Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:22][CH2:21]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:29])[CH2:24][CH2:25]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6]
Reactant: CN1CCCNCC1
Reactant: O=C(O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(-c4ccccc4)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 0.035 g (0.078 mmol) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.044 g (0.39 mmol) of 1-methyl homopiperazine, 0.032 g (0.10 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.032 mL (0.23 mmol) of triethylamine in N,N-dimethylformamide (2 mL) are stirred overnight at room temperature. The mixture is concentrated under reduced pressure and the residue is diluted with water which causes a solid to precipitate from solution. The colorless solid is collected by filtration, washed with water and dried to provide 0.032 g (75%) of 3-chloro-N-(2-{4-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]piperidin-1-yl}-5-phenylpyridin-3-yl)benzamide (124) as a colorless solid. [M+H]+=546.3.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH2:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH2:7][CH3:8])[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=1>CC(C)=O.C(O)(=O)C.[Fe]>[Cl:23][C:24]1[N:29]=[C:28]2[C:27]([NH:31][C:3](=[O:16])[C:4]([CH2:5][CH3:6])([CH2:7][CH3:8])[CH2:9][N:10]2[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:26][N:25]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCC(CC)(CNC1CCCC1)C(=O)OC
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a solution of methyl2-[(cyclopentylamino)methyl]-2-ethyl-butanoate (Intermediate 252; 7.1 g, 31.3 mmol) in acetone (150 mL) was added potassium carbonate (5.3 g, 38.0 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 6.1 g, 31.3 mmol). The black mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent removed in vacuo to yield a black gum, which was dissolved in acetic acid (175 mL) and iron (7.0 g, 125 mmol) added and the reaction heated at 80° C. overnight. The resulting solution was filtered and the solvent removed in vacuo, the black solid/gum was quenched with water (75 mL) and to this was added sodium carbonate until basic, the resultant black emulsion was filtered through a pad of celite. The obtained mixture was extracted with DCM (3×150 mL), dried and the solvent removed in vacuo to yield a black solid. This was passed through a bond elute column (50 g) eluting with 0-1% MeOH in DCM to afford a brown solid, which was triturated with diethyl ether to yield the title compound as a white solid (3.05 g, 30%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([NH:19][C:20]3[C:21](=[CH:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=3)[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2cccc2)c(N)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)NC1(CCN(Cc3ccccc3)CC1)c1cccn1-2

Procedure:
510 g (0.027 mole) of 1-benzyl-4-piperidone and 2 ml. of glacial acetic acid are added to a solution of 50 g (0.027 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 80 ml. of absolute ethanol. The solution is refluxed for 43 hours and concentrated to an oil which is washed with water. The oil is recrystallized from isopropanol to give 1'-benzyl-7-methoxy-4,5-dihydrospiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 123°-124° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=O)[C:42]([F:45])([F:44])[F:43])[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:49][OH:50].N1C=CC=CC=1>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[N:49][OH:50])[C:42]([F:43])([F:44])[F:45])[CH:36]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 65 °C
Yield: 100 %

Procedure:
A mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.180 g, 0.274 mmol), hydroxylamine hydrochloride (0.023 g, 0.329 mmol) and pyridine (0.355 mL) in MeOH (1.9 mL) was heated in a microwave oven to 65° C. for 48 hours. After concentration of the reaction mixture to dryness, a solution of the residue was washed with sat. NaHCO3 (15 mL), the organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (184 mg, 100% yield) as a light yellow foam: MS m/z 672.3 (M+H)+; HPLC 96.0% @ 220 nm and 91.4% @ 254 nm, RT=2.01 minutes.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OCC)=[CH2:11]>C([O-])(=O)C.[Hg+]>[CH:10]([O:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH2:11]
Reactant: C=COCC
Reactant: OCCC1CCCCC1
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: C=COCCC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Cyclohexylethyl alcohol was mixed with ethyl vinyl ether. Mercury acetate was added thereto and this mixture was stirred at room temperature for 12 hours. The resultant reaction mixture was extracted with ethyl acetate and water, and the extract was washed with water and then distilled under reduced pressure to obtain cyclohexylethyl vinyl ether (X-1) as the target compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]2.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][C:37]=4[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc2c(cc1OCCCCl)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1OCCCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Yield: 117.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6 mmol), K2CO3 (0.60 g, 4.1 mmol). Kl (100 mg), 6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mmol), and acetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours. The cooled reaction was poured into 100 ml of water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to yield 1.7 g of a brown oil. The oil was purified by preparative HPLC (Waters Associates Prep LC/SYSTEM 500) to afford 1.0 g of a light brown solid. This was combined with an additional sample (2,3 g total) and recrystallization from ethanol yielded 1.7 g. A subsequent recrystallization from ethanol gave 1.25 g (36%) of 6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-as a beige powder, m.p.=129°-130° C. ANALYSIS: Calculated for C20H24FN2O4: 69.01%C 6.46%H 6.19%N Found: 68.77%C 6.43%H 6.16%N
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[indane-1,4′-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. mp 110-112°. FDMS m/e=376 (M+ of free base). α[D]589=−11.60 (c=0.46 methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].[F:15][C:16]([F:27])([F:26])[C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC>CN(C=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:17]([C:16]([F:26])([F:27])[F:15])[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]2[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Reactant: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A yellow solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (1.32 g, 4.94 mmol, Intermediate 8, step b) and 1,1,1-trifluoro-3-phenylpropan-2-one (0.980 g, 5.21 mmol) in DMF (4.95 mL) was treated with tributylamine (1.23 mL, 5.19 mmol) and stirred at 130° C. under air (capped) for 2 hours. The homogeneous orange solution was then cooled to room temperature and partitioned with ether (8 mL) and 1 M NaH2PO4 (8 mL). The organic layer was washed with 1 M NaH2PO4 (1×8 mL), dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a heptane to 30% DCM/heptane gradient to yield the title compound as a nearly colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.O.[Br:17]Br>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:17])([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccccc1CBr
Yield: 45 %

