Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([OH:11])[CH:10]=1)[C:7](=O)[CH2:6][CH:5]2[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]2[CH2:7][CH2:6][CH:5]([CH3:13])[C:4]=2[CH:3]=1
Reactant: CC1CC(=O)c2c(O)cc(F)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCc2c(O)cc(F)cc21
Temperature: 170 °C

Procedure:
5 g of 5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-one was heated to 80° C. until all the solid was melted. After adding aluminium chloride (9.3 g) to this melt the reaction mixture was heated to 170° C. during 17 hours. After cooling water and ethyl acetate were added and the mixture was heated on a steam bath until everything was dissolved. The organic layer was separated and washed with water and brine. After removing the solvent the compound was purified by chromatography with the add of heptane/ethylacetate (9:1) resulting in 2.2 g of 6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol as a semi-solid, M.S. (C.I.) (M/Z): 167 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:18])=[O:19])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:45])[NH2:39])=[CH:36][CH:37]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-5-(quinoline-8-sulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]\[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1.C1(C2C=CC=CC=2)C=CC(C(C2C=CC(C3C=CC=CC=3)=CC=2)=C/C=C/C(NCCCCC2C=NC=CC=2)=O)=CC=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]\[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Agent: O=C(/C=C/C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1)NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C\C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 39 %

Procedure:
As in Example 134, a solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.2 g) and 3-pyridinebutanamine (0.42 g) in tetrahydrofuran (7 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was contaminated with a minor amount of the (E)-isomer. The mixture was separated by HPLC (ethyl acetate) and the desired product was crystallized from ether (2×) to yield 0.48 g of (Z)-5,5-bis(3-methoxyphenyl)-N-[4-(3-pyridinyl)-butyl]-2,4-pentadienamide mp 69°-73° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH:34]=[O:35].[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH:39]=[C:40](B1OC(C)(C)C(C)(C)O1)[NH:41]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:36][C:37]1[C:38]2[CH:39]=[C:40]3[C:2]4[N:7]=[C:6]([C:8]5[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]6[O:15][C:14]([C:16]7[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=7)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=6[CH:27]=5)[CH:5]=[CH:4][C:3]=4[CH:34]([OH:35])[N:41]3[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=O)c(Cl)n3)cc12
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C4O)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
To a degassed solution of 5-(6-chloro-5-formylpyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.29 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (94 mg, 0.35 mmol) in 1,4-dioxane (3 mL) and water (200 μL) was added CS2CO3 (189 mg, 0.58 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (30 mg, 0.05 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred for 3 hours. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with (30% ethyl acetate/DCM) to provide 5-(10-fluoro-5-hydroxy-5H-pyrido[2′,3′:3,4]pyrrolo[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 22%) MS (M+H)+: 615.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]([O:12][CH3:13])=[O:11].COC1C=CC=CC=1OC>CO>[CH3:13][O:12][C:10]([CH2:9][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: Oc1ccccc1
Reactant: COC(=O)CCl
Solvent: COc1ccccc1OC
Solvent: CO
Product: COC(=O)COc1ccccc1

Procedure:
Illustrative Embodiment 1 is repeated with a mixture of 32 g of phenol, 56 g of methyl chloroacetate, 13 g of methanol and 8 g of dimethoxy benzene (as a gas chromatograph standard). Methyl phenoxy acetate is formed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.CN1CCOCC1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CN(C=O)C>[S:12]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:1][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:3]2)([OH:15])(=[O:13])=[O:14]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(O)CCC(=O)Nc1ccc2c(S(=O)(=O)O)cccc2c1

