Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=4)[CH:11]=3)=[C:7]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:6]=2[CH:28]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=4)[CH:11]=3)=[C:7]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:6]=2[CH:28]=1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccc(Cl)cc12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccc(Cl)cc12

Procedure:
Following the procedure described in Step 3 of Example 1,1-[5-chloro-2-(6-hydroxy-naphthalen-2-yl)-benzofuran-3-yl]-pentan-1-one was prepared 1-[5-chloro-2-(6-methoxy-naphthalen-2-yl)-benzofuran-3-yl]-pentan-1-one (5.6 g, 14.25 mmol), and boron tribromide (1M solution, 45 mL, 45 mmol) in methylene chloride (200 mL). After work-up, stirring of the solid residue with methanol and filtering afforded the title compound as a solid. (3.2 g), A sample was dissolved in chloroform and filtered through a plug of celite. The solvent was evaporated and the residue was crystallized from methanol to give white crystals, mp 156-157° C. Mass spectrum (+APCl, [M+H]+) m/z 379. 1HNMR (400 MHz, DMSO-d6): δ10.15 (br s,1H), 8.29 (d, 1H, J=1.2 Hz), 8.01 (d, 1H, J=2.2 Hz), 7.93 (d, 1H, J=8.8 Hz), 7.86 (d, 1H, J=8.6 Hz), 7.77-7.72 (m, 2H), 7.46 (dd, 1H, J=8.8, 2.2 Hz), 7.22 (d, 1H, J=2.2 Hz), 7.18 (dd, 1H, J=8.8, 2.4 Hz), 2.69 (t, 2H, J=7.3 Hz), 1.55-1.47 (m, 2H), 1.15-1.05 (m, 2H), and 0.68 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C23H19ClO3: Calculated: C, 72.92; H, 5.05; N, 0.00. Found: C, 72.73; H, 4.99; N, 0.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][C:36]([F:41])([F:40])[CH2:35]1)(=[O:33])=[O:32]>>[F:41][C:36]1([F:40])[CH2:37][CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC(F)(F)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(F)(F)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-difluoropiperidine. MS (ESI): mass calcd. for C21H19F3N4O2S, 448.12; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35-8.27 (m, 2H), 8.12-8.05 (m, 1H), 8.01-7.94 (m, 1H), 7.74-7.67 (m, 1H), 7.65-7.58 (m, 1H), 7.44-7.38 (m, 1H), 7.32-7.24 (m, 2H), 3.04-2.96 (m, 2H), 2.95-2.88 (m, 2H), 1.96-1.82 (m, 2H), 1.69-1.61 (m, 2H).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1c[nH]c(Br)c1
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccccc1-c1cc(C=O)c[nH]1
Temperature: 105 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
5-Bromo-1H-pyrrole-3-carbaldehyde (174 mg), [2-(methylthio)phenyl]boronic acid (202 mg) and sodium carbonate (254 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (58 mg) was added, and the mixture was further degassed and stirred at 105° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as pale-yellow crystals (yield 150 mg, 69%).
