Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)C>P([O-])([O-])([O-])=O>[CH2:5]([OH:6])[C@@H:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])[OH:7]
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 30 °C
Yield: 98 %

Procedure:
D-arabitol was dissolved in a 0.1M phosphate buffer (pH=6.0) in such amount that the final concentration thereof was 5%(w/v), whereby a solution was prepared in an amount of 320 ml. Using the solution as the base culture medium (reaction solution), the above microbial cells collected and washed were added thereto in an amount of about 10%(w/v) in terms of wet weight. In order to prevent pH decrease of the culture medium during the progress of culturing or incubation (reaction), calcium carbonate was further added in an amount of 2%(w/v). Culturing was conducted with shaking at 30° C. Also, as the carbon source, glucose was added in an amount of 1%(w/v) at the beginning of the culturing, and after 6 hours from the beginning of the culturing, ethanol was added in an amount of 5%(w/v). After 24 hours from the beginning of the culturing, xylitol had been formed in an amount of 4.9 g per one dl of the culture broth (98% yield based on the D-arabitol).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:26]([CH2:29][CH3:30])[CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)=[CH:20][CH:21]=1)[CH3:24]
Reactant: CCN(CC)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 4 h
Yield: 95.5 %

Procedure:
7.9 g tert-butyl 4-(4-hydroxyphenoxy)-piperidine-1-carboxylate (see WO2006/64218), 5.2 g (2-chloroethyl)-diethylamine hydrochloride and 16.6 g potassium carbonate are placed in 250 ml acetone. The reaction mixture is stirred at reflux temperature. After 4 hours the inorganic salts are suction filtered and the mixture is evaporated to dryness. The residue is combined with ethyl acetate. The organic phase is washed with a saturated NaHCO3 solution, dried and evaporated to dryness. 10.1 g of the product are obtained as an oil.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[CH:14][N:15]=3)[N:12]=2)[CH2:3]1.Cl.F[C@H]1CCNC1.Cl.F[C@@H]1CCNC1>>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[CH:14][N:15]=3)[N:12]=2)[CH2:3]1
Reactant: F[C@@H]1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)C1
Agent: Cl
Agent: F[C@@H]1CCNC1
Agent: F[C@H]1CCNC1
Product: F[C@H]1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)C1

Procedure:
The title compound was prepared in analogy to the compound of Example 124 using (S)-(+)-3-fluoropyrrolidine hydrochloride as starting material instead of (R)-(−)-3-fluoropyrrolidine hydrochloride (tR 3.89 min (conditions 4), MH+=348.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.29 (m, 1H); 7.92 (m, 2H); 7.81 (d, 1H); 7.75 (m, 1H); 7.49 (dd, 1H); 7.43 (s, 1H); 6.81 (d, 1H); 5.46 (m, 1H); 4.38 (s, 2H); 3.62 (m, 4H); 2.21 (m, 2H)).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:38]=[CH:37][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].O>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:38]=[CH:37][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:22][CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25][CH2:26]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
1.6 ml (1.6 mmol) of a 1M aqueous solution of lithium hydroxide are added to a solution of 400 mg (0.8 mmol) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoate in 5 ml of tetrahydrofuran and the medium is stirred at ambient temperature for 20 h. After addition of water and of acetic acid up to a pH of 4, the reaction medium is extracted with ethyl acetate. The organic phase is dried over sodium sulphate then filtered and concentrated under vacuum. 400 mg (100%) of (S)-3-(4-but-2-ynyloxybenzoylamino)-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[C:20]1([NH:26][C:27]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Reaction time: 0.08 h
Yield: 74.1 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 3.0 g of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring the mixture for 5 minutes, 1.6 g of phenyl isocyanate was added and the mixture was stirred for 20 minutes. Water was added, extraction was performed with ethyl acetate and the organic layer was washed with water, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (ethyl acetate), to obtain 3.4 g of a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([NH:25]C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:33]([C:39]([F:42])([F:41])[F:40])([C:35]([F:38])([F:37])[F:36])[OH:34])=[N:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:33]([C:39]([F:42])([F:40])[F:41])([C:35]([F:36])([F:38])[F:37])[OH:34])=[N:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 211.1 %

Procedure:
1-(2-Chloro-phenyl)-5-{4-[4-(N-BOC-amino)-piperidin-1-yl]-phenyl}-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (210.0 mg, 0.34 mmol) prepared in Example 330 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 200.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@H]1O
Yield: 33.8 %

