Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)C>O>[C:21]1([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)=[N:13]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)N1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Yield: 86.5 %

Procedure:
A stirred solution of 6.4 g of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carboxylic acid ethyl ester, 6.1 g of potassium hydroxide in 60 ml of water, and 120 ml of ethanol was refluxed under nitrogen for 32 hours. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with diethyl ether. The extract was washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated to give 4.4 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole as a solid. The solid was dissolved in ethyl acetate/diethyl ether and treated with ethereal hydrogen chloride to precipitate the hydrochloride salt. Recrystallization from methanol/diethyl ether gave 2.5 g (45%) of 1-phenyl-3-(1-piperazinyl-1H-indazole hydrochloride, mp 265°-267°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[O:30]C>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:27]2[CH:28]=[C:23]([F:22])[C:24]([OH:30])=[C:25]([F:29])[CH:26]=2)=[O:9])[CH:10]=1
Reactant: COc1c(F)cccc1F
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc(F)c(O)c(F)c1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoic acid (3.2 g, 13.5 mmol) in dichloromethane (40 mL), oxalyl dichloride (1.7 mL, 27.1 mmol) was added. Then N,N-dimethylformamide (50 mL) was added dropwise. After the vigorous evolution of gas ceased, the mixture was stirred at 25° C. overnight prior to removal of the volatiles under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. Aluminum trichloride (2.7 g, 20.4 mmol) was added in portions, and the mixture was stirred for 10 minutes. Then 1,3-difluoro-2-methoxybenzene (2.0 g, 13.8 mmol) was added, and the mixture was stirred at 0° C. for 2 hours. Then the reaction was allowed to warm to 25° C. overnight. The reaction was quenched with ice-water (30 mL) and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with sodium hydroxide (2 M), water, hydrochloric acid (10%), and brine prior to drying over sodium sulfate. Crude product was obtained after dichloromethane was removed under reduced pressure. The sample was dissolved in tetrahydrofuran/methanol/water (30 mL, v/v/v=2:3:1), and lithium hydroxide monohydrate (700 mg) was added. The mixture was stirred for 1 hour at 25° C. The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the extracts were washed with brine, dried over sodium sulfate, and concentrated to a crude product under reduced pressure. The residue was purified by silica column chromatography to give 1.46 g of white solid (30% yield, purity: 95%). 1H-NMR (CDCl3, 400 MHz): δ 7.59-7.62 (m, 1H), 7.49-7.50 (m, 1H), 7.36-7.42 (m, 3H); HPLC-MS method: Method 2, retention time 3.81 min; MS ES+ (m/z): 345 (M−1)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12](OC)=[O:13])=[CH:4][C:3]=1[F:16].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(=O)=O.CC(C)=O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][OH:13])=[CH:4][C:3]=1[F:16]
Reactant: COC(=O)Cn1ccc2cc(F)c(Br)cc21
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCCn1ccc2cc(F)c(Br)cc21
Yield: 96.1 %

Procedure:
Methyl 2-(6-bromo-5-fluoro-1H-indol-1-yl)acetate (D77) (10.2 g, 35.7 mmol) was dissolved up in 81 mL of THF and cooled in a cardice/acetone bath before the addition of LiAlH4 (2N in THF solution) (17.83 mL, 35.7 mmol). The reaction mixture was left to stir in the cardice/acetone bath for 30 mins. Whilst still in the bath the reaction mixture was quenched by the dropwise addition of saturated sodium sulfate aqueous solution. The solid formed was filtered off and washed with ethyl acetate. The filtrate was washed with brine. The organic layer was passed through a hydrophobic frit and concentrated to afford title compound (8.852 g). LCMS (A): m/z (M+H)+ 258/260, C10H9BrFNO requires 257/259 (acidic).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([N:15](C)[C:16](=O)C)[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:15][CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(N(C)C(C)=O)c2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN1CCN(c2cccc(NC)c2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To N-[3-(4-ethyl-piperazin-1-yl)-phenyl]-N-methyl-acetamide (104.9 mg) obtained in Step C, water (2 ml) and concentrated sulfuric acid (0.4 ml) were added, followed by stirring at 80° C. for 8 hours. To this, 5M-NaOH aqueous solution was added, to adjust the pH to 9, followed by extraction with ethyl acetate (10 ml×2), and the organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, followed by purification by silica gel column chromatography (dichloromethane/methanol=20/1 to 10/1), to obtain the desired compound (76.1 mg, 86%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].I[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[C:16]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was synthesized in analogy to example 116, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone and 4-iodobenzotrifluoride.
Reaction SMILES: C(O)=O.[C:4]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:27][C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[N:18](COCC[Si](C)(C)C)[C:13]3=[CH:12][C:11]=2[Cl:39])=[CH:6][CH:5]=1.S(=O)(=O)(O)[O-].[K+]>>[C:4]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:27][C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[NH:18][C:13]3=[CH:12][C:11]=2[Cl:39])=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Product: COC(=O)c1cc(Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)ccc1C

