Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CC(=O)CC>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1NCCn2c1cc1cc(OCCCCl)ccc12

Procedure:
The suspension consistent of 0.5 g (2.4 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1, intermediate a), 0.41 g (2.6 mmol) potassium carbonate and 0.29 ml (0.47 g, 3.0 mmol) 1-bