Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[F:19][C:20]([F:31])([F:30])[C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:23]([C:22]([F:26])([F:27])[C:21]([F:28])([F:29])[C:20]([F:31])([F:30])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Cl)cc1N
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2[nH]1
Yield: 47 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (20 g, 96.61 mmol) in DMSO (200 ml) was added 2,4-dichlorophenol (15.8 g, 96.93 mmol) and potassium carbonate (26.7 g, 193.18 mmol). The resulting solution was stirred overnight at 90° C. and then quenched by the addition of water (1000 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline as a yellow solid (23 g, 71%). Next, the 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline (22 g, 65.96 mmol) was added to ethanol (200 ml) and hydrogen chloride (16 ml, 197.9 mmol). This was followed by the addition of Zn powder (21.4 g, 395.8 mmol) at room temperature in portions. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (500 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (4×200 ml). The combined organic layers were dried and concentrated under reduce pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine as a red oil (15 g, 75%). Finally, a solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (14 g, 46.12 mmol) in heptafluorobutanoic acid (150 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (400 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 2%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (10.4705 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:17]([C:19](O)=[O:20])[CH3:18].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:13]1([NH:12][C:3]2[C:4]([C:5](=[O:6])[NH:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C@@H:17]([NH:16][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH3:18])[CH2:15][CH2:14]1
Reactant: CNC(=O)c1cccc(N)c1NC1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-2-(cyclopropylamino)-N-methylbenzamide (1.31 g, 6.38 mmol) in DMF (3 mL) was added Boc-L-Ala-OH (1.21 g, 6.38 mmol), 1,1′-dimethyltriethylamine (2.22 mL, 12.8 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (3.99 g, 7.66 mmol) the resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by column chromatography on a silica gel column using EtOAc:DCM (1:1) as eluent to give (S)-tert-butyl 1-(2-(cyclopropylamino)-3-(methylcarbamoyl)phenylamino)-1-oxopropan-2-ylcarbamate: 1H NMR (400 MHz, CDCl3) δ 8.56 (br, 1H), 8.14 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 6.99 (dd, J=8, 8 Hz, 1H), 6.24 (br, 1H), 6.01 (br, 1H), 4.38 (br, 1H), 3.00 (d, J=4 Hz, 3H), 2.58 (br, 1H), 1.60 (s, 3H), 1.48 (s, 9H), 0.64-0.59 (m, 2H), 0.54-0.49 (m, 2H); LC-MS (ESI) m/z 377.2 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:10]1(C)[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.[CH:21](O)([CH3:23])[CH3:22]>>[C:1]([O:9][CH:21]([CH3:23])[CH3:22])(=[O:8])[C@H:2]([CH2:4][C:5]([O:7][CH:10]([CH3:15])[CH3:11])=[O:6])[OH:3]
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: CC(C)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-malic acid was dissolved in isopropanol and p-toluenesulphonic acid (cat) was added and stirred at room temperature for 24 h. The reaction mixture was concentrated and distilled to give (S)-diisopropyl malate as colorless liquid. The residual material in the distillation flask was dissolved in EtOH and processed as above. Distillation afforded additional diester, raising the total yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([SH:9])[N:3]=1.OO.C(O)(=[O:14])C.[OH-:16].[Na+]>>[NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9]([OH:14])=[O:16])[N:3]=1
Reactant: CC(=O)O
Reactant: Nc1cc(N)nc(S)n1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: Nc1cc(N)nc(S(=O)O)n1
Reaction time: 0.5 h

Procedure:
To a solution of 50 g of 4,6-diamino-2-mercaptopyrimidine (Aldrich, Milwaukee, Wis., USA) in 2N NaOH (220 mL) was added 750 mL of a 3% hydrogen peroxide solution. The solution was maintained at a temperature less than 20° C. Stirring was continued for a further 30 minutes and the clear pale yellow solution was acidified with acetic acid (ca. 50 mL). The precipitate was washed with H2O and air dried, to give 33 as 58 g (95 % yield) of an off-white amorphous acid (m.p. 168°-170° C. decomp.). For analysis, a sample was dissolved in dilute aqueous ammonia and reprecipitated with acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43](=[O:46])[CH2:44][CH3:45].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:42][C:43](=[O:46])[CH2:44][CH3:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCC(=O)CBr