Reaction SMILES: C(Cl)(=O)C.[CH:5]([O:8][CH2:9][C@@H:10]1[CH2:14][O:13]C(C)(C)[O:11]1)([CH3:7])[CH3:6]>CO>[CH:5]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:14][OH:13])([CH3:7])[CH3:6]
Reactant: CC(C)OC[C@@H]1COC(C)(C)O1
Solvent: CO
Solvent: CC(=O)Cl
Product: CC(C)OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Acetyl chloride was added dropwise into a solution of MeOH (30 mL) at 0° C. with stirring for 5 min. A solution of (4R)-4-(isopropoxymethyl)-2,2-dimethyl-1,3-dioxolane (1.7 g) (the product from step (i), in MeOH (30 mL), was added dropwise to the reaction mixture. The solution was then warmed to room temperature and stirred for 2 h. The reaction mixture was evaporated to give the subtitle compound as clear oil. Yield: 0.8 g
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[ClH:35].O1CCOCC1>O1CCCC1>[ClH:35].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNCc1cn(S(=O)(=O)c2ccc(C(C)O)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(1-hydroxyethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (176 mg) in tetrahydrofuran (2 mL) was added 4 mol/L hydrogen chloride-dioxane solution (3 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 95.5 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:5][CH:4]=1.[I-:16].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(CCCCCCBr)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(CCCCCCI)cc1

Procedure:
6-(4-Methoxyphenyl)hexyl iodide [VIa; Ar is 4-CH3OC6H4, R is H] was prepared from 16.3 g. of 6-(4-methoxyphenyl)hexyl bromide (Preparation C11) and 9.93 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.3 g. of product as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]3[CH:38]=[C:37]([OH:39])[C:36]([O:40][C:41](=[O:43])[CH3:42])=[CH:35][C:34]=3[C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])/[C:27](O)=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:60]1([CH:66]([O:73][C:74]([C:76]2[N:77]3[C@H:80]([S:81][CH2:82][C:83]=2[CH2:84][S:85][C:86]2[N:91]4[N:92]=[C:93]([C:95]([O:97][CH:98]([C:105]5[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=5)[C:99]5[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=5)=[O:96])[N:94]=[C:90]4[N:89]=[C:88]([CH3:111])[CH:87]=2)[C@H:79]([NH2:112])[C:78]3=[O:113])=[O:75])[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:60]1([CH:66]([O:73][C:74]([C:76]2[N:77]3[C@H:80]([S:81][CH2:82][C:83]=2[CH2:84][S:85][C:86]2[N:91]4[N:92]=[C:93]([C:95]([O:97][CH:98]([C:105]5[CH:106]=[CH:107][CH:108]=[CH:109][CH:110]=5)[C:99]5[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=5)=[O:96])[N:94]=[C:90]4[N:89]=[C:88]([CH3:111])[CH:87]=2)[C@H:79]([NH:112][C:27](=[O:28])/[C:26](/[C:24]2[N:25]=[C:21]([NH:20][C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:22][CH:23]=2)=[N:30]\[O:31][CH2:32][C:33]2[CH:38]=[C:37]([OH:39])[C:36]([O:40][C:41](=[O:43])[CH3:42])=[CH:35][C:34]=2[C:44]([O:46][CH:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:45])[C:78]3=[O:113])=[O:75])[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: CC(=O)Oc1cc(C(=O)OC(c2ccccc2)c2ccccc2)c(CO/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)OC(c2ccccc2)c2ccccc2)c(CO/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
To an ice-cooled solution of the product obtained in Step 3 (0.63 g) and (6R, 7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.5 g) in dry dichloromethane (20 ml) was added dicyclohexylcarbodiimide (0.178 g), and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 0.15 g of the objective compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[ClH:16].[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(N2CCCCC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc(N2CCCCC2)c1

Procedure:
To a solution of N-(3-nitrophenyl)piperidine (12 g) in methanol (50 ml) was added conc. hydrochloric acid (12 ml) and, by using 10% palladium/carbon as a catalyst, catalytic reduction was conducted at normal temperature under normal pressure. After completion of the reaction, the catalyst was removed and the solvent was distilled off. Ethyl ether was added to the residue and the mixture was filtered off to obtain N-(3-aminophenyl)piperidine dihydrochloride (13.2 g) as a colorless solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.O.[NH2:33][NH2:34].O>CN(C=O)C>[N+:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: NN
