Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>[OH-].[Na+].O1CCCC1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:2]3[C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
44.2 g (250 mmol) of 1,2,3,4-tetrahydroisoquinoline-3-(R)-carboxylic acid were dissolved in 500 ml of 1N aqueous sodium hydroxide solution and, while stirring, 150 g (300 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride dissolved in 500 ml of tetrahydrofuran were added. During this, the reaction temperature was kept below 25° C., and the pH of the solution was adjusted to pH 10 by adding 1N NaOH. The reaction mixture was stirred at room temperature for 12 hours (h).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26].CC1CCNCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: CC1CCN(c2cc(F)cc(C(=O)O)c2)CC1
Agent: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.60 g, 2.2 mmol) in DMF (2 ml) is added 3-fluoro-5-(4-methylpiperidin-1-yl)benzoic acid (0.63 g, 2.64 mmol), prepared from 4-methylpiperidine according to conditions described in general procedure E, HBTU (1.25 g, 3.3 mmol) and diisopropylamine (1.15 ml, 6.6 mmol). This mixture is stirred at room temperature overnight and diluted with CH2Cl2 (5 ml), washed with 0.05 N NaOH, dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel (90% EtOAc in hexane) to give 3-fluoro-5-(4-methylpiperidin-1-yl)-N-[4-(2-morpholin-4-ylethoxy)-1-naphthyl]benzamide as a white solid (0.53 g). Mp: 116-118° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (d, 6.3 Hz, 3H), 1.15-1.25 (m, 2H), 1.67 (d, J=12 Hz, 2H), 2.55 (bs, 4H), 2.74 (t, J=12.3 Hz, 2H), 2.86 (s, 2H), 3.59 (t, J=4.5 Hz, 4H), 3.82 (d, J=12.9 Hz, 2H), 4.29 (t, J=5.7 Hz, 2H), 6.93 (d, J=12.6 Hz, 1H), 7.00 (d, J=8.1Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.51-7.55 (m, 2H), 7.81-7.84 (m, 1H), 8.17-8.20 (m, 1H), 10.21 (s, 1H); MS 492 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:41])OC4C=CC=CC=4)[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9].C(C(NC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O)CC)C>CN(C)C=O>[CH2:11]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:41])[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:8][CH3:9])[CH3:12]
Reactant: OC1CCNCC1
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Agent: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(O)CC4)c3)ccc21
Reaction time: 2 h
Yield: 29.6 %

Procedure:
N,N-Dimethylformamide (4 ml) and 4-hydroxypiperidine (360 mg, 3.56 mmol) were added to a mixture (456 mg) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 96; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (1.37 mg, 0.294 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[NH:36][C:35](=[O:37])[NH:34][C:33]2=[O:38])[CH2:28][CH2:27]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:26]3[CH2:27][CH2:28][CH:29]([CH:32]4[NH:36][C:35](=[O:37])[NH:34][C:33]4=[O:38])[CH2:30][CH2:31]3)=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C1NC(=O)C(C2CCNCC2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(C2CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in DMF (2.0 mL) was added 5-(piperidin-4-yl)imidazolidine-2,4-dione (37 mg, 0.2 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 2 h, the solvent was removed under reduced pressure and the crude product was purified by Prep HPLC to give 5-(1-(2-((S)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)piperidin-4-yl)imidazolidine-2,4-dione (30 mg) in 42% yield. 1H NMR (500 MHz, CD3OD): in δ 8.27 (s, 1H), 7.21 (s, 1H), 5.54 (d, J=17 Hz, 1H), 4.82 (d, J=17 Hz, 1H), 4.69-4.54 (m, 2H), 4.18-3.95 (m, 4H), 3.30-2.96 (m, 4H), 2.71-2.62 (m, 1H), 2.58-2.48 (m, 1H), 2.21-2.12 (m, 1H), 1.91-1.84 (m, 2H), 1.66-1.31 (m, 2H); MS (ESI) 541 (M+H); Rf=2.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][CH:61]=1)[O:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][O:55][C:54]2[CH:59]=[CH:60][CH:61]=[C:52]([F:51])[CH:53]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCOc1cccc(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCOc4cccc(F)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 71.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (97 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(3-fluorophenoxy)-1-ethanol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 67%).
Reaction SMILES: [Br:1]C1OCC=C1.[CH3:7][C:8]1[CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:13])[O:11][CH:12]=1.[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[Br-:1].[CH3:7][C:8]1[CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:13])[O:11][C:12]=1[P+:26]([C:27]1[CH2:32][CH:31]=[CH:30][CH2:29][CH:28]=1)([C:33]1[CH2:34][CH:35]=[CH:36][CH2:37][CH:38]=1)[C:20]1[CH2:25][CH:24]=[CH:23][CH2:22][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1=COC(=O)C1c1ccccc1
Reactant: BrC1C=CCO1
Solvent: c1ccccc1
Product: CC1=C([P+](C2=CCC=CC2)(C2=CCC=CC2)C2=CCC=CC2)OC(=O)C1c1ccccc1
Product: [Br-]
Yield: 109.8 %

