Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[N:7]([C@@H:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:41])[CH2:24][CH:25]([NH2:40])[CH:26]([OH:39])[CH2:27][O:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[C:31]([F:37])[C:30]=1[F:38])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:18]([O:22][C:23](=[O:41])[CH2:24][C@H:25]([NH:40][C:12](=[O:14])[CH:11]([N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:6]1=[O:17])[CH2:15][CH3:16])[C@H:26]([OH:39])[CH2:27][O:28][C:29]1[C:30]([F:38])=[C:31]([F:37])[CH:32]=[C:33]([F:36])[C:34]=1[F:35])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1cccc(NC(C)=O)c1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCC(C(=O)N[C@@H](CC(=O)OC(C)(C)C)[C@H](O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A stirred mixture of (S)-2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyric acid (100 mg, 0.42 mmol), 3-amino-5-(2,3,5,6-tetrafluorophenoxy)-4-hydroxy-pentanoic acid tert-butyl ester (163 mg, 0.462 mmol), HOBt (62 mg, 0.462 mmol), DMAP (56 mg, 0.462 mmol) and THF (5 mL) was cooled to 0° C. then EDC (89 mg, 0.462 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (50-50% ethyl acetate/hexane) to afford the title compound as a white foam (221 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.37-1.38 (9H, 2 s), 1.86-1.96 (1H, m), 2.15-2.25 (4H, m), 2.55-2.71 (2H, m), 3.70-4.64 (5H, m), 5.30-5.39 (1H, m), 6.30-6.35 (1H, m), 6.75-6.86 (1H, m), 7.17-7.31 (2H, m), 8.31-8.47 (2H, m).
Reaction SMILES: C[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[O-][CH2:40]C.[Na+]>C(O)C>[CH:23]1([O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2/[CH:31]=[CH:40]/[C:21]2[S:22][C:4]3=[N:3][CH:2]=[C:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=4)[C:6](=[O:19])[N:5]3[CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OC1CCCC1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2cn3c(=O)c(-c4ccc(OC(F)(F)F)cc4)cnc3s2)c1OC1CCCC1
Yield: 46.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.012 mmol) with 2-cyclopentyloxy-3-methoxybenzaldehyde (330 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 251 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.54-1.62 (m, 6H), 1.75-1.82 (m, 2H), 3.77 (s, 3H), 4.80-4.87 (m, 1H), 6.84-6.93 (m, 2H), 6.98 (d, J=4.8 Hz, 2H), 7.46-7.52 (m, 5H), 7.98 (d, J=4.2 Hz, 1H), 8.10 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.49 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8](=O)([O-])[O-:9].[Na+:12].[Na+]>CO>[C:4]([O:9][CH3:8])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Na+:12]
Reactant: O=C1C=CC(=O)O1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]

Procedure:
1 mole of maleic anhydride is dissolved in 1000 ml methanol and 0.5 mole of sodium carbonate is added. The solution is filtered and the methanol is distilled off under pressure. After drying the product in a vacuum oven 152 g of sodium methyl maleate is obtained.
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.Cl.[NH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.C(N(CC)CC)C>C(O)C>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH:21]1[NH:20][C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)c1csc2ncnc(O)c12
Agent: Cl
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1csc2ncnc(NC3Cc4ccccc4C3)c12
Yield: 62.1 %

Procedure:
Using 4-hydroxy-5-isopropylthieno[2,3-d]pyrimidine (200 mg, 1.03 mmol), phosphorus oxychloride (1.0 ml), 2-aminoindan hydrochloride (200 mg, 1.2 mmol), triethylamine (1.0 ml, 7.2 mmol) and dry ethanol (5 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (190 mg, 0.64 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
(±)-(E)-3-[4-Oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 600 mg, 1.78 mmol) was suspended in DCM (30 ml). TEA (0.248 ml, 1.78 mmol) was added and the pH was adjusted to 5 with AcOH. 4-Fluorobenzaldehyde (265 mg, 2.14 mmol) and NaBH(OAc)3 (566 mg, 2.67 mmol) were added and the resulting mixture was stirred overnight at RT, then washed with 5% NaHCO3, brine and dried over Na2SO4. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (660 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O.Cl>[C:1]1([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCN(c2ccccc2)CC1
Temperature: 50 °C

