Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[OH-].[K+].[CH2:38]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:38][O:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (44 mg, 0.085 mmol) was dissolved in THF (0.85 ml) to give a colorless solution. The reaction was cooled in an ice bath. Crushed KOH (64 mg, 1.14 mmol), catalytic 18-crown-6, and iodomethane (9 μl, 0.147 mmol) were added successively to the cooled solution. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-100% EtOAc) to afford 22 mg (49%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid. MS: [M+Na]+=551.
Reaction SMILES: [CH:1]([C:4]1[NH:9][C:8](=O)[C:7]([C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br-:13].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C1(C)C=CC=CC=1>[Br:13][C:8]1[N:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[C:11]#[N:12]
Reactant: CC(C)c1ccc(C#N)c(=O)[nH]1
Reactant: [Br-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc(C#N)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of the product of Example 8B (4.35 g, 0.0269 mol), tertrabutylammonium bromide (10.4 g, 0.0323 mol) and phosphorous pentoxide (8.01 g, 1.05 mol) in toluene (80 mL) was heated under reflux for 5 hours. The reaction mixture was then cooled to room temperature, water (80 mL) was added, and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with toluene (20 mL) and the organic layer separated. The aqueous layer was washed with toluene (50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as a yellow oil (5.64 g, 93%).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=O)[CH3:2].C([O:20][C:21](=[O:37])[CH2:22][CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([C:31](=[NH:34])[NH:32]O)=[CH:26][C:25]=1[CH2:35][CH3:36])(C)(C)C>>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:34]=[C:31]([C:27]3[CH:28]=[C:29]([CH3:30])[C:24]([CH2:23][CH2:22][C:21]([OH:37])=[O:20])=[C:25]([CH2:35][CH3:36])[CH:26]=3)[N:32]=2)[CH:10]=[C:11]([CH3:13])[N:12]=1)[CH3:15]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1CCC(=O)O

Procedure:
The title compound is prepared in analogy to Example 8 starting from 2-(diethylamino)-6-methyl-isonicotinic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester; LC-MS: tR=0.88 min; [M+1]+=423.17.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1C=CC=C[C:10]=1C>C1C=CC=CC=1>[CH:5]1[C:6]2[C:1](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccccc1C
Reactant: Cc1ccccc1
Solvent: c1ccccc1
Product: c1ccc2ccccc2c1

Procedure:
The substitution of (6) toluene, (7) dimethylbenzene and (8) naphthalene, respectively, for the benzene of Example 1 both as a charge material and an extractant, resulted in the production of the corresponding mononitro compound in yields comparative thereto.
Reaction SMILES: [CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34]OS(C)(=O)=O)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.[NH:45]1[CH:49]=[CH:48][CH:47]=[N:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:44][CH:2]([CH3:1])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34][N:45]2[CH:49]=[CH:48][CH:47]=[N:46]2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1
Reactant: c1cn[nH]c1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCn1cccn1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl(3S, 5R)-3-{(2-methylpropyl)[(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (127 mg) and pyrazole (41 mg) in N,N-dimethylacetamide (3 ml) was added cesium carbonate (326 mg), and the mixture was stirred at 60° C. for 3 days. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (72 mg).
Reaction SMILES: C[CH:2]([CH3:4])[O-:3].[Al+3].CC(C)[O-:8].CC(C)[O-].[S:14]([C:18]1C=[C:22]([C:23]([OH:25])=[O:24])[C:21](C(O)=O)=[CH:20][CH:19]=1)([OH:17])(=[O:16])=[O:15].[O-]CC.[Mg+2:33].[O-]CC>O>[S:14]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([O-:25])=[O:24])[C:4]=1[C:2]([O-:8])=[O:3])([OH:17])(=[O:16])=[O:15].[Mg+2:33]
Reactant: CC(C)[O-]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Agent: CC[O-]
Agent: [Al+3]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1C(=O)[O-]
Temperature: 60 °C