Procedure:
5-Bromo-2,5-dihydrofuran-4-methyl-2-oxo-3-phenylfuran (3.46 g) and triphenylphosphine (4.14 g) in benzene (50 mls), were heated under reflux overnight. The colourless salt was filtered off, washed with benzene, then ether (2 portions), and dried to give the title compound as a white solid, (6.13 g, 85%), m.p. 214°-217° C. (decomp), acetonitrile/ethyl acetate. (Found: C, 67.21; H, 4.61; Br, 15.65%. C29H24BrO2P requires C, 67.58; H, 4.69; Br, 15.51%); νmax (CH2Cl2) 1775(s)cm-1 ; δH (CDCl3) 2.14 (3H,d,J4Hz), 7.1-8.5 (20H,m) and 9.75 (1H,d,J7Hz); [mass spectrum: +ve ion (thioglycerol) MH+, 435].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH2:15]([O:17][C:18](=[O:40])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:36]=[C:35]3[C:31]([CH2:32][CH2:33][NH:34]3)=[C:30]([O:37][CH3:38])[CH:29]=2)=[O:27])=[CH:21][C:20]=1[F:39])[CH3:16].N1C=CC=CC=1>ClCCl>[CH2:15]([O:17][C:18](=[O:40])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:36]=[C:35]3[C:31]([CH2:32][CH2:33][N:34]3[S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=3)(=[O:11])=[O:10])=[C:30]([O:37][CH3:38])[CH:29]=2)=[O:27])=[CH:21][C:20]=1[F:39])[CH3:16]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-Trifluoromethylbenzenesulphonyl chloride (45.1 mg, 0.18 mmol, 1.1 equiv.) was added to a mixture of crude 2-fluoro-4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester (60 mg, 0.24 mmol, 1 equiv.) and pyridine (0.11 mL, 1.34 mmol, 8 equiv.) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by preparative HPLC to afford 2-fluoro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, 14.4 mg (33% yield). LC @215 nm; Rt 1.73: 100%, m/z (ES+): 567 (M+H+.).
Reaction SMILES: Br[CH:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[CH3:11][C:7]1[N:6]=[C:5]([C:3]2[N:22]=[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]3[C:2]=2[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Reactant: Nc1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nc3ccccn3c2-c2ccc3ncccc3c2)n1
Temperature: 80 °C
Yield: 24.8 %

Procedure:
A solution of 2-bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone of Step D (60 mg, 0.176 mmol)in dimethylformamide (1 mL) was treated with 2-aminopyridine (50 mg, 0.53 mmol, 3 equiv), and heated to 80° C. over 4.5 hours. After cooling down, the mixture was treated with water and extracted with ethyl acetate. The organics were concentrated in vacuo and reverse phase column chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided the title compound (14.7 mg, 25%). HPLC tR=1.71 min, LCMS 337.3 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][N:11]=[N:12][C:8]=2[CH:7]=1>S(=O)(=O)(O)O>[N+:1]([C:7]1[C:8]2[N:12]=[N:11][NH:10][C:9]=2[CH:13]=[CH:14][C:6]=1[CH3:5])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Product: Cc1ccc2[nH]nnc2c1[N+](=O)[O-]
Yield: 94 %