Procedure:
6-Amino-1-naphtalenesulfonic acid (Dahl's acid) (1 eq, 0.5 mmol,) was dissolved in DMF containing N-methylmorpholine (NMM) (2 eq), and succinic anhydride (10 eq) was then added. After over night reaction the solvent was removed under reduced pressure and the product was purified by preparative RP-HPLC (Reversed Phase HPLC). The column (Phenomenex Luna C18 10μ, 22×250 mm) was eluted at 10 ml/min with a gradient of 5 to 15% acetonitrile (ACN) in 0.1% aq TFA over 40 min. The desired peak fractions collected from six consecutive runs were pooled and lyophilized affording 146 mg of pure N-(−5-Sulfo-naphthalen-2-yl)-succinamic acid 2. Analytical RP-HPLC: tR=16.7 min, (Phenomenex Luna 5μ, 4.6×250 mm, 5-15% ACN in 0.1% aq TFA over 20 min at 1 ml/min, λ=214 nm). Electrospray MS: [M+H]+ of product expected at 324.0 m/z, found at 324.0 m/z.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C.Cl[C:44]([O:46][CH2:47][CH3:48])=[O:45]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-(2-aminophenyl)piperidin-3-one (0.9 g) obtained in Step 2 of Example 43 in 20 ml of dichloromethane was cooled to 0° C. 0.54 ml of triethylamine and 0.37 ml of ethyl chloroformate were added to the reaction mixture, which was then stirred for about 3 hours at room temperature. 20 ml of ice water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 600 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16]C1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:16][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1ccc(-c2nccnc2Cl)cc1
Product: COc1ccc(-c2nccnc2Cl)cc1
Yield: 54 %

Procedure:
Use the method used to make 2-chloro-3-(4-chlorophenyl)-pyrazine, using 4-methoxyphenylboronic acid to obtain 2-chloro-3-(4-methoxyphenyl)-pyrazine (54% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9]O.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:13][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)COCCN1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)COCCN1CCBr
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a solution of 2-(3,3-dimethyl-morpholin-4-yl)-ethanol (7.2 g, 45 mmol) and CBr4 (16.4 g, 49 mmol, 1.1 equiv.) in THF (150 mL) was added dropwise a solution of PPh3 (12.9 g, 49 mmol, 1.1 equiv.) in THF (75 mL). The resulting slurry was stirred at room temperature for 19 hours, at which time the slurry was diluted with hexanes and filtered. The filtrate was concentrated in vacuo and the resulting oil was diluted with CH2Cl2. The solution was then washed twice with NaHCO3 (aqueous, saturated) and brine. The aqueous layers were back-extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was distilled (65° C., 0.5 torr) to provide 4-(2-Bromo-ethyl)-3,3-dimethyl-morpholine (5.4 g, 54%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 3.69 (t, 2H), 3.28 (s, 2H), 3.28 (t, 2H), 2.70 (t, 2H), 2.58 (t, 2H), 0.99 (s, 6H); LC/MS found 222.02 (M++H, C8H17BrNO requires 222.05).
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[N:5]=[C:6]([OH:14])[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1.[CH3:15][OH:16]>>[OH:14][C:6]1[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=[C:4]([CH2:3][O:16][CH3:15])[N:5]=1
Reactant: CO
Reactant: Oc1nc(CCl)nc2c1SCCC2
Agent: [Na]
Product: COCc1nc(O)c2c(n1)CCCS2

Procedure:
Sodium metal (0.46 g, 0.02 gr. atm.) was dissolved in methanol (100 ml) and the product from step A was added. The reaction mixture was refluxed for 4 hours and then most of the solvent was removed in vacuo. The addition of water afforded 1.2 g of title compound which was dried and used in step C without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:13]([OH:17])(=[O:16])[C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>[O-]S([O-])(=O)=O.[Cu+2].O.CC(O)(C)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[CH:15]=[C:14]([C:13]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: C#CC(=O)O
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Difluorobenzyl azide (III) (3.5 g, 20.7 mmoles) is suspended in a H2O-tBuOH 1:1 mixture (80 ml), then propiolic acid (1.59 g, 22.8 mmoles), an ascorbic acid 1M solution (2.1 ml) and a CuSO4 0.3 M solution (0.7 ml) are added thereto. The reaction mixture is kept at 40° C., under stirring and is completed after 2 h. The mixture is left to cool at room temperature thereby precipitating the product. The solid is filtered off on a Buchner filter, washed with ethyl ether and dried under vacuum.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:23].[Mn+2:24].[Cl-:25]>CO>[Cl:23][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]1[Cl:25].[Mn+2:24]
Reactant: [Cl-]
Reactant: c1ccc(CC2CNCCNCCNCCNCCN2)cc1
Agent: [Mn+2]
Solvent: CO
Product: ClN1CCNCCNCCNCCNCC1(Cl)Cc1ccccc1
Yield: 89 %