Procedure:
The same classes of materials were also prepared by using appropriate metal alkoxides and hydroxysulfonic or sulfocarboxylic acids in water. Thus, aluminum isopropoxide was mixed with 5-sulfophthalic acid in 2:3 molar ratio and the mixture was heated to about 60° C. for about ½ hr. Aluminum isopropoxide was hydrolyzed and the salt was obtained as aqueous solution and was used as such for inkjet coatings. Magnesium ethoxide was similarly hydrolyzed from its mixture with the same acid in 1:2 molar ratio to obtain magnesium sulfophthalate in aqueous solution.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[C:13]1([CH:19]2[CH2:22][CH:21]([C:23](OC)=[O:24])[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[O:24]=[C:23]([CH:21]1[CH2:22][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C1CC(c2ccccc2)C1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C1CC(c2ccccc2)C1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (16.0ml. of a 1.43M solution in hexane) was added dropwise to a stirred solution of dimethyl methylphosphonate (2.86g.) in dry tetrahydrofuran (25ml.) at -78° C. in an atmosphere of argon. After 10 minutes, a solution of the methyl 3-phenylcyclobutanecarboxylate mixture (2.18g.) in dry tetrahydrofuran (25ml.) was added, and stirred at -78° C. for 2 hours. The reaction mixture was then neutralised by the addition of glacial acetic acid, warmed to room temperature and the tetrahydrofuran was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate extract was dried over magnesium sulphate and evaporated under reduced pressure, to give dimethyl 2-oxo-2-(3-phenylcyclobutyl)-ethylphosphonate, as a mixture of cis and trans isomers. The n.m.r. spectrum in deuteriochloroform showed the following characteristic features (δ values):
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]1[O:14][C:15]([CH3:18])=[CH:16][N:17]=1)=[C:6]2[O:19][CH3:20])=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][C:31]2[S:32][CH2:33][C:34](=[O:36])[N:35]=2)[CH:25]=[CH:26][CH:27]=1>>[NH:9]1[CH2:10][CH2:5][CH2:6][CH2:7][CH2:8]1.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][C:31]2[S:32]/[C:33](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]3[O:14][C:15]([CH3:18])=[CH:16][N:17]=3)=[C:6]4[O:19][CH3:20])/[C:34](=[O:36])[N:35]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1c(-c2ncc(C)o2)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Product: C1CCNCC1
Product: COc1c(-c2ncc(C)o2)cnc2ccc(/C=C3\SC(NCCc4cccc(F)c4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-3-(5-methyl-oxazol-2-yl)-quinoline (example 16d), 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (example 16e), benzolic and piperidine to give 2-[2-(3-Fluoro-phenyl)-ethylamino]-5-[1-[4-methoxy-3-(5-methyl-oxazol-2-yl)-quinolin-6-yl]-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 489 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][N:34]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=2[N:19]=1)=[O:13]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][N:34]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=2[N:19]=1)=[O:13]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a stirred solution of 0.058 ml (0.74 mmol) 2-methoxyethanol in 2 ml dioxane at room temperature was added 49 mg (1.24 mmol) sodium hydride (60% dispersion in mineral oil) and stirring continued for 10 minutes. 200 mg (0.49 mmol) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 1 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/toluene) afforded 109 mg (50%) 2-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 467 (M+Na+, 16), 445 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([Na:10])[CH:9]=[CH:8][CH:7]=[CH:6]1)=[O:4].Cl[C:12]([O:14][CH3:15])=[O:13]>O1CCCC1>[CH3:15][O:14][C:12]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])([Na:10])[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1([Na])C=CC=C1
Solvent: C1CCOC1
Product: COC(=O)C1=CC=CC1([Na])C(=O)OC
Yield: 52 %

Procedure:
To a tetrahydrofuran solution of methoxycarbonyl cyclopentadienyl sodium (28 mmol/28 mol) preparated by the Rausch method, a tetrahydrofuran solution of methyl chloroformate (2g/30 ml) was added under cooling with ice. When the solution reached room temperature, it was filtered and concentrated under reduced pressure. Then, methylene chloride was added thereto to precipitate slightly pink precipitates. The precipitates were collected by filtration and dried to obtain 1.23 g of dimethoxycarbonylcyclopentadienyl sodium.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:18][C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 20 °C
Yield: 75.3 %

Procedure:
The ester (56a) (210 mg, 0.356 mmol) in dichloromethane (0.5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (0.5 ml), stirred and warmed to 20° C. over 30 minutes. The solution was evaporated to dryness under reduced pressure, redissolved in dichloromethane and concentrated (×3). The residue was triturated with ethyl acetate and diluted with ether to afford the title compound 162 mg (85%) as a colorless solid: m.p. 165-8° C. (decomposition); [α]D23 -38.8° (c 0.1, CH3OH); IR (KBr) 3332, 3275, 1723, 1658, 1649, 1597, 1581, 1562, 1526, 1432, 1385, 1258, 1218, 1206; 1H NMR (d6 -DMSO) δ8.96 (1H, d, J=7.3), 8.34 (1H, s), 7.85 (1H, dd, J=7.3), 7.58 (3H, m), 7.35 (5H, m), 6.29 (1H, t, J=7.3), 5.26 (2H, m), 5.15 (2H, s), 4.69 (3H, m), 2.75 (2H, m). Anal. Calcd. C27H23N3O9Cl2 : C, 53.66; H, 3.84; N, 6.95. Found: C, 53.36; H, 3.90; N, 6.81. M.S. (+FAB); 604 (M+ +1), 285, 241, 195, 173, 149, 91.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH2:14][OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1CO
Yield: 94.8 %

Procedure:
5-Benzyloxy-2-methoxybenzaldehyde (150.4 g) was suspended in methanol (600 ml) and to the gently warmed stirred mixture was added, in portions, sodium borohydride (15.0 g). The methanol was evaporated and the reidue partitioned between dichloromethane and water. The organic layer was washed with water, then saturated sodium chloride, dried with anhydrous magnesium sulphate and evaporated to dryness. The residue crystallised from dichloromethane/petroleum spirit (40°-60°) to give 5-benzyloxy-2-methoxybenzyl alcohol (143.8 g, 95%), m.p. 50°-51°.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCC1.Cl.C12NC(CC1)[CH2:21][O:20][CH2:19]2>>[CH:5]12[N:1]([C:6]3([C:10]#[N:11])[CH2:9][CH2:12][CH2:7]3)[CH:2]([CH2:3][CH2:4]1)[CH2:21][O:20][CH2:19]2
Reactant: C1CC2COCC1N2
Reactant: O=C1CCC1
Reactant: N#CC1(N2CCCC2)COC1
Agent: Cl
Product: N#CC1(N2C3CCC2COC3)CCC1