Procedure:
8-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane (18.1 g, 82.5 mmol) was dissolved in a mixture of acetic acid (150 mL), water (150 mL), and conc. hydrochloric acid (38 mL) and the resulting solution was heated to 50° C. for 18 hrs. The reaction mixture was cooled in an ice-water bath, and sodium hydroxide pellets were added in portions until the mixture was neutralized. This mixture was extracted with dichloromethane (3×300 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a dark oil. Chromatography on silica gel, eluting with hexane—10% ethyl acetate gave the product as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=1.C(=O)(O)[O-].[Na+].CC(O)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2[NH:31][CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([O:23][CH3:22])[CH:29]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Reactant: COc1cc(CN)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(CNc2nnc(Cl)cc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (162 mg, 0.5 mmol), C-(2-Methoxy-pyridin-4-yl)-methylamine (211 mg, 1 mmol), and sodium bicarbonate (840 mg, 20 mmol) were added to IPA (2.5 mL). The reaction was ran in microwave (150° C., 15 min). Water (5 mL) was added to the reaction and the mixture was extracted with DCM (2×5 mL). The organic layer was dried over sodium sulfate and reduced. The crude was subjected to Flash chromatography (2% MeOH/DCM) for further purification.
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O>C(O)(=O)C.O>[OH:1][C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[C:7]([Br:15])=[C:6]([O:13][CH3:14])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(OC)c(C=O)c(O)c1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Br)c(O)c(C=O)c(OC)c1Br
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A solution of 1.0 g (3.83 mmol) of 2-hydroxy-3-bromo-4,6-dimethoxybenzaldehyde (see R. Royer, et al, Eur. J. Med. Chem., 12:455 (1977) as an example of how to obtain this material) in 50 ml of glacial acetic acid was warmed to 60° C. N-Bromosuccinimide (0.68 g, 3.83 mmol) was added in one portion and the solution was cooled to ambient temperature. The reaction mixture was diluted with 200 ml of water and the solids were filtered and air dried. The solid was crystallized from ethanol. There was obtained 1.1 g (3.24 mmol, 84%) of 2-hydroxy-3,5-dibromo-4,6-dimethoxybenzaldehyde as a white solid; mp 103°-104° C.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16]([Cl:19])(=[O:18])=[O:17])[C:7]=1[OH:20])(=O)C.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[ClH:19].[NH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[C:8]([S:16](=[O:17])(=[O:18])[NH:25][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]=1[OH:20]
Reactant: CCCCN
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Product: CCCCNS(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O
Product: Cl

Procedure:
This compound is prepared analogously to Examples 11 c and 11 d from 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol and butylamine.
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5]1>C(O)C>[CH:9]1([N:6]2[CH2:7][CH2:8][CH:4]([NH:2][CH3:1])[CH2:5]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN
Reactant: BrC1CCN(C2CCCCC2)C1
Solvent: CCO
Product: CNC1CCN(C2CCCCC2)C1

Procedure:
A mixture of 40% aqueous methylamine (93 g), ethanol (200 ml) and 3-bromo-1-cyclohexylpyrrolidine (92.8 g, 0.4 mol) was heated to 150° C. in a steel bomb for 20 hr. After cooling, the mixture was concentrated and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform solution was dried (sodium sulfate), concentrated, and the residue distilled to obtain 40 g (55%), bp 172°-176° C./40 mm. A portion of the distillate was converted to the fumarate salt which was recrystallized from ethanol-water. This was converted back to the free base and distilled, bp 75°-80° C./0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[B:9]([OH:11])[OH:10].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[B:9]1[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]1
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of (2-fluoro-4-methylphenyl)boronic acid (500 mg, 3.24 mmol) in diethyl ether (20 mL) was added pinacol (360 mg, 3.24 mmol) and 4-toluenesulfonic acid monohydrate (30 mg, 162 μmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid, 740 mg, in a 97% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 12 H), 2.34 (s, 3 H), 6.82 (d, 1 H), 6.93 (d, 1 H), 7.60 (d, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=[O:15]>CC(C)=O>[ClH:12].[Cl:12][CH2:13][C:14](=[O:15])[CH2:16][S:8][C:7](=[NH:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: COc1ccc(C(=N)SCC(=O)CCl)cc1
Product: Cl
Yield: 119 %

