Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]3[N:43]=[C:42]([S:44][C:45]4[CH:46]=[C:47](CO)[CH:48]=[CH:49][CH:50]=4)[CH:41]=[CH:40][N:39]=3)=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>ClCCl>[Br:5][CH2:2][C:49]1[CH:50]=[C:45]([S:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH2:27][CH2:26][O:25][CH2:30][CH2:29]4)=[CH:36][CH:35]=3)[N:43]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a stirred mixture of tetrabromomethane (370 mg, 1.12 mmol) and triphenylphosphine (293 mg, 1.12 mmol) in dichloromethane (10 mL), was added (3-(2-(4-morpholinophenylamino)pyrimidin-4-ylthio)phenyl)methanol (400 mg, 1.01 mmol) portionwise. After being stirred at room temperature for 1 hour, another batch of tetrabromomethane (370 mg, 1.12 mmol) and triphenylphosphine (293 mg, 1.12 mmol) was added to the mixture and the whole was stirred at room temperature for 1 hour. All of the volatiles were removed in vacuo, and the residue was flash chromatographed on silica gel using ethyl acetate:dichloromethane (0:100→10:90) as eluant to give the product (208 mg, 45%).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:36]2[CH:37]=[N:32][CH:33]=[N:34][CH:35]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless foam. MS: 501.1 (MH+).
Reaction SMILES: Cl.O1CCO[CH:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[O:13][CH:12]([CH3:19])[CH2:11]2.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[CH3:19][CH:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][CH2:3][N:30]3[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]3)[CH:9]=2)[C:14](=[O:18])[O:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A 1:1 solution of dioxane:3N HCl was added to a flask containing of 780 mg (3.2 mmol) of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. The reaction was then stirred at room temp overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. The crude aldehyde was redissolved in DCM. To the solution was added boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.9 g, 9.0 mmol). the reaction mixture was allowed to stir overnight before being quenched with 10 mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford 850 mg of tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate as a golden oil. 1H NMR (500 MHz; CDCl3): 8.02 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.09 (s, 1H), 4.68 (m, 1H), 3.49 (m, 4H), 2.94 (m, 4H), 2.88 (m, 2H), 2.51 (m, 4H), 1.54 (d, J=6.8 Hz, 3H), 1.48 (s, 9H). LC-MS (IE, m/z): 375 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10](=O)[CH:11]([CH3:13])[CH3:12].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ncc(Br)cn1
Reactant: CC(C)C=O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1nnc2ncc(Br)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 5-bromo-2-hydrazinopyrimidine (2.65 mmole) in dichloromethane (40 mL). To this solution was added isobutyraldehyde (2.65 mmole) followed by 2 drops of acetic acid. The reaction mixture was stirred at room temperature for 2 hours after which was added iodobenzene diacetate (2.77 mmole). The resulting reaction mixture was stirred at RT for another 2 hours. The mixture was evaporated in vacuo and purified by preparative TLC eluting with 5% methanol and dichloromethane mixture to give 6-bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyrimidine.
Reaction SMILES: Br.[CH3:2][CH:3]([CH3:15])[CH2:4][C@H:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:8])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)C>[F:69][C:66]1[CH:65]=[CH:64][C:63]([CH:56]([C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[N:57]2[CH2:58][CH2:59][N:60]([C:6](=[O:8])[C@@H:5]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:4][CH:3]([CH3:2])[CH3:15])[CH2:61][CH2:62]2)=[CH:68][CH:67]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCCC1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a suspension of (S)-4-methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide (0.28 g, 1.0 mmol, Example 22, Step A) and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) in dry DMF (6 mL) was added solid O-benzotriazol-1-yl -N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.39 g, 0.99 mmol) under nitrogen atmosphere at 0° C. The resulting reaction mixture, which became a clear solution after addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate, was stirred at that temperature for 20 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.29 g, 1.0 mmol) was then added. After additional 3 hours stirring while the reaction mixture was allowed to slowly warm up to ambient temperature, reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×100 mL), brine (2×100 mL), and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20:80:1 EtOAc:hexane:MeOH) to provide 0.37 g (79%) of the pure titled compound as a white foam. APCI-MS m/z 470.3 (MH+).
Reaction SMILES: N[C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC[C@H](C)[C@@H](Br)C(=O)O
Reaction time: 2 h
Yield: 87.5 %

