Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[Si:12]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH:39]([O:40][Si:41]([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38][C:37](=[C:58](O)[CH3:59])[C:36](=[CH2:61])[CH:35]1[O:62][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Na+]>C(Cl)Cl.C(OCC)C>[Si:12]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH:39]([O:40][Si:41]([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38][C:37](=[CH:58][CH2:59][Cl:1])[C:36](=[CH2:61])[CH:35]1[O:62][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C1C(=C(C)O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(OCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Solvent: CCOCC
Product: C=C1C(=CCCl)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(OCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -25 °C
Yield: 95.3 %

Procedure:
N-chlorosuccinimide (140 mg) was suspended in 10 ml of methylene chloride, and 74 mg of dimethyl sulfide was added at 0° C. The mixture was stirred, and cooled to -25° C. A solution of 958 mg of (4-(3-tert-butyldiphenylsilyloxypropoxy)-3,5-bis-(tert -butyldiphenylsilyloxy)-2-methylenecyclohexylidene) ethanol in 2 ml of methylene chloride was added dropwise, followed by stirring at 0° C. for 2 hours. A sodium chloride aqueous solution was added to the reaction mixture, and extraction was conducted with diethyl ether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. There resulted 931 mg of (4-(3-tert-butyldiphenylsilyloxypropoxy)-3,5-bis-(tert-butyldiphenylsilyloxy)-2-methylenecyclohexylidene)ethyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:25]O>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:25])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl2 (60 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (300 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the corresponding product (gray solid, 12.58 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])[CH:7]=1.N[C:32]1C=C2C(=[CH:39][CH:40]=1)NN=C2C1C=CC=CC=1.FC1C=CC(S(C)(=O)=O)=C(S(Cl)(=O)=[O:55])C=1>N1C=CC=CC=1>[CH:40]([O:55][CH:26]([CH3:25])[CH3:21])([CH3:39])[CH3:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: CS(=O)(=O)c1ccc(F)cc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Solvent: c1ccncc1
Product: CC(C)OC(C)C

Procedure:
5-Fluoro-2-methylsulfonyl-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be prepared as described in Example 2 from 0.52 g of 5-amino-3-phenyl-1H-indazole, 5 ml of pyridine and 0.68 g of 5-fluoro-2-methylsulfonylbenzenesulfonyl chloride. The residue obtained is purified by chromatography on a column of 50 g of silica (particle size 40-63 μm), eluting with pure dichloromethane. After recrystallization from 5 ml of acetonitrile and washing with acetonitrile and then with diisopropyl ether, 0.07 g of 5-fluoro-2-methylsulfonyl-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is obtained in the form of a white solid melting at 224° C. (analysis: C20H16FN3O4S2, % calculated C, 53.92; H, 3.62; F, 4.26; N, 9.43; O, 14.37; S, 14.40. % found C, 53.74; H, 3.31; N, 9.35; S, 14.10).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](B3OCC(C)(C)CO3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:40]1[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>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>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:11]2[CH:10]=[CH:9][C:8]([NH:21][C:22]([C:24]3[N:25]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH:26]=[C:27]([C:29]#[N:30])[N:28]=3)=[O:23])=[C:7]([C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:12]=2)=[CH:41][CH:42]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)COB(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)nc2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-amide (as prepared in the previous step, 32.0 mg, 0.0600 mmol), 5-bromo-pyridin-2-ylamine (10.4 mg, 0.0660 mmol) and Pd(PPh3)4 (7.0 mg, 0.0060 mmol) in 1.0 mL of 1,4-dioxane was added 2.0 M Na2CO3 aqueous solution (0.24 mL, 0.48 mmol). The resulting mixture was stirred at 80. C for 6 h under Ar. After cooling to RT, the mixture was treated with 30 mL of EtOAc, washed with H2O (3×15 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2-3% MeOH/DCM) to afford 24 mg (78%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C28H34N6O2Si, 515.3 (M+H), found 515.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.[C:47]([O:56]C(C)(C)C)(=[O:55])[C:48]1[C:49](=[CH:51][CH:52]=[CH:53][CH:54]=1)N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:54]2[CH:53]=[CH:52][CH:51]=[CH:49][C:48]=2[C:47]([OH:56])=[O:55])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccccc1C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl anthranilate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[ClH:20]>C(OCC)C>[Cl-:20].[CH2:1]([NH2+:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cl
Reactant: CCCCCNCCCCc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: CCCCC[NH2+]CCCCc1ccc([N+](=O)[O-])cc1
Product: [Cl-]

Procedure:
n-Pentylamine was reacted with 4-(4-nitrophenyl)butanoyl chloride to provide the corresponding amide. Nine grams of N-n-pentyl-4-(4-nitrophenyl)butyramide were reacted with 96 ml. of a 1 molar solution of diborane in tetrahydrofuran to provide, following isolation as described in Example 1, 7.8 g. of N-n-pentyl-4-(4-nitrophenyl)butylamine. The amine was dissolved in diethylether and reacted with hydrogen chloride to afford, following crystallization from isopropanol, 5.8 g. of N-n-pentyl-4-(4-nitrophenyl)-butylaminium chloride. M.P. 144°-146° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([CH3:21])[C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:20][C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[N:13]([CH3:21])[CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(C#N)cc1
Yield: 63 %

