Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]([N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:30]=1)[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)CN=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N=Cc1ccccc1
Reaction time: 24 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide (11.34 g, 54 mmol) in THF (100 ml) was added dropwise to a mixture of (benzylidene-amino)-acetic acid methyl ester (3.83 g, 21.63 mmol) and 4-chloromethyl-1-trityl-1H-imidazole (21.6 g, 60.18 mmol) in THF (200 ml) at −78° C. The resultant solution was warmed to ambient temperature and stirred for 24 hours. After removal of THF, the reaction mixture was subsequently partitioned between ethyl acetate and brine. The aqueous layer was washed two times with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, filtered and concentrated to give the crude title compound of 53A.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][CH:18]([NH2:27])[C:17]1=[O:28])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:29]([CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CO>[CH2:5]([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][CH:18]([NH:27][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:17]1=[O:28])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium cyanoborohydride (0.152 g, 0.0014 mol) was added to a solution of 1-benzyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.45 g, 0.0014 mol) and benzylpyruvic acid (0.48 g, 0.0028 mol) in methanol (35 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. Additional benzylpyruvic acid (0.48 g, 0.0028 mol) was added, and the reaction mixture stirred for an additional 18 hours. Concentrated hydrochloric acid (0.5 ml) was added and the resulting solution stirred for 1 hour. The solvents were removed under reduced pressure and the residue treated with dichloromethane (100 ml) to precipitate sodium chloride. After filtration, the solvent was removed under reduced pressure and the residue chromatographed on silica gel (30 g). Elution with ethyl acetate/methanol/acetic acid (90:10:0.2) gave 1-benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as an oil; NMR(CDCl3) 7.35(m,14H), 5.10(s, 2H), 4.60(m,2H), 3.00(m, 12H).
Reaction SMILES: [CH2:1]([N:4]([C@H:14]1[CH2:19][CH2:18][C@H:17](C2C=CC(CNC)=CC=2)[CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3].Br[CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CO>[CH2:1]([N:4]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:7]2[CH:8]=[CH:9][C:10]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:11][C:6]=2[CH2:5][NH:4][CH3:1])[CH2:18][CH2:19]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CNC)cc2)CC1
Reactant: OCCCBr
Solvent: CO
Solvent: ClCCl
Product: C=CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-N-allyl-N-(4-chlorobenzoyl)-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Oil. Rf value: 0.56 (alumina, methylene chloride/methanol=50:1, v:v).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1ccc(Cl)c(Cl)c1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (5.0 mg) with purity >90%: MS (pos) m/z 459.2, 461.2, 463.2.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C>ClC(Cl)C.C(O)(C(F)(F)F)=O>[CH3:9][CH:8]([CH3:10])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])[C:6]([OH:38])=[O:5]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc4ccccc4n3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc4ccccc4n3)cc2)cc1)C(=O)O
Yield: 58 %

Procedure:
Step 14B [9058-121-2]: 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester (164 mg) was dissolved in dichloroethane (12 mL) and hydrolyzed with TFA (4 mL) at room temperature over a period of 4 hrs. Solvent was removed and crude was purified by column chromatography (Eluent 10% MeOH/DCE) to afford 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid in 58% yield (84.8 mg).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][CH2:13][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:4]1[CH2:5]3.[ClH:24].Cl.[CH:26]1[CH:35]=[CH:34][C:33]2CCCN3[C:32]=2[C:27]=1[C@H]1CNC[C@H]1C3>>[ClH:24].[ClH:24].[C:26]1([C:10]2[CH:1]=[C:2]3[C:7]4=[C:8]([CH2:11][CH2:12][CH2:13][N:6]4[CH2:5][C@@H:4]4[CH2:14][NH:15][CH2:16][C@H:3]34)[CH:9]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Agent: Cl
Product: c1ccc(-c2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)cc1

Procedure:
Following the procedure described in EXAMPLE 7, Part A, (±)-cis-tert-butyl 5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate, an intermediate from EXAMPLE 11, was converted into the title compound as an oil. 1H NMR (CDCl3): δ 6.90 (s, 2H), 3.90-3.77 (m, 1H), 3.61-3.52 (m, 1H), 3.35-3.25 (m, 2H), 3.20-3.12 (m, 2H), 3.08-2.95 (m, 2H), 2.85-2.68 (m, 3H), 2.57-2.47 (m, 1H), 1.98-1.88 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[Br:18][C:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(N2CCOCC2)oc2ccccc12
Solvent: ClCCl
Product: O=c1c(Br)c(N2CCOCC2)oc2ccccc12
Yield: 91.5 %

