Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13]Br>C(OCC)C>[Br:13][CH:4]1[C:5](=[O:8])[CH2:6][CH2:7][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]1=2
Reactant: BrBr
Reactant: O=C1CCOc2ccccc2C1
Solvent: CCOCC
Product: O=C1CCOc2ccccc2C1Br
Yield: 70 %

Procedure:
To a solution of 2,3-dihydro-5H-benzo[b]oxepin-4-one (1 eq, 1.6 mmol, 260 mg), in anhydrous diethyl ether (10 ml), bromine was added dropwise (1.1 eq, 1.76 mmol, 90 ul), and the reaction allowed to stir for an hour. The reaction was absorbed onto silica and purified on the ISCO companion running a gradient from 0% ethyl acetate/petrol to 15% ethyl acetate/petrol, with the product seen at 9% ethyl acetate. This gave 5-bromo-2,3-dihydro-5H-benzo[b]oxepin-4-one as an oil (270 mg, yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (59.4 mg, 48%).
Reaction SMILES: [F:1][C@:2]1([C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32]([CH3:40])[CH:31]=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C@:2]1([C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=[C:32]([CH3:40])[CH:31]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl (1R,2R)-1-fluoro-2-{[(4-hydroxyphenyl)sulfonyl]amino}cyclopentanecarboxylate (0.42 g, 1.3 mmol, 1 eq) in DMF (4 mL) was added cesium carbonate (0.86 g, 2 eq) followed by 4-chloromethyl-2-methyl-quinoline. The brown reaction mixture was stirred for 3 days, and then taken up in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated. Purification using silica chromatography eluting with 40-70% ethyl acetate/hexanes afforded methyl (1R,2R)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate as an off white solid (0.23 g, 41%). MS: 473.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:40])[C:26]1[CH:38]=[CH:37][C:36]([OH:39])=[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:27]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>CCCCCCC.CCOC(C)=O>[CH3:23][O:24][C:25](=[O:40])[C:26]1[CH:38]=[CH:37][C:36]([O:39][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH:27]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1ccc(OCCCCCCCCCCCCCCC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Yield: 96.4 %

Procedure:
15-Bromo-pentadecanoic acid tert-butyl ester (598 mg, 1.59 mmol), 4-hydroxy isophthalic acid 3-tert-butyl ester 1-methyl ester (400 mg, 1.59 mmol) and K2CO3 (329 mg, 2.38 mmol) were placed in a flask with acetonitrile (25 ml) and refluxed under N2. The reaction was followed via TLC (4:1 heptane/AcOEt). After 13 h the sample was concentrated under vacuum to near dryness. AcOEt (50 ml) and water (25 ml) were added to the residue. The phases were separated and the organic phase was washed with water and brine (25 ml each), dried over MgSO4 and concentrated to yield an oil (841 mg, 97%).
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:28]([O:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC1=C[C@H]2CC(OC(=O)c3ccccc3)O[C@H]2C1
Temperature: 25 °C

Procedure:
Purified lactol 7 (591.5 mg, 3.84 mmol, 1 eq.), was dissolved in CH2Cl2 (7 ml) and stirred at r.t. Dimethylaminopyridine (23.5 mg, 0.19 mmol, 5 mol %) was added as a solid. Triethylamine (647.5 μl, 4.61 mmol, 1.2 eq.) and benzoyl chloride (534.5 μL, 4.61 mmol, 1.2 eq.) were added via syringe. The reaction mixture was stirred at r.t. for 36 h, filtered over basic alumina and the organic phase was concentrated to give the crude material. The material was purified by column chromatography eluting with petrol/EtOAc (3:1) to give the benzoyl acetal 55 (as an approximately 1.3:1 mixture of diasteroisomers, 706.7 mg, 71%) as pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:12][C:13]1[S:17][CH:16]=[C:15]([C:18]([N:20]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][CH2:22][CH2:21]2)=[O:19])[CH:14]=1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:24]2([O:23][CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:14]=[C:13]([CH3:12])[S:17][CH:16]=3)=[O:19])[CH2:25]2)[CH2:26][CH2:27]1
Reactant: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 9-bromo-1-nonanol (0.335 g) in acetonitrile (3 mL) was added to a solution of (5-methylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 104, step b) (0.28 g) and triethylamine (0.278 mL) in acetonitrile (7 mL). The resulting mixture was stirred at 60° C. overnight. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (30 mL), washed with brine (2×15 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a white solid. Yield 0.3 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([OH:33])=O.[CH3:34][NH:35][CH2:36][CH2:37][NH:38][CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[ClH:70]>C(Cl)Cl>[Cl:70][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([N:35]([CH3:34])[CH2:36][CH2:37][NH:38][CH3:39])=[O:33]
Reactant: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Reactant: Cl
Reactant: CNCCNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNCCN(C)C(=O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A vial was charged with (±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (5 mg, 0.01 mmol), N,N′-dimethylethylenediamine (0.007 mL, 0.066 mmol), HOBt (3 mg, 0.02 mmol), i-Pr2NEt (0.006 mL, 0.032 mmol) and CH2Cl2 (1 mL). EDC.HCl (4 mg, 0.021 mmol) was added. The mixture was stirred at rt for 1 d and evaporated to dryness. The residue was purified by preparative HPLC to afford (±)-(E)-2-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-N-methyl-N-(2-(methylamino)ethyl)acetamide (1.0 mg, 14%). LC-MS Method 1 tR=1.55, min, m/z=548, 550.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH:7]1[NH2:16])[CH2:13]2.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH:7]1[NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 12 h