Procedure:
The title compound (76 mg, 34%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (129 mg, 0.46 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (95 mg, 0.46 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][N:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=1)=[O:18]>>[CH:26]([C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][N:31]=[C:30]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:29]=2)[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cccc(NC(=O)c2ccnc(Br)c2)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(C)C)c3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-(3-isopropyl-phenyl)-isonicotinamide were converted to the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:20][CH2:19][CH2:18][C:17]4[S:16][C:15]([C:21]5[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=5)=[N:14][C:13]=4[C:12]=3[CH:29]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:32]CCOC>>[CH:26]([N:22]1[C:21]([C:15]2[S:16][C:17]3[CH2:18][CH2:19][O:20][C:11]4[CH:10]=[CH:9][C:8]([C:7]5[C:2](=[O:32])[NH:3][CH:4]=[CH:5][CH:6]=5)=[CH:29][C:12]=4[C:13]=3[N:14]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3F)cc1-2
Reactant: COCCOC
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Temperature: 80 °C
Yield: 89 %

Procedure:
To a solution of 306 (0.275 g, 0.675 mmol) in DME (5 mL) was added 10% aq HCl (5 mL). The reaction mixture was allowed to stir and heat at 80° C. for 18 hours before cooling, concentrating under reduced pressure, and diluting with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure to 50 mL of EtOAc and the solids were collected by filtration to give 330 (244 mg, 89%). 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 9.00 (t, J=15.9, 1H), 8.10 (s, 1H), 7.67 (ddd, J=16.8, 8.8, 5.2, 2H), 7.37 (d, J=5.1, 1H), 7.08 (d, J=8.4, 1H), 6.31 (t, J=6.7, 1H), 5.88 (dt, J=13.2, 6.6, 1H), 4.58-4.20 (m, 2H), 3.46 (t, J=5.0, 2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 406.1 (M+H)
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][C:32]1[CH:41]=[C:40]([OH:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.C[Si](Cl)(C)C.N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[OH:42][C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32](/[CH:31]=[CH:1]/[C:3]2[N:4]=[C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][N:6]3[C:17]=2[C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: Cc1cc(O)c2ccccc2n1
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3cc(O)c4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of compound 5f (150 mg, 0.367 mmol) and 2-methylquinolin-4-ol (292 mg, 1.84 mmol) in 4 mL of DMF was added TMSCl (469 μL, 3.67 mmol) dropwise. The resulting mixture was stirred at 90° C. for 16 h. After cooling to rt, the mixture was treated with 60 mL of EtOAc and washed with water (3×20 mL) and brine (15 mL). The solvent was removed in vacuo and the residue was treated with DCM (5 mL). To this mixture was added imidazole (50.0 mg, 0.734 mmol), and the resulting mixture turned clear and was purified by flash column chromatography on silica gel (0:1-1:19 MeOH/DCM) to afford compound 64a as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 11.97 (br. s., 1H), 8.26 (d, J=7.8 Hz, 1H), 7.88-8.03 (m, 3H), 7.43-7.83 (m, 6H), 7.22 (t, J=7.5 Hz, 1H), 6.49 (s, 1H), 6.03 (d, J=5.6 Hz, 1H), 3.94 (br. s., 4H), 3.82 (br. s., 4H), 1.55 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H31N5O4, 550.2 (M+H). found 550.5.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.C(OC(C1CCNCC1)=O)C.CC1(C(O)=O)CC1.O[Li].O>C1COCC1.CCO.O>[CH3:17][C:14]1([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Agent: CC1(C(=O)O)CC1
Agent: CCOC(=O)C1CCNCC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
First step: Using the general procedure I for the preparation of amide, 2.60 g of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester was prepared from 1.89 g of piperidine-4-carboxylic acid ethyl ester and 1.40 g of 1-methyl-cyclopropanecarboxylic acid as a light yellow oil. ES-MS m/e: 240.3 (M+H+). Second step: To a stirred solution of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (2.60 g, 0.011 mmol) in THF, EtOH, H2O (50 ml, 1/1/1) was added LiOH.H2O (686 mg, 16.3 mmol). After two hours at RT, the reaction mixture was concentrated under vacuo. The crude residue was diluted in CH2Cl2 and aqueous HCl (1N) was added until pH=2. The organic phase was collected, dried over Na2SO4 and concentrated under vacuo to afforded 1.98 g (86%) of the title product as a white powder. ES-MS m/e: 212.1 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[C:18]([C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:23]=[CH:22][CH:21]=1)#[N:19]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(C#N)c3)cc2C1

Procedure:
The title compound was prepared from N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide and 3-cyanophenyl boronic acid in a similar manner to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CCCCCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccccc1Oc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ccc(Cl)cn2)nc1

