (1H,br.dd,J=6 & 11 Hz), 3.78 (1H,dd,J=2 & 11.5 Hz), 3.84 (1H,br.dd,J=2 & 11 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2[C:3]([N:8]=1)=[N:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1Br
Product: Cc1nc2ncccc2n1-c1ccccc1
Yield: 46.8 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 3-Bromo-2-nitropyridine (101 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown viscous oil (49 mg, 47% yield). 1H NMR (DMSO) δ 2.54 (s, 3 H), 7.35-7.68 (m, 6 H), 7.77 (d, J=8.8 Hz, 1 H), 8.58 (br s, 1 H); 13C NMR δ 14.0, 118.9, 120.1, 126.8, 128.5, 129.6, 130.1, 133.9, 143.0, 151.6, 156.7. HRMS (FAB): cal. for C13H12N3 [M-FH+]: 210.1031; found: 210.1026.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C@@H:6]1[C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:7]1>CN(C=O)C.O.C(Cl)Cl>[N:1]([C@H:11]1[CH2:10][CH2:9][N:8]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:7][C@@H:6]1[F:5])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@@H](F)C1
Temperature: 100 °C

Procedure:
Sodium azide (0.48 g, 0.0073 mol) was added to a solution of tert-butyl (3S,4R)-3-fluoro-4-(tosyloxy)piperidine-1-carboxylate, 4.3-1, Peak-1 (0.7 g, 0.00187 mol) dissolved in DMF (15 mL). The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled and diluted with water and methylene chloride. After separation, the organic layer was dried over Na2SO4, filtered and concentrated in vacuum to provide the desired product, 4.4 (0.4 g). The obtained product was taken for the next reaction without any purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH3:34])[C:16]=1[C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1.[OH-].[Na+]>O>[CH:8]([C:14]1[NH:13][C:12]([CH3:11])=[C:16]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[C:15]=1[CH3:34])=[O:9]
Reactant: Cc1c[nH]c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(C=O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Phosphoryl chloride (2.43 g) was slowly added dropwise to N,N-dimethylformamide (15.9 g) at room temperature, and stirred at room temperature for 30 minutes. To this mixture, an N,N-dimethylformamide solution of the 2-(2,4-dimethyl-pyrrol-3-yl)-5-benzoylbenzimidazole (2.5 g) obtained in Example 7 was slowly added dropwise. After stirring for 2 hours, 50 ml of a 1 N sodium hydroxide aqueous solution was added, heated to 80° C., and stirred for 2 hours. After the starting material was disappeared, reaction mixture was slowly added to water, and precipitate was collected by filtration. The solid was dried in vacuo to afford 2-(2-formyl-3,5-dimethyl-pyrrol-4-yl)-5-benzoylbenzimidazole (1.63 g, 60%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: O=C1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
10% palladium on carbon (350 mg) was added to an ethanol solution (50 ml) of 4-(3,4-dichlorophenoxy)piperidine (7.1 g) and 1,4-cyclohexanedione (6.47 g), and the mixture was stirred at 50 to 60° C. for 5 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to afford the title compound as a pale brown powder (5.2 g).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1C(O)=O.[N-:12]=[N+]=[N-].[Na+].O>O=S(Cl)Cl>[CH3:1][C:2]1[C:3]([NH2:12])=[C:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1ccnc(C)c1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2,4-dimethylnicotinic acid (3.0 g, 20 mmol) was added in SOCl2 (20 mL) at 0° C. and warmed to 60° C. After stirring for 1 hr, the reaction was concentrated under vacuum. The residue was dissolved in acetone (20 mL) and NaN3 (1.9 g, 30 mmol) followed by H2O (20 mL). The reaction was warmed to 70° C. and stirred for 1 hr at the same temperature. The reaction was cooled to room temperature and concentrated under vacuum to a half volume and poured into H2O (50 mL) and extracted with ethyl acetate (50 mL×5) and dried over MgSO4. The ethyl acetate was concentrated under vacuum to afford the crude compound. The compound was used for the next step without further purification. 1HNMR (CDCl3, 400 MHz) δ 2.10 (s, 3H), 2.30 (s, 3H), 4.65-4.70 (b, 2H), 6.85 (d, J=4.78 Hz, 1H), 7.75 (d, J=4.78 Hz, 1H). Exact mass calculated for C7H10N2 122.08. found 123.1 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccccc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccccc2)C1
