Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][C@H:13]([CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[C@H:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>>[ClH:32].[Cl:33][C:28]1[CH:27]=[C:26]([C@@H:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:14][C@@H:13]2[CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@@H](COc2ccccc2C(=O)O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1OC[C@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To 2-{[(6R*,7R*)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methoxy}benzoic acid (50 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was washed with ethyl acetate-hexane to give the title compound (20 mg).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>>[CH3:22][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1cccc(C=O)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1

Procedure:
6-[4-(3-Methyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and m-tolualdehyde. Mass spectrum (ES) MH+=285.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].Cl.Cl.[NH2:15][C@@H:16]([CH3:29])[C:17]([NH:19][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:15][C@@H:16]([CH3:29])[C:17]([NH:19][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])=[O:12])=[N:5][CH:4]=1)=[O:2]
Reactant: O=Cc1cnc(NCC(=O)O)s1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
Following the general procedure as described in Example 24, except using 2-(5-formylthiazol-2-ylamino)acetic acid, 1.00 HCl (582 mg, 2.62 mmol), (S)-tert-butyl 2-((S)-2-aminopropanamido)propanoate hydrochloride (661 mg, 2.62 mmol), 1-hydroxy-7-azabenzotriazole (175 mg, 1.29 mmol), CH2Cl2 (30 mL), EDC (588 mg, 3.07 mmol) and stirring at room temp for 18 h, 781.5 mg (78%) of the title compound is isolated by filtration as a light pink solid. LC/MS (Condition A): ret. T=2.64 min, (M+H)+ 385. 1H NMR (500 MHz, methanol-d4) δ ppm 9.66 (1 H, s), 7.97 (1 H, s), 4.37-4.53 (1 H, m), 4.21-4.32 (1 H, m), 4.16 (2 H, d, J=0.92 Hz), 1.47 (9 H, s), 1.38 (6 H, dd, J=15.72, 7.17 Hz).
Reaction SMILES: [CH2:1]([N:4]([C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[C:14]([OH:16])=O)[C:5](=[O:7])[CH3:6])[CH2:2][CH3:3]>CCO>[OH:16][C:14]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:7])[CH:6]=1
Reactant: CCCN(C(C)=O)C1=C(C(=O)O)CCCC1
Solvent: CCO
Product: CCCn1c2c(c(O)cc1=O)CCCC2

Procedure:
Cyclisation of a 60:40 mixture of the ethyl and methyl esters of 2-(N-n-propyl-acetamido) cyclohex-1-ene-1-carboxylic acid (34.82 g; 0.141 mole) as described in Example 8 afforded the title product as a white crystalline solid, m.p. (EtOH) 277° -278° C
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O.C(OCC)(=O)C.CCCCCC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1c([N+](=O)[O-])c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.0 g) in concentrated sulphuric acid (10 ml) at 0° C. was treated with fuming nitric acid (9 ml) during 15 minutes, keeping the temperature at 5°-15° C. After 30 minutes the mixture was poured onto excess ice, and the precipitated solid was filtered off and dissolved in ethyl acetate. After drying over anhydrous magnesium sulphate, filtration, and evaporation in vacuo a brown oil was obtained. This oil was dissolved in the minimum of ethyl acetate and diluted with hexane. A pale yellow solid crystallized and this was discarded. The filtrate was evaporated in vacuo to give a solid which was recrystallized from toluene-hexane to furnish a yellow solid. One further recrystallization from the same solvent pair gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitro-3-trifluoromethylpyrazole as white crystals, m.p. 214°-215° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:14][N:15]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:17]=[N:16]1
Reactant: C[C@H](O)c1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](O)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of (S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (30.0 mg, 0.151 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.8 mg, 0.302 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potassium carbonate (62.6 mg, 0.453 mmol) and 4:1 dioxane:water (5 mL) was heated to 85° C. for 1 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel and extracted with DCM. The organic layer was dry-loaded onto silica gel, and the material was purified via column chromatography, eluting with 10% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z 245.08 (100) [MH+]. HPLC: tR=2.00 min (ZQ3, polar—5 min).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([CH2:14][O:15][C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[N:23]([CH2:24][CH2:25][OH:26])[C@@:17]2([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]3)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:7]=[C:6]([CH2:14][O:15][C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[N:23]([CH2:24][CH2:25][O:26][S:43]([CH3:42])(=[O:45])=[O:44])[C@@:17]2([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:18][CH2:19]3)[CH:5]=[C:4]([C:3]([F:33])([F:2])[F:34])[CH:9]=1
Reactant: OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 0 °C
Yield: 98.5 %

