Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([N:27]([CH3:39])[CH:28]=[N:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:31]=1[CH3:38])[CH3:26].[CH3:40][O:41][N:42]=[C:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1Cl>CS(C)=O.O>[CH2:25]([N:27]([CH3:39])[CH:28]=[N:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([O:37][CH:44]2[CH2:45][CH2:46][CH2:47][CH2:48][C:43]2=[N:42][O:41][CH3:40])=[CH:32][C:31]=1[CH3:38])[CH3:26]
Reactant: CCN(C)C=Nc1cc(C)c(O)cc1C
Reactant: CON=C1CCCCC1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C)C=Nc1cc(C)c(OC2CCCCC2=NOC)cc1C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
At from 0 to 5° C., 239 mg (2.13 mmol) of potassium tert-butoxide and 26 mg 18-crown-6 (0.10 mmol) were added a little at a time and with stirring to 200 mg (0.97 mmol) of N-ethyl-N′-(4-hydroxy-2,5-dimethylphenyl)-N-methylformamidine (cf. WO 2007/031513) in 3 ml of DMSO, and stirring was continued for about 15 minutes. At from 0 to 5° C., a solution of 313 mg (1.94 mmol) of 2-chlorocyclohexanone O-methyl oxime in 0.5 ml of DMSO was added to this mixture with stirring, and stirring was continued for about 20 hours at from 20 to 25° C. With cooling and a little at a time, 50 ml of water were added, and the mixture was extracted with MTBE. The combined organic phases were dried and then freed from the solvent. Cheomatography on alumina using cyclohexane/MTBE mixtures gave 100 mg of the title compound.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)[CH3:2].BrCC[CH2:44][CH2:45][C:46]([O:49][Si:50]([CH2:55][CH3:56])([CH2:53][CH3:54])[CH2:51][CH3:52])([CH3:48])[CH3:47].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:1][CH2:2][CH2:44][CH2:45][C:46]([O:49][Si:50]([CH2:55][CH3:56])([CH2:51][CH3:52])[CH2:53][CH3:54])([CH3:47])[CH3:48])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:35])[CH3:36])[CH2:18]1)([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28]
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCCBr
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93.4 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (262 mg, 0.434 mmol), 1-bromo-5-triethylsilyloxy-5-methylhexane (266 mg, 0.860 mmol), a 1M potassium hydroxide methanol solution (3 ml) and tetrahydrofuran (2 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (3 hours at room temperature), worked up and purified by column chromatography (hexane:toluene=4:1) to give the titled compound (320 mg, 93%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>C(OCC)(=O)C.CCCCCC>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([C:2]5[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=5)([OH:35])[C:29]=4[C:36]=3[CH3:37])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: CN(C)c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(N(C)C)cc3)C(C)(C)O4)CC2)cc1
Yield: 73 %

Procedure:
Using 4-bromo-N,N-dimethylaniline and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 73%. mp. 144–146° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1.Cl[CH2:19][CH:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[O:22]([CH2:21][CH:20]([OH:29])[CH2:19][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OC(CCl)COc1ccccc1
Reactant: Cn1c(=O)c2c(ncn2CCCN)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(ncn2CCCNCC(O)COc2ccccc2)n(C)c1=O
Reaction time: 8 h

Procedure:
A mixture of 75 g of 7-(3-aminopropyl)-theophylline and 27.4 g of 1-chloro-3-phenoxy-2-propanol is heated for 8 hours at 130° to 140° C. After the melt has been cooled to 70°-90° C., ethanol is added to it, followed by brief boiling under reflux. After standing overnight, the untreated and precipitated aminopropyl theophylline hydrochloride is filtered off under suction, the filtrate is acidified with alcoholic hydrochloric acid, heavily concentrated and acetone added until crystallisation begins. The reaction product then separates and is recrystallised from methanol. Yield 30.2 g. Melting point of the hydrochloride: 183°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:31][C@@H:29]([C:26]4[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=4)[CH3:30])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ncc([C@@H](C)N)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (130 mg, 0.41 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (85 mg, 0.55 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (3 mL) and N,N-diisopropylethylamine (140 μL, 0.83 mmol) was subjected to microwave irradiation at 180° C. for 3 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a white solid.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2Cl)=[CH:16][CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCOCC1.NC1C(C)=CC=CC=1>[CH:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(Cl)c(C(=O)C3CCCCC3)cnc12
Solvent: C1COCCO1
Solvent: Cc1ccccc1N
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)C3CCCCC3)cnc12
Yield: 18.2 %