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)OC(C)(C)C)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A solution of tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.07 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl)amide (1.0M solution in THF; 0.186 ml), followed by 1-bromo-2-butanone (0.08 ml). The resultant solution was allowed to reach room temperature and stirred for a further 72 h. Methanol (1 ml) was added and the resultant solution concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5, ethyl acetate and methanol:ethyl acetate 1:9) to give the title compound (0.07 g) as a gum.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([C:14](=NO)[CH:15]=C)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CCC.[CH3:19]C1C=CC=CC=1C>C(C(CCCC)C([O-])=O)C.[Cu+2].C(C(CCCC)C([O-])=O)C>[CH2:3]([C:2](=[CH2:19])[C:1]#[N:4])[CH2:15][CH2:14][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccccc1C
Reactant: C=CC#N
Reactant: C=CC(CCCCCCCCC)=NO
Agent: [Cu+2]
Agent: CCCCC(CC)C(=O)[O-]
Product: C=C(C#N)CCCCCCCCC
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A solution of 80.7 g of acrylonitrile and 5.3 g of copper(II) 2-ethylhexanoate in 250 g or o-xylene was heated to the boil (97° C.), after which 151.5 g of 99% pure alpha-nonylacrolein oxime were added dropwise in the course of 15 minutes, the temperature increasing to 115° C. during the addition. When the addition was complete, refluxing was continued for a further 10 minutes, after which the reaction mixture was cooled to -8° C. and the precipitated acrylamide was filtered off under suction. Fractional distillation of the mother liquor gave 121 g (89%) of alpha-nonylacrylonitrile of boiling point 122°-124° C./ 12 mbar.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[N:11]=[C:10]([CH:12]=[CH:22][CH:23]=[O:24])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: O=CC=Cc1cccc(-n2cccn2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:25]([O:16][CH:15]([C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:24][CH2:23][C:5]1=2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)O
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)C(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol (500 mg, 1.55 mmol) and isobutyric acid (274 mg, 3.1 mmol) in DCM (100 mL) were added EDC.HCl (657 mg, 3.4 mmol), DMAP (19 mg, 0.16 mmol) and TEA (346 mg, 3.4 mmol). The reaction mixture was stirred at RT for 16 h and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4% MeOH-DCM) followed by reverse phase purification to yield 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl isobutyrate (310 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.53 (d, 2H), 7.2 (d, 1H), 7.18 (s, 1H), 7.04 (d, 2H), 6.97 (d, 1H), 5.98 (t, 1H), 4.4 (dd, 1H), 4.14 (dd, 1H), 3.64 (q, 2H), 2.73 (m, 2H), 2.6 (m, 1H), 2.49 (s, 3H), 2.43 (s, 3H), 2.37 (m, 1H), 1.15 (d, 3H), 1.09 (d, 3H). Separation by chiral HPLC provided enantiomers 54a and 54b.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:6][NH:7][NH2:8])[CH2:5][CH2:4]1.[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>C(O)C>[ClH:1].[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:7]([CH2:6][CH:3]2[CH2:5][CH2:4]2)[N:8]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCC1CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CC2CC2)n1
Yield: 89.6 %

Procedure:
A mixture of Example 27B (13.5 g, 85 mmol) and 4,4-dimethyl-3-oxopentanenitrile (11.69 g, 93 mmol) in ethanol (50 mL) was refluxed at 90° C. for 6 hours. The mixture was concentrated under reduced pressure and ethyl acetate (20mL) added to the residue. The white solid precipitate was filtered, washed with ether and dried to yield 17.5 g (90%) of title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42-0.54 (m, 4H), 1.16-1.27 (m, 1H), 1.28 (s, 9H), 4.02 (d, J=7.12 Hz, 2H), 5.53 (s, 1H), 6.91 (s, 2H), 14.05 (s, 1H); H); MS (DCI) m/z 294 [M+H]+.
