Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[C:7]([Cl:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:25](=[C:32]([S:35][CH2:36][CH:37]([OH:45])[CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2)[CH3:17]>C(N(CC)CC)C>[ClH:15].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:25](=[C:32]([S:35][CH2:36][CH:37]([O:45][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:38][N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2)[CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(O)CN1CCOCC1)NCC2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(CN1CCOCC1)OC(=O)c1ccccc1)NCC2
Product: Cl

Procedure:
40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chloride are added to 4.34 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile and the reaction mixture is refluxed for 45 minutes, then cooled down. After filtering and evaporating the solvent under reduced pressure, the residue is dissolved in isopropanol and acidified by adding abs. ethanolic hydrogen chloride solution. In this way 3.77 g of the named hydrochloride crystallize out, m.p.: 207° C. (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:46]([CH3:48])[CH3:47])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)[NH:32][CH:33]=4)=[CH:25][CH:24]=3)=[CH:22][C:16]=2[N:15]=1)=[O:8])=[O:4].[ClH:49].O1CCOCC1>CO>[Cl-:49].[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:46]([CH3:48])[CH3:47])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[NH+:30]=[C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][NH2+:35]5)[NH:32][CH:33]=4)=[CH:27][CH:28]=3)=[CH:22][C:16]=2[N:15]=1)=[O:8])=[O:4].[Cl-:49]
Reactant: Cl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)ccc2[nH]1)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc(-c4c[nH]c([C@@H]5CCC[NH2+]5)[nH+]4)cc3)ccc2[nH]1)C(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of tert-butyl (2S)-2-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.1525 mmol) in MeOH (0.15 mL) is added HCl in dioxane (381.2 μL of 4 M, 1.525 mmol), stirred at rt overnight, then concentrated to afford 4-(4-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-2-((S)-pyrrolidin-1-ium-2-yl)-1H-imidazol-3-ium chloride (100 mg, 0.1529 mmol, 100.3%) as a light brown solid. LC-MS shows presence of desired compound which is used as such in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=2)=[N:23][CH:24]=1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][N:30]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:6]=[CH:5]4)[C:29](=[O:33])[CH:28]=2)=[N:23][CH:24]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Reactant: Brc1ccc2c(cnn2CCN2CCCC2)c1
Product: Cl
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Yield: 72 %

