Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[CH2:17]([O:19][CH2:20][CH2:21]Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:19][CH2:20][CH2:21][N:7]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6]1)[CH3:18]
Reactant: CCOCCBr
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (2.0 g, 8.83 mmol, WO00/24745, page 48, preparation 2) was added to a solution of 2-ethoxyethyl bromide (1.18 mL, 10.45 mmol) and potassium carbonate (1.32 g, 9.56 mmol) in N,N-dimethylformamide (35 mL) and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 100:0 to 70:30 to yield the title product, 1.63 g.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([Cl:24])[CH:18]=1>COCCOC.CO>[Cl:24][C:19]1[CH:18]=[C:17]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:23]=[CH:22][C:20]=1[NH2:21]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Solvent: CO
Solvent: COCCOC
Product: Cn1nccc1-c1ccc(N)c(Cl)c1
Yield: 74 %

Procedure:
Prepared using Method C (Preparation 85) using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-2-chloroaniline in DME/MeOH 2/1 for 10 minutes at 150° C. under microwave irradiation. Purified using silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a white powder (77 mg, 74%). 1H-NMR (500 MHz, CDCl3): δ 3.86 (s, 3H), 4.26 (s, br, 2H), 6.22 (d, J=2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 7.1 (dd, J=2 Hz, 8.3 Hz. Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.48 (d, J=2 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[SH:24][CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C.Cl>COCCOCCOC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([S:24][CH2:25][C:26]([OH:28])=[O:27])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)CS
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: O=C(O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.40 g, 1.05 mmol), mercaptoacetic acid (0.11 mL, 1.60 mmol), triethylamine (0.59 mL, 4.2 mmol) in diglyme (2.5 mL) was heated with stirring at 130° C. under an atmosphere of nitrogen for 18 hours. The product mixture was treated with 1 M aq HCl at 0° C. The resulting yellow solid was filtered, washed with diethyl ether to provide the title acid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:15][N:16]=1>O.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([OH:24])=[C:17]([C:14]2[S:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=2)[CH:22]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Add a solution of sodium hydroxide (2.60 g, 65 mmol) in water (50 mL) to a solution of 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (5.76 g, 16 mmol) in methanol (100 mL) at 0° C. under nitrogen, warm the mixture to room temperature, and stir for a total of 1.5 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate by filtration to afford 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid (5.21 g, 95%): APCI mass spectrum m/z 338 [C16H18ClNO3S—H]−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:24](OC)[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C>[CH2:12]([O:11][CH2:10][C@@H:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:24]=[CH:25][N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)=[CH:32][CH:33]=2)[C:19]1=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C=CN(Cc2ccc(-n3ccnc3)cc2)C(=O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of N-tert-butoxycarbonyl-O-benzyl-L-serine (1.48 g) and 2,2-dimethoxyethyl[4-(1H-imidazol-1-yl)benzyl]amine (1.31 g) in acetonitrile (50 ml) were added HOBt (842 mg) and WSC hydrochloride (1.05 g), under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the mixture was added N,N-dimethylaminopyridine (catalytic amount), and the mixture was stirred overnight. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol=20:1). To the obtained product were added p-toluene sulfonic acid (856 mg) and toluene (60 ml), and the mixture was refluxed for 30 minutes and cooled. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate:methanol=20:1) to give amorphous of the title compound (1.14 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:70][C:71]1[CH:77]=[CH:76][C:74]([NH2:75])=[CH:73][CH:72]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:75][C:74]2[CH:76]=[CH:77][C:71]([F:70])=[CH:72][CH:73]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 4-fluoroaniline (9.6 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 46%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)(=O)=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1
Reactant: c1c[nH]cn1
Product: c1ccc(COc2cccc(CCCn3ccnc3)c2)cc1
Yield: 44 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(3-benzyloxyphenyl)propyl methanesulfonate was allowed to react with imidazole to give 1-[3-(3-benzyloxyphenyl)propyl]imidazole. The yield was 44%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 82-83° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:36]([NH:43][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reaction time: 8 h