Procedure:
2-(4-morpholinyl)-4H-benzopyran-4-one (2.0 g, 8.0 mmol) is dissolved in CH2Cl2 (20 mL). N-Bromosuccinimide (1.6 g, 8.2 mmol) is added and the reaction mixture waned slightly and the starting material disappears immediately as evidenced by TLC. The solvent is removed in vacuo and the colorless residue is taken up in EtOAc (200 mL) and washed with water (4×30 mL), brine (50 mL) and dried (MgSO4). Rotary evaporation gives the desired product (2.27 g, 92%) as colorless crystals. mp: 145°-6° c ; IR (mull) 3337, 3016, 2922, 2871, 2855, 1698, 1609, 1585, 1502, 1462, 1378, 1367, 1341, 1303, 1295, 1260, 1234, 996, 812 cm-1 ; 1H NMR (CDCl3, δ) 8.22 (dd, J=7.9, 1.8 Hz, 1H), 7.63 (ddd, J=8.2, 7.4, 1.4 Hz, 1H), 7.44-7.28 (m, 2H), 3.90-3.84 (m, 4H), 3.76-3.69 (m, 4H); LRMS m/e (rel intensity) 311 (55), 309 (55), 253 (14), 231 (17), 230 (100), 172 (21), 121 (20), 120 (15), 110 (61), 41 (16); UV (EtOH) λ max (ε) 216 (18,400), 238 (18,600), 317 (17,040); High resolution MS calc'd. for C13H12 NO3Br: 309.0001. Found: 308.9990. Anal. calc'd. for C13 H12NO3Br: C, 50.34; H, 3.90; N,4.52. Found: C, 50.40; H,4.05; N, 4.46.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:26]([NH2:31])=[N:27][NH:28][C:29]=1[CH3:30]>Cl.CCO>[ClH:23].[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][CH:12]=[C:11]2[NH:31][C:26]1[NH:27][N:28]=[C:29]([CH3:30])[C:25]=1[CH3:24])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1[nH]nc(N)c1C
Reactant: COCCOc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: COCCOc1cc2nccc(Nc3[nH]nc(C)c3C)c2cc1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Yield: 48 %

Procedure:
6-(tert-Butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline (0.461 g, 1.288 mmol), 4,5-dimethyl-1H-pyrazol-3-amine (0.175 g, 1.546 mmol), and 2 drops of aq HCl (0.161 ml, 0.322 mmol) in EtOH (3.06 ml) were heated at 80° C. overnight. The reaction was cooled to rt and the precipitate was filtered, washed with MeCN, and vacuum-dried to yield 6-(tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(2-methoxyethoxy)quinolin-4-amine, hydrochloride (0.290 g, 0.618 mmol, 48.0% yield). m.p. 181-184° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (s, 1H), 11.20 (br. s., 1H), 9.22 (br. s., 1H), 8.48 (d, J=7.07 Hz, 1H), 7.63 (s, 1H), 6.64 (d, J=7.07 Hz, 1H), 4.36 (t, J=4.29 Hz, 2H), 3.78 (t, J=4.29 Hz, 2H), 3.35 (s, 3H), 2.24 (s, 3H), 1.84 (s, 3H), 1.35 (s, 9H). MS: m/z: 433.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.C1OCCOCCOCCOCCOC1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.O>[CH3:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1
Reactant: CSc1ccccc1-c1cc(C=O)c[nH]1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (3 mL) were added a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (5 mL), 15-crown-5 (182 mg) and pyridin-3-ylsulfonyl chloride (135 mg) under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as colorless crystals (yield 170 mg, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[O:30]>CC(C)=O>[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:34])=[O:30]
Reactant: COC(=O)CCC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CCC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.1 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g; 0.011 mole). Then methoxycarbonylpropionyl chloride (1.66 g; 0.011 mole) was added, dropwise, during 5 minutes at -10°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[N:6]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(N)cccc2n1

Procedure:
400 mg (1.7 mmol) of 2-acetylamino-5-nitroquinoline and 105 mg of 10% Pd—C are stirred in 20 ml of ethyl acetate-MeOH (3:1) for 4 hours in a hydrogen atmosphere at room temperature. The batch is filtered, concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 210 mg of product.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[CH2:10][CH2:11][CH2:12][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2c(c1O)CCC2
Product: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Yield: 52 %