Procedure:
A solution of 2-phenylmethyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 6D (1.5 g, 4.9 mmole) and anhydrous manganese(II) chloride (0.62 g, 4.9 mmole) in anhydrous methanol was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and the solvent removed in vacuo. The yellow gummy solid was purified by stirring vigorously in acetone to give 1.89 g (89% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 395/397 [(M-Cl)+, 100/31]; Anal. calcd. for C17H31Cl2 nN5 : C, 47.34; H, 7.24; Cl, 16.44; N, 16.24. Found: C, 46.84; H, 7.51; Cl, 16.38; N, 15.86.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])[CH3:3].[H-].[Na+].[CH3:35]I>C1COCC1.CN(C=O)C>[CH3:32][O:31][C:6]1[CH:7]=[C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:17][CH2:18]2)=[O:12])[CH:9]=[CH:10][C:5]=1[C:2]([O:1][CH3:35])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)OC
Reaction time: 0.03 h
Yield: 35 %

Procedure:
(4-(2-Hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (crude material from step 1) was dissolved in a mixture of THF (3 mL) and DMF (3 mL). NaH (28 mg, 0.69 mmol) was added and the reaction mixture was allowed to stir for 2 minutes. MeI (54 μL, 0.86 mmol) was then added and the reaction mixture was allowed to stir for 1 h. The reaction mixture was evaporated to dryness and the residue was suspended in 25 mL of dichloromethane. The suspension was washed two times with a 1M solution of hydrochloric acid, followed by two washes with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by column chromatography utilizing a gradient of 0-35% ethyl acetate in hexanes give (3-methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (94 mg, 35% over 2 steps). ESI-MS m/z calc. 446.2. found 447.5 (M+1)+; Retention time: 7.60 minutes (15 min run). 1H NMR (400 MHz, DMSO) δ 7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.17-6.98 (m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m, 1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 4H) and 1.50 (s, 6H).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)CBr>CN.CO.CN(C)C=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH2:7][CH2:6][NH2:3]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CN(C)C=O
Solvent: CO
Product: NCCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
Triethylamine (5.28 g; 52.2 mmol) was dissolved in 40% methylamine in methanol (100 ml). While the mixture was stirred at room temperature, 3,5-dibromobenzyl bromide (17.2 g; 52.2 mmol) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid (150 ml), and the mixture was extracted with diethyl ether (150 ml), to thereby exclude impurities. The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 11.3 g of the target compound as orange oily matter (yield: 77.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C@@H:12]([C:17]([OH:19])=[O:18])[C:13]([SH:16])([CH3:15])[CH3:14]>CO.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[NH:11][C@@H:12]([C:17]([OH:19])=[O:18])[C:13]([CH3:15])([CH3:14])[S:16]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Solvent: O
Product: CC1(C)SC(c2ccc(Cl)cc2Cl)N[C@H]1C(=O)O

Procedure:
3.5 g (20 mmoles) of 2,4-dichlorobenzaldehyde dissolved in 17 ml of methanol are added to a solution containing 3.0 g (20 mmoles) of D-penicillamine in 65 ml of water while stirring. After stirring for 16 hours, the precipitate is filtered, washed with 50% methanol and dried to give the title acid in a yield of 5.82 g (95%), m.p.: 150°-151° C., [α]D20 =+353° (c=0.45, dimethylsulphoxide).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.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:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: OB(O)c1cccc(Cl)c1
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: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cncc(-c2cccc(Cl)c2)c1
Temperature: 25 °C

Procedure:
A three neck flask was charged with 5-bromonicotinic acid (2 g, 9.90 mmol), 3-chlorophenylboronic acid (1.55 g, 9.90 mmol), a 0.4 M solution of sodiumcarbonate in water (37 mL, 14.8 mmol) and Acetonitrile (37 mL). The solution was degassed under vacuum and tetrakistriphenylphoshine Pd(0) (0.57 g, 0.495 mmol) was added and the reaction refluxed overnight under nitrogen. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was partially evaporated under reduced pressure and the remaining solution acidified to pH=2 with 1N HCl. The resulting solid was collected by filtration and dried under vacuum. 1H NMR [(CD3)2SO]: δ 9.15-9.05 (m, 2H), 8.45 (s, 1H), 7.85 (s, 1H), 7.80-7.65 (m, 1H), 7.60-7.42 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH:11]=2)[CH:9]=O)[CH2:3][CH2:2]1.ClC1C=CC([N:25]2[C:33](C(NC)=O)=[C:32]3[C:27](C=[C:29]([NH:41]S(C)(=O)=O)[C:30](C4CC4)=[CH:31]3)=N2)=CC=1.CC1C=CC(N)=NC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCO.C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]3[C:8](=[CH:9][N:41]([C:29]4[CH:30]=[CH:31][C:32]([CH3:27])=[CH:33][N:25]=4)[N:12]=3)[CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Agent: Cc1ccc(N)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Temperature: 100 °C
Yield: 43 %