Procedure:
N-t-Butoxycarbonyl-L-alanine (377 mg, 2.0 mmol), HOBT (283 mg, 2.1 mmol) and EDC hydrochloride (420 mg, 2.2 mmol) were dissolved in 5 mL of DMF. Benzylamine (230 μL, 2.1 mmol) was added followed by triethylamine (280 μL, 1.9 mmol). The mixture was stirred overnight and the solvent was evaporated. The residue was partitioned between ethyl acetate and 10% citric acid and the organic phase was washed sequentially with 10% sodium bicarbonate and brine. The solution was dried and evaporated to yield 498 mg of a waxy solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[NH:5])C.[NH2:22][NH:23][C:24](=O)[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[O-].[Na+]>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]4[NH:22][N:23]=[C:24]([CH2:25][O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:5]=4)[CH:7]=3)[NH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)COCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nc(COCc5ccccc5)n[nH]4)cc23)cc1
Temperature: 90 °C

Procedure:
To a suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine.2HCl (307 mg, 0.96 mmol) and N-amino-2-(phenylmethoxy)acetamide (259 mg, 1.44 mmol) in anhydrous methanol (3.0 mL) in a screw-top pressure tube was added freshly prepared sodium methoxide (615 μL of a 3.12 M solution in methanol). The tube was sealed and heated in a 90° C. oil bath for 17 h. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily brown residue. Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43) gave a pale solid (155 mg) which was re-chromatographed using 30% hexanes in ethyl acetate to remove traces of color.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[N:13]#[C:14][C:15]#[N:16].N1C=CC=CC=1>CN(C)C=O>[C:14]([C:15]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:16]=1)#[N:13]
Reactant: Cc1ccc(C(=O)CN)cc1
Reactant: N#CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
2.0 g (11 mmol) of 2-amino-4'-methylacetophenone hydrochloride was measured out in a 100-ml round bottom flask. To the material was then added 40 ml (40 mmol) of a 1 mol/l N,N-dimethylformamide solution of cyanogen at a temperature of 0° C. To the mixture was then added 1.7 g (22 mmol) of pyridine. The mixture was then heated at a temperature of 60° C. with stirring for 18 hours. The reaction mixture was then allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography to obtain 1.55 g (yield: 77 %) of 2-cyano-4- (p-tolyl)imidazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]([C:29](=[CH2:35])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:35]=[C:29]([C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:28])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: C=C(CC(=O)OC)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COC(=O)CC(=Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C(=O)OCc1ccccc1

Procedure:
A solution of 4-bromo-1-(triisopropylsilyloxy)benzene (33.23 g, 100 mmole), methyl 3-(benzyloxycarbonyl)-3-butenoate (28.11 g, 120 mmole), Pd(OAc)2 (2.24 g, 10 mmole), P(o-tolyl)3 (6.09 g, 20 mmole), and (i-Pr)2NEt (34.8 mL, 200 mmole) in propionitrile (350 mL) was deoxygenated (3×evacuation/N2 purge cycles) then was heated to reflux. After 18 hr the mixture was concentrated, and the residue was chromatographed on silica gel (10% EtOAc/hexanes) to give a yellow oil. The oil was taken up in 5% EtOAc/hexanes (100 mL), and the solution was allowed to stand at RT. After 72 hr the mixture was filtered and the filtrate was concentrated to give crude methyl (±)-4-(4-triisopropylsilyloxyphenyl)-3-(benzyloxycarbonyl)-3-butenoate as a mixture of olefin isomers. This was used immediately in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:11][CH:10]=1)(=[O:24])=[O:23]
Reactant: OCc1ccc(C2OCCO2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C2OCCO2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirred solution of (4-(1,3-dioxolan-2-yl)phenyl)methanol (prepared as described in WO2012168359, which is incorporated herein by reference in its entirety, 1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20.0 mmol) in DCM (40 mL) was added dropwise a solution of methanesulfonyl chloride (0.77 mL, 10.0 mmol) in DCM (10 mL). The reaction mixture was stirred at this temperature for 40 minutes and then at room temperature for 18 hours. The reaction mixture was washed with water and the organic phase dried (magnesium sulfate). The filtrate was evaporated at reduced pressure to afford the title compound which was used immediately without further purification.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].Cl>C(O)(C)C>[CH:19]([N:22]1[CH2:27][CH2:26][C:25]2[NH:2][C:4]3[C:18]([C:24]=2[CH2:23]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)([CH3:21])[CH3:20]
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Reactant: CC(C)N1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)N1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 40, from 13.8 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 7.5 g of 1-isopropyl-4-piperidone by boiling the starting materials in 120 ml of isopropanol containing hydrogen chloride for 4 hours. Melting point: 204° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:20]1([CH2:19][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (300 mg, 1.23 mM), benzyl bromide (210 mg, 1.23 mM), and potassium carbonate (170 mg, 1.23 mM) in 15 mL DMF was stirred at room temperature for 6 hours. The mixture was diluted with 80 mL H2O and chilled in the refrigerator. The resultant white precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 325 mg (79%) of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSO-d6) δ 7.7 (dd, 1H, J=1 and 8 Hz), 7.45-7.0 (m, 7H), 5.6 (s, 2H), 3.8 (s, 3H), 3.05 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 3421, 1726, 1676, 1636, 1473, 1450, 1435, 1288, 1122, 764, 745, and 706. MS (ES) m/e 334.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].Cl.[CH:18](OCC)=[O:19]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:18][OH:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1cc(C)cc(C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1cc(C)cc(C)c1
Reaction time: 12 h