Procedure:
3-cyclohexylcarbonyl-4-chloro-8-methoxyquinoline (5.0 g, 0.017 mol) was heated under reflux in a mixture of 1,4-dioxan (50 ml) and o-toluidine (2.0 ml) for 2 hours. The reaction mixture was evaporated and the residue dissolved in dichloromethane, washed with sodium hydrogen carbonate solution and brine. The organic solution was dried, evaporated and chromatographed (silica gel, dichloromethane) to affort an oil, which on trituration with hexane-ether gave 3-cyclohexylcarbonyl-4-(2-methylphenylamino)-8-methoxyquinoline as yellow crystals (0.58 g, 9.4%) m.p. 115°-7° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH:38]=[C:37]([CH:39]=O)[CH:36]=[N:35]2)[CH2:30][CH2:29]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:39]([C:37]3[CH:36]=[N:35][N:34]([CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)[CH:38]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C=O)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 64 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-formyl-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester were reacted in a similar fashion as for the synthesis of III. The resulting product was treated with 20 equivalents of trifluoroacetic acid in dichloromethane at 40° C. overnight. The solution was concentrated and neutralized to afford the title compound as a tan solid (64%). Mp. 203-5° C. 1H NMR (d-4 methanol): 8.27 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 6.42 (m, 1H), 6.37 (m, 1H), 5.32 (m, 1H), 4.87 (m, 3H), 4.44 (m, 1H), 3.33 (m, 2H), 3.25 (m, 2H), 2.98 (s, 1H), 2.90-2.72 (m, 4H), 2.36 (d, J=8 Hz, 1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.57 (d, J=8 Hz, 1H). MS: 452.9 (M+H). HPLC retention time: 1.60 minutes (G Method).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2].C([Li])CCC.[CH3:16][C:17]1[N:18]=[C:19](S(C)=O)[O:20][CH:21]=1.O>O1CCOCC1>[CH:1]([N:5]([C:19]1[O:20][CH:21]=[C:17]([CH3:16])[N:18]=1)[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2]
Reactant: CCCC(=O)NC(C)CC
Reactant: Cc1coc(S(C)=O)n1
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)N(c1nc(C)co1)C(C)CC
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
N-s-Butyl-butyramide (0.99 g, 0.0069 m) in dry dioxan (10 ml) was cooled to 10° C. under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 15 minutes at 10° C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry dioxan (10 ml) was added and the mixture allowed to warm to room temperature. It was stirred for 3 hours and then hydrolysed with water. The solvent was removed in vacuo and the ether extract of the residue was chromatographed on silica using ether. The resulting compound (title product) was distilled in vacuo as a colourless oil 0.95 g, b.p. 75°-76° C./0.5 mm.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCCBr
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.15 g, 17.5 mmol, 1.00 equiv), 4-bromobutyronitrile (2.10 mL, 21.0 mmol, 1.20 equiv, Aldrich), potassium carbonate (4.85 g, 35.0 mol, 2.00 equiv), and potassium iodide (581 mg, 3.50 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added and the mixture was extracted with CH2Cl2 (4×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.65 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=CC2[C:4](=CC(S(O)(=O)=O)=CC=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.N1[CH2:35][CH2:34][O:33][CH2:32]C1>>[NH2:1][C:2]1[CH:11]=[C:35]([S:17]([OH:20])(=[O:19])=[O:18])[C:34]([O:33][CH3:32])=[CH:4][C:3]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: C1COCCN1
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Fc1nnnc(F)c1F
Product: COc1cc(S(=O)(=O)O)c(N)cc1S(=O)(=O)O