Procedure:
13.38 g (80.0 mmol) 4-Methoxy-thiobenzamide, 15.23 g (120 mmol) 1,3-dichloroacetone and 400 ml acetone were stirred at room temperature for 3 days. The precipitate was isolated and dried, yielding 21.0 g (quant.) 4-methoxy-thiobenzimidic acid 3-chloro-2-oxo-propyl ester hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccccn2)cc1
Solvent: CCO
Product: Nc1ccc(C(O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
In ethanol (50 ml) was dissolved (4-nitrophenyl)—(2-pyridyl)methanol (2.30 g), and to the mixture was added dried 10% palladium on carbon (0.12 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 19 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give (4-aminophenyl) (2-pyridyl)methanol (1.90 g) as pale yellow crystals.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].[ClH:19]>CC(=O)CC>[OH2:2].[ClH:19].[F:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6](=[O:16])[N:5]2[CH2:4][CH:3]=[O:2])=[N:10][CH:11]=1
Reactant: COC(Cn1c(=O)ccc2ncc(F)cc21)OC
Agent: Cl
Solvent: CCC(C)=O
Product: O
Product: O=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 10 °C

Procedure:
To a suspension of 158 g of 1-(2,2-dimethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 1.26 L of 2-butanone, 79 mL of 12 mol/L hydrochloric acid was added at room temperature, and the mixture was refluxed for 3 hours. After cooling the reaction mixture to 10° C., the solid product was obtained by filtration and washed with 2-butanone to give 152 g of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde hydrochloride monohydrate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]([NH:7][OH:8])=[NH:6].[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[CH3:21])[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCC(CC)Oc1ccc(C(=N)NO)cc1Cl
Solvent: c1ccncc1
Product: CCC(CC)Oc1ccc(-c2noc(-c3ccccc3C)n2)cc1Cl
Temperature: 100 °C
Yield: 18.5 %

Procedure:
To a solution of 3-chloro-4-(1-ethyl-propoxy)-N-hydroxy-benzamidine (64 mg, 0.25 mmol) (prepared by General procedure B) in pyridine (1 mL) was added a solution of 2-methylbenzoyl chloride (77 mg, 0.5 mmol) in pyridine (1 mL). The mixture was heated at about 100° C. overnight. The solvent was removed under reduced pressure and the crude product was purified via SFC(CO2/pure MeOH; gradient: 5% hold for 0.5 min, ramp at 7.3% to 50% over 6.5 min, hold at 50% for 1 min) to give 3-[3-chloro-4-(1-ethyl-propoxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole (16.5 mg, 18.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH3:20])[C:13]=2[CH3:21])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:19]([C:14]1[C:13]([CH3:21])=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[O:11][C:5]1[C:4]([CH3:22])=[CH:3][C:2]([NH:1][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCc1c(O)ccc(Oc2c(C)cc(N)c3c2CCC3)c1C
Product: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(CC)c2C)c2c1CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To 4-(7-amino-5-methylindan-4-yloxy)-2-ethyl-3-methylphenol (12 mg) was added diethyl oxalate (150 mg), and the mixture was stirred under an argon atmosphere at 120° C. for 3 hours. The reaction mixture was purified by thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=2/1) to give the title compound (15 mg).
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:24]=[CH:23][C:22]3[S:21](=[O:26])(=[O:25])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH3:27])[C:13]=3[CH:12]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:24]=[CH:23][C:22]3[S:21](=[O:25])(=[O:26])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH3:27])[C:13]=3[CH:12]=2)/[C:8]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1c2ccccc2S(=O)(=O)c2ccc(/C(=C\C3CCCC3)C(=O)O)cc21
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2ccccc2S(=O)(=O)c2ccc(/C(=C\C3CCCC3)C(=O)Nc3ccn(C)n3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
480 mg of (E)-3-cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acrylic acid, 122 mg of commercial 1-methyl-1H-pyrazol-3-ylamine and 0.76 ml of N,N-diisopropylethylamine are dissolved in 7 ml of dimethylformamide. 571 mg of HATU and 204 mg of HOAT are added, and the mixture is stirred at room temperature for one hour. The reaction mixture is then diluted by addition of 100 ml of ethyl acetate and washed five times with in each case 30 ml of water. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane (100%)=>:ethyl acetate (100%). This gives 360 mg of (E)-3-cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)acrylamide.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].CO[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1>C(OCC)C>[CH3:7][C:6]([CH3:8])=[CH:5][CH2:4][CH2:3][C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1
Reactant: COC1=CC(=O)CC1
Reactant: CC(C)=CCCBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)=CCCC1=CC(=O)CC1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Magnesium turnings 2.1 g (0.086 mole) were added to 50 ml diethyl ether with stirring. 1-Bromo-4-methyl-3-pentene 10 g (0.061 mole) was added dropwise over 30 minutes. The reaction was allowed to warm from 25° C. to 40° C. during the addition and aged for 30 minutes. A solution of 3-Methoxy-2-cyclopenten-1-one, 10 g (0.089 mole) in diethyl ether was added at 25° C. The resulting mixture was aged 30 minutes then quenched with 20% aqueous acetic acid (50 ml). The organic layer was dried over sodium sulfate, filtered and distilled to give 6.6 g (65% yield) of 3-(4-methyl-3-pentenyl)-2-cyclopenten-1-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([Cl:22])=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([N:15]=1)=[CH:13][C:12]([C:10]([C:4]1[C:3]([F:23])=[C:2]([N:1]([S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:7]=[C:6]([F:8])[C:5]=1[F:9])=[O:11])=[CH:21][CH:20]=2
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (700 mg, 2.0 mmol, 1 eq.) in DCM (35 mL) was added TEA (5.6 mL, 400 mmol, 22 eq.) and propane-1-sulfonyl chloride (2.1 mL, 20 mmol, 10 eq.). The resulting mixture was stirred at rt for 1 h, washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (980 mg, 90%).
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C[C:19]([O-])([CH3:21])[CH3:20].[K+].[Br-].[Li+]>C1(C)C=CC=CC=1>[CH2:9]([N:13]([C:6]1[CH:5]=[CH:4][C:3]([N:13]([CH2:14][CH2:20][CH2:19][CH3:21])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:2][CH:1]=1)[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]
Reactant: Clc1ccc(Cl)cc1
Reactant: CC(C)(C)[O-]
Reactant: CCCCNCCCC
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(N(CCCC)CCCC)cc1
Reaction time: 12 h
Yield: 77 %