Procedure:
A solution of 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol (1.424 g, 7.904 mmol) in POCl3 (11.0 mL) was heated at 110° C. in a sealed flask under N2 for 2 h. The crude mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 50% NaOH to pH 7. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the crude sub-title compound as a brown solid (0.82 g, 52%), which was used without further purification. LCMS calc. for C8H8N2O2 (M+H)+: m/z=199.0. Found: 199.2.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:5]=1[C:6]([CH:8](C(=O)C)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.O>C(O)C>[N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:5]=1[C:6](=[O:7])[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: CC(=O)C(C(=O)c1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=C(CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1ccccc1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of 2-(2-nitro-4-trifluoromethylbenzoyl)-1-phenylbutan-1,3-dione (28.5 g) in ethanol (300 ml) was added to a mixture of concentrated sulphuric acid (225 ml) and ethanol (225 ml). The resultant solution was stirred and heated at 100° C. for 1 hour. The cooled solution was poured onto a mixture of ice and water (2 l) and extracted with dichloromethane (3×250 ml). The combined organic layers were washed with water (2×100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from petroleum spirit (bp 60°-80° C.) to give 1-(2-nitro-4-trifluoromethylphenyl)-3-phenylpropan-1,3-dione (19.6 g) as an off-white solid mp 101°-103° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][NH2:33].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:32][NH2:33])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NN
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (240 mg, 1.13 mmol) and 4-methylmorpholine (131 μL, 1.19 mmol) in THF (3 mL) was added isobutyl chloroformate (147 μL, 1.13 mmol). After 1 h the reaction mixture was added through a syringe filter to a stirring solution of hydrazine (1.24 mL, 1.24 mmol, 1 M in THF) in THF (1 mL). After stirring a further 30 min at room temperature, the reaction mixture was poured into NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (MeOH/DCM) to give 152 mg (59%) of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 as a white solid. LCMS-ESI (m/z) calculated for C14H14N2O: 226; found 227 [M+H]+, tR=1.62 min (Method 10).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:8]([CH2:9][CH2:10][CH:11]=[CH:12][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: C=CCCC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)CCC=Cc1cccnc1

Procedure:
A solution of 3-bromopyridine (7.9 g), methyl 4-pentenoate (7.15 g), palladium acetate (0.11 g) and tri-o-tolylphosphine (0.6 g) in 50 ml of triethylamine is refluxed for 24 hours under argon and the solvent evaporated. The residue is taken up in methylene chloride (50 ml) and washed with water (2×40 ml). The organic phase is dried and evaporated to yield 3-(4-methoxycarbonylbut-1-enyl)pyridine as a colorless liquid; NMR (CDCl3) 3.72 (s, 3 H), 6.40 (s, 1 H); IR (film) 1725 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH2:43][CH3:44])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:43]([O:42][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:2]2[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[C:39]2[C:35]=1[CH2:36][N:37]([CH3:41])[C:38]2=[O:40])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOc1ccc(N)c2c1CN(C)C2=O
Product: CCOc1ccc(Nc2nc(Nc3ccc(CP(=O)(OCC)OCC)cc3OC)ncc2C(F)(F)F)c2c1CN(C)C2=O

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-4-ethoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 206A). MS (ES+): m/z 624.28 (100) [MH+]; HPLC: tR=1.16 min (UPLC, purity).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to a solution of 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one (5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h at r.t. Water (1.41 mL, 78.3 mmol) was added, and the mixture heated at 40° C. overnight. Solvent was removed under vacuum, and the oily residue purified by column chromatography (eluent: DCM, then 10% MeOH in DCM). Yield 3.56 g (75%). MS (m/z): [M+H]+=485.
Reaction SMILES: Cl.CN.[B-](F)(F)(F)F.CCOC([C:14](C#N)=[N:15]OC(N(C)C)=[N+](C)C)=O.CCN(C(C)C)C(C)C.[CH3:35][O:36][C:37]1[C:38]([CH3:62])=[C:39]([C:46]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[NH:54][CH:53]=[C:52]([C:58]([OH:60])=O)[C:51]3=[O:61])=[O:47])[N:40]2[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]2.Cl>CN(C=O)C>[CH3:35][O:36][C:37]1[C:38]([CH3:62])=[C:39]([C:46]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[NH:54][CH:53]=[C:52]([C:58]([NH:15][CH3:14])=[O:60])[C:51]3=[O:61])=[O:47])[N:40]2[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]2
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: COc1c(C)c(C(=O)c2ccc3[nH]cc(C(=O)O)c(=O)c3c2)n2ccccc12
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
0.36 g (5.31 mmol) of methylamine hydrochloride, 1.3 g (3.99 mmol) of TOTU and 1.37 g (10.63 mmol) of DIEA are added to 1 g (2.66 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 23 ml of anhydrous DMF. The reaction medium is stirred at ambient temperature under a nitrogen atmosphere for 8 h. 0.36 g (5.33 mmol) of methylamine hydrochloride is added to the reaction medium. After 18 h at ambient temperature, the reaction medium is hydrolysed with a 1N solution of HCl and then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 0.06 g of a yellow solid is obtained.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:23][C:24](Cl)=[O:25]>C(Cl)Cl>[C:24]([C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=[CH:2][CH:3]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cccc2c3ccccc3c3ccccc3c12
Reaction time: 3 h
Yield: 97 %

Procedure:
Triphenylene (1 equivalent) is reacted at 0° C. with 2.1 equivalents of AlCl3 and 21.0 equivalents of CH3COCl in CH2Cl2. After stirring at room temp. for 3 hours, the reaction product (acetyltriphenylene) was obtained in 97% yield, and is used in step b).