Procedure:
A formic acid (2.7 mL, 70.4 mmol) solution of methyl 5-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H imidazo[4,5-b]pyridin-2-yl]oxy}-2-methylbenzoate (140 mg, 0.23 mmol) and saturated potassium bisulfate (0.27 mL) was stirred at 80° C. for 1 h. The reaction was partitioned between EtOAc and brine. The organic layer was separated, and concentrated to give methyl 5-{[5-(biphenyl-4-yl)-6-chloro-1-H imidazo[4,5-b]pyridin-2-yl]oxy}-2-methylbenzoate as a white solid, which was used in the next step without further purification. LC-MS: calculated for C27H20ClN3O3 456.89, observed m/e: 470.2 (M+H)+ (Rt 2.3/4 min).
Reaction SMILES: C[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[CH2:25](Cl)Cl.CCOC(C)=O.CCCC(C)C>>[CH3:25][C:7]1[CH:2]=[N:3][C:4]2[N:5]([C:8]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[N:6]=1
Reactant: Cc1cnn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: Cc1cnc2ncc(-c3cccc(-c4ccccc4C#N)c3)n2n1

Procedure:
1H NMR (400 MHz, CDCl3) δ 2.72 (3H, s), 7.50 (1H, td, J 7.6, 1.3 Hz), 7.59-7.67 (3H, m), 7.70 (1H, td, J 7.7, 1.4 Hz), 7.82 (1H, dd, J 7.8, 1.0 Hz), 8.14 (1H, dt, J 7.6, 1.6 Hz), 8.29 (2H, m), 8.37 (1H, s); MS (ES+) m/z 312 [M+H]+. 3′-(3-Methylimidazo[1,2-b][1,2,4]triazin-7-yl)biphenyl-2-carbonitrile: mp 211-216° C. (CH2Cl2-EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 2.73 (3H, s), 7.50 (1H, td, J 7.6, 1.3 Hz), 7.59-7.66 (3H, m), 7.70 (1H, td, J 7.7, 1.4 Hz), 7.82 (1H, dd, J 7.8, 1.4 Hz), 8.10 (1H, dt, J 7.6, 1.5 Hz), 8.29 (2H, t, J 1.4 Hz), 8.26 (1H, s), 8.36 (1H, s); MS (ES+) m/z 312 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:24]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14][CH:13]=[CH:12]2)[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=CCBr
Reactant: C=CC=CCCNCc1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC=CC2CCN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.4 %

Procedure:
A solution of N-benzylhexa-3,5-dien-1-amine (338 mg, 1.81 mmol) and triethylamine (0.378 mL, 2.72 mmol) in acetonitrile (15 mL) was treated with ethyl 4-bromobut-2-enoate (0.249 mL, 1.81 mmol). The mixture was stirred at room temperature for 72 hours, then heated to reflux for 6 hours. The mixture was cooled to room temperature and treated with water (15 mL), then extracted with ethyl acetate (3×15 mL). The combined organic phases were dried over magnesium sulfate and concentrated to provide a pale yellow oil. The pale yellow oil was purified by radial thin-layer chromatography, eluting with 10% ethyl acetate/hexane, to provide an oil (165 mg, 30%). 1H NMR (300 MHz, CDCl3) δ7.4-7.2 (m, 5H), 5.62 (m, 2H), 4.1-3.9 (m, 2H), 3.6-3.3 (m, 2H), 2.95 (m, 1H), 2.65 (m, 2H), 2.3-2.1 (m, 6H), 1.78 (m, 1H), 1.57 (m, 1H), 1.19 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 300.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30]([NH2:32])=[O:31])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.[CH3:36]O>O1CCCC1>[CH2:1]([N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([C:30]([NH2:32])=[O:31])[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[CH3:36]
Reactant: COC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(N)=O
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cccc(-c2ccc(CC(C(N)=O)C(=O)O)cc2)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 46 %

