Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=CC(S(CC(C)=CCO)(=O)=O)=[CH:5][CH:4]=1.O1CCCC1.C([Li])CCC.Cl[CH2:29][CH:30]=[C:31](C)[CH:32]=[CH:33][C:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH2:36][C:35]=1[CH3:42]>CCCCCC.O>[CH3:42][C:35]1[CH2:36][CH2:37][CH2:38][C:39]([CH3:40])([CH3:41])[C:34]=1[CH:33]=[CH:32][CH:31]=[CH:30][CH2:29][CH2:8][CH:3]=[CH:4][CH3:5]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CCCl
Reactant: COc1ccc(S(=O)(=O)CC(C)=CCO)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC=CCCC=CC=CC1=C(C)CCCC1(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of 1.28 g. of 1-(p-methoxyphenylsulfonyl)-2-methyl-4-hydroxy-but-2-ene in 15 ml. of tetrahydrofuran (THF) was added at -70°C. 4.25 ml. of 2.37 M solution of n-butyllithium in hexane. The mixture was stirred at -70°C. for 30 minutes and a solution of 1.78 g. of 1-chloro-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-penta-2,4-diene in 5 ml. of THF was added at -70°C. The solution was stirred at -70°C. for 50 minutes and allowed to warm to 70°C. The mixture was poured into water and extracted with diethyl ether. The extracts were washed with water, dried and concentrated to give 2.6 g. of 1-hydroxy-3,7-dimethyl-4-(p-methoxyphenyl-sulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene which was chromatographed on silica get to give 0.48 g. of 1-hydroxy-3,7-dimethyl-4-p-methoxyphenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene (20% yield) having a UV in isopropanol at λmax = 241-2 mμ (ε24,625).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C([C:10]1C=[CH:13][N:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH:11]=1)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[CH:10]=[CH:11][N:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH:13]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccn(-c2cccc3ncccc23)c1
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1ccn(-c2cccc3ncccc23)c1
Temperature: 22 °C
Reaction time: 15 h
Yield: 106.6 %

Procedure:
0.5 mL (5.73 mmol) of oxalyl chloride is added to a solution, cooled to a temperature in the region of 5° C., of 0.42 g (1.76 mmol) of 3-carboxy-1-(quinol-5-yl)-1H-pyrrole in 10 mL of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, concentrating the reaction mixture to dryness under reduced pressure (2.7 kPa) gives 0.55 g of 3-chlorocarbonyl-1-(quinol-5-yl)-1H-pyrrole hydrochloride in the form of a cream-coloured solid which is used directly in the following step.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(OCC)c1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.4 %

Procedure:
A mixture of (±)-2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.0061 mol), described in International Patent Specification WO 00/39082, tributyl (1-ethoxyethenyl)-stannane (0.0091 mol) and Pd(PPh3)4 (0.0007 mol) in dioxane(30 ml) was stirred at 80° C. for 24 hours, cooled and poured out into ice water. EtOAc was added and the mixture was filtered over celite. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.8 g of (±)-4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-(1-ethoxyethenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:11]=1C(O)=O.CC1NC2CCCC(=O)C=2C(C2C=CC=C([N+]([O-])=O)C=2)C=1C(OCCC#N)=O.[OH-].[Na+]>COCCOC.O>[CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[CH:11]=1
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Agent: CC1=C(C(=O)OCCC#N)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC1=CC(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Reaction time: 20 h

Procedure:
2-Methyl-4-(3-nitrophenyl) -5-oxo-1,4,5, 6,7,8-hexa-hydro-3-quinolinecarboxylic acid. To a suspension of 2-cyanoethyl 2-methyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylate (0.47 g) in ethylene glycol dimethyl ether (2 mL) was added 1N sodium hydroxide (4 mL). The mixture was stirred for 20 h, during which time all of the solid went into solution. The mixture was diluted with water, washed with ethyl acetate, and acidified by addition of concentrated hydrochloric acid. The resulting precipitate was collected by vacuum filtration and dried to give the acid as a yellow solid (0.31 g); mp 253°-255° C.; MS: 328 (M); NMR: 1.63-2.00 (m,2, CH2), 2.20 (m,2, CH2), 2.31 (s,3, CH3), 2.49 (m,2, CH2), 5.01 (s,1, CH), 7.49-7.61 (m,2, Ar), 7.97 (m,2, Ar), 9.24 (s, 1, NH). Analysis for C17H16N2O5 : Calculated: C, 62.19; H, 4.91; N, 8.53; Found.: C, 62.16; H, 5.02; N, 8.33.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:17][CH2:18][C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11][N:10]1[CH:14]=[N:15][CH:16]=[C:9]31.[Cu][C:20]#[N:21].N.C(OCC)(=O)C>CN1CCCC1=O>[CH:16]1[N:15]=[CH:14][N:10]2[CH2:11][CH2:12][CH2:13][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:20]#[N:21])=[CH:3][C:4]=4[CH2:18][O:17]3)[C:9]=12
Reactant: N#C[Cu]
Reactant: Brc1ccc2c(c1)COC21CCCn2cncc21
Agent: N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)COC21CCCn2cncc21
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.93 mmol of 5-bromo-6′,7′-dihydro-3H,5′H-spiro[2-benzofuran-1,8′-imidazo[1,5-a]pyridine] and 9.63 mmol of copper(I) cyanide in 10 ml of N-methyl-pyrrolidone is heated to 150° C. for 72 h. The reaction mixture is cooled to room temperature and poured into a mixture of 25% aqueous ammonia and ethyl acetate. The mixture is stirred vigorously for 15 minutes and the layers are separated. The aqueous layer is extracted with ethyl acetate and the combined organics are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) followed by crystallization from diethyl ether to afford the title compound as a beige solid. Rf=0.15 (dichloromethane-2M ammonia in ethanol 97:3); Rt=4.66 (gradient II).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:8][CH2:7]1)[CH2:2][CH3:3].C[Al](C)C.CCCCCCC.CO[C:22]([C:24]1[N:25]([CH3:41])[N:26]=[C:27]2[C:32]=1[CH:31]=[CH:30][CH:29]=[C:28]2[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:23].[OH-].[Na+]>C1C=CC=CC=1>[CH:6]1([CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[C:22]([C:24]2[N:25]([CH3:41])[N:26]=[C:27]3[C:32]=2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])=[O:23])[CH2:8][CH2:7]1
Reactant: COC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Reactant: CCCNCC1CC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCCN(CC1CC1)C(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 79 °C
Yield: 47.1 %