Procedure:
Even the side-chain brominations of o-nitrotoluene in a carbon tetrachloride/water mixture using elementary bromine and under UV-irradiation, which have been described recently in German Democratic Republic patent specifications Nos. 74279 and 82463, provide only o-nitrobenzyl bromide in a yield of 45 to 55%. The process described in German Democratic Republic patent specification 118609 affords a somewhat better yield when o-nitrotoluene is brominated in carbon tetrachloride under irradiation with visible or ultra-violet light or using peroxide as catalyst; but in this process too it was not possible to obtain either o-nitrobenzal bromide or a complete sidechain bromination of o-nitrotoluene to yield o-nitrobenzyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Product: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C

Procedure:
(4-Hydroxy-2-methylphenoxy)acetic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester were coupled as described in Example 24, Step C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:7]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cccc(Br)c2C1
Solvent: Cc1ccccc1
Product: Brc1cccc2c1CCC(N1CCCC1)=C2

Procedure:
To a solution of 8-bromo-2-tetralone (10 gm, 44.4 mMol) in toluene (175 ml) was added pyrrolidine (6.6 ml), and the solution was stirred at reflux for three hours. The volatiles were removed in vacuo to give 8-bromo-3-pyrrolidino-1,2-dihydronaphthalene as a brown oil. To this oil in p-dioxane (60 mL) was added methyl iodide (20 mL, 322 mMol), and the resulting solution was stirred at reflux for eighteen hours. The reaction mixture was diluted with water (60 mL) and acetic acid (3.2 mL), and heating was continued for an additional three hours. After this time the solution was cooled to room temperature and the volatiles removed in vacuo. The residue was suspended in water and extracted well with diethyl ether. The organic phases were combined, washed with saturated aqueous NaHCO3, dried with Na2SO4 and concentrated in vacuo to give an orange oil. Purification by flash chromatography (33% diethyl ether in hexane) gave the title compound as a light orange oil (6.88 gm, 65%).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)=[CH:10][C:9]=2[NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2N)cc1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of methyl chloroglyoxylate (184 μl, 2.0 mmol) in dichloromethane (1.5 ml) was added dropwise at a slow speed to a mixture of 3-amino-4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl (415 mg, 1.0 mmol), sodium hydrogencarbonate (168 mg, 2.0 mmol), water (5 ml) and dichloromethane (7 ml), and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (456 mg, 90.9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]([C:18]([N:21]([CH3:23])[CH3:22])=[N:19][OH:20])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[OH-].S(OC)(O[CH3:37])(=O)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]([C:18]([N:21]([CH3:22])[CH3:23])=[N:19][O:20][CH3:37])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=NO)N(C)C
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)N(C)C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N′-hydroxy-2,N,N-trimethyl-benzamidine (200 mg) in DMF (5 mL) was added a solution of LiOH (31 mg) in water (2 mL), before adding dimethyl sulfate (0.21 mL, 0.27 g). The mixture was stirred at room temperature over night and poured onto water. The aqueous layer was extracted with MTBE and the combined organic layers were washed with water, dried (Na2SO4) and evaporated to yield the title compound (170 mg, 83%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH:12]([CH3:14])[CH3:13].[CH3:15][CH2:16][O:17]CC.O>C(O)(=O)C.Br>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:16](=[O:17])[CH3:15])[CH:7]=[CH:8][C:3]=1[OH:2])[CH:12]([CH3:14])[CH3:13]
Reactant: CCOCC
Reactant: COc1cccc(OC)c1CC(C)C
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(CC(C)C)c1O