Procedure:
10 ml of ethyl 2-(3,5-dimethylphenyl)acetate are dissolved in 80 ml of ethyl formate. 5 g of 50% NaH are added portionwise and then the mixture is stirred at AT for 12 hours. The mixture is poured onto a 1N HCl solution and then extraction is carried out with AcOEt. The organic phase is evaporated to produce the expected compound, used as is in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([C:22](=[O:23])[CH2:21][N:17]3[CH2:18][CH2:19][CH:14]([C:12]([C:10]4[S:11][C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=4)=[O:13])[CH2:15][CH2:16]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Reactant: O=C(CCl)c1ccc2c(c1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)OCCO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (333 mg, 1.2 mmol) and 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (256 mg, 1.2 mmol) in DMF (4 ml) was treated with DIPEA (199 ul, 1.2 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Chromatography on SiO2 (hex/EtOAc 1:1, EtOAc) and crystallisation from ether gave 350 mg (65%) of title compound as a yellowish solid.
Reaction SMILES: [NH2-].[Na+].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>O1CCCC1>[CH2:3]([NH:10][C:23]1[CH:24]=[C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:20]=[CH:21][C:22]=1[CH3:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: NCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(OCc2ccccc2)cc1NCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
100.0 g (2.56 mol) of sodium amide was added to 700 g (6.53 mol) of benzylamine under an argon atmosphere, and the mixture was stirred for 10 minutes at 60° C. A solution of 222.20 g (0.801 mol) of 1-benzyloxy-2-bromo-4-methylbenzene was dissolved in 400 ml of tetrahydrofuran was added dropwise to the above mixture over 50 minutes. The mixture was stirred for 50 minutes while maintaining the temperature at 60° C. Methanol was added under cooling with ice, and the mixture was poured into ice water. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by column chromatography (silica gel, 10:1 mixture of n-hexane and ethyl acetate). The crude product thus obtained was recrystallized from n-hexane to obtain 175.80 g (yield: 72.3%) of the title compound as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37](Cl)=[O:38]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:37](=[O:38])[CH2:36][O:23][C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]1=2
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C(F)(F)F)ccc1Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 106.9 %

Procedure:
To a flask charged with 2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-nitrophenol (1.75 g, 5.33 mmol) and cesium carbonate (8.69 g, 26.7 mmol) was added DMF (21.33 ml) followed by chloroacetyl chloride (0.854 ml, 10.66 mmol), dropwise over 5 min. The resulting solution was maintained at rt for 1 h. Quenched reaction with saturated ammonium chloride (25 mL) and diluted with EtOAc (25 mL). Separated layers, and extracted aqueous layer with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated via rotary evaporation to provide 4-(2-methoxy-4-(trifluoromethyl)phenyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.10 g, 5.70 mmol, 107% yield) as a yellow solid. The crude product was used in the next step without further purification.