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2-hydroxyethyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 67; 173 mg, 0.37 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Triethylamine (0.062 ml, 0.44 mmol) was added followed by methanesulphonyl chloride (0.029 ml, 0.37 mmol). The mixture was extracted between water and dichloromethane (×3) and the organics dried (MgSO4) and concentrated in vacuo to give the title compound as a clear oil (201 mg, 100%).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C@H:9]2[CH2:11][C@H:10]2[CH2:12][CH2:13][O:14][C:15]2[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][C:16]=2[CH3:29])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH:33]([CH3:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[Cl-].[Zn+2].[Cl-]>[CH:33]([C:32]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([C@H:9]3[CH2:11][C@H:10]3[CH2:12][CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:17][C:16]=3[CH3:29])[CH2:7][CH2:8]2)[O:30][N:31]=1)([CH3:35])[CH3:34]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Reactant: CC(C)C(=N)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of tert-butyl (6-{2-[(1S,2R)-2-(cyanopiperidin-4-yl)cyclopropyl]ethoxy}-5-methylpyridin-3-yl)acetate (650 mg, 1.63 mmol), N-hydroxy-2-methylpropanimidamide (1.38 eq., 230 mg) and zinc chloride (1.58 eq., 350 mg) in 5 mL of DMF was stirred 2 hrs at 80° C., then PTSA (1.0 eq, 280 mg) was added and stirred for additional 2 hrs at 85° C. The mixture was cooled to room temperature and then quenched by said aq soln of NaHCO3. The mixture was extracted with EtOAc (2×75 mL), and the combined organics were then washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by ISCO column (40 g silica gel) using ethyl acetate in hexane (0-40% EA, 400 ml, and 40-100% EA 200 ml) to give the product. LCMS (ESI) m/z 485 [M+H]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28](=[O:51])[NH:29][CH2:30][C@@H:31]1[O:35][C:34](=[O:36])[N:33]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[S:44][CH2:45][C:46](=O)[NH:47][N:48]=3)=[C:39]([F:50])[CH:38]=2)[CH2:32]1)([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1>[C:23]([O:27][C:28](=[O:51])[NH:29][CH2:30][C@@H:31]1[O:35][C:34](=[O:36])[N:33]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[S:44][CH2:45][C:46](=[S:10])[NH:47][N:48]=3)=[C:39]([F:50])[CH:38]=2)[CH2:32]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=S)CS3)c(F)c2)C(=O)O1
Yield: 112.9 %

Procedure:
Lawesson's reagent (0.0715 g, 0.177 mmol) and {3-[3-fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-carbamic acid tert-butyl ester (0.100 g, 0.236 mmol) in dioxane (5 ml) are heated at 65° C. for 6 hours. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give bright yellow solid (0.088 g, 85%); 1HNMR (300 MHz, DMSO-d6) δ 1.34 (s, 9H), 3.28 (t, J=5.5 Hz, 2H), 3.82 (dd, J=6.0, 9.1 Hz, 1H), 4.01 (s, 2H), 4.14 (t, J=9.3 Hz, 1H), 4.70-4.78 (m, 1H), 7.24 (t, J=5.8 Hz, 1H), 7.45 (dd, J=2.2, 8.8 Hz, 1H), 7.60 (dd, J=2.2, 14 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 8.07 (t, J=6.0 Hz, 1H); mp 134-6; MS (m/z): [M+H]+=441.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C-:14]#[N:15].[Na+]>CN(C)C=O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:14]#[N:15]
Reactant: OCCCCCCCCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCCCCCCCCCO
Temperature: 0 °C

Procedure:
A solution 4.6 g. of 11-bromoundecanol and 1.6 g. of sodium cyanide in 40 ml. of dimethylformamide is heated at 80° C. for 18 hours, cooled, and poured into ice-water. The mixture is extracted with methylene chloride and the extract is dried over anhydrous magnesium sulfate. Evaporation of the solution affords 12-hydroxydodecanonitrile as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[CH2:6]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].CO>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[N:19][OH:20])[CH2:6]1
Reactant: NO
Reactant: COC(=O)CC1CC(=O)c2ccc(OC)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC1CC(=NO)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
(6-Methoxy-3-oxo-indan-1-yl)-acetic acid methyl ester (12.0 g), hydroxylamine hydrochloride (4.6 g), and sodium acetate (5.5 g) dissolved in water (40 mL) and methanol (50 mL) are stirred at reflux temperature for 3 h. After cooling to room temperature, water (100 mL) is added and the solution is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is evaporated to give the product as a brown oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH:6]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])[CH2:7][C:8](O)=[O:9].Cl>C(O)C>[CH2:1]([O:3][C:8](=[O:9])[CH2:7][CH:6]([NH2:5])[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])[CH3:2]
Reactant: NC(CC(=O)O)c1cc(F)ccc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(N)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (4 ml) was added dropwise at room temperature to a round-bottom flask containing ethanol (50 ml). 3-Amino-3-(2,5-difluorophenyl)propionic acid (2.94 g) was added to the ethanolic hydrochloric acid solution thus prepared, and the mixture was stirred at 50° C. for three hours. Subsequently, the mixture was concentrated under reduced pressure, and the residue was admixed with 1N sodium hydroxide solution (100 ml) and extracted immediately with dichloromethane (3×50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. The product (3.2 g) was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=O)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>O1CCCC1>[CH:21]1([CH2:19][NH:18][C:16]2[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:14]3[N:15]=2)[CH2:22][CH2:23]1
Reactant: COc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3nc(NCC4CC4)nn23)cc1
Reaction time: 8 h