Reaction SMILES: [Br-:1].[CH2:2]([N+:4]1[N:5]=[CH:6][N:7]([NH2:9])[CH:8]=1)[CH3:3].[C:10](#N)[CH3:11]>[N+]([O-])([O-])=O.[Ag+].CO>[Br-:1].[CH3:3][C:2]1([N+:4]2[N:5]=[CH:6][N:7]([NH2:9])[CH:8]=2)[CH2:11][CH2:10]1
Reactant: CC#N
Reactant: CC[n+]1cn(N)cn1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Br-]
Solvent: CO
Product: CC1([n+]2cn(N)cn2)CC1

Procedure:
To a preweighed Erlenmeyer flask, 1.0303 g, 4.7 mmol, of 1-ethyl-4-amino-1,2,4-triazolium bromide was measured out under nitrogen conditions. Methanol, 25 ml, was added to dissolve the salt, resulting in a clear solution, homogeneous. In a second preweighed Erlenmeyer flask, 0.8045 g, 4.7 mmol, of silver nitrate was measured out. Acetonitrile, 4 ml, was added along with 15 ml of methanol to dissolve the salt, resulting in a clear, homogeneous solution. The silver nitrate solution was added, dropwise, to the 1-methylcyclopropyl-4-amino-1,2,4-triazolium bromide solution, resulting in an immediate clouding and precipitation in the solution. The reaction mixture was allowed to stir at ambient temperature for thirty minutes. At the end of the thirty minutes the reaction mixture was filtered through a filter of celite removing the silver halide. The reaction vessel was rinsed three times, 10 ml each, with fresh methanol and the solution transferred to a 500 ml round bottom flask. The flask was placed on a rotary evaporator, the solvent was removed, leaving an oil. The oil was dissolved in a minimal amount of methanol and transferred to a preweighed Schlenk flask, placed in an oil bath at 60° C., and vacuum dried for 24 hours. The product was an oil which solidified upon standing, yield 0.9285 grams, 4.7 mmoles. Melting point 53° C., DSC onset 210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].Cl[C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C(=O)C.C(OCC)C.C(OCC)(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:25])[CH3:24]
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
2-Amino-5-methanesulfonylamino-benzenesulfonamide (Example 17d, 23.27 g, 87.81 mmol) was dissolved in N,N-dimethylacetamide (100 mL) and diethyl ether (100 mL). Ethyl 3-chloro-3-oxo-propionate (13.88 g, 92.20 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with ethyl acetate (400 mL) and was extracted with water (400 mL). The aqueous layer was back-extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and most of the solvent was removed in vacuo to a volume of ˜100 mL. To the stirred solution was added hexanes (100 mL) upon which a precipitate formed. The precipitate was collected by vacuum filtration, washed with hexanes and dried under high vacuum to afford the analytically pure product, N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (31.22 g, 85.53 mmol, 97.4% yield) as a light-brown solid. 1H NMR (400 MHz, CD3OD) δ: 1.31 (3H, t, J=7.0 Hz), 3.00 (3H, s), 3.59 (2H, s), 4.25 (2H, quartet, J=6.9 Hz), 7.42-7.45 (1H, m), 7.86 (1H, m), 7.92 (1H, d, J=8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11](=[O:27])[NH:12][C:13](=[O:26])[N:14]([CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[C:15]=1[CH3:16].C(OC([NH:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:37]COS(C)(=O)=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C(OC(C)=O)(C)C.CS(O)(=O)=O>CN(C=O)C.O>[NH2:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:37][N:12]1[C:11](=[O:27])[C:10]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])=[C:15]([CH3:16])[N:14]([CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccccc1
Reactant: COc1cccc(-c2c(C)n(Cc3c(C)cccc3F)c(=O)[nH]c2=O)c1Cl
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(C)cccc3F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Temperature: 50 °C
Reaction time: 17 h

Procedure:
7b (120 g, 0.271 mol), 1d (128.34 g, 0.407 mol) and K2CO3 (93.64 g, 0.407 mol) were charged to the reaction vessel under an inert atmosphere and suspended in DMF. The resulting slurry was warmed to 50° C. and stirred for 17 hours. The reaction was incomplete so additional 1d (50 g, 0.158 mol) and DMF (300 mL) were added. The reaction was complete after 32 hours and the mixture was cooled to RT. i-PrOAc (1 L) and water (1 L) were added and stirred for 30 minutes. The layers were separated and MeSO3H (52.8 mL, 0.813 mol) was added slowly to the organic layer controlling the exotherm (24.4° C. to 41.0° C.). The mixture warmed to 60° C. and was stirred for 3 hours. The mixture was cooled to RT and was added slowly to a mixture of K2CO3 (186.99 g, 1.35 mol) in water (975 mL). After stirring for 15 minutes, the organic layer was separated and extracted with a H3PO4 solution (94 g of 85% H3PO4 in 975 mL water). The aqueous layer was slowly added to K2CO3 (186.99 g, 1.35 mol) in water (975 mL), followed by i-PrOAc (1100 mL). The mixture was stirred for 10 minutes and the layers separated. The i-PrOAc layer was dried (NaSO4) and concentrated to give 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 7c as a foaming solid (145.5 g, 0.25 mol, 95% crude yield, uncorrected for purity).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.Cl[CH2:11][C:12](O)=O.C(=S)=[S:16]>>[S:16]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:12]=[CH:11]1