Procedure:
30 mmol of p-dichlorobenzene (4.4 g), 70 mmol of di-n-butylamine (9.0 g), 70 mmol of KOtBu (7.9 g), 30 mmol of lithium bromide (2.6 g) and 44 mg of trans-di-μ-acetatobis[2-[bis(1,1-dimethylethyl)phosphino]μ-2-methylpropyl-C,P]dipalladium(II) (0.2 mol %) are suspended in 75 ml of toluene and placed in a pressure tube under protective gas. After 12 hours at 140° C., an aqueous work-up is carried out. After the aqueous phase has been extracted twice with toluene, the combined organic phases are dried over magnesium sulfate and freed of the solvents on a rotary evaporator. Distillation gives 1,4-bis(N,N-dibutylamino)benzene as a virtually colorless liquid having a boiling point of 143° C./10 torr; yield: 77%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13]CC)[C:7]([OH:9])=[O:8])[CH3:2].S(=O)(=O)(O)O.O=[CH:22][C:23]([Cl:26])([Cl:25])[Cl:24].C(O)(=O)C1C=CC=CC=1>O>[OH:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[C:7](=[O:8])[O:9][CH:22]2[C:23]([Cl:26])([Cl:25])[Cl:24]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1cc2c(cc1O)C(C(Cl)(Cl)Cl)OC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
To a stirred solution of 16.8 g (80 mmoles) of 3,4-diethoxybenzoic acid in 100 ml. of concentrated sulfuric acid were added dropwise over thirty minutes 16 g (110 mmoles) of chloral. The reaction mixture was stirred at 25° C. for twelve hours. Thin layer chromatographic analysis indicated two components, one of which appeared to be the starting benzoic acid. Six grams of chloral were added to the reaction mixture and stirring was continued for two hours. An additional 10 g of chloral were added and the mixture was stirred for another twelve hours. The reaction mixture was then added to 50 g of ice and 50 g of water, and a solid precipitate formed. The solid product was collected by filtration and then crystallized from ethyl acetate to give 3.3 g of white crystals having a melting point above 260° C. The crystals were dissolved in ethanol and the precipitate which formed was collected, m.p. 143°-144° C. 150 mg. NMR and analysis were consistent for a structure representing 5-hydroxy-6-ethoxy-3-(trichloromethyl)phthalide.