Procedure:
5-Bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole (200 mg, 0.68 mmol) and 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (160 mg, 0.68 mmol) were reacted according to the procedure in Example 63 (step c) to provide the title compound (119 mg, 36%) as a brown solid: mp 95-101° C. deliquesced; 1H NMR (500 MHz, CD3OD) δ 8.63 (s, 1H), 8.23 (s, 1H), 8.00-7.98 (dd, J=8.3, 2.1 Hz, 1H), 7.82 (d, J=19 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.66-7.64 (2 overlapping d, J=8.5, 7.6 Hz, 2H), 7.47-7.44 (dd, J=8.9, 1.8 Hz, 1H), 6.41-6.39 (dd, J=7.5, 2.8 Hz, 1H), 6.16 (d, J=2.6 Hz, 1H), 5.30 (s, 2H), 4.87 (t, J=5.9 Hz, 2H), 3.86 (t, J=5.9 Hz, 2H), 3.72 (m, 2H), 3.19-3.13 (m, 2H), 2.18-2.15 (m, 2H), 2.03-1.99 (m, 2H); ESI MS m/z 450 [M+H]+; HPLC (Method D) 97.4% (AUC), tR=11.9 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[O:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:18][N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1
Reactant: O=C1CCOCC1
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN(C)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Into a solution of 4-methoxybenzylamine (4.12 g) and tetrahydro-4H-pyran-4-one (3.00 g) in 1,2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (6.99 g). After stirring at room temperature for 2 hours, 37% formalin solution (2.5 ml) and sodium triacetoxyborohydride (6.99 g) were added thereto. After stirring for additional one hour, the reaction mixture was mixed with an aqueous solution of sodium bicarbonate and was extracted with dichloromethane. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate) to obtain N-methyl-N-(tetrahydropyran-4-yl)-4-methoxybenzylamine (3.56 g) as a light yellow, oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].[CH3:10][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>CN(C=O)C>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:10])=[CH:5][CH:4]=1
Reactant: Nc1nc(O)ccc1Br
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
To a solution of 6-amino-5-bromo-pyridin-2-ol (1.0 g) in DMF (30 mL) was added at 0° C. 0.5 M potassium bis(trimethylsilyl)amide in toluene (11.7 mL, 5.83 mmol) under Ar atmosphere. After stirring for 10 minutes, dimethyl sulfate (0.64 mL, 5.26 mmol) was added at 0° C. The mixture was allowed to warm to room temperature, and was stirred for an additional two hours. Buffer (pH 7) was added and mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness. Purification of the residue by flash chromatography (hexane/toluene 45:55) gave pure 3-bromo-6-methoxy-pyridin-2-ylamine (260 mg, 13% overall).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (20 g, 0.09 mol) in MeOH (400 mL) was added Ni (2 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a pad of Celite and the filtrate was evaporated under vacuum to give crude product, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=10:1) to give methyl 1-(4-aminophenyl)cyclopropanecarboxylate (11.38 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.1 Hz, 2 H), 6.86 (d, J=7.8 Hz, 2 H), 4.31 (br, 2 H), 3.61 (s, 3 H), 1.55-1.50 (m, 2 H), 1.30-1.12 (m, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:8][C:9]([F:25])([F:24])[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[N:11]=1>>[F:24][C:9]([F:8])([F:25])[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:19])[N:11]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: COC(=O)CCNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 75 %

Procedure:
This compound was synthesized from methyl 3-aminopropanoate and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (120 mgs, yield 75%). MS (ESI) m/z: Calculated for C14H12F3N3O4: 343.08. found: 344.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH:27]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Agent: Br
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,1′-biphenyl-3-ylmethylamine hydrobromide gave the title compound as an oil. M+(LC/MS(ESI)): 496.5. HPLC (Condition A), Rt: 4.99 min (HPLC purity: 90.9%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:4][CH2:3]1.[N:23]#CBr.O>C1C=CC=CC=1>[C:1]([N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:6][CH2:7]1)#[N:23]
Reactant: CN1CCC(=C2c3ccccc3CCc3ccncc32)CC1
Reactant: N#CBr
Solvent: O
Solvent: c1ccccc1
Product: N#CN1CCC(=C2c3ccccc3CCc3ccncc32)CC1
Yield: 36.9 %

Procedure:
To a solution of 400 mg (1.35 mmole) of 11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-c]pyridine in 5.0 mL of benzene at room temperature and under an argon atmosphere was added dropwise a solution of 168 mg (1.59 mmole) of cyanogen bromide in 4 mL of benzene. After 30 min. the mixture was poured into water and extracted once with EtOAc. The organic layer was isolated, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography [21/2% MeOH in CH2Cl2 ] to give 150 mg (37%) of the title compound as a solid: m.p. 212°-214° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:16]([OH:18])[CH3:17].[CH3:19]CCCC>>[C:10]1([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:19])[CH2:2][C:16](=[O:18])[CH3:17])=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCO
Product: CC(=O)CC(C)c1ccc(-c2ccccc2)cc1