Procedure:
The (2R,3S)-2-amino-3-methylpentanoic acid (D-allo-isoleucine, 1g, 7.62 mmol) was dissolved in a mixture of HBr 48% (6.95 mL, 61 mmol) and H2O (10.5 mL). At 0° C., a solution of NaNO2 (1.68 g, 24.4 mmol) in H2O (5 mL) was added over a period of 30 min. The reaction was stirred for two hours. The reaction mixture was degassed in vacuo and extracted with EtOAc (2×20mL). The extracts were washed with water (15 mL), dried (Na2SO4), filtered and evaporated to give 1.3 g (87% yield) of the (2R, 3S)-2-bromo-3-methylpentanoic acid as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[NH:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: C1CCNC1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N6CCCC6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.8 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (56 mg, 0.082 mmol) in THF (2 mL) was added polystyrene carbodiimide (0.15 mg, 0.17 mmol) and 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol), and then the reaction mixture was stirred at room temperature under nitrogen. After 15 min, pyrrolidine (11 mg, 0.16 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen. After 5 h, the reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic). The resulting product was lyophilized from acetonitrile (3 mL) and water (1 mL) to give (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(pyrrolidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone (1.7 mg, 2.8%) as a mixture of diastereomers and as a dark red solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 6.64 (s, 1H), 6.17 (s, 0.3H), 6.01 (s, 0.7H), 4.96-4.87 (m, 2H), 3.74 (s, 3H), 3.64 (s, 1H), 3.57 (s, 3H), 3.52 (d, J=18.0 Hz, 3H), 3.46-3.39 (m, 6H), 3.26-3.20 (m, 1H), 3.08-3.02 (m, 2H), 2.08 (s, 3H), 1.93-1.87 (m, 4H), 1.28 (d, J=6.0 Hz, 2.1H), 1.22 (d, J=6.0 Hz, 0.9H); MS (ESI+) m/z 737 (M+H); HPLC 94.4% (AUC), tR 10.71 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=[C:14]([C:27]([O:29]CC)=[O:28])[CH:13]=2)=[CH:8][CH:7]=1.C1COCC1.[Na].Cl>C(O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[N:15]=[C:14]([C:27]([OH:29])=[O:28])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)cc1

Procedure:
To a stirred solution of Ethyl 5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate (prepared according to the procedure of Example 63, step 1) (0.1 g) in ethanol (5 mL)-THF (3 mL) was added 2N-Sodium hydroxied solution in water (1 mL) and the mixture was heated at reflux temperature for 1.5 hours. After cooling, 2N-HCl solution (2 mL) and water (20 mL) were added to the mixture. The whole was extracted with CH2Cl2 (50 mL×2), the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized with isopropanol-water to give the title compound (0.08 g).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[CH:6][NH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[I:14]I.[I-]>>[CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([I:14])[NH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc(C)c1CC
Reactant: II
Agent: [I-]
Product: CCOC(=O)c1[nH]c(I)c(C)c1CC

Procedure:
reacting ethyl 3-ethyl-4-methylpyrrole-2-carboxylate with iodine and iodide to form ethyl 3-ethyl-5-iodo-4-methylpyrrole-2-carboxylate;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-])=O)(=[O:15])=[O:14].O.NN>[Ni]>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:24])([F:23])[F:25])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([CH3:1])=[CH:11]2)(=[O:14])=[O:15]
Reactant: Cc1cnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3[N+](=O)[O-])cccc2c1
Agent: [Ni]
Agent: NN
Solvent: O
Product: Cc1cnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)cccc2c1
Yield: 22.5 %

Procedure:
In a similar fashion using route 6 general procedure 14, N-(3-Methylquinolin-8-yl)-2-nitro-4-trifluoromethylbenzenesulfonamide (Intermediate 158) (60 mg, 0.14 mmol), Raney nickel (10 mg, 20% wt) and hydrazine hydrate (20 mg, 0.43 mmol) gave the title compound (12 mg, 22%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[C-]#N.[Na+].O>CN(C)C=O>[C:9]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)#[N:10]
Reactant: [C-]#N
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Br)cn1
Temperature: 150 °C
Reaction time: 7 h
Yield: 69.9 %

Procedure:
In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O.CCOCC.CCCCCC>CN(C)C=O>[CH3:12][Si:3]([CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Agent: [K]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Yield: 94.9 %

Procedure:
Chloromethyl-dimethyl-4-fluorobenzylsilane (2.01 g, 9.33 mmol) and potassium phthalimide (1.90 g), 10.27 mmol) were heated in dry dimethylformamide (30 ml) at 70° C. for 5 hours and then the mixture was poured into water and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, ether/hexane--20/80) afforded N[(dimethyl-4-fluorobenzylsilyl)methyl]phthalimide as a white powder (2.90 g, 95% yield) 1H NMR (CDCl3, TMS) δ: 0.20 (s,6H), 2.25 (s,2H), 3.27 (s,2H), 6.83-7.13 (m,4H), 7.67-7.97 (m,4H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH:3]=1.[H][H]>[Ni].C(O)(C)C>[CH3:1][CH:2]1[CH2:7][C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1=CCOC2(CCCCC2)C1
Agent: [Ni]
Solvent: CC(C)O
Product: CC1CCOC2(CCCCC2)C1
Yield: 93 %