Procedure:
1,3-Dimethoxy-2-(iso-butyl)benzene (11.3 g) was dissolved in acetic acid (250 ml) and 48% hydrobromic acid (150 ml). The resultant solution was heated to reflux for 2 days, cooled, and ether and water added. The ether layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated to dryness. The concentrate was chromatographed by HPLC (column eluted with a gradient of 1 to 10% ethyl acetate in hexane) to yield 3.87 g of the title product.
Reaction SMILES: [C:1]1([CH3:21])[C:2]([S:7]([NH:10][C:11]([CH3:20])([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[B].[CH3:23]OCOC>>[C:1]1([CH3:21])[C:2]([S:7]([N:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][C:13]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23]2)(=[O:8])=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)NC(C)(C)Cc1ccccc1
Reactant: COCOC
Agent: [B]
Product: Cc1ccccc1S(=O)(=O)N1Cc2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a nitrogen-blanketed mixture of N-toluenesulfonyl-1,1-dimethyl-2-phenyl-ethylamine (8.30 g, 0.027 mol.) in dimethoxymethane (50 mL) was added boron trifluororo etherate (BF3 ·OEt2, 9.9 mL, 0.081 mol.). The mixture was stirred at room temperature for 12 hours while monitoring by gas chromatography. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), separated, and the organic layer is washed with saturated sodium bicarbonate (2×100 mL) and dried over sodium sulfate (Na2 SO4). The drying agent was filtered off and the filtrate was concentrated at 40°/50 torr to give 8.55 g of N-toluenesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (yield=99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12](#[N:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:13][C:12]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC#N
Reactant: COc1ccc(C=O)cc1Br
Product: COc1ccc(C(O)CC#N)cc1Br

Procedure:
Alkylation of 3-bromo-4-methoxybenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(3-bromo-4-methoxyphenyl)-3-hydroxypropanenitrile as a pale orange oil. Yield (10.32 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.93 (d, J=4.4 Hz, 1H), 4.85-4.81 (m, 1H), 3.81 (s, 3H), 2.86 (ABd, J=16.4, 4.8 Hz, 1H), 2.79 (ABd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[CH3:10]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: Br[Mg]c1ccccc1
Product: CC(O)(c1ccccc1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and phenyl magnesium bromide generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.32-7.16 (m, 6H), 7.11 (dd, J=2.03, 8.48 Hz, 1H), 6.49 (d, J=8.55 Hz, 1H), 6.02 (s, 1H), 5.16 (s, 2H), 1.74 (s, 3H); MS (ES) m/z 274/276 ([M+H]+, 100%); Anal. Calc. For C14H14BrNO: C, 57.55; H, 4.83; N, 4.79. Found: C, 57.67; H, 4.83; N, 4.79.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([O:24][C:25]([C@@H:27]1[CH2:31][C@@H:30]([OH:32])[CH2:29][C@H:28]1[C:33](=[O:45])[NH:34][C@:35]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][C@H:36]1[CH:38]=[CH2:39])=[O:26])([CH3:23])([CH3:22])[CH3:21].[F:46][C:47]1[CH:48]=[C:49]([C:53]2[N:62]=[C:61](O)[C:60]3[C:55](=[C:56]([CH3:66])[C:57]([O:64][CH3:65])=[CH:58][CH:59]=3)[N:54]=2)[CH:50]=[CH:51][CH:52]=1.N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C.C1COCC1>[C:20]([O:24][C:25]([CH:27]1[CH2:31][CH:30]([O:32][C:61]2[C:60]3[C:55](=[C:56]([CH3:66])[C:57]([O:64][CH3:65])=[CH:58][CH:59]=3)[N:54]=[C:53]([C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([F:46])[CH:48]=3)[N:62]=2)[CH2:29][CH:28]1[C:33](=[O:45])[NH:34][C:35]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH:36]1[CH:38]=[CH2:39])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 18 h
Yield: 94.3 %

Procedure:
PPh3 (787 mg, 3.0 mmol) was added to a stirred solution of the alcohol 15 (550 mg, 1.5 mmol) and the quinazolinol 127 (430 mg, 1.5 mmol) in a mixture of dry THF (40 mL) and dry DMF 10 mL. The reaction mixture was put under inert atmosphere (N2) at room temperature and DIAD (591 μL, 3.0 mmol) was added. The reaction mixture was stirred for 18 h whereafter the solvents were evaporated. The residue was dissolved in CHCl3 and washed with brine in a separatory funnel. The organic phase was dried with Na2SO4, evaporated on silica and purified by flash chromatography (heptane:ethyl acetate 2:1 to 1:1) which gave the title compound as a white-beige solid (896 mg, 94%), LRMS (M+H) 634.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([O:25][C:26](=[O:38])[NH:27][CH:28]([CH3:37])[C:29](=[O:36])[NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:34][CH2:35][CH:31]([NH:30][C:29](=[O:36])[CH:28]([NH:27][C:26]([O:25][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:38])[CH3:37])[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 61.5 %

Procedure:
A suspension of 1.4 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.92 g (7.5 mmol) of [1-methyl-2-oxo-2-[(3-pyrrolidinyl)amino]ethyl]-carbamic acid 1,1-dimethylethyl ester, 1.5 g (15 mmol) of triethylamine and 75 ml of acetonitrile was heated at reflux for five hours. The solvent was removed in vacuo and the residue was partitioned between chloroform/water (250 ml each) and acidified to pH 2.0 at 0° with 6.0M hydrochloric acid. The solid was removed by filtration, washed with water and dried in vacuo to give 2.4 g of the title compound, mp 185°-187°.