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in ethyl ether (20 ml) was added dropwise to a stirring mixture of 2-adamantylamine hydrochlbride (9.35 g, 0.05 mole) and triethylamine (30.65 ml) in methylene chloride (200 ml) and ethyl ether (200 ml) over a 30 minute period. The solution was stirred for 12 hours, the solid filtered and washed with ethyl ether and the filtrate stripped to an oily material which was taken up in ethyl acetate and hexane and allowed to stand overnight. The solid was filtered, the filtrate concentrated and chilled and the product as an orange solid filtered and dried. The structure was confirmed by NMR.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.C(OCC)(=O)C>[C:34]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)C(F)(F)F)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of N-{5-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2,2,2-trifluoroacetamide (1.5 g, 3.78 mmol) produced in Example 30 (iv) in tetrahydrofuran (20 mL) were added pyridine (20 mL) and acetyl chloride (403 μL, 5.67 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (300 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (740 mg, 45%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[O:23]([C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([NH:36][CH2:35][CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:31][CH:32]=3)=[O:8])=[CH:4][N:3]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(C(F)(F)F)c(C(=O)NCCc3ccc(Oc4ccccc4)cc3)cn2)CC1

Procedure:
In analogy to example 1 methyl 6-chloro-4-(trifluoromethyl)nicotinate was reacted with N-methylpiperazine and then, using 4-phenoxyphenethylamine in the coupling step, converted to 6-(4-methyl-piperazin-1-yl)-N-[2-(4-phenoxy-phenyl)-ethyl]-4-trifluoro-methyl-nicotinamide. Off-white solid. MS (ISP): 485.2 ([M+H]+)
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10]([CH3:21])([C:16]([O:18][CH2:19]C)=[O:17])[CH2:11]2.CO.O>ClCCl>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10]([CH3:21])([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2
Reactant: CCOC(=O)C1(C)Cc2cccc(OC)c2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)C1(C)Cc2cccc(O)c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 15.2 ml (15.24 mmol) of a 1 M solution of boron tribromide in dichloromethane were added to a solution of 1.19 g (5.08 mmol) of ethyl 4-methoxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate in 20 ml of dichloromethane. Stirring at 0° C. was continued for one hour. 16 ml of methanol were then added, and the reaction mixture was stirred overnight. 10 ml of water and 10 ml of dichloromethane were then added. After phase separation, the aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over magnesium sulfate. After filtration, the solvent was evaporated to dryness under reduced pressure. This gave 897 mg (4.35 mmol, 86% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([CH:15]([C:18]#[N:19])[C:16]#[N:17])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:14][CH3:22])=[C:15]([C:18]#[N:19])[C:16]#[N:17])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=C(C#N)C#N)c1ccc(OCc2ccccc2)cc1
Yield: 79.7 %

Procedure:
Compound 31B (3.7 g, 13.39 mmol) was dissolved in 1,4-dioxane (30 mL) and water (5 mL). To this solution was added to sodium bicarbonate (9.0 g, 107 mmol) portionwise to control the gas formation. To the resulting suspension was added dimethyl sulfate (8.96 mL, 94 mmol). The reaction was heated under reflux for 2 hours. The reaction mixture was concentrated, and partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 7:3/hexanes: EtOAc to provide 3.1 g of the desired product: 1H NMR (DMSO-d6): δ 7.64-7.68 (m, 2H), 7.34-7.69 (m, 5H), 7.22-7.26 (m, 2H), 5.22 (s, 2H), 3.92 (s, 3H). MS (DCI(+)): m/z 308 (M+NH4).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:17](Cl)(=[O:19])[CH3:18]>CCOCC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.3 %

Procedure:
Triethylamine (14.55 mL, 104.43 mmol) was added to an ice-bath cooled solution of 4-methoxyphenol (5.185 g, 41.77 mmol) in anhydrous ether (200 mL) under nitrogen atmosphere. Acetyl chloride (5.94 mL, 83.53 mmol) was added drop-wise and reaction mixture then allowed to warm to room temperature and stir for a further 10 min. The reaction mixture was partitioned between ethyl acetate and sat aqueous sodium bicarbonate solution. The phases were separated and the organic phase was dried over sodium sulphate, filtered and filtrate solvents removed in vacuo to afford the title compound (7.45 g, quant) as a brown liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[C:11]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][NH:21][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=2[O:9][CH3:10])=[CH:22][CH:23]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1c(Cl)ccnc1C
Reactant: CC(C)(C)c1ccc(CON)cc1
Product: COc1c(NOCc2ccc(C(C)(C)C)cc2)ccnc1C
Yield: 80 %