Procedure:
A solution of 4-methyl-1-oxaspiro[5.5]undec-3-ene (1.66 kg, 10.0 mols), isopropyl alcohol (100 ml) and Raney nickel (100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4-methyl-1-oxaspiro [5.5] undecane (1.56 kg, yield: 93%, purity: 99% sum of the isomers).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[C:22]=2[S:29][CH3:30])[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[C:22]=2[S:29]([CH3:30])=[O:6])[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Solvent: ClCCl
Product: CS(=O)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
3-Chloroperoxybenzoic acid (2.0 g) was added to a solution of 5-cyclopropyl-4-(3,4-dichloro-2-methylsulphenylbenzoyl)isoxazole (1.86 g) in dichloromethane while maintaining the temperature around -15° C. The mixture was stirred at -15° C. for 1 hour and at room temperature for 1 hour. It was recooled to -15° C. and filtered. The filtrate was evaporated to dryness and the residue was purified by dry column flash chromatography eluted with a mixture of ethyl acetate and n-hexane. The product was recrystallized from a mixture of ethyl acetate and n-hexane to give 5-cyclopropyl-4-(3,4-dichloro-2-methylsulphinylbenzoyl)isoxazole (compound 285, 0.3 g) as a white solid, m.p. 110°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:8][NH:9]2)=[C:4](NCCCC=O)[C:3]=1[F:24].[OH-].[K+].[K]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([OH:14])=[O:13])=[CH:8][N:9]2[NH:9][CH2:8][CH2:7][CH3:6])=[CH:4][C:3]=1[F:24]
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c(F)c(NCCCC=O)c2c1=O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: CCCNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21

Procedure:
7-Chloro-6-fluoro-1,4-dihydro-4-oxo-1-propylamino-3-quinolinecarboxylic acid [VI; lower-alkyl=(CH2)2CH3 ] was prepared from 10.5 g of ethyl 7-chloro-6-fluoro-5-[(formyl)propylamino]-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Preparation 3C) and 4.4 g of 85% potassium hydroxide in ethanol solution according to the procedure described above in Preparation 4B. There was obtained 5.7 g of product in the form of its potassium salt hemihydrate, m.p. 267° C. (decompn.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[K+:14]>>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([F:9])=[C:6]([O-:13])[CH:7]=1.[K+:14]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: [OH-]
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c([O-])cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-4,5-difluoro-2-nitrobenzene (5.12 g, 26.5 mmol) and 15% aqueous KOH (19.9 g) solution was stirred at reflux for 3 hours, then cooled to rt, and filtered to give the title compound as a yellow crystalloid (5.67 g, 93.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:24][O:23]1)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)([OH:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCCCC1(c2ccc(F)cc2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.3 g, 5 mmol) was dissolved in DMF (10 mL) and stirred for 5 min. Sodium hydride (709 mg, 17.7 mmol) was then added portionwise under nitrogen. This was followed by addition of 2-butyl-2-(4-fluorophenyl)oxirane (3.4 g, 17.7 mmol) at RT and the reaction mixture was stirred for 18 h. After completion of reaction, the reaction mixture was poured into ice water and the product extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by silica gel (#100-200 mesh) column chromatography using 1% MeOH in DCM as eluent. The pure compound was converted into the oxalate salt. 1H NMR (CDCl3, oxalate salt) δ (ppm): 7.30 (m, 3H), 7.10 (d, 1H), 6.95 (m, 3H), 4.20 (m, 1H), 4.0 (m, 1H), 3.62 (m, 2H), 2.70 (m, 3H), 2.50 (s, 3H), 2.20 (m, 1H), 2.0 (m, 1H), 1.80 (m, 1H), 1.22 (m, 3H), 1.0 (m, 1H), 0.80 (t, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([NH2:24])[N:16]=[C:17]([NH2:23])[N:18]=4)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([NH2:24])[N:16]=[C:17]([NH2:23])[N:18]=4)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccc3c4c(N)nc(N)nc4ccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccc(O)cc2)n1

Procedure:
Treat a suspension of 3.2 g. of 7-[(4-methoxyphenyl)-methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 100 ml of methylene chloride at -5° C. with 34 ml. of 0.92 M boron tribromide in methylene chloride. Keep the reaction at 20° C. for 18 hours and dilute with 100 ml. of water. Filter the resulting precipitate, stir in an aqueous potassium carbonate solution, filter, wash with water and dry. Crystallize the precipitate twice from methanol and once from dimethylformamide to obtain 0.63 g. of the title product, m.p. 292° C. (dec.), NMR (dDMSO): δ 5.33 (singlet, N--CH2 --C6H5O), 6.67 (doublet, J=9 Hz, 5H), 6.72 (doublet, J=3 Hz, 9H), 7.51 (doublet, J=3 Hz, 8H), 7.75 (doublet, J=9 Hz, 6H) p.p.m.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[C:4](C)[CH:3]=1.N[C:29]1C=CC(S(C(C)C)(=O)=O)=C(C=1)C#N.BrC1C=CC(CCCC(Cl)=O)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH3:24])[CH3:29])(=[O:22])=[O:21])=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2C)cc1C#N
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1C#N
Agent: O=C(Cl)CCCc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Yield: 92 %

Procedure:
Using a procedure analogous to that used to prepare 8B, 9B (364 mg, 1.62 mmol) was reacted with 4-(4-bromophenyl)butyric acid chloride to give 9C (667 mg, 92%). MS (ESI) m/z 449.1, 451.1 (M+H)+.