Procedure:
To a solution of N-propylcyclopropanemethyl amine (0.69 mL, 4.8 mmol) in 12 mL of benzene was slowly added a 2M solution of trimethylaluminum in heptane (2.4 mL, 4.8 mmol), and the solution was stirred for 75 m. The solution was transferred with a pipette to a solution of 35b (0.200 g, 0.597 mmol) in 10 mL of benzene. The solution was heated to 79° C., stirred for 2 d, then cooled to 0-5° C. A 2 M aqueous NaOH solution (20 mL) was slowly added, and the mixture was extracted with three 20 mL portions of dichloromethane. The combined organic layers were washed with 40 mL of a saturated NaCl solution, dried over MgSO4, filtered, and concentrated to a brown oil. Column chromatography (0→20% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (35c: 0.117 g; 47%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([CH3:24])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]3([C:45](O)=[O:46])[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)([CH3:24])[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23][C:45]([C:42]4([C:40]5[CH:39]=[CH:38][C:37]6[O:33][CH2:34][O:35][C:36]=6[CH:41]=5)[CH2:44][CH2:43]4)=[O:46])[CH:17]=3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccc(S(C)(c2ccc(OC)cc2)c2ccc(-c3cc(N)ccc3C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(C)(c2ccc(OC)cc2)c2ccc(-c3cc(NC(=O)C4(c5ccc6c(c5)OCO6)CC4)ccc3C)cc2)cc1
Temperature: 65 °C

Procedure:
4′-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamine (˜10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) were dissolved in chloroform (25 mL) followed by addition of TCPH (4.1 g, 12 mmol) and DIEA (5.0 mL, 30 mmol). The reaction mixture was heated at 65° C. for 48 h. The volatiles were removed under reduced pressure. The residue was distributed between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5% NaHCO3 (2×150 mL), water (1×150 mL), brine (1×150 mL) and dried over MgSO4. Evaporation of the solvent yielded crude 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid 4′-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide as a pale oil, which was used without further purification. ESI-MS m/z calc. 629.0, found 630.0 (M+1) (HPLC purity ˜85-90%, UV254 nm).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].CC(C)(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C.P(=O)(O)(O)O.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:4][C:2]([NH:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)Nc1cccnc1N1CCNCC1
Reaction time: 1 h

Procedure:
Isobutylene (10 ml) is condensed into a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 200 mg) in methylene chloride (10 ml) at -70°. Phosphoric acid (85%, 50 μl) is added and the mixture stirred for 60 minutes. Boron trifluoride etherate (200 μl) is added dropwise and the resulting suspension is stirred 8 hours at reflux and overnight at 20°-25° allowing the isobutylene to evaporate. The suspension is diluted with water and ammonium hydroxide is added until basic to pH paper and then extracted with methylene chloride (3×). The combined extracts are dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to a liquid which is flash chromatographed (silica gel, 230-400 mesh), eluting with methanol/chloroform (3/20). The appropriate fractions are pooled and concentrated to give an oil. The NMR, CMR, IR, and MS (m/e) M+234 support the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9](N)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[BrH:12]>[Cu](Br)Br>[Br:12][C:9]1[N:10]=[C:3]2[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: Br
Agent: Br[Cu]Br
Product: Brc1nc2c(Br)cccn2n1

