Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>C(Cl)Cl>[CH3:9][N:10]([O:11][CH3:12])[C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CNOC
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(=O)N(C)OC
Reaction time: 1 h
Yield: 88.8 %

Procedure:
Triethylamine (19.6 g, 194 mmol) was added dropwise to a suspension of N,O-dimethylhydroxylamine hydrochloride (6.93 g, 71 mmol) in anhydrous CH2Cl2 at 0° C. Heptanoylchloride (9.60 g, 65 mmol) was then added dropwise and the reaction was stirred 1 hour. The crude product mixture was poured into water and the separated aqueous phase was extracted with CH2Cl2. The combined organic layers was washed with aq. HCl, sat. NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo to give 10 g (89%) N-methyl-N-methoxyheptanamide as a yellow oil.
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[CH2:6]([O:13][NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][N:14]([CH:2]([CH3:3])[CH2:4][CH3:5])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Reactant: CCC(C)Br
Product: CCC(C)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 36.7 %

Procedure:
Using the general method of Compound 42 Part B, 2-bromobutane (2.37 mL, 21.7 mmole) was reacted with 1-benzyloxy-3-phenylurea (4.87 g, 20.1 mmole) to provide 2.2 g of 1-benzyloxy-1-(1-methylpropyl)-3-phenylurea.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([S:20][NH2:21])[N:3]=1.O.CC(C)=[O:25].ClC1C=C(C=CC=1)C(OO)=O>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([S:20]([NH2:21])=[O:25])[N:3]=1
Reactant: NSc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 0 °C

Procedure:
A mixture of 2-amino-9-β-D-ribofuranosyl-9H-purine-6-sulfenamide (18) (1.57 g, 0.005 mol), ethanol (700 mL) and water (50 mL) was vigorously stirred and cooled in an ice bath. After the temperature of the suspension had decreased to <10° C., acetone was added to the ice bath to obtain a temperature of <0° C. With continual stirring a solution of commercially available (Aldrich Chem Co.) 3-chloroperoxybenzoic acid (80-85%, 1.0 g, 0.0046-0.0049 mol) in ethanol (40 mL) was added dropwise over a period of approx. 15 min. The reaction flask was stoppered, the mixture was allowed to stir and warm as the ice melted, and then stirred at ambient temperature for a total reaction time of 19 hr. The reaction mixture was filtered (Whatman GF/A glass microfiber filter) to remove a trace of undissolved solid and then the filtrate was evaporated in vacuo and at a temperature of >25° C. to near dryness. The product was washed from the evaporation flask with acetone (50-100 mL) and the solid was collected by filtration, suspended in diethyl ether (50 mL), refiltered, dried under vacuum at ambient temperature: (1.3 g, 0.0042 mol, 85%), m.p. 183°-185° C. dec. with prior sintering and darkening. IR (KBr): 1040 (vs, S=O), 3000-3600 (NH2, OH)cm-1 : UV: λmax (pH 1) 333 nm (ε2,900): λmax (pH 7) 326 nm (ε10,700): λmax (pH 11) 325 nm (ε8,700): 1H NMR (DMSO-d6): δ 5.85 (d, 1, J =5.52 Hz, C1'H), 6.49 (s, 2, SONH2, exchanged with D2O), 6.98 (s, 2, NH2, exchanged with D2O), 8.45 (s, 1, C8 e,uns/H/ ), and other sugar protons. Anal. Calcd. for C10H14N6O5S.1/2C2H5OH (353.32): C, 37.39: H, 4.82: N, 23.80: S, 9.07. Found: C, 37.29: H, 4.56: N, 23.78: S, 8.92.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([N:17](C(OCC(C)C)=O)[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:35][C:36]([O:38]C)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:36]([CH2:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([NH:17][C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:15])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)([OH:38])=[O:37]
Reactant: COC(=O)CBr
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(OCC(=O)O)cc1
Reaction time: 18 h

