Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH:17]=1)[OH:16])[CH:4]([CH3:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[C:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]1=O)(=O)[CH3:20]>>[CH2:1]([CH:3]([C:11]1[CH:17]=[C:15]([OH:16])[C:14]2[CH:19]([CH3:20])[C:22]3[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]=3[O:18][C:13]=2[CH:12]=1)[CH:4]([CH3:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CC(=O)C1CCC(C)CC1=O
Reactant: CCCCCC(C)C(CC)c1cc(O)cc(O)c1
Product: CCCCCC(C)C(CC)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Condensation of 5-(1-ethyl-2-methylheptyl)resorcinol and 2-acetyl-5-methylcyclohexanone as described in Example 1 gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1c(OCCN(Cc2ccccc2)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1c(N)cccc1OCCN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a mixture of N-benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (520 mg, 1.30 mmol) and 10% palladium on carbon (120 mg ) in ethanol (40 mL) at 50° C. was added a solution of hydrazine hydrate (1.3 g) in ethanol (10 mL). The reaction was allowed to stir for 3 hr then the catalyst filtered through celite and the solvent removed. Purification by chromatography (30% ethyl acetate-hexane) afforded 380 mg (78.9%) of a clear oil; MS EI m/e 371 (M+); IR (film) 3400,3350,1680 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(Cl)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 2-chloro-4-methoxyphenylboronic acid (187 mg, 1.0 mmol) to afford after chromatographic purification the title compound (133 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 7.23 (d, 1H, J=8.8 Hz), 7.01 (s, 2H), 6.97 (s, 1H), 6.84 (dd, 1H, J=8.5, 2.6 Hz), 3.84–4.24 (m, 2H), 3.84 (s, 3H), 3.68–3.74 (m, 1H), 3.24–3.54 (m, 4H), 2.86–3.26 (m, 3H), 1.84–1.8 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 441 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[CH3:14][O:15][C:16]1[CH:39]=[CH:38][C:19]([CH2:20][C@H:21]([CH:35]([CH3:37])[CH3:36])[CH2:22][C@H:23]([NH:27][C:28](=[O:34])[O:29]C(C)(C)C)[C@@H:24]2[CH2:26]O2)=[CH:18][C:17]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45]>CS(C)=O>[CH3:14][O:15][C:16]1[CH:39]=[CH:38][C:19]([CH2:20][C@H:21]([CH:35]([CH3:37])[CH3:36])[CH2:22][C@H:23]2[C@H:24]([CH2:26][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]3=[O:7])[O:29][C:28](=[O:34])[NH:27]2)=[CH:18][C:17]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45]
Reactant: O=C1CCCCN1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCOc1cc(C[C@@H](C[C@@H]2NC(=O)O[C@H]2CN2CCCCC2=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.115 g of piperidin-2-one and 0.136 g of potassium tert-butoxide in 3 ml of dimethyl sulphoxide is stirred at room temperature over 30 minutes, admixed with 0.25 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (font size changed from Arial 10 to 11) (Example 1b) and subsequently stirred further at room temperature overnight. The reaction mixture is poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow oil. Rf=0.33 (95:5 dichloromethane-methanol); Rt=3.94 (gradient I).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][NH:26][CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1([CH2:42][C:43](O)=[O:44])[CH:41]=[N:40][CH:39]=[N:38]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:43](=[O:44])[CH2:42][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Reactant: O=C(O)Cn1cncn1
Product: CCC(CC)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1cncn1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methylvalerohydrazide and using 1,2,4-triazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methyl-2′-[2-(1H-1,2,4-triazol-1-yl)acetyl]valerohydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[CH3:11].CS[C:16]1[N:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:19][N:20]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:24][O:23][C:21]([N:17]1[CH2:18][CH2:19][NH:20][C:16]1=[N:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[NH:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11])=[O:22]
Reactant: COC(=O)N1CCN=C1SC
Reactant: Cc1c(N)cc(C#N)c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)N1CCNC1=Nc1cc(C#N)c2[nH]cnc2c1C
Temperature: 85 °C
Yield: 75 %

Procedure:
A mixture of 6-Amino-7-methyl-1H-benzimidazole-4-carbonitrile (10) (22.3 g, 0.13 mol), 4,5-dihydro-2-(methylthio)-1H-imidazole-1-carboxylic acid, methyl ester (29) (27.1 g, 0.155 mol) and glacial acetic acid (223 mL) is heated to about 85° C. for about 3 hours. The reaction mixture is allowed to cool to ambient temperature and is then concentrated in vacuo. At ambient temperature, water (223 mL) is then added to the oily residue obtained, and the pH of the resultant solution is adjusted to about 8.1 with 6N aqueous NaOH. The solids that formed are filtered, washed with water (75 mL), and dried to provide 2-(7-Cyano-4-methyl-1H-benzimidazol-5-yl-imino)-imidazolidine-1-carboxylic Acid Methyl Ester (30) (29.1 g, 75% Yield), as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:10]#[N:11])=[C:4]([Cl:18])[CH:3]=1.[NH4+].[OH-:20]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:10]([NH2:11])=[O:20])=[C:4]([Cl:18])[CH:3]=1