Reactant: O=C(CCc1cccc([N+](=O)[O-])c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(CCc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 7 h
Yield: 23.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(3-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (415 mg, 11.0 mmol, prepared in Synthetic Example 9) in DMF (10 ml) was added hydrazine monohydrate (80%, 160 μl, 3.99 mmol, 4.0 eq.), and the mixture was then stirred at 100 to 110° C. for 7 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (389 mg, 94%).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:30][CH:31]=3)=[O:36])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(-c4ccccc4)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and [1,1′-biphenyl]-4-carbonyl chloride: ESMS m/e: 560.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH2:31](OB(C=C)OCCCC)[CH2:32]CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:31]=[CH2:32])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB(OCCCC)OCCCC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(Br)ccc2o1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=Cc1ccc2oc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a mixture of 2027 mg (4.7 mmol) {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56) and 289 mg (0.25 mmol) Pd(Ph3)4 in 40 ml toluene were added 1.84 ml of a 5.4M solution of sodium methoxide in methanol and 957 mg (5.2 mmol) vinylboronic acid dibutyl ester and the solution was heated at 90° C. for 3 h. The reaction mixture was poured on 5% aqueous citric acid. Extraction with ethyl acetate, washing of the organic phase with brine. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 2:1) to give 1530 mg (4.04 mmol) {2-[(5-Vinyl-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (57).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>CC(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(C)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of p-cresol (14.6 g, 0.135 mole) and anhydrous potassium carbonate (37.2 g, 0.27 mole) in dry acetone (200 ml) was heated under reflux for 30 minutes. The mixture was then cooled to room temperature and ethyl bromoacetate (16.6 ml, 0.15 mole) added. The mixture was heated upto reflux again and maintained at this temperature for 41/2 hours, then allowed to cool before pouring into water (1000 ml). The aqueous mixture was extracted with ether (2×250 ml) and the organic solution washed with dilute hydrochloric acid (1×200 ml) and water (1×200 ml), then dried (MgSO4) and evaporated to dryness to give a quantitative yield of the title compound as a yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10](Cl)[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]=[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19]>>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:14][C:11]1=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/C(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC(Cl)C=O
Product: COC(=O)[C@H]1C=C(c2ccccc2)OC(=O)[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
Prepared according to the general procedure from 3-(tert-butyldimethylsilyloxy)-2-chloropropanal and (E)-methyl 4-oxo-4-phenylbut-2-enoate using 0.5 mol % 1 as the catalyst in 80% yield as a 3:1 mixture of diastereomers. The diastereomers were separated by silica gel chromatography (15:1 hexanes/EtOAc) and characterized separately. [α]D20 (c 1.07, CHCl3)=+133.6; 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.40-7.37 (m, 3H), 5.94 (d, 1H, J=7.1 Hz), 4.26 (dd, 1H, J=10.6, 5.7 Hz), 3.88 (t, 1H, J=10.1 Hz), 3.76 (dd, 1H, J=13.7, 7.4 Hz), 3.72 (s, 3H), 3.08-3.02 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 167.7, 152.5, 131.9, 129.8, 128.8, 125.0, 98.1, 59.7, 52.6, 42.5, 38.7, 25.9, 18.4, −5.4, −5.6; IR (thin film) ν 3062, 2953, 2929, 2886, 2857, 1778, 1739, 1254, 1197, 1176 cm−1; HRMS (EI) calcd for C20H25O5Si [M]+ 376.1706, found 376.1697; 97% ee (3R,4S)-isomer as determined by HPLC (AD-H, 100:1 hexanes/i-PrOH), tr (3R,4S)=21.8 min, tr (3S,4R)=15.2 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:39][CH:38]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.050 g, 0.13 mmol) and EtOH (4.