Procedure:
To a stirred solution of 5-cyclopropyl-2,4-dinitrobenzaldehyde (prepared according to the synthesis of Compound (1)) (50 mg, 0.212 mmol) in EtOH (750 mL) was added 5-methylpyridin-2-amine (25 mg, 0.23 mmol) and the resultant solution stirred at RT for 2d after which time a solid had precipitated from solution. Triphenylphosphine (167 mg, 0.64 mmol) was added in a single portion and the reaction then heated at 100° C. in a sealed tube for 4 h. Upon cooling to RT, the reaction was diluted with DCM (2 mL) and the organics were washed with aq. 30% hydrogen peroxide solution (2 mL). The organics were separated and filtered through a plug of MgSO4 and then purified by automated column chromatography (Biotage SP4, Grace 4 g silica cartridge) eluting with EtOAc:n-heptane (gradient elution, 0% equil. (2 CV), 0% (1CV), 0 to 100% (35 CV), 100% (5 CV)) to give (ii) (27 mg, 43%). ESI-MS: calculated [M+H]+ 295.1. observed [M+H]+ 295.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:3][CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccnc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(Nc2ccnc3ccccc23)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of 4-aminoquinoline (H. Shinkai et al., J. Med. Chem., 2000, 43, pp. 4667-4677) (251 mg), chlorotriphenylmethane (533 mg), and triethylamine (266 μL) in methylene chloride (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% ethyl acetate-hexanes) to give quinolin-4-yltritylamine as a pale yellow foam (610 mg).
Reaction SMILES: Br[CH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].ClC1C=C(C(F)(F)F)C=CC=1OC1C=CC([N+]([O-])=O)=C(O)C=1.ClC1C=C(C(F)(F)F)C=C(Cl)C=1OC1C=CC([N+]([O-])=O)=C(O)C=1.[Cl:59][C:60]1[CH:76]=[C:75]([C:77]([F:80])([F:79])[F:78])[CH:74]=[C:73]([F:81])[C:61]=1[O:62][C:63]1[CH:64]=[CH:65][C:66]([N+:70]([O-:72])=[O:71])=[C:67]([OH:69])[CH:68]=1.ClC1C=C(C(F)(F)F)C=CC=1OC1C=CC([N+]([O-])=O)=C(C=1)OC(C)(C(OCC)=O)C(OCC)=O>>[Cl:59][C:60]1[CH:76]=[C:75]([C:77]([F:80])([F:79])[F:78])[CH:74]=[C:73]([F:81])[C:61]=1[O:62][C:63]1[CH:64]=[CH:65][C:66]([N+:70]([O-:72])=[O:71])=[C:67]([CH:68]=1)[O:69][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1O
Reactant: CCOC(=O)C(CBr)C(=O)OCC
Agent: CCOC(=O)C(C)(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Agent: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Agent: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Product: CCOC(=O)C(C)(Oc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC

Procedure:
Similarly by using diethyl bromomethylmalonate in place of diethyl bromomalonate, and carrying out the reaction with 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenol, 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitrophenol or 5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrophenol, diethyl 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]-2-methylmalonate (IV-2), diethyl 2-[5-(2,6-dichloro-4-trifluoromethylphenoxy)- 2-nitrophenxoy]-2-methylmalonate (IV-3) and diethyl 2-[5-(2-chloro-6-fluoro-4-trifluoro methylphenoxy)-2-nitrophenoxy]-2-methylmalonate (IV-4) were obtained. The physical properties of these compounds are shown in Table 2.