Reactant: N#CC(c1ccccn1)c1c(Cl)cc(N)cc1Cl
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C(c1ccccn1)c1c(Cl)cc(N)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of (±)-α-(4-amino-2,6-dichlorophenyl)-2-pyridineacetonitrile (0.324 mol) in H2SO4 90% (900 ml) was stirred at 90° C. for 2 hours, then poured out on ice and basified with a concentrated NH4OH solution. The precipitate was filtered off, washed with H2O and centrifuged. The residue was dried, yielding 86.0 g (90%) of (±)-α-(4-amino-2,6-dichlorophenyl)-2-pyridineacetamide (interm. 43).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[C:13]([C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([C:16]1[CH:17]=[C:18]([C:22]([NH:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cncc(C(=O)O)c1
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cncc(C(=O)Nc2ccc(F)cc2NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.082 g, 0.495 mmol) in dichloromethane were added the title compound from Step A (0.090 g, 0.545 mmol), HATU (0.207 g, 0.545 mmol), HOAt (0.074 g, 0.545 mmol), and diisopropylethylamine (0.35 mL, 1.98 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 314.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.33 (s, 1 H), 9.29 (s, 1 H), 8.72 (s, 1 H), 8.02 (br s, 1 H), 7.19-7.16 (m, 1 H), 6.91 (d, J=10.5 Hz, 1 H), 6.50-6.47 (m, 1 H), 4.64 (br s, 1 H), 2.69 (s, 3 H), 2.45-2.44 (m, 1 H), 0.78-0.77 (m, 2 H), 0.52-0.51 (m, 2 H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:37])[CH2:35][CH3:36]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and propionic acid (9.0 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43]([O:49][CH2:50][CH2:51]O)[CH2:44][O:45][CH2:46][CH2:47][OH:48]>>[ClH:1].[OH:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:49][CH2:50][CH2:51][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCOCCOCCO
Product: COc1cc(C(=O)OCCOCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,2′-(ethane-1,2-diylbis(oxy))diethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C37H41Cl2F2N3O7: [(M)+]748. found: 748.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:26][CH2:27][CH:28](O)[CH2:29][F:30]>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:28]([CH2:29][F:30])[CH2:27][F:26])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: OC(CF)CF
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC(CF)CF)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 1,3-difluoro-2-propanol in analogy to Example 9c): MS (ISN): 438.1 (M−H)−.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]([NH2:21])[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13].[S:22](Cl)(Cl)(=[O:24])=[O:23]>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]([NH:21][S:22]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:24])=[O:23])[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]1)=[O:13]
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2Cl)CC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Product: CC1CCN(C(=O)C(CCc2ccccc2Cl)NS(=O)(=O)c2ccccc2)CC1

Procedure:
Examples 6-38 are prepared from 4-(2-chlorophenyl)-1-(4-methylpiperidin-1-yl)-1-oxobutan-2-amine hydrochloride and the appropriate sulfonyl chloride in a manner similar to the synthesis of Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cccc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
2,6-dichloroaniline (360 g.) was dissolved in dimethylformamide (1.5 l.) and added to sodium hydride (obtained by washing sodium hydride in mineral oil (214 g; 50%) with petrol) suspended in dimethylformamide (4.1) at 10° C. When the addition was completed the temperature of the mixture was allowed to rise to the ambient temperature and then cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (600 g.) in dimethylformamide (1.5 l.) was slowly added, and the mixture stirred at the ambient temperature for 20 hours. The mixture was poured into salt/iced water (20.1) and the resultant mixture acidified with concentrated hydrochoric acid. The precipitate was collected by decanting off the supernatant liqui and recrystallised from methylated spirit to yield 2(2,6-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 97°-99° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Product: CS(=O)(=O)c1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-(methylsulfonyl)benzene. MS (+ESI) m/z: 451.1.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH2:10][N:5]12.C([N:19](CC)CC)C.ClC(OCC)=O.N>O.CC(C)=O>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH:12]([C:14]([NH2:19])=[O:16])[CH2:11][CH2:10][N:5]12
Reactant: O=C(O)C1CCn2c(cc3ccccc32)C1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)C1CCn2c(cc3ccccc32)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A stirred suspension of 27 g (126 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid in 30 ml of water and 450 ml of acetone was cooled to 0° C. and treated in succession with 14.7 g (145 mmol) of triethylamine and 17.3 g (159 mmol) of ethyl chloroformate. After 0.5 hour, 6.3 ml of 0.880 ammonia was added and stirring was continued for 1 hour. The solvent was removed under reduced pressure and the residue was triturated with aqueous ethanol. The product was filtered off and dried to give 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide, as a white solid of melting point 165°-168° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.[Mg].BrCCBr.[CH2:17]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25])[CH:18]([CH3:20])[CH3:19].Cl>O1CCCC1.II.C(OCC)(=O)C>[CH2:17]([C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]=2)[OH:25])[CH:26]=[CH:27][CH:28]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cccc(C=O)c1