Procedure:
4'-Hydroxy- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide (0.5 g) was added to a solution of methyl bromoacetate (0.12 ml) in acetone (20 ml) containing potassium carbonate (0.166 g). The mixture was stirred for 18 hours and then heated under reflux for 1 hour and cooled. The solvent was removed by evaporation and water (20 ml) was added to the residue. The mixture was then extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed successively with 2M sodium hydroxide solution (15 ml), water (20 ml) and brine (10 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue was dissolved in dimethoxyethane (5 ml) and methanol (5 ml). 2M Sodium hydroxide solution (1 ml) was added and the mixture was stirred for 18 hours and evaporated to dryness. Water (20 ml) was added to the residue and the mixture was washed with ethyl acetate (2×15 ml). The aqueous phase was acidified to pH2 with 2M hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined organic phases were extracted with saturated aqueous sodium bicarbonate solution (2×15 ml) and the combined aqueous phase was acidified with 6M hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (15 ml) and brine (15 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue crystallised from ether to give 4'-carboxymethoxy-N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide (0.123 g) as a solid, m.p. 165°-166° C.; microanalysis found: C, 55.9; H, 4.5; N, 9.9%; C20H19N3O6S requires: C, 55.9; H, 4.46; N, 9.78%; 1H NMR (d6 -DMSO): 2.24 (s, 3H), 3.84 (s, 3H), 4.67 (s, 2H), 6.78-6.95 (m, 2H), 7.16 (d, 2H), 7.27 (d, 1H); 7.49-7.66 (m, 3H), 8.06 (d, 1H), 9.50 (br s, 1H); mass spectrum (-ve ESP): 428 (M-H)-.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][O:13]1>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][C:12](=[O:17])[O:13][CH2:14][CH2:15][OH:16]
Reactant: O=C1OCCO1
Reactant: CO[Si](CCCN)(OC)OC
Product: CO[Si](CCCNC(=O)OCCO)(OC)OC
Reaction time: 24 h

Procedure:
3-Aminopropyltrimethoxysilane (20 g, 0.111 mol) was mixed with ethylene carbonate (9.82 g, 0.111 mol) under slow stirring. The mixture became slightly warm. Stirring continued for 24 hours to give 2-hydroxylethyl N-(3-trimethoxysilylpropyl)carbamate. Hexylene glycol (39.3 g, 0.333 mol) was added drop-wise under stirring to a mixture of 2-hydroxylethyl N-(3-trimethoxysilylpropyl)carbamate (29.8 g, 0.111 mol), and sulfuric acid (0.1 g) and then heated at 50° C. and 15 mm Hg pressure for 4 hours. The methanol that formed was removed by distillation. The product was a clear, low viscosity liquid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:7]\[CH:8]([OH:10])[CH3:9])/[C:4]([NH2:6])=[O:5])[CH3:2].N1C=CC=CC=1.C1COCC1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.Cl>[CH2:1](/[C:3](=[CH:7]\[CH:8]([O:10][C:24](=[O:25])[CH2:23][Cl:22])[CH3:9])/[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC/C(=C\C(C)O)C(N)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC/C(=C\C(C)OC(=O)CCl)C(N)=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
25 (rac-Ethyl (2E)-4-hydroxypent-2-enamide) (886 mg, 6.0 mmol), pyridine (969 μl, 12 mmol) and DMAP (147 mg, 1.2 mmol) are dissolved in toluene (30 ml) and THF (10 mL) and cooled to 0° C. Chloroacetylchloride (954 μl, 12 mol) in toluene (4 ml) is added dropwise under stirring at ≦2° C. over 15 min. The reaction mixture is stirred for 2.5 hours at 0° C. The resulting suspension is then poured in 2 M HCl (25 ml) and extracted with tBuOMe (250 and 150 ml). The organic phases are washed with 2 M HCl (25 ml), saturated NaHCO3 (15 ml) and brine (25 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. yielding 33 (rac-Ethyl (2E)-4-(chloroacetoxy)pent-2-enamide) (1.26 g, 95%) as a beige solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:55]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=2[N:49]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:48]=1>CN(C=O)C.C1COCC1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH:3]1[CH2:46][C:47]1[C:55]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=2[N:49]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:48]=1
Reactant: BrCc1nn(Cc2ccccc2)c2c1CCCC2
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
To a stirring solution of 164 mg (0.36 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of DMF at 0° C. is added 0.430 mL (0.78 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 120 mg (0.39 mmol, 1.1 equiv.) of 3-Bromomethyl-4,5,6,7-tetrahydro-1-benzyl-1H-indazole in 2 mL of DMF is added. The resulting solution is stirred for 3 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 175 mg of the title compound as a white solid: mp 173°-176° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-6.84 (m, 18H), 5.02 (s, 2H), 4.99 (m, 1H), 4.22 (s, br, 2H), 4.10 (dd, 1H, J=5.3, 8.7), 3.823 (s, 3H), 3.36 (dd, 1H, J=8.6, 15.6), 3.09 (dd, 1H, J=5.3, 15.6), 2.54-2.38 (m, 4H), 1.67 (m, 4H), 1.04 (d, 6H, J=6.6); low resolution MS (FAB)m/e 682 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[CH2:12]=O.[OH-].[Na+]>C(O)(=O)C>[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: c1cc[nH]c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1c[nH]c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of morpholine (22 mmoles) in acetic acid (10 ml) there is added pyrrole (20 mmoles) dropwise at 0° C. Formaldehyde (37% aq., 20 mmoles) is then added dropwise. The reaction mixture is stirred for 2 hours at ambient temperature. The solution is cooled to 0° C. and is brought to alkaline pH (10-11) using 20% aqueous NaOH solution. After extraction with DCM, the organic phases are washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product in the form of a white solid which is used directly in the next Step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][N:11]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[S:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=S(=O)(NC1CCCC1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)nc1)N(CCCOCc1ccccc1)C1CCCC1
Temperature: 40 °C
Yield: 105.1 %