Procedure:
31.9 g of 2-amino-5-hydroxy-naphthalene-1,7-disulphonic acid are subjected to a condensation reaction with trifluorotriazine and then with morpholine as described in Example 1. A diazo compound obtained by the customary route by direct diazotisation of 28.3 g of 1-amino-4-methoxy-benzene-2,5-disulphonic acid is added to the resulting suspension of the monofluorotriazinyl compound at 5°-10°, the pH simultaneously being kept at 7.0-7.5 by sprinkling in sodium bicarbonate. When the coupling has ended, the dyestuff of the formula ##STR19## is salted out, filtered off with suction, dried and ground. The red dyestuff powder dissolves readily in water and dyes cotton a brilliant reddish-tinged orange (colour code number 5).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][NH:7]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:29][CH2:28][CH2:27][NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][NH:7]2
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c[nH]c12
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c[nH]c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A solution of 5-amino-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.48 mmol), N-2-pyridyl-1,2-ethanediamine (406 mg, 2.96 mmol) and triethylamine (0.410 mL, 2.94 mmol) in DMSO (2 mL) was stirred at 100° C. After 8 h, to the solution was added N-2-pyridyl-1,2-ethanediamine (102 mg, 0.744 mmol) and triethylamine (0.200 mL, 1.43 mmol) and stirred at 100° C. for another 8 h. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol. The resulting solid recrystallized by CH3CN, and dried to yield 5-amino-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (132 mg, 23%) as a pale yellow solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH:54]([NH:57]C(=O)OC(C)(C)C)[CH2:53][CH2:52]1>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:48][CH2:49][CH2:50][N:51]3[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCCO)CC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: NC1CCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tert-butyl 1-(3-hydroxypropyl)piperidin-4-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.70 (s, 2 H), 8.33 (s, 1 H), 8.07 (d, J=2.0 Hz, 2 H), 7.43 (d, J=8.4 Hz, 2 H), 7.33 (dd, J=8.6, 2.2 Hz, 2 H), 4.33 (t, J=5.4 Hz, 2H), 3.24-3.13 (m, 2 H), 3.03-2.89 (m, 1 H), 2.84 (t, J=6.0 Hz, 2 H), 2.30-2.16 (m, 2 H), 2.15-2.06 (m, 2H), 2.04-1.93 (m, 2 H), 1.78-1.65 (m, 2 H); MS (ESI) m/z 479.1 (M−H)−; MS (ESI) m/z 481.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12].[CH:16]([O-])=[O:17].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:16]=[O:17])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C[O-]
Reactant: O=C(NCc1ccc(I)cc1Cl)C1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CNC(=O)C2CC2)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a solution of 2.20 g of N-[(2-chloro-4-iodophenyl)methyl]cyclopropanecarboxamide and 0.57 g of sodium formate in 20 mL of N,N-dimethylformamide in an autoclave, 0.26 g of dichlorobis(triphenylphosphine) palladium (II) was added, and stirred under carbon monoxide atmosphere of 1.5 MPa at 90° C. for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and diluted with 60 mL of ethyl acetate and washed with water (30 mL×2). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluted with ethyl acetate to obtain 1.20 g of the aimed product as white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Br
Reactant: CC(C)(C)N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Bromo4-methoxyphenylsulfonyl chloride (2.80 g, 9.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was treated with triethylamine (1.76 mL, 12.6 mmol), followed by the dropwise addition of t-butylamine (1.33 mL, 12.6 mmol). The mixture was allowed to stand for 2 hours and then was poured onto a mixture of 5% citric acid solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were dried and concentrated. Crystallization of the crude solid from ethyl acetate/hexane gave 3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide (2.43 g, 77%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C[O:8][C:9](=[O:21])[CH2:10][C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:13]=2[S:14][CH:15]=1.Cl[CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:26][N:25]=1>C(#N)C.ClCCl>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[O:26][N:25]=[C:24]([CH2:23][O:20][C:16]3[C:13]4[S:14][CH:15]=[C:11]([CH2:10][C:9]([OH:8])=[O:21])[C:12]=4[CH:19]=[CH:18][CH:17]=3)[CH:28]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)Cc1csc2c(O)cccc12
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Reaction time: 20 h
Yield: 38 %

Procedure:
Cesium carbonate (0.31 g, 90 mmol) was added to a stirred solution of compound 77B from the preceding step (0.14 g, 0.63 mmol) and commercially available 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole (0.14 g, 0.63 mmol) in 15-20 mL of acetonitrile at room temp. After 20 hours the mixture was stripped of solvent in vacuo. The residue was dissolved in dichloromethane and filtered through a short column of Celite® over silica gel, eluting with several column volumes of solvent. The filtrate was stripped of solvent in vacuo, and the residue recrystallized from DMF to afford 0.1 g (38% yield) of the title compound as a snow-white solid; mp 155-156° C. Calc for C21H16ClNO4S: C, 60.94; H, 3.90; N, 3.38. found: C, 60.67; H, 3.72; N, 3.41. Step 4. Preparation of {7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid (Compound 77D)
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])(OCC1C=CC=CC=1)=O>>[CH:13]1([CH2:12][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH:22][C:36]([C@@H:35]2[CH2:39][CH2:40][CH2:41][NH:34]2)=[O:37])(=[O:11])[OH:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: O=C(NC[C@@H](O)CP(=O)(O)CC1CCCCC1)[C@@H]1CCCN1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 7 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-proline as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.32-4.18 (m, 1H), 4.13-3.95 (m, 1H), 3.55-3.20 (m, 4H), 2.52-2.35 (m, 1H), 2.15-1.99 (m, 3H), 1.95 (br. d, 2H), 1.80-1.58 (m, 6H), 1.52 (dd, 2H), 1.40-1.15 (m, 3H), 1.13-0.95 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 42.01. LCMS m/z: [M+H]+=333.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[OH-].[K+]>O>[F:11][C:12]1[CH:18]=[C:17]([O:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=[CH:15][C:13]=1[NH2:14]
Reactant: Nc1ccc(O)cc1F
Reactant: Clc1ccnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1F
Temperature: 25 °C

Procedure:
100 mg (660 μmol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine (from example XVIII), 166 mg (1.31 mmol) of 2-fluoro-4-hydroxyaniline and 73.5 mg (1.31 mmol) of powdered potassium hydroxide are heated at 260° C. for 8 hours. For work-up, the mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [NH4+:1].[Cl-].[NH4+].[OH-].[CH:5]([CH2:18][C:19]([O-])=[S:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.O>[CH:5]([CH2:18][C:19]([NH2:1])=[S:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-]C(=S)CC(c1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of NH4Cl (0.29 mol, 2.0 eq) and NH4OH (300 ml) in methanol (200 mL) was added a solution of benzhydrylthioacetate (38.2 g, 0.145 mol) in methanol (50 ml) maintaining the temperature below 20° C. The reaction was stirred for 1 hour and diluted with water (100 ml) resulting in the formation of a precipitate. The precipitate was collected, washed with water and dried to give benzhydrylthioacetamide (31 g) as colorless solid.