Procedure:
180 mg (0.4 mmol) of methyl 2-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethyl)malonamate (prepared in Example 16(d)) in 2 ml of methanol, 2 ml of tetrahydrofuran and 250 μl (0.5 mmol) of aqueous 2N sodium hydroxide solution are introduced [lacuna]. The reaction medium is stirred at room temperature for 36 hours, acidified to pH 3 with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 80 mg (46%) of the desired product, with a melting point of 117° C., are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[N:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.Cl[CH2:24][C:25]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[O:37][CH3:38]>>[CH3:38][O:37][C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]([O:35][CH3:36])=[CH:34][C:25]=1[CH2:24][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[N:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: CSc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cn1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(SC)nc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 125 (g), from tert-butyl (3'RS,4'RS)-3'-hydroxy-6-methylsulphanyl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by alkylation with 2-chloromethyl-1,4-dimethoxy-naphthalene [J. Amer. Chem. Soc. 64, 2657 (1942)] there was obtained tert-butyl (3'RS,4'RS)-3'-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-6-methylsulphanyl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate in the form of a colourless solid; MS: 526 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]>C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][C@H:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: CCO
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Reaction time: 164 h

Procedure:
(RS)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine-D-tartrate (461 g) is dissolved in ethanol (700 ml) under reflux. After gradual cooling to lab temperature, the mixture is stirred for 164 hours. The precipitated crystals are sucked off and washed with ethanol. The yield is 150 g (32%). Optical purity is 98% ee (CE).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(Cl)Cl.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: Brc1ncccn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: OC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.48 h
Yield: 53.5 %

Procedure:
To a solution of 2-bromopyrimidine (0.20 g, 1.258 mmol) in dry methylene chloride (3.0 mL) was dropwise added 1.6 M of n-butyllithium in hexane (0.86 mL) at −78° C. The reaction mixture was stirred for 29 min at −78° C. and 1,4-dioxa-spiro[4.5]decan-8-one (0.196 g, 1.26 mmol) in CH2Cl2 (3 mL) was added dropwise. The reaction was stirred at −78° C. for 50 min and quenched with an aqueous solution of NH4Cl. After being warmed to room temperature, the mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to provide 0.50 g of crude product. Purification by column chromatography on silica gel eluting with 0→50% EtOAc in hexanes provided 0.159 g (54%) of desired product as a light brown-yellow solid. MS (M+H)+ 237.2.
Reaction SMILES: O=S1(=O)N=CC2C=C(C(C)(C)C)C=C(I)C=2O1.[O:18]=[S:19]1(=[O:35])[N:24]=[CH:23][C:22]2[C:25]([O:33][CH3:34])=[C:26]([Cl:32])[C:27]([O:30][CH3:31])=[C:28]([Cl:29])[C:21]=2[O:20]1>>[O:35]=[S:19]1(=[O:18])[NH:24][CH2:23][C:22]2[C:25]([O:33][CH3:34])=[C:26]([Cl:32])[C:27]([O:30][CH3:31])=[C:28]([Cl:29])[C:21]=2[O:20]1
Reactant: COc1c(Cl)c(OC)c2c(c1Cl)OS(=O)(=O)N=C2
Agent: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Product: COc1c(Cl)c(OC)c2c(c1Cl)OS(=O)(=O)NC2