Procedure:
The titled amide was prepared according to general procedure B using p-cyanobenzoyl chloride (1.65 g.; 0.01 mole), the trans-2-(dimethylamino)cyclohexylamine (1.42 g.; 0.01 mole) and triethylamine (1.01 g.; 0.01 mole) but using CH2Cl2 for extraction. The crude solid was crystallized from ether to give colorless needles, 1.71 g. (63% yield), m.p. 160°-161°. uv λmax 236 nm (ε 17,900); sh 285 (2,550). ir NH 3320; N-alkyl 2780; C=N 2220; C=O 1635; C=C 1610, 1500; amide II 1550; aromatic 860. NMR in CDCl3 (60 MHz) was in accord. Mass spectrum M+ 271.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([CH:37]2[CH2:39][CH2:38]2)[CH:27]2C(=O)O[C:30](C)([CH3:34])[O:29][C:28]2=[O:36])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>CN(C=O)C>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([CH:37]2[CH2:38][CH2:39]2)[CH2:27][C:28]([O:29][CH2:30][CH3:34])=[O:36])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(C(c2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C2CC2)C(=O)O1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C1CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 5-((3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl) (cyclopropyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.07 g) in DMF (40 mL) was added ethanol (20 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.55 g) as a pale-yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12](OC(OCC)(OCC)C)[CH3:13]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12]([CH3:13])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1cccc(I)c1
Solvent: CC(=O)O
Product: Cc1nnc(-c2cccc(I)c2)o1
Temperature: 150 °C
Yield: 92 %

Procedure:
In a schlenck tube, a mixture of 3-iodobenzohydrazide (510 mg, 1.95 mmol) and 1,1,1-triethoxyethane (1.14 ml, 6.23 mmol) in acetic acid (15 ml) was heated at 150° C. for 3 h. The solvent was evaporated and the crude redissolved in ethyl acetate and washed with 4% solution of NaHCO3, water and brine. The organic layer was dried, filtered and concentrated under vacuum to give the title compound as a white solid (92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1)=O.O=P(Cl)(Cl)Cl.Cl>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:14]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:13][CH2:12][CH2:11][C:5]2=1
Reactant: CCOC(=O)C1(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)CCC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reaction time: 3 h

Procedure:
32 g of the product obtained in Step A are heated at reflux in a solution of 400 ml of toluene and 35 ml of POCl3. After 3 hours, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 300 ml of ethanol, and 5 g of sodium borohydride are slowly added. After 30 minutes, 300 ml of water are added and the ethanol is distilled off. After extraction of the residue with dichloromethane, drying and evaporation under reduced pressure, the oily residue obtained is converted into the hydrochloride in an ethanolic hydrogen chloride solution. The expected product is isolated by filtration and drying in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]([CH2:34][P:35](=[O:36])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(c1ccc2[nH]ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.56 g 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide are dissolved in 25 ml dimethylformamide. To this, 3.11 g potassium carbonate and 2.93 ml diethoxy-phosphorylmethyl trifluoro-methanesulphonate are added dropwise. The mixture is stirred overnight at ambient temperature, divided between water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with water and once with saturated sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo, the residue is dissolved in hot ethyl acetate and after cooling to ambient temperature the precipitated solid is suction filtered. Further product is obtained by freeing the mother liquor in vacuo from the volatile constituents and chromatographing the residue on silica gel (cyclohexane/ethyl acetate 50:50 to 25:75).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[CH:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:34]1[CH:33]=[N:32][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:35]=1)=[O:37])[CH3:2]
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Product: CCOC(=O)C(C(=O)c1cnn(Cc2ccccc2)c1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (0.9 g, 41%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 1-benzyl-1H-pyrazole-4-carboxylic acid (Kalla R. V.; Elzein E.; Perry T.; Li X.; Palle V.; Varkhedkar V.; Gimbel A.; Maa T.; Zeng D.; Zablocki J. Journal of Medicinal Chemistry (2006), 49(12), 3682-92).MS: 516.1 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33]>>[OH:12][CH:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=3)[N:14]([CH3:13])[C:15](=[O:33])[CH2:16][CH2:17]4)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: OC1CCCc2c(Br)cncc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4O)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], Suzuki reaction of (rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ol with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as light red powder. MS: 309.5 (M+H+).
Reaction SMILES: N[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH3:12])[CH3:11])=[O:7])=[CH:4][C:3]=1[F:23].N([O-])=O.[Na+].[S:28](=[O:30])=[O:29].[ClH:31]>O.CC(O)=O.O.O.[Cu](Cl)Cl>[F:23][C:3]1[CH:4]=[C:5]([C:6]([NH:8][CH2:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH3:12])[CH3:11])=[O:7])[CH:21]=[CH:22][C:2]=1[S:28]([Cl:31])(=[O:30])=[O:29]
Reactant: O=S=O
Reactant: Cl
Reactant: CC(C)(CNC(=O)c1ccc(N)c(F)c1)Oc1ccc(F)cc1
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Cl)c(F)c1)Oc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
4-Amino-3-fluoro-N-[2-(4-fluorophenoxy)-2-methylpropyl]benzamide (Preparation 94, 441 mg, 1.24 mmol) in 6 M of HCl in water (2 mL) was cooled at −5° C. Sodium nitrite (94.0 mg, 1.36 mmol) in water (0.5 mL, 30 mmol) was added slowly. After 20 minutes, sulfur dioxide in AcOH (8:25, sulfur dioxide:AcOH, 3 mL) and copper(II) chloride dihydrate (0.21 g, 1.2 mmol) were added to the reaction mixture. Vigorous gas evolution occurred. After 2 hours, the reaction was poured onto ice and water. The resulting solid was collected by filtration and washed with water and dried to afford a dark brown solid.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:15](=[O:18])[CH2:16][Br:17])[CH:11]=[CH:12][C:13]=1[Cl:14])(=[O:7])=[O:6])(=[O:3])[CH3:2].[CH2:19]([NH:21][C:22]([NH:24][CH2:25][CH:26]([O:28][CH3:29])[CH3:27])=[S:23])[CH3:20].CCOCC>C(OCC)(=O)C>[BrH:17].[C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:15]2([OH:18])[CH2:16][S:23][C:22](=[N:24][CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[N:21]2[CH2:19][CH3:20])[CH:11]=[CH:12][C:13]=1[Cl:14])(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCNC(=S)NCC(C)OC
Reactant: CC(=O)NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Br
Product: CCN1C(=NCC(C)OC)SCC1(O)c1ccc(Cl)c(S(=O)(=O)NC(C)=O)c1