Procedure:
Nitric acid (40 ml, excess) was added drop wise over 20 minutes to a stirred solution of 5-methyl-1H-benzotriazole (2.66 g, 20 mmol) in conc. sulphuric acid (40 ml) at 0° C. Stirring was continued at room temperature for 90 minutes by which time TLC (A) indicated complete reaction. The solution was poured onto ice to precipitate a flocculent white solid. The solid was collected by filtration and washed with water to afford [23] in 94% yield. Rf (A) 0.60 δH(400 MHz; DMSO-d6) 2.79 (3H, s, CH3) 7.52 (1H, d, J8.4, BT) 8.36 (1H, br s, BT) 16.26 (1H, s, NH); m/z (EI−HR) 178.04937 [(M) calc. for C7H6N4O2 178.04908].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(O)(=O)C.CCOCC>C(O)C.Cl.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(N)ccc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Chloro-5-nitroanisol (10 g, 0.053 mol), iron powder (15 g, 0.26 mol) and glacial acetic acid (20 ml, 0.355 mol) were combined in 125 ml ethanol. Concentrated HCl (2 drops) was added and the mixture refluxed 2 hours. Additional iron powder (5 g) and concentrated HCl (1 drop) were added and reflux continued for an additional 16 hours. The reaction mixture was cooled, poured into equal volumes each of ice/water and ether, filtered and the layers separated. The aqueous layer was extracted with fresh ether and the combined ether layers extracted with 1N HCl. The original aqueous and 1N HCl extract were combined, the pH adjusted to 6 with saturated Na2CO3 and extracted with fresh ether. The last ether extract was dried over MgSO4 and stripped to yield title product, 82 g, m.p. 77°-79° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[F:31][C:32]([F:44])([F:43])[CH:33]([CH3:42])[O:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:41]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH:33]([CH3:42])[C:32]([F:31])([F:43])[F:44])=[CH:36][CH:37]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:27])=[O:26]
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1)C(F)(F)F

Procedure:
Brown solid. MS (ESI): 567.13 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and (4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[C:16]([C:17]4[C:22]=2[C:21]=1[CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:14]=[C:13]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)[CH:12]=3)=[O:6].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].[I-].[K+]>O1CCCC1>[ClH:1].[ClH:1].[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[C:16]([C:17]4[C:22]=2[C:21]=1[CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:14]=[C:13]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:12]=3)=[O:6])[CH3:30]
Reactant: CCNCC
Reactant: O=C(CCCCl)c1ccc2c(c1)-c1ccc(C(=O)CCCCl)c3cccc-2c13
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCC(=O)c1ccc2c(c1)-c1ccc(C(=O)CCCN(CC)CC)c3cccc-2c13
Product: Cl
Reaction time: 72 h

Procedure:
A solution of 15.0 g (0.037 mole) of 3,9-bis(4-chlorobutyryl)fluoranthene, 100 ml of diethylamine, 2.0 g of potassium iodide and 100 ml of tetrahydrofuran (THF) is heated at reflux with stirring for 3 days and filtered. The filtrate is poured onto ice water and the oil which separates is decanted and dissolved in ether. The ether solution is washed with a water-saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is acidified with ethereal HCl, and the resulting precipitate is recrystallized twice from methanol-butanone to yield 3,9-bis(4-diethylaminobutyryl)fluoranthene dihydrochloride. M.P. 236°-239°C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])/[CH:25]=[CH:26]\[CH2:27]O)[CH2:21][CH2:22][CH3:23].C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:27]/[CH:26]=[CH:25]\[Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Reaction time: 2.5 h
Yield: 160.6 %