Reactant: S=C=S
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C(O)CCl
Product: c1ccc2sccc2c1

Procedure:
In further detail, a compound (XIV) is reacted with a benzoyl chloride in the presence of a Lewis acid (e.g. aluminum chloride or tin tetrachloride) to obtain a compound (XV). Usually, this reaction can be carried out by the use of or without a solvent (e.g. carbon disulfide or nitrobenzene) in a temperature range of room temperature to about 100° C. Then, the compound (XV) is reacted with chloroacetic acid in a temperature range of approximately 80°-130° C. to obtain benzothiophene or a derivative thereof (IIb).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([O:20][CH3:23])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(CO)c(O)c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(CO)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To 190 mg of 4-hydroxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1 mL of iodomethane, 200 mg of K2CO3 and 3 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 200 mg of 4-methoxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](O)=[O:23])[C:13](=[O:29])[CH:12]=[CH:11]2.[CH2:30]([N:32](CC)CC)[CH3:31].C(OC(Cl)=O)C.[NH2:43]N>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([C:22]3[O:23][C:30]([CH3:31])=[N:32][N:43]=3)[CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:29])[CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Reactant: NN
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(F)c(-c3c(=O)ccn4c(-c5ccc(F)cc5F)cccc34)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 3-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-4-fluorobenzoic acid (Example 31, 1.0 g, 2.53 mmol) in CH2Cl2 (20 mL) was added triethyl amine (511 mg, 5.06 mmol) and ethylchloroformate (409 mg, 3.79 mmol) at 0° C. The mixture was warmed to ambient temperature and allowed to stir for an additional 1 h. The reaction was quenched with aqueous NH4Cl, extracted with CH2Cl2 and washed with 0.5 N HCl (1×), brine, dried over MgSO4, and concentrated in vacou. The crude mixture was dissolved in CH2Cl2 and was added to a hydrazine solution (25.3 mmol of hydrazine in 10 mL CH2Cl2) via cannula. After stirring for 10 min at room temperature, the reaction was concentrated in vacuo to yield a solid. The crude solid was washed with MeOH and ether/EtOAc (1/1) to remove impurity. The resulting solid was added MeOH (5 mL) and trimethyl orthoacetate (20 mL) and heated to 110° C. for 2 hrs. LCMS revealed the reaction was complete and the mixture was concentrated in vacuo. The crude material was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to give the title compound as a yellowish solid (450 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6](=[N:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].[Br:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(#N)C(C)C>[Br-:25].[CH2:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([N:16]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[N+:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C(N(CCCC)CCCC)N(CCCC)CCCC
Reactant: CCCCBr
Agent: CC(C)C#N
Product: CCCCN(CCCC)C(N(CCCC)CCCC)=[N+](CCCC)CCCC
Product: [Br-]

Procedure:
A mixture of 1.7 grams (5 mmol) of penta-n-butylguanidine (made as described earlier), 0.686 grams (5 mmol) of 1-bromobutane and 10 ml of isobutyronitrile was heated under reflux for 20 hours. Upon vacuum stripping, a pale yellow oil was obtained which crystallized to a pale brown solid upon standing. Upon recrystallization from a mixture of hexane and ethyl acetate, the desired N,N,N′,N′,N″,N″-hexa-n-butylguanidinium bromide was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:16][C:17]([O:19]C(C)(C)C)=O)=[C:4]([NH:8][C:9](OC(C)(C)C)=[O:10])[S:5][C:6]=1[CH3:7].C(OCC)(=O)C(OCC)=O.O>C(O)(=O)C>[CH3:7][C:6]1[S:5][C:4]2[NH:8][C:9](=[O:10])[C:17](=[O:19])[NH:16][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1sc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)c1C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Solvent: O
Product: Cc1sc2[nH]c(=O)c(=O)[nH]c2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
Crude di-t-butyl 4,5-dimethylthiophene-2,3-dicarbamate (9.7 g) was dissolved in 70 ml of acetic acid and 70 ml of diethyl oxalate and heated at reflux for three hours. 70 ml of water was added to the hot solution to precipitate the product. After 24 hours of stirring at room temperature the title compound was isolated by filtration, recrystallised from ethanol/acetic acid (65:35) to yield 1.5 g (41%) of crystals. M.p.>300° C. MS: 196. 1H-NMR (DMSO-D6, δ): 2.0 (s, 3H), 2.2 (s, 3H), 11.8 (s, 1H), 12.1 (s, 1H).