Procedure:
3.7 g (0.01 mol) of 3'-acetylsulfamoyl-2-bromo-4'-chloroacetophenone are stirred at 20° C during 24 hours in 20 ml of ethyl acetate with 1.8 g (1.01 mol) of 1-ethyl-3-(2-methoxypropyl)thiourea, 60 ml of ether are added and the amorphous oily precipitate is solidified by trituration after under 40 ml of ether decanting the solvent. Amorphous solid substance capable of flowing, decomposition starting at 65° C.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.[OH-].[Na+]>C1COCC1.O>[CH:16]1[CH:15]=[C:14]2[C:13]([CH:4]=[O:5])=[CH:12][NH:11][C:19]2=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccccc12

Procedure:
[a-2H; a-13C]-DMF (7.52 mmol) was dissolved in THF (4 ml), phosphorus oxychloride (3.76 mmol) was added to the resulting solution with stirring in an ice bath, a solution (50 ml) of the indole (35) (3.76 mmol) in THF was further added to the resulting mixture, followed by stirring of the mixture at room temperature for 3 hours. After the confirmation of the completion of the reaction using the TLC method, the reaction system was cooled in an ice bath, water (30 ml) and 2M NaOH aqueous solution were added till an alkaline solution was obtained, the resulting alkaline solution was extracted with methylene chloride-methanol (95:5) mixed solvent (100 ml×3), the extract was washed with a saturated sodium chloride aqueous solution (100 ml×3) and then dried over anhydrous magnesium sulfate. After filtration under reduced pressure, the solvent was distilled off from the filtrate and the resulting residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=94/6) to thus give an aldehyde (36) in a yield of 2.68 mmol (71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:6]([O:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=O)=O.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:32]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)OCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)co2)cc1OC
Temperature: 130 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
In 25 ml of acetic acid was dissolved 2 g of 6-[2-(3,4-dimethoxybenzoyloxy)acetyl]-3,4-dihydro-carbostyril. Thereto was added 2 g of ammonium acetate. The mixture was stirred at 130° C. for 3 hours with heating. The solvent was removed by distillation. The residue was dissolved in ethanol. The solution was treated with active carbon, and then recrystallization was conducted to obtain 120 mg of 2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)oxazole as light brown acicular crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[I:10])[CH:5]=[O:6].[C:14](Cl)(=[O:16])[CH3:15].C(N(C(C)C)CC)(C)C.CN(C=[O:31])C>>[C:14]1(=[O:16])[N:1]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=2[I:10])[CH:5]=[O:6])[C:15]1=[O:31]
Reactant: CCOc1cc(C=O)cc(N)c1I
Reactant: CC(=O)Cl
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C=O)cc(-n2c(=O)c2=O)c1I
Temperature: 50 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
To a solution of 3-amino-5-ethoxy-4-iodo-benzaldehyde (0.27 g, 0.93 mmol, 1.0 equiv; intermediate 25) and acetyl chloride (0.138 mL, 0.153 g, 1.95 mmol, 2.1 equiv) in anhydrous DMF (5 mL) was added diisopropylethylamine (0.48 mL, 0.36 g, 2.78 mmol, 3.0 equiv) and the mixture stirred at 50° C. for 48 h. Removal of the solvent under reduced pressure and purification of the crude reaction mixture with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) yielded 0.11 g (35%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.0 Hz, 3H), 2.29 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.06 (s, 1H), 7.76 (br s, 1H), 8.42 (s, 1H), 9.96 (s, 1H). MS (ISP): 334.0 [M+H]+.