Procedure:
2,8-Dibromo-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.50 g, 2.3 mmol) with copper(II) bromide (0.140 g, 0.627 mmol) and 48% aqueous hydrobromic acid (5 mL, 40 mmol) in a manner analogous to Step 68a. the reaction product was isolated as a pale yellow solid (0.55 g, 85%). MP=150-151° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.99 (d, J=6.7 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H). MS=276, 278, 280 (MH)+. 69b) N(2),N(8)-Bis-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 2,8-dibromo-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3611 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (90.0 mg, 0.433 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (42.0 mg, 0.0726 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as an off-white solid (0.022 g, 13%). MP=271-273° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.17 (s, 1H), 8.71 (d, J=9.3 Hz, 1H), 8.51 (s, 1H), 8.14 (d, J=5.1 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.65 (t, J=7.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.31 (d, J=6.9 Hz, 1H), 7.18-7.08 (m, 2H), 6.88 (t, J=7.0 Hz, 1H), 3.15 (s, 3H), 3.11 (s, 3H). MS=458 (MH)+.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.Br.[C:13]([O:17][C:18](=[O:24])[CH2:19][S:20][C:21](=[NH:23])[NH2:22])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[C:13]([O:17][C:18](=[O:24])[CH2:19][S:20][C:21]1[NH:23][CH:3]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:22]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(CBr)c1cccnc1
Reactant: CC(C)(C)OC(=O)CSC(=N)N
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CSc1nc(-c2cccnc2)c[nH]1

Procedure:
150 mg (0.534 mmol) 2-Bromo-1-(pyridin-3-yl)-ethanone hydrobromide, 144.8 mg (0.534 mmol) of carbamimidoylsulfanyl-acetic acid tert-butyl ester hydrobromide and 207 mg (1.6 mmol) of diisopropylethylamine in 5 ml of acetonitrile were stirred at room temperature for 3 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 34 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@H:29]([NH:32][C:14](=[O:16])[C@@H:9]([N:8]([CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH3:13])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@@H](C(=O)N[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4R,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.40 (d, J=7.4, 2H), 7.34 (t, J=7.5, 2H), 7.25 (t, J=7.3, 1H), 4.79-4.68 (m, 1H), 4.44-4.32 (m, 1H), 3.82 (d, J=13.2, 1H), 3.36 (d, J=13.0, 1H), 2.94 (s, 3H), 2.80-2.65 (m, 2H), 2.46 (s, 1H), 2.35 (dd, J=9.2, 2.7, 1H), 2.31-2.25 (m, 2H), 1.99 (dt, J=14.0, 7.0, 1H), 1.83-1.72 (m, 2H), 1.70-1.56 (m, 2H), 1.49 (d, J=4.5, 1H), 1.48 (s, 9H), 1.41-1.23 (m, 3H), 0.89 (t, J=7.4, 3H); MS (ESI+) m/z 430 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1>C(O)(C)C>[ClH:2].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:25])[CH:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (130 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), and 4-bromo-2-fluoroaniline (95 mg, 0.5 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol and ether and dried to give 4-(4-bromo-2-fluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (124 mg, 60%) as an off-white solid. HPLC characteristics:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc([N+](=O)[O-])cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (63 mg, 74%), MS (ISP) m/z=340.5 [(M+H)+], mp 309° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][NH:30][CH3:31].[BH4-].[Na+]>CO>[CH3:29][N:30]([CH2:18][C:17]1[CH:16]=[C:15]([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:31]
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (45 mg, 0.12 mmol) and 33% dimethylamine solution (50.2 mg, 0.366 mmol) in methanol (5 mL) was stirred at room temperature for 1 h. Then the mixture was cooled to 0° C., sodium borohydride (6.95 mg, 0.184 mmol) was added portionwise. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was purified by prep-HPLC to give 9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (21 mg, yield 44%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.59 (s, 3H), 2.75 (s, 3H), 4.11-4.27 (q, 2H), 4.31-4.34 (d, J=10.4 Hz, 1H), 4.68-4.71 (d, J=10.4 Hz, 1H), 7.17-7.30 (m, 9H), 7.33-7.37 (t, J=7.6 Hz, 1H), 7.56-7.58 (d, J=7.6 Hz, 1H), 7.60-7.64 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 396 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:4]=1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2Cl)n1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3Cl)n2)cc1
Yield: 54.1 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(2,4-dichlorophenyl)ethenyl]-1,3-oxazole (257 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (35.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (246 mg) as a-colorless crystal powder.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:48]=[CH:47][CH:46]=[CH:45][C:38]=1[C:39](N(OC)C)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:38]2[CH:45]=[CH:46][CH:47]=[CH:48][C:37]=2[F:36])=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccccc1F
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccc3F)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2-fluoro-N-methoxy-N-methylbenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][N:12]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=2[CH2:8][CH2:9][CH2:10][C:11]1=[O:13]
Reactant: CI
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.58 g of 2,3,4,5-tetrahydro-8-nitro-2-oxo-1H-1-benzazepine dissolved in 30 ml of abs. dimethylformamide were added to 650 mg of 55% NaH in 20 ml of abs. dimethylformamide. The mixture was stirred for 1 hour, then cooled to 0° C. and 1.35 ml of methyl iodide were slowly added dropwise thereto. After 45 minutes the mixture was poured on ice, extracted with ethyl acetate, washed with NaCl solution, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate=1/1) yielded 2.46 g of 2,3,4,5-tetrahydro-1-methyl-8-nitro-2-oxo-1H-1-benzazepine as orange crystals of m.p. 151°-152° C.