Procedure:
A mixture of 1.5 grams (0.0068 mole) 2-(5-chloropyridin-2-yloxy)phenol, 1.3 grams 2-chloro-5-nitropyridine, 1.0 grams potassium carbonate, and 40 ml of methyl ethyl ketone was heated at reflux overnight. Excess water was added and the aqueous mixture extracted with 200 ml of ethyl ether. The ether extract was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and the solvent was evaporated to yield a solid which was suspended in hexane and filtered. Yield 1.4 grams, m.p. 82°-84°; ir (Nujol): 6.15, 6.25 (C=N, NO2), 13.30 (broad), 13.70 microns; NMR (CDCl3): δ6.55 (s, ArH), 6.75 (d, ArH), 6.95 (s, ArH), 7.35 (s, 4H, ArH), 7.40-7.65 (m, ArH), 8.05 (d, ArH), 8.40 (AB quartet, ArH), 8.95 (d, ArH).
Reaction SMILES: [N:1]1([CH:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]#[C:16][C:17](O)=[O:18])=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.ClCCl>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:17](=[O:18])[C:16]#[C:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[CH:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8]4)=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)C#Cc1ccc2c(c1)CCC2N1CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(C#Cc1ccc2c(c1)CCC2N1CCCC1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 0.1 g (0.39 mmol) of (1-pyrrolidin-1-ylindan-5-yl)propynoic acid and 47 mL (0.43 mmol) of N-methylmorpholine in 5 mL of absolute THF is combined with 56 mL (0.43 mmol) of isobutyl chloroformate at −15° C. and stirred for ten minutes. Then 87 mg (0.43 mmol) of 4′-chlorobiphenyl-4-ylamine are added at ambient temperature and the reaction mixture is stirred for 14 hours. Then 3 mL of dichloromethane are added to the reaction mixture and this is stirred for 48 hours. Then the reaction mixture is filtered, the filtrate is evaporated down, combined with water and extracted with dichloromethane. The organic phase is evaporated down. The purification is carried out by preparative HPLC (eluant: dichloromethane/methanol/ammonia=8:2:0.2). Yield: 9 mg (5.7% of theory); C28H25ClN2O (M=440.97); calc.: molecular ion peak (M+H)+: 441/443; found: molecular ion peak (M+H)+: 441/443.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccc(F)cc2N1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)c(F)cc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-fluoro-3,4-dihydroquinolin-2(1H)-one (122-2; 15 g, 0.090 mol) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (19.22 g, 0.108 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (150 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.0 (bs, 1H), 7.34-7.32 (d, J=7.2 Hz, 1H), 6.59-6.57 (d, J=8.8 Hz, 1H), 2.95-2.91 (t, J=7.6 Hz, 2H), 2.65-2.61 (t, J=−7.6 Hz, 2H). MS (M+1): 245.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:4]=1[NH2:5].I[C:20]1[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:24]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][N:23]1[CH:24]=[C:20]([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=2)[CH:21]=[N:22]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: CN(C)CCn1cc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cnn(CCN(C)C)c2)ccc1N
Yield: 27.9 %

Procedure:
A solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (313 mg, 1.256 mmol), 2-(4-iodo-1H-pyrazol-1-yl)-N,N-dimethylethanamine (Preparation 62, 270 mg, 1.019 mmol) and Pd(dppf)Cl2.DCM (80 mg, 0.098 mmol) was dissolved in THF (4.5 mL) and 2M sodium carbonate in water (1.5 mL) and heated to 60° C. for 18 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between water and DCM and the aqueous layer extracted with DCM three times. The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in DCM to give the title compound (74 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:28](=O)([O-])[O-:29].[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:28]=[O:29])=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2ccc(C=O)n2-c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
1.67 g (5.3 mmol) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 33) were dissolved in 30 ml of dimethylformamide, 0.50 ml (5.3 mmol) of phosphorous oxychloride was added to the resulting solution, and the mixture was then stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was gradually added to ice-water and the pH of the mixture was adjusted to a value of 8-9 by the addition of sodium carbonate. The mixture was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 5:1 by volume mixture of hexane and ethyl acetate, to give 0.90 g (yield 50%) of the title compound as a white powder, melting at 135-137° C.
Reaction SMILES: [CH2:1]([C@H:4]1[NH:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][O:6][CH2:5]1)[CH:2]=[CH2:3].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[S:26](Cl)(=[O:28])=[O:27])[CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C@H:4]1[N:11]([S:26]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[N:16]=[CH:17][CH:18]=[CH:19]3)(=[O:27])=[O:28])[CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][O:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1COCc2ccccc2CN1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Yield: 55.9 %

Procedure:
A solution of compound 18l (1.2 g, 5.9 mmol), quinoline-8-sulfonyl chloride (1.5 g, 6.5 mmol), TEA (1.8 g, 17.7 mmol) and DMAP (366 mg, 3 mmol) in 20 mL of DCM was stirred at rt overnight. The mixture was concentrated and the residue was purified by CC to give the desired compound 18 (1.3 g, 56% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.94 (m, 1H), 8.46 (d, J=7.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.43 (dd, J=4.0, 8.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 6.98 (m, 1H), 6.91 (m, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.69 (m, 1H), 5.07-4.86 (m, 5H), 4.58 (d, J=15.0 Hz, 1H), 4.54 (m, 1H), 4.01 (d, J=12.5 Hz, 1H), 3.68 (d, J=12.5 Hz, 1H), 2.47 (m, 1H), 2.09 (m, 1H). LCMS (m/z): 395.5 (MH+).