Procedure:
As Example 14 using 4-acetyl biphenyl as the starting material. 4-(p-phenyl-phenyl)-2-pentanone was obtained as a colourless solid, m.p. 67° C. from ethanol/pentane.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Na+].[CH3:9][NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:27]([O:66][CH3:67])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:64][CH3:65])[C@@H:37]([CH3:63])[C:38]([NH:40][C@@H:41]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:42]([O:44][CH2:45][C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]([CH3:14])[CH3:13].C([BH3-])#N.[Na+].Cl.C([O:81][C:82](=[O:111])[CH2:83][C@@H:84](OC)[C@@H](N(C(=O)[C@H](C(C)C)NC(OCC1C=CC=CC=1)=O)C)[C@@H](C)CC)(C)(C)C>>[C:82]([CH2:83][CH2:84][CH2:9][N:10]([CH3:2])[C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:27]([O:66][CH3:67])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:64][CH3:65])[C@@H:37]([CH3:63])[C:38]([NH:40][C@@H:41]([CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:42]([O:44][CH2:45][C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH:12]([CH3:14])[CH3:13])([OH:111])=[O:81]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1cccc2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1cccc2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
24 mg (24 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(1-naphthylmethoxy)-1-oxo-3-phenylpropane-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide sodium trifluoroacetate (intermediate 21) and 31.5 μl of 15% aqueous amber aldehyde acid solution (49 μmol) were dissolved in 900 μl of a 1:1-dioxane/water composition and heated for 1 hour at a temperature of 100° C. After a short cooling period 1.7 mg (27 μmol) of sodium cyanoborohydride were added. The reaction composition was formulated with 0.1 of N hydrochloric acid to pH 3 and heated for 2 hours at a temperature of 100° C. It was reheated again for 2 hours at 100° C. after the same amounts of amber aldehyde acid solution, sodium cyanoborohydride, and hydrochloric acid had been added once again. Afterwards, the reaction composition had been separated directly by means of preparative HPLC. The yield was 20.1 mg (86% o. th.) of the title compound.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:22])[NH:15]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[N:24]([O-])=[O:25].[Na+]>O>[N:24]([C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:11]=1[CH2:12][CH2:13][C:14](=[O:22])[NH:15]2)=[O:25]
Reactant: COc1ccc(-c2cn3ccccc3n2)c2c1NC(=O)CC2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2N=O)c2c1NC(=O)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a suspension of 5-(imidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (2.5 g) in 300 ml of water was added 1.71 ml of concentrated hydrochloric acid. The mixture was heated and the solution was cooled to 50° C. and 10 ml of aqueous solution having dissolved therein 0.65 g of sodium nitrite was added dropwise to the solution at 50° C. with stirring. After completion of addition, the reaction was continued for 2 hours and the reaction mixture was allowed to stand overnight at room temperature. Crystals which precipitated were collected by filtration, and recrystallized from methanol to give 1.9 g of 5-(3-nitrosoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: C1(O)C=CC=CC=1.ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:20]1[C:25]([NH2:26])=[C:24](Cl)[C:23]([Cl:28])=[C:22](Cl)[C:21]=1[Cl:30].Cl.[H][H]>[Ta]>[Cl:28][C:23]1[CH:24]=[C:25]([CH:20]=[C:21]([Cl:30])[CH:22]=1)[NH2:26]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: [H][H]
Agent: [Ta]
Agent: Cl
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 97 %

Procedure:
200 parts of phenol, 131 parts of a tetrachloroaniline/pentachloroaniline mixture corresponding to the composition mentioned in Example 3, 1 part of ruthenium-on-charcoal catalyst (5% strength) which has already been used for 10 previous similar experiments, and 12 parts of aqueous hydrochloric acid (57% strength) are reacted in a tantalum autoclave, during the course of 3.5 hours at 165° C., whilst stirring, at a hydrogen pressure of 50 bars. After the usual working up, 90 parts of 99% strength 3,5-dichloroaniline are isolated. Yield: 97% of theory.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(C)cc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(C)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.20 g, 0.342 mmol) and (S)-(5-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (0.085 g, 0.411 mmol) in DMF (4 ml) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 5 h, the reaction was diluted with EtOAc and washed with 1N HCl, water then brine. The organic phase was dried (Na2SO4), filtered and concentrated. The yellow residue was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV) to give (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (32.7 mg, 0.052 mmol, 15.05% yield) as a pale yellow oil. LCMS (M+H) calcd for C36H51N4O6: 635.38. found: 635.5.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[CH3:26][C:27]1[O:31][N:30]=[C:29]([NH2:32])[CH:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:32][C:29]3[CH:28]=[C:27]([CH3:26])[O:31][N:30]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Reactant: Cc1cc(N)no1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3cc(F)ccc32)no1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-methyl-isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.040 gms. 5-methyl-isoxazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0147 gms.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][N:13]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=2)=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: NNc1cc(C2CCC2)c(Cl)nn1
Agent: Cl
Product: Oc1ccc(C=NNc2cc(C3CCC3)c(Cl)nn2)cc1
Yield: 83.2 %