Procedure:
A mixture of 1 g (3.84 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 1.32 g (9.59 mmol) of K2CO3 and 0.88 mL (4.99 mmol) of [(3-bromopropoxy)methyl]benzene in 8 mL of anhydrous DMF is heated for 12 hours at 40° C. After cooling to room temperature, the medium is taken up in 300 mL of EtOAc, washed successively with water (2×100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 1.65 g of N-[3-(benzyloxy)propyl]-6-chloro-N-cyclopentylpyridine-3-sulfonamide are thus obtained in the form of an oil.
Reaction SMILES: O[CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.N12CCCN=C1CCCCC2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.O>[N:39]([CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CN=[N+]=[N-])CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [1-(hydroxymethyl)cyclopropyl]carbamate (1 g, 5.3 mmol) in N,N-dimethylformamide (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture was stirred at 80° C. for 3 hours, another batch of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and the mixture was stirred at 80° C. for another 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were used for next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=2[F:10])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: OC1(Cc2ccc(Cl)cc2F)CCN(Cc2ccccc2)CC1

Procedure:
A sample of 4-chloro-2-fluorobenzyl bromide is converted to its Grignard reagent which is reacted with N-benzyl-4-piperidone to provide 1-benzyl-4-(4-chloro-2-fluorobenzyl)-4-piperidinol. The above is performed in a manner consistent with the procedure of Example 2A. This product is distilled at 175°-180° C., 0.18 mm to provide an orange oil which is converted in ether to its hydrogen chloride salt. The salt is recrystallized four times from an ethyl alcohol-ether mixture to provide the purified salt, m.p. 211.5°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C]=O.[C:16]([OH:30])(=[O:29])[C:17]1[C:18](=[CH:22][C:23](=[CH:27][CH:28]=1)[C:24]([OH:26])=[O:25])[C:19]([OH:21])=[O:20].[CH:31]([OH:33])=[O:32]>[OH-].[Na+]>[C:6]([OH:8])(=[O:7])[C:27]1[C:23](=[CH:22][C:18](=[C:17]([CH:28]=1)[C:16]([OH:30])=[O:29])[C:19]([OH:21])=[O:20])[C:24]([OH:26])=[O:25].[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[C:31]([OH:33])=[O:32]
Reactant: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)O
Reactant: O=CO
Agent: [C]=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1Cl