Procedure:
A solution of triphenylphosphine (5.32 g) in DCM (60 mL) was added to a solution of (Z)-3-tributylstannanylprop-2-en-1-ol (Intermediate 13, 6.4 g) and carbon tetrabromide (9.18 g) in DCM (60 mL) and the mixture was stirred for 2.5 hours. The mixture was evaporated to low volume and pentane was added. The solids were removed by filtration and the filtrate was evaporated to dryness. Pentane was added and the solids were again removed by filtration and the filtrate was evaporated to dryness to give ((Z)-3-bromoprop-1-enyl)-tributylstannane (12.14 g) as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[Li+].CC([N-]C(C)C)C.CN(C1C=CC=CC=1)[CH:31]=[O:32]>O1CCCC1.C(OC)(C)(C)C>[Br:13][C:14]1([CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH2:15]1)[CH:31]=[O:32]
Reactant: Fc1cccc(Br)c1
Reactant: CN(C=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=CC1(Br)C=CC=C(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a solution of diisopropylamine (2.27 mol, 320 mL) in anhydrous tetrahydrofuran (800 mL) in a 5 L flask at 0° C. add 1.6 M butyllithium (1.16 L, 1.86 mol) in hexanes dropwise over 1.5 h. Stir the resulting yellow solution at 0° C. for 30 min. In a separate 12 L flask dissolve 1-bromo-3-fluorobenzene (203 mL, 1.86 mol) in anhydrous tetrahydrofuran (650 mL) and cool to −78° C. Transfer the preformed LDA solution to an addition funnel via cannula and add dropwise to the 1-bromo-3-fluorobenzene solution over 2 h so the temperature does not rise above −70° C. Stir the resulting slurry at −78° C. for 30 min. Add a solution of N-methyl-N-phenyl formamide (230 mL, 1.86 moles, 1.00 equiv.) in anhydrous tetrahydrofuran (1.15 L) dropwise at −78° C. over one hour while maintaining the temperature below −70° C. Stir the reaction cold for 2 h while slowly allowing it to rise to room temperature overnight. Dilute the reaction with methyl tert-butyl ether (3 L), quench with 1M hydrochloric acid (4 L) and stir vigorously for 3 h. Separate the layers and extract the aqueous layer with methyl tert-butyl ether (1 L). Wash the combined organic phases with 1M hydrochloric acid (2×1 L), water (1 L), brine (1 L), dry over magnesium sulfate, filter and concentrate to an orange oil that slowly solidifies to obtain the title compound (394 g, 105%). 1H NMR (CDCl3) δ 10.37 (s, 1H), 7.50 (d, 1H), 7.44 (m, 1H), 7.17 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH:25]([CH3:27])[CH3:26]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH:25]([CH3:26])[CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as example 101 from 6-Bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-6-methyl-4-(1-methylethyl)2(1H)-pyridinone. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.69 (d, J=1.26 Hz, 1H) 6.02 (s, 1H) 5.05 (quin, J=6.57 Hz, 1H) 4.41 (d, J=4.80 Hz, 2H) 3.21 (quin, J=6.76 Hz, 1H) 2.16 (s, 3H) 1.47 (s, 3H) 1.45 (s, 3H) 1.11 (s, 3H) 1.09 (s, 3H); MS (ES) [M+H]+ 445.1, 446.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(O)(=O)C>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:22][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Reaction time: 0.33 h

Procedure:
A stirred solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (3.0 mmol) in glacial acetic acid (5.0 ml) was heated to 70° C., then succinic anhydride (4.0 mmol) was added. The temperature was held at 100° C. for 20 min after which the reaction mixture was concentrated in vacuo to afford a light brown syrupy, which crystallised on standing. Trituration with a mixture of Et2O/CH2Cl2 3:1 followed by filtration and washing yielded the product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[C:11](=O)([O-])[O-].[K+].[K+].[I-].[K+].CCO[C:22]([CH3:24])=O>CC(C)=O>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])[CH:22]=[CH2:24]
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1Br
Temperature: 25 °C

Procedure:
Mix 3-bromo-4-hydroxy-benzonitrile (1.520 g, 8.0 mmol), alkyl bromide (1.161 g, 9.6 mmol), potassium carbonate (3.317 g, 24 mmol) and potassium iodide (133 mg, 0.1 mmol) in acetone (80 mL). Heat the mixture to reflux for 12 h. Cool to ambient temperature, add EtOAc, wash the organic layer with water, and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to obtain the desired intermediate.