Procedure:
The title compound was prepared in accordance with the general method of intermediate A from cyclobutanone and 3-oxa-8-aza-bicyclo[3.2.1]octane hydrochloride (CAS 904316-92-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][CH:14]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2c(Cl)cncc2Cl)cc1
Product: CN(C(=O)Oc1ccc(Oc2c(Cl)cncc2Cl)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridine-4-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (41%, white crystals). HPLC-MS m/z=389.1 (M+1), Rt: 4.97 min.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:27]=[C:28]([Sn](C)(C)C)[N:29]=1.CC1N(COCC[Si](C)(C)C)C([Sn](C)(C)C)=CN=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[N:29]=[C:25]([CH3:24])[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:27]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc([Sn](C)(C)C)cn1COCC[Si](C)(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ncc([Sn](C)(C)C)n1COCC[Si](C)(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1COCC[Si](C)(C)C
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 59 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), a mixture of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethyl stannyl)-1H-imidazole and 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethyl stannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2 min and then it was stirred at 120° C. for 35 min under the microwave irradiation. It was filtered, concentrated and purified by prep-TLC (EtOAc) to give 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (238 mg, 59%). LC-MS m/z 506 [M+H+]
Reaction SMILES: [C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]1=2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9]([NH:26][CH:27]2[CH2:36][CH2:35][CH2:34][C:33]3[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:42])[F:43])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]2=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (4.31 g, 11.56 mmol), trifluoro-methanesulfonic acid 5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Step D, 3.10 g, 10.51 mmol), HOBt (Aldrich, 1.28 g, 9.46 mmol), and CH2Cl2 (30 mL) was added EDC (Aldrich, 3.02 g, 15.76 mmol). The reaction was stirred at RT overnight and diluted with CH2Cl2 (100 mL). The organic phase was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (16-30% EtOAc-hexane) to afford the title compound as an off-white solid. MS (ESI): 651 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[F:26])([C:15]([F:18])([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1)#[N:29].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH:25][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:35][N:34]=3)=[O:37])[CH:22]=[CH:21][C:20]=2[F:26])([C:15]([F:16])([F:18])[F:17])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)(F)F)CCOC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)(F)F)CCOC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of [5-(5-amino-2-fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (50 mg, 0.128 mmol), 5-cyano-2-pyridinecarboxylic acid (28.4 mg, 0.192 mmol) and HOAT (31.3 mg, 0.230 mmol) in 0.5 mL DMF was cooled to 0-5° C. EDC (36.7 mg, 0.192 mmol) and DIPEA (33 mg, 0.256 mmol) were added. The resulting solution was allowed to warm up to rt over night. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The layers were washed with saturated aqueous NaHCO3 solution, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 4/1->3/1 to give 63.3 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClC(Cl)C>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])(=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1cccc(C(=O)c2ccccc2)c1C
Temperature: 25 °C

Procedure:
To a stirred solution of 2,3-dimethylbenzoyl chloride (35 g, 208 mmol) at 0° in dry dichloroethane (80 ml) was added anhydrous aluminium chloride (27.7 g, 208 mmol) portionwise over two minutes. The mixture was stirred for fifteen minutes and dry benzene (40 ml) was added. After warming to room temperature over fifteen minutes, the mixture was heated to reflux for four hours. The dark solution was cooled, poured onto ice (200 ml) containing concentrated hydrochloric acid (20 ml) and extracted with ether (3×100 ml). The combined organic layers were washed with 10% sodium hydroxide (2×50 ml), 10% sodium carbonate (50 ml) and brine (50 ml). After drying the organic layer over sodium sulphate, the solvent was removed under reduced pressure and the red oil (36 g) so obtained was chromatographed (SiO2 (400 g) using petroleum ether (60°-80°) and chloroform (0-12%) as eluent). This gave the desired 1-benzoyl-2,3 -dimethylbenzene (18.2 g, 42%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.Cl.[Cl:6][C:7]([Cl:12])=[CH:8][CH2:9][O:10][NH2:11]>>[Cl:6][C:7]([Cl:12])=[CH:8][CH2:9][O:10][N:11]=[CH:3][CH2:2][Cl:1]
Reactant: O=CCCl
Reactant: NOCC=C(Cl)Cl
Agent: Cl
Product: ClCC=NOCC=C(Cl)Cl
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To 2.94 g of 40% aqueous chloroacetaldehyde solution was added 2.94 g of O-(3,3-dichloro-2-propenyl)hydroxylamine hydrochloride with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 1.94 g (yield, 96%) of chloroacetaldehyde O-(3,3-dichloro-2-propenyl)oxime, nD23.2 1.5038.