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.032 g, 0.16 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70° C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 15%) in ethyl acetate/dichloromethane (v:v; 4:1). afforded a yellow solid. This material was triturated with diethyl ether, and the pale yellow precipitate was collected by filtration, successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.002 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=5.0 Hz, 4H) (morpholine protons), 2.63 (br s, 4H, piperazine N(CH2)2), 3.69 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.40 (d, J=4.9 Hz, 2H pyridine 3-H and 5-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.5 Hz, 2H, pyridine 2-H and 6-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(COS(C)(=O)=O)c2ccccc21
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A well-stirred solution of 3-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (10, 450 mg, 1.82 mmol) [as prepared following the procedure of D. J. Oliveira and F. Coelho, Synth. Commun. 30 (12) pg. 2143 (2000)] in 10 mL of dichloromethane was cooled in an ice-bath, then treated successively with triethylamine (TEA) (283 mg, 2.18 mmole) and methanesulfonyl chloride (229 mg, 2.0 mmol). This was allowed to stir under nitrogen for 15 min. diluted with dichloromethane, then washed with saturated NaHCO3, dried (Na2SO4) and evaporated. This residue was purified by chromatography to give 0.43 g (73% yield) of the desired compound as an unstable brown solid. 1H NMR (CDCl3) δ 1.67 (s, 12H), 4.79 (s, 2H), 7.28 (t, 1H), 7.36 (t, 1H), 7.67 (m, 2H), 7.51 (bd, 1H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:25]1[CH2:26][CH:23]([C:21]2[CH:22]=[C:17]([C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[N:9][N:8]([C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([N:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)[N:7]=5)[C:16]=4[CH:15]=3)[CH:18]=[N:19][CH:20]=2)[CH2:24]1
Reactant: C1CNCCN1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)c1
Yield: 13 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 114 was obtained as an off-white solid (14.3 mg, 13%). 1H NMR (400 MHz, DMSO) δ 9.36-9.31 (s, 1H), 9.20-9.14 (d, J=2.1 Hz, 1H), 9.10-9.05 (s, 1H), 8.70-8.62 (m, 2H), 8.57-8.52 (t, J=2.0 Hz, 1H), 7.81-7.74 (t, J=8.1 Hz, 1H), 7.28-7.22 (d, J=7.7 Hz, 1H), 6.85-6.78 (d, J=8.4 Hz, 1H), 5.08-5.00 (dd, J=8.3, 6.1 Hz, 2H), 4.77-4.70 (t, J=6.3 Hz, 2H), 4.47-4.38 (m, 1H), 3.65-3.56 (m, 4H), 2.99-2.75 (m, 4H).; MS (ESI) m/z: 414.2 [M+H]+
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]1>C1CCCCC1.C(Cl)Cl>[CH:17]1([C:22]([O:24][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:7])[CH3:6])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]1
Reactant: O=C(O)C1CC=CC1
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(OC(=O)C1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.85 g, 85 mmol) in cyclohexane (85 mL) was treated with a solution of cyclopent-3-enecarboxylic acid (4.77 g, 42.5 mmol) in methylene chloride (43 mL), and the mixture was stirred for about 16 hours at room temperature during which time a colorless solid precipitated. The precipitate was collected by filtration and rinsed with hexanes. The combined filtrates were concentrated in vacuo to yield a residue. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes gradient over 2 column volumes, then 5% ethyl acetate/hexanes for 2 column volumes, then a 5-40% ethyl acetate/hexanes gradient over 10 column volumes to yield 2-phenylpropan-2-yl cyclopent-3-enecarboxylate (8.84 g, 38.4 mmol, 90% yield) as a yellow oil.
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[ClH:7].Cl.[NH:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH2:10].Cl>O>[ClH:7].[ClH:7].[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1
Reactant: NNc1cccnc1
Reactant: C/C=C(\N)C#N
Agent: Cl
Solvent: O
Product: Cc1cc(N)n(-c2cccnc2)n1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A solution of aminocrotononitrile (8.21 g, 100 mmol) and 3-hydrazinopyridine dihydrochloride (20.7 g, 114 mmol) in water (50 mL) was mixed with conc. hydrochloric acid (15 mL), and the mixture was heated under reflux for 30 minutes. The solution was allowed to cool to room temperature, and the reaction solvent was evaporated under reduced pressure, and the resulting crystals were collected by filtration. The crystals obtained were washed with water and air dried to give the title compound (13.6 g, 55% yield).