Procedure:
3-Chloro-4-cyclobutyl-6-hydrazinopyridazine (0.50 g, 2.5 mmol) and 4-hydroxybenzaldehyde (0.31 g, 2.5 mmol) were stirred in 0.2M hydrochloric acid (15 ml) for 2 hours. The precipitated imine was then collected by filtration and dried to give the title compound (0.63 g, 83%). MS (ES+) 305 [MH]+, 303 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[Si:13]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a magnetically stirred solution of 2-amino-5-nitrophenol (5.62 g, 36.5 mmol) and chloro-t-butyldimethylsilane (5.00 g, 33.2 mmol) in dry dichloromethane (66 mL) was added triethylamine (5.55 mL, 39.8 mmol) at 25° C. The reaction mixture was stirred at ambient temperature for 4 hours and partitioned between diethyl ether (200 mL) and saturated ammonium chloride. The aqueous layer was separated and the ether layer washed (saturated ammonium chloride, 1x; water, 1x; brine, 1x), dried (MgSO4), filtered, and evaporated in vacuo. Crystallization from ethyl acetate/hexanes gave 7.5 g (84%) of O-t-butyldimethylsilyl-2-amino-5-nitrophenol
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](N(OC)C)=[O:16])=[O:12])[C:4]=2[CH:3]=1.C(=O)=O.[CH3:30][C:31](C)=O.C([Mg]Br)=C>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:16])[CH:30]=[CH2:31])=[O:12])[C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: CON(C)C(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: C=C[Mg]Br
Agent: O=C=O
Solvent: C1CCOC1
Product: C=CC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[[(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepin-10yl)-carbonyl]amino]-N-methoxy-N-methylacetamide (3.2 grams) in anhydrous tetrahydrofuran (35 mL) at -70° C. (dry ice/acetone bath) under a nitrogen atmosphere was added dropwise a solution of vinylmagnesium bromide (1.0M in tetrahydrofuran; 28 mi) in tetrahydrofuran (15 mL). The ice bath was removed, and the reaction was stirred to room temperature for one hour. The reaction was poured into 1M NaH2PO4 (250 mL) and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate extracts were washed with 1M NaH2PO4 (2×250 mL) and brine (250 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (500 mL) using 9:1 methylene chloride:ethyl acetate to yield a colorless glass. The yield of the title compound was 2.25 grams (77%).
Reaction SMILES: ClCCl.Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][N:6]=1.[CH2:19](N(CC)CC)[CH3:20]>C(O)C>[CH:19]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][N:6]=1)=[CH2:20]
Reactant: COC(=O)c1cnc(Cl)c(C(=O)OC)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1ncc(C(=O)OC)cc1C(=O)OC

Procedure:
A dichloromethane adduct of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.359 g) was added to a mixture of dimethyl 2-chloropyridine-3,5-dicarboxylate (1.01 g), potassium vinyl trifluoroborate (1.18 g), triethylamine (1.22 mL), and ethanol (10 mL), and the resultant mixture was stirred at 95° C. for 1 hour in an argon atmosphere. The solvent in the reaction mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (880 mg).