Procedure:
Prepared analogously to Example 1 from 4-chloro-3-methoxy-2-methylpyridine and O-(4-tert-butylbenzyl)hydroxylamine. Yield: 80%; m.p.: 113° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9]Br)[CH3:2].[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][C:14]=2[O:13]1.[OH-].[K+]>COCCOC>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9][O:21][C:16]1[CH:17]=[CH:18][C:19]2[O:20][CH2:12][O:13][C:14]=2[CH:15]=1)[CH3:2]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOCCCC(C)=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOCCCC(C)=CCOc1ccc2c(c1)OCO2
Reaction time: 2 h

Procedure:
2.21 g (0.01 mol) of 6-ethoxy-1-bromo-3-methyl-2-hexene are added at 5° and while stirring to 1.38 g (0.01 mol) of 3,4-methylendioxyphenol and 0.56 g (0.01 mol) of potassium hydroxide in 50 cc of 1,2-dimethoxyethane. After stirring at 5° for 2 hours the mixture is stirred at 20°-25° during the course of 60 hours, is subsequently filtered and the filtrate is evaporated at reduced pressure. The residue is taken up in ether, is washed with water, dried with sodium sulphate, and the ether is distilled off. After chromatography of the residue on silica gel with hexane/ethyl acetate 9 : 1, 5-(6-ethoxy-3-methyl-2-hexenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5192.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].C[Si](Cl)(C)C.N1C=CC=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl.CC(N(C)C)=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[C:12]([OH:14])=[O:13])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Nc1ccc2c(c1C(=O)O)CCCC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of Example 128C (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M trimethylsilyl chloride in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of 4-fluorobenzenesulfonyl chloride (0.042 g, 0.24 mmol) in dimethylacetamide (1 mL), shaken for 16 hours at ambient temperature, and concentrated. The concentrate was acidified to pH 1.0 with 5% aqueous HCl and extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4); filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(+)) m/e 367 (M+NH4)+, 372 (M+Na)+; MS (ESI(−)) m/e 348 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.77 (dd, 2H), 7.40 (t, 2H), 7.00 (d, 1H), 6.65 (d, 1H), 2.65 (m, 4H), 1.67 (m, 4H).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:17])[CH2:15][Cl:16])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)(Cl)Cl.[Fe]>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:17])[CH2:15][Cl:16])=[C:11]([Br:1])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1Br
Reaction time: 17 h

Procedure:
16 parts by weight of bromine are added dropwise to a mixture of 23 parts by weight of 3-(p-tert.-butyl-phenyl)-2-methyl-propyl chloride and 0.5 part by weight of iron powder. The reaction temperature rises to 35° C. Stirring is continued for 17 hours, the product is dissolved in chloroform, the solution is washed with water, with aqueous NaHCO3 solution and again with water and is dried over Na2SO4, the solvent is evaporated and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)[O:15][CH2:14]1.C(=O)(O)[O-:25].[Na+]>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:25])[CH2:20][CH2:21][C:16]2([O:23][CH2:13][CH2:14][O:15]2)[CH2:17][CH2:18]1
Reactant: O=C1CCCCC12OCCO2
Reactant: Brc1ccccn1
Reactant: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(c2ccccn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-pyridine (10 g, 63.3 mmol) in tetrahydrofuran (200 mL) at −78° C. under an argon atmosphere was added a solution of n-butyllithium (26 mL of 2.5N solution, 65 mmol). The solution was stirred at −78° C. for 10 minutes and then a solution of cyclohexanedione monoethylene ketal (10 g, 64 mmol) in tetrahydrofuran(50 mL) was added. The reaction was allowed to warm to room temperature and poured into a saturated solution of sodium bicarbonate (mL) the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed over silica gel eluting with 25% to 50% ethyl acetate/hexane to give the product.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH3:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[CH3:34])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(C)c(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)ccc3C)c(=O)n(C3CCCC3)c12
Yield: 34.6 %

Procedure:
1-Cyclopentyl-3-(2,5-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (46 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-2,5-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].FC1C=[C:17]([C:23]#[N:24])[CH:18]=[C:19]([CH:22]=1)[C:20]#N.C(Cl)(=O)C1C=CC=NC=1.N>>[F:13][C:11]1[CH:12]=[C:3]([CH:4]=[C:5]([C:6]2[N:7]=[C:22]([C:19]3[CH:20]=[N:24][CH:23]=[CH:17][CH:18]=3)[O:9][N:8]=2)[CH:10]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(F)cc(C(N)=NO)c1
Reactant: N#Cc1cc(F)cc(C#N)c1
Agent: N
Agent: O=C(Cl)c1cccnc1
Product: N#Cc1cc(F)cc(-c2noc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-5-fluoro-N′-hydroxybenzimidamide (Prepared from 5-fluoroisophthalonitrile using the procedure described in Example 4A.) and nicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.77 (m, 1 H), 8.2 (m, 2 H), 8.4 (m, 1 H), 8.6 (m, 1 H), 8.9 (m, 1 H), 9.4 (m, 1 H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.