Yield: 10.2 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (100 mg, 0.46 mmol), styrene (1 mL, 8.41 mmol) and NaH (200 mg, 60% dispersion in oil, 8.30 mmol) in DMF (3 ml) at 200° C. for 5 h to obtain 15 mg (4.7% yield) of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]=[N+]=[N-])[CH:5]=[C:6]([Cl:8])[CH:7]=1>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [N-]=[N+]=NCCCc1cc(Cl)cc(Cl)c1
Agent: [Ni]
Product: NCCCc1cc(Cl)cc(Cl)c1
Yield: 100.7 %

Procedure:
3-(3,5-Dichlorophenyl)propylazide (0.0506 mol) was reacted with Raney nickel substantially as described in Example 7F above to obtain 10.4 g (100%) of an oily product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH2:4][CH3:5].[CH2:17](N(CC)CC)[CH3:18].FC(F)(F)S([O-])(=O)=O.C1([S+](C2C=CC=CC=2)C=C)C=CC=CC=1.[NH4+].[Cl-]>ClCCl>[CH2:4]([C@H:3]1[CH2:2][O:1][CH2:18][CH2:17][N:6]1[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:5]
Reactant: CCN(CC)CC
Reactant: CC[C@@H](CO)NS(=O)(=O)c1ccc(C)cc1
Agent: C=C[S+](c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: CC[C@H]1COCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)—N-(1-hydroxybutan-2-yl)-4-methylbenzene-sulfonamide (800 mg, 3 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.92 mL, 6.6 mmol) was added. The mixture was stirred at 0° C. for 10 minutes. Diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.25 g, 3.45 mmol), dissolved in dichloromethane (10 mL) was added dropwise over 5 minutes. The mixture was stirred while allowed to warm up to room temperature overnight. Saturated aqueous NH4Cl was added and the phases were separated. The aqueous phase was extracted with 2×30 mL of DCM. The combined organic phases were dried with MgSO4 and filtered. The filtrate was concentrated on silica gel and purified by flash chromatography (100% Hex to 60% EtOAc/Hex) to give (S)-3-ethyl-4-tosylmorpholine (j-3) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.3 Hz, 2H), 7.30 (t, J=8.3 Hz, 2H), 3.77-3.60 (m, 3H), 3.60-3.44 (m, 2H), 3.44-3.19 (m, 3H), 2.43 (s, 3H), 1.67 (dtd, J=28.6, 14.0, 7.4 Hz, 2H), 1.31-1.12 (m, 2H), 0.97-0.84 (m, 3H); LC-MS: m/z=270 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:24][O:25][NH2:26]>>[CH3:24][O:25][N:26]=[C:18]([CH2:17][C:16]([CH3:22])([CH3:21])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[CH3:19]
Reactant: CC(=O)CC(C)(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: CON
Agent: Cl
Product: CON=C(C)CC(C)(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one O-methyloxime as about a 2.9 to 1 mixture of E and Z isomers as a tan solid after recrystallization from aqueous methanol, mp 148-150° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:23]1([C:29]2[N:30]=[C:31]([NH:40][CH2:41][CH2:42][CH3:43])[S:32][C:33]=2[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].O>CN(C)C=O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][N:40]([C:31]2[S:32][C:33]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:30]=2)[CH2:41][CH2:42][CH3:43])=[CH:4][CH:5]=1
Reactant: CCCNc1nc(-c2ccccc2)c(CCC(=O)OC)s1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)OC)s1
Yield: 77.8 %

Procedure:
To a solution of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (433 mg) and methyl 3-[4-phenyl-2-[N-(1-propyl)amino]-5-thiazolyl]propionate (400 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 55.2 mg) at 0° C. and the mixture was stirred at said temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionate (595 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C[C:25]([C:33]([OH:35])=O)([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)O)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:54]1[C:62]2[C:57](=[CH:58][C:59]([C:63]3[N:67]=[CH:66][N:65](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:64]=3)=[CH:60][CH:61]=2)[C:56]([C:87]2[CH:88]=[C:89](O)[CH:90]=[CH:91][CH:92]=2)=[N:55]1.Cl>O1CCCC1>[NH:65]1[CH:66]=[N:67][C:63]([C:59]2[CH:58]=[C:57]3[C:62](=[CH:61][CH:60]=2)[NH:54][N:55]=[C:56]3[C:87]2[CH:88]=[CH:89][CH:90]=[C:91]([O:35][CH2:33][CH2:25][N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:92]=2)=[N:64]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)(C)CC(O)(C(=O)O)N1CCNCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 27.1 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), tert-butylcarboxypiperazinylethanol (0.610 g, 2.65 mmol) and diethylazodicarboxylate (0.418 mL) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 1.25 mmol). The mixture was stirred at ambient temperature for 21 h and poured into aqueous 6N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ethyl acetate (3×). The aqueous fraction was added to aqueous 6N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was stirred with trifluoracetic acid (3.0 mL) at ambient temperature for 70 min. Purification by preparative HPLC (5–70% acetonitrile/water) gave the title compound (0.132 g, 27% yield). ES-MS (m/z) 390 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: ClCc1cn2cc(Cl)ccc2n1
Product: Clc1ccc2nc(CN3CCN(c4ccc(Cl)c(Cl)c4)CC3)cn2c1
Yield: 41.6 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.493 g) and 1-(3,4-dichlorophenyl)piperazine (Aldrich; 0.636 g) are converted to 0.404 g of the title compound after chromatography on silica gel and crystallization from ethyl ether/hexane; mp 122.5-123.5° C.; MS m/z 394; IR (mineral oil) 1339, 1488, 804, 1072, 2807 cm-1 ; 1H NMR (CDCl3) δ2.72, 3.21, 3.77, 6.72, 6.94, 7.13, 7.26, 7.52, 8.14.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:8]1[CH:9]=[CH:10][N:11]=[C:7]1[NH:6][C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc[nH]1)n1ccnc1

Procedure:
To a stirred suspension of 2-aminoimidazole sulfate (667 mg, 5.05 mmol) in CH2Cl2 (25 mL) was added 1,1′-carbonyldiimidazole followed by DIPEA (2.70 mL, 15.50 mmol). The resultant mixture was stirred at room temperature overnight then concentrated under reduced pressure and provided 1.53 g of imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide as a brown solid.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH:10]=[C:9]([O:12][Si](C(C)(C)C)(C)C)[NH:8]2)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:26][C:27]([CH3:29])=[O:28]>O1CCCC1.CCCCCC>[OH:28][C:27]([CH:10]1[CH2:11][N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)[NH:8][C:9]1=[O:12])([CH3:29])[CH3:26]
Reactant: Cc1ccc(N2CC=C(O[Si](C)(C)C(C)(C)C)N2)cc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(N2CC(C(C)(C)O)C(=O)N2)cc1
Temperature: -78 °C
Yield: 63.2 %

Procedure:
A solution of 1-p-tolyl-3-(t-butyldimethylsiloxy)-pyrazoline (218 g, 0.75 mole) in 750 ml anhydrous tetrahydrofuran was added dropwise over a 30 minute period to a solution of n-butyllithium (51.5 g, 0.80 mole) in 350 ml n-hexane and 3.0 l anhydrous tetrahydrofuran stirred under nitrogen and cooled to -78° C. in a dry ice-acetone bath. The mixture was stirred for another 30 minutes then treated with one portion of acetone (58. g, 1.0 mole), and stirred at -78° C. for an additional 30 minutes. After removal of the dry ice-acetone bath, one portion of 250 ml 5% aqueous hydrochloric acid was added and the mixture was stirred an additional 25 minutes. The mixture was extracted with 1.0 l of ether and then with a (1:1) mixture of ether and ethyl acetate. The combined extracts were dried over magnesium sulfate. After removal of solvent, the residue was digested in a hot (3:2) mixture of ether and n-hexane. Upon cooling to 0° C. and filtering, 111 g of 4-(1-hydroxy-1-methylethyl)-1-p-tolyl-3-pyrazolidinone was obtained. Analysis was confirmed by infrared and NMR spectra.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][SiH:5]1[CH2:10][CH2:9][CH:8](Br)[CH2:7][CH2:6]1.Cl[SiH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.Cl[SiH]1CCC(C2C=CC(OC(F)(F)F)=CC=2)CC1>>[F:1][CH2:2][CH2:3][CH2:4][Si@H:5]1[CH2:10][CH2:9][C@H:8]([Si@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH3:27])=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1
Reactant: FCCC[SiH]1CCC(Br)CC1
Reactant: CCCc1ccc(C2CC[SiH](Cl)CC2)cc1
Agent: FC(F)(F)Oc1ccc(C2CC[SiH](Cl)CC2)cc1
Product: CCCc1ccc([C@H]2CC[Si@H]([C@H]3CC[Si@H](CCCF)CC3)CC2)cc1

Procedure:
The above compound was obtained in the same manner as Example 23, using 4-(3-fluoropropyl)-4-silacyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-n-propylbenzene instead of 4-(4,4-difluorobutyl)-4-silacyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethoxybenzene, respectively.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH2:13][N:14]3[CH2:17][CH:16]([F:18])[CH2:15]3)[N:6]3[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([F:26])[C:24]=4[CH:25]=[C:5]3[C:4]=2[N:3]=1.[CH3:27][NH:28][C:29]([C:31]1[C:35]2[CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:34]=2[O:33][C:32]=1[C:55]1[CH:56]=[N:57][C:58]([CH3:61])=[CH:59][CH:60]=1)=[O:30].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:23]1[C:24]2[CH:25]=[C:5]3[C:4]4[N:3]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:34]6[O:33][C:32]([C:55]7[CH:56]=[N:57][C:58]([CH3:61])=[CH:59][CH:60]=7)=[C:31]([C:29]([NH:28][CH3:27])=[O:30])[C:35]=6[CH:36]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:12][CH2:13][N:14]4[CH2:17][CH:16]([F:18])[CH2:15]4)[N:6]3[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(C)nc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2C(CCN2CC(F)C2)Cc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(C)nc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CCN3CC(F)C3)C4)cc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of 2-chloro-11-fluoro-6-(2-(3-fluoroazetidin-1-yl)ethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (100 mg, 0.269 mmol), N-methyl-6-(N-methylmethylsulfonamido)-2-(6-methylpyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.295 mmol), K2CO3 (75 mg, 0.537 mmol), Pd2(dba)3 (15 mg, 0.027 mmol) and X-Phos (10 mg, 0.054 mmol) in dioxane/H2O (4 mL/10 d) was stirred at 110° C. for 4 hours under N2 atmosphere. The mixture was then filtered through Celite and concentrated. The residue was purified by column chromatography (PE:EA=2:1) to afford the desired product of 5-(11-fluoro-6-(2-(3-fluoroazetidin-1-yl)ethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(6-methylpyridin-3-yl)benzofuran-3-carboxamide (85 mg, yield: 44.9%). 1H-NMR (CDCl3, 400 MHz) δ 8.97 (s, 1H), 8.17 (t, J=6.0, 2.0 Hz, 1H), 8.00 (s, 1H), 7.61 (t, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.24 (d, J=6.8 Hz, 2H), 7.12 (s, 2H), 6.73˜6.77 (m, 1H), 5.97 (d, J=4.8 Hz, 1H), 4.97˜5.14 (m, 1H), 4.95 (d, J=6.0 Hz, 1H), 3.49˜3.56 (m, 4H), 3.33 (s, 3H), 3.00˜3.06 (m, 3H), 2.95 (d, J=4.8 Hz, 3H), 2.62 (s, 3H), 2.58 (s, 3H), 2.33˜2.36 (m, 1H), 1.59˜1.56 (m, 2H). MS (M+H)+: 711.