Procedure:
This compound is prepared by essentially the same method as described in Example 8 except that the 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine is replaced by 2,2-dioxo-5,7-dimethoxy-6,8-dichloro-1,2,3-benzoxathiazine. Thereby is obtained 2,2-dioxo-3,4-dihydro-5,7-dimethoxy-6,8-dichloro-1,2,3-benzoxathiazine.
Reaction SMILES: [K].[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]=1[OH:16])([CH3:5])([CH3:4])[CH3:3].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(O)(C)(C)C>[C:12]([C:8]1[CH:9]=[C:10]([CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])[CH:11]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=CC(=O)OC
Agent: [K]
Solvent: CC(C)(C)O
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
To 500 parts by volume of dry t-butyl alcohol in a flask fitted with mechanical stirrer, inert gas inlet, thermometer, condenser and dropping funnel are added 2.1 parts of potassium metal. After the ensuing reaction is complete, there are added 37.3 parts of 2,6-di-t-butylphenol, followed rapidly by 17.7 parts of methyl acrylate. The stirred reaction mixture is heated to 50° C. for 18 hours and allowed to cool. The solvent is removed under reduced pressure and the residual mass neutralized by addition of dilute hydrochloric acid. This mixture is then extracted with two portions of 200 parts by volume each of ethyl ether. The combined ethereal extracts are washed with two portions of 100 parts by volume each of water and then dried over anhydrous sodium sulfate. The ether layer is removed by filtration and concentrated on a steam bath. The residual oily mass is then vacuum distilled. The fraction collected at 125°-130° C./0.1 mm Hg crystallizes upon standing to yield methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, M.P. 63.0°-64.5° C. Recrystallization from hexane yields a white solid, M.P. 66°-66.5° C.
Reaction SMILES: O.NN.[C:4]([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:7])([CH3:6])[CH3:5].CO>C(Cl)Cl>[C:4]([O:8][CH2:9][CH2:10][CH2:11][O:12][NH2:13])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OCCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OCCCON
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Hydrazine hydrate (1.36 mL, 43.3 mmol) was added to a solution of 2-(3-tert-Butoxy-propoxy)-isoindole-1,3-dione (6.0 g, 21.7 mmol) in CH2Cl2 (50 mL) with MeOH (5 mL), and the reaction stirred 1 h at room temperature. The precipitate was removed by filtration, and the filtrate was purified by silica gel chromatography (6% MeOH/CH2Cl2) to give 2.4 g (75%) of compound 29A as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.94 (br s, 2H), 3.71 (t, 2H, J=6.4 Hz), 3.38 (t, 2H, J=6.4 Hz), 1.70-1.79 (m, 2H), 1.15 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CC(C)O
Solvent: CCCCO
Product: Clc1nc(Nc2ccccc2)c2ncn(C3CCSC3)c2n1
Reaction time: 20 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.055 ml of aniline in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for 20 hours, left to return to ambient temperature, diluted with 5 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum to a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 173 mg of expected product is thus obtained in the form of white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[CH3:19][O:20][CH2:21][N:22]=[C:23]=[O:24]>>[CH3:19][O:20][CH2:21][NH:22][C:23]([NH:1][CH:2]1[CH2:3][C:4]([CH3:18])([CH3:17])[N:5]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([CH3:8])([CH3:9])[CH2:7]1)=[O:24]
Reactant: COCN=C=O
Reactant: CC1(C)CC(N)CC(C)(C)N1Cc1ccccc1
Product: COCNC(=O)NC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1

Procedure:
51 parts of N-methoxymethyl-N'-1-benzyl-2,2,6,6-tetramethylpiperidin-4-yl urea are obtained by reacting 49.1 parts of 4-amino-1-benzyl-2,2,6,6-tetramethylpiperidine with methoxymethyl isocyanate in the same way as described in Example 23(b).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[NH:26])[NH:24][OH:25])=[CH:13][CH:12]=2)[C:8]2[C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[C:42]([O:25][NH:24][C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:8]3[C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:13]=1)=[NH:26])(=[O:44])[CH3:43]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-butyl-1-[[2'-(hydroxycarbamimidoyl)biphenyl-4-yl]methyl]bezimidazole-7-carboxylate (1.83 g) in dichloromethane (20 ml) was added triethylamine (0.46 g) and acetic anhydride (0.46 g), and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was partitioned between ethylacetate and water and the organic layer was washed with an aqueous solution of NaHCO3 and water. The solution was dried and concentrated to dryness to give a pale yellow solid (1.99 g, quant.)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[C-:13]#[N:14].[Na+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]#[N:14]
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccccc1C(F)(F)F
Yield: 93 %

Procedure:
To a solution of 2-(trifluoromethyl)benzyl bromide (1.50 g) in ethanol (15 mL) was added a solution of sodium cyanide (461 mg) in water (15 mL) at ambient temperature, and the mixture was heated for 3 hours under reflux . After evaporation of the organic solvent, the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give [2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) as an oil.