Procedure:
For example, when the photocarbonylation reaction is effected by dissolving 4-chlorophthalic acid in an aqueous solution of sodium hydroxide (4-6N) and blowing carbon monoxide into the solution at a temperature of 60°-80° C. under a pressure of 1-10 atm, the reaction product consists mainly of the desired trimellitic acid, and by-product is scarcely formed except a small amount of formic acid. The reaction for obtaining pyromellitic acid from 5-chlorotrimellitic acid proceeds similarly as above.
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.I[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH2:36][N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[C:39]([C:48]([C:50]3[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=3)=[O:49])=[CH:38]2)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH2:36][N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=4)[C:39]([C:48](=[O:49])[C:50]4[CH:51]=[C:52]([O:60][CH3:61])[C:53]([O:58][CH3:59])=[C:54]([O:56][CH3:57])[CH:55]=4)=[CH:38]3)=[CH:30][CH:29]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(I)cc3)c2c1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Yield: 48 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 48% yield, as a light yellow paste. 1H-NMR (CDCl3) 1.43 (s, 3H); 1.46 (s, 9H); 1.49 (s, 3H); 3.84 (s, 6H); 3.9 (s, 3H); 3.91 (s, 3H); 4.00 (d, 2H, J=11.34 Hz); 4.1 (d, 2H, J=11.35 Hz); 5.08 (s, 2H); 5.19 (s, 1H); 6.95 (d, 1H, J=2.04 Hz); 7.00 (dd, 1H, J=2.18, 8.75 Hz); 7.11 (s, 2H); 7.3 (d, 2H, J=8.5 Hz); 7.35 (d, 2H, J=8.49 Hz); 7.74 (s, 1H); 8.25 (d, 1H, J=8.7 Hz).
Reaction SMILES: [Cl:1][C:2]1C=CC=C[C:3]=1C(O[Si](C)(C)C)C#N.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([OH:29])[C:26](=[NH:28])[OH:27]>>[ClH:1].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([OH:29])[C:26](=[NH:28])[O:27][CH2:2][CH3:3]
Reactant: N=C(O)C(O)c1ccccc1Cl
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1Cl
Agent: Cl
Product: CCOC(=N)C(O)c1ccccc1Cl

Procedure:
By the procedure of Example 2, 2-(2-chlorophenyl)-2-trimethylsiloxyethanenitrile (15 g.) in 375 l. of saturated ethanolic hydrogen chloride was converted to ethyl 1-(2-chlorophenyl-1-hydroxymethanecarboximidate hydrochloride [13.4 g., 85%; m.p. 127°-129° C. (dec); ir (KBr) 3125, 3003, 2899, 1653, 1531 cm-1 ].
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)CC3C=CC(OC)=CC=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:47][CH2:46][C@@H:45]([NH:48]C(=O)OC(C)(C)C)[C@H:44]([O:56][Si:57]([CH:64]([CH3:66])[CH3:65])([CH:61]([CH3:63])[CH3:62])[CH:58]([CH3:60])[CH3:59])[CH2:43]1.C1(OC)C=CC=CC=1>ClCCl>[NH2:48][C@@H:45]1[CH2:46][CH2:47][N:42]([C:10]2[C:9]([Cl:8])=[C:14]([NH:15][C:16]3[N:21]=[C:20]([NH:22][CH:32]4[CH2:33][CH2:34]4)[C:19]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]4[N:17]=3)[CH:13]=[C:12]([C:40]#[N:41])[CH:11]=2)[CH2:43][C@H:44]1[O:56][Si:57]([CH:61]([CH3:63])[CH3:62])([CH:64]([CH3:66])[CH3:65])[CH:58]([CH3:59])[CH3:60]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
TFA (1 mL, 3.24 mmol) was added to a solution of tert-butyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (184 mg, 0.219 mmol) and anisole (20 μl, 0.183 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at 30° C. overnight. LCMS showed completion of reaction. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10), the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-4% methanol/dichloromethane). 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (126 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][CH:10]=2)[N:7]=1.[N:12]([S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[C:13]=[O:14]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([C:8]([C:13]([NH:12][S:15]([C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[O:14])=[CH:9][CH:10]=2)[N:7]=1
Reactant: Cc1cc(C)c2cccn2n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)c1ccc2c(C)cc(C)nn12
Temperature: 25 °C
Yield: 11.5 %

Procedure:
To a solution of 0.40 g (2.7 mmol) of 2,4-dimethylpyrrolo[1,2-b]pyridazine in 15 mL of dichloromethane at -78° C. was added, by syringe pump over a period 70 min, a solution of 0.62 g (2.7 mmol) of methyl 2-(isocyanatosulfonyl)benzoate. The reaction mixture was allowed to warm to room temperature. The residue was purified by flash chromatography to give 0.12 g of a white solid, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[Cl:6][CH:7]([O:9][C:10](Cl)=[O:11])[CH3:8]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:10](=[O:11])[O:9][CH:7]([Cl:6])[CH3:8]
Reactant: COCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 11.9 ml 2-Methoxy-ethanol and 17.98 ml 1-chloroethyl-chloroformate in 200 ml absolute CH2Cl2 13.3 ml pyridine were added at 5–10 ° C. in an argon atmosphere. The mixture was stirred at RT for 5 h and washed successively with 1 N HCl, with an aqueous solution of KHSO4/K2SO4 and water. The organic phase was dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue purified by destillation. Kp.=88° C. (5.5 mbar). Yield: 22.4 g.