Reactant: CC(C)Cc1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)Cc1cccc(C(O)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A mixture of 1-bromo-3-isobutylbenzene (3.16 g), magnesium (1.08 g), 1,2-dibromoethane (2.78 g) and iodine (10 mg) in tetrahydrofuran (10 ml) was refluxed for 1.5 hours. The mixture was cooled to 25° C., and a solution of 3-isobutylbenzaldehyde (2.40 g) in tetrahydrofuran (10 ml) was added at 25° C. After stirred for 1 hour at the same temperature, the mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (200 g) eluting with 5% ethyl acetate in hexane to give bis(3-isobutylphenyl)methanol (2.90 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)CC4C=CC(OC)=CC=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([O:38][CH2:39][C:40]#[N:41])[CH:3]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:32]4[CH:36]=[CH:35][O:34][N:33]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([O:38][CH2:39][C:40]#[N:41])[CH:3]=1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3OCC#N)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 2.5 h
Yield: 12.1 %

Procedure:
To a solution of 1-(4-bromo-2-(cyanomethoxy)-5-fluorophenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (53.1 mg, 0.083 mmol) in DCM (830 μl) at RT was added trifluoromethanesulfonic acid (22.11 μl, 0.249 mmol). The resulting solution was stirred for 2.5 hours and LCMS indicated that the reaction had not proceeded. Additional 0.010 mL was then added and the resulting mixture stirred for 16 hr. The reaction mixture was concentrated by sending a stream of N2 gas into the uncapped reaction vial. The residue was then dissolved in 1 ml of DMSO and 0.050 mL of saturated NaHCO3 was added and the resulting mixture was stirred for 5 minutes. The solution was then passed through a 0.20 micron filter. An additional 0.5 ml was used to sinse the reaction vial and the solution was passed through the same filter. The DMSO solution was purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 5 to 30% MeCN in water (containing 0.1% ammonium hydroxide as an additive), flow rate 40 mL/min to yield 1-(4-bromo-2-(cyanomethoxy)-5-fluorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5.2 mgs, 12% yield). 1H NMR (500 MHz, DMSO-d6) □=ppm 5.13-5.22 (m, 2 H) 6.22 (s, 1 H) 6.73 (dd, J=9.21, 4.41 Hz, 2 H) 7.70 (d, J=8.56 Hz, 1H) 7.75 (dd, J=8.92, 1.85 Hz, 1 H) 7.89 (d, J=6.10 Hz, 1 H) 8.18 (d, J=9.27 Hz, 1 H) 8.20-8.23 (m, 1 H) 8.37 (s, 1 H). m/z (ESI) 518.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:24][OH:25]>C(O)C.C(#N)C>[CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][N:5]([C:10]2[CH:17]=[CH:16][C:13]([C:14]([NH:24][OH:25])=[NH:15])=[CH:12][CH:11]=2)[CH2:4]1
Reactant: N#Cc1ccc(F)cc1
Reactant: NO
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CN(C)C1CCN(c2ccc(C(=N)NO)cc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(dimethylamino)pyrrolidine (1.1 g), p-fluorobenzonitrile (1.2 g), potassium carbonate (2.8 g) and acetonitrile (15 ml) was stirred at 80° C. for 12 h. The reaction solution was then filtered, and the precipitate was washed with acetonitrile, the solvent was removed in vacuo, and the residue was taken up again in ethyl acetate. The ethyl acetate phase was washed twice with water and then dried over sodium sulfate, and the solvent was removed in vacuo. The product obtained in this way was dissolved in abs. ethanol (48.7 ml), and hydroxylamine (1.4 ml) was added to the solution. The reaction mixture was heated under reflux for 12 h. The precipitate obtained after cooling the reaction solution was filtered off and washed with a little ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16]C=1OC)[CH:6]=[CH:5]2.[C:22]([NH2:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-:32].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:16][C:17]1[O:32][C:14]([CH2:13][NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:30][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:3]=3)[N:8]=2)=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Reactant: O=C([O-])[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(CNc2ccc3cc(NC(=O)c4ccccc4)ccc3n2)o1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(6-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (prepared from 6-bromo-2-chloroquinoline and 5-methyl-2-furanmethanamine as described in example 43, step A, 200 mg, 0.631 mmol) was dissolved in 5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. Benzamide (107 mg, 0.884 mmol), cesium carbonate (308 mg, 0.948 mmol) bis(dibenzylideneacetone)palladium (29 mg, 0.032 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55 mg, 0.095 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->60:40 gradient). The title compound was obtained as a white solid (110 mg, 49%), MS: m/e=358.3 (M+H+).