Procedure:
To cyclopropanecarboxylic acid [5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (WW-005) ((0.07 g, 0.227 mmol), BH3 (1M in tetrahydrofuran, 1.2 mL, 1.2 mmol) was added dropwise and the mixture was stirred overnight. The reaction was quenched with methanol and the solvents were removed under reduced pressure. The crude product was purified by preparatory HPLC. LCMS method: 1, 4.45 min, MI: 295 [M+1]. 1H NMR (DMSO): 0.18-0.22 (m, 2H), 0.35-0.41 (m, 2H), 1.04-1.08 (m, 1H), 2.87 (t, 2H), 3.86 (s, 3H), 6.64 (t, 1H), 6.97 (d, 1H), 7.06 (d, 2H), 7.32 (d, 1H), 7.46 (t, 1H), 7.96 (d, 2H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Si:39]([O:46][C:47]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[CH:53][C:52]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>O1CCCC1.CCCCCC.C(OC)(C)(C)C>[C:63]1([C:52]2[CH:51]=[C:48](/[CH:49]=[CH:7]\[C:6]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:4]([O:3][CH3:2])[CH:5]=3)[C:47]([O:46][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])=[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:58])[CH:53]=2)[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(-c2ccccc2)cc(C=O)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2cc(-c3ccccc3)cc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (0.24 g, 0.46 mmol) in tetrahydrofuran (4 mL) was cooled to 0° C. and butyllithium (0.28 mL of a 1.6 N solution in hexane, 0.46 mmol) was added dropwise. The brick red solution was stirred at 0° C. for 20 min, then a solution of 23 (0.13 g, 0.3 mmol) in tetrahydrofuran (2 mL) was added dropwise. The temperature was allowed to rise to room temperature overnight, than the reaction was diluted with tert-butylmethyl ether (ca 100 mL) and washed with water (ca 50 mL, containing 1 mL 2N HCl) then brine (30 mL). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (elution with cyclohexane:AcOEt 10:1) to give 0.05 g of 24 still impure with 20% of the E isomer.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])(=[O:13])=[O:12])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and piperazine according to Method 1 to give 25 mg (12%) of a white solid: 1HNMR (CD3OD) δ 7.91–6.79 (m, 9H), 3.49–3.30 (m, 8H), 2.48 (s, 3H); MS (ESI) 356.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[C:25]([CH3:31])=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1>>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[C:25]([CH3:31])[CH:26]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Product: Cc1cc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)ccc1OCc1ccccn1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 1, 4,7-dichloro-6-nitroquinazoline was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 7-chloro-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline in 81% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17](=O)[CH3:18])(=[O:8])=[O:7].Cl.[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[NH:30])[NH2:29].C[O-].[Na+]>CO>[CH3:24][O:25][C:26]([C:27]1[CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:8])=[O:7])[C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH3:18])[NH:29][C:28]=1[NH2:30])=[O:31]
Reactant: COC(=O)CC(=N)N
Reactant: CC(=O)C(=Cc1ccccc1S(=O)(=O)CCCCCl)[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of 3.2 g of 4-{2-[(4-chlorobutyl)sulfonyl]phenyl}-3-nitro-3-buten-2-one in 25 ml of methanol in a 100 ml single-neck flask at 0° C. was added 1.41 g of amidino-acetic acid methyl ester hydrochloride, followed by 2.2 ml of 25% sodium methoxide in methanol. The mixture was warmed to room temperature and stirred overnight. After removal of the methanol, the residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to give a crude product, which was purified via column chromatography on silica gel, eluting with 60:40 toluene:ethyl acetate. Recrystallization from isopropyl acetate provided 1.08 g of an orange product, m.p. 218° C. 1H-NMR (d6 -DMSO) δ 1.71-1 95(m,4H); 2.45(s,3H); 2.48-2.55(m,2H); 3.34(s,3H); 3.69(m,2H); 6.49(s,1H); 6.87(br s,2H); 7.33-7.44(m,2H); 7.56(t,1H,J=8 Hz); 7.79(d,1H,J=8 Hz); 9.51(br s,1H). Mass spectrum: 444 (M+H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:33])=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][S:43][C:44]1[S:45][CH:46]=[CH:47][CH:48]=1>C(OCC)(=O)C.O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:33])=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:41][CH2:42][S:43][C:44]3[S:45][CH:46]=[CH:47][CH:48]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCNCC1
Reactant: BrCCSc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To 4 mL of an N,N-dimethylformamide solution containing 0.29 g of ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.25 g of potassium carbonate and 0.20 g of 2-(2-bromoethylthio)thiophene were added and stirred at 60-70° C. for 2 hours. Water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.27 g of ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:26]([OH:28])=[O:27])[CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 6, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 3-carboxyphenylboronic acid was prepared the title compound as an off-white solid, MS (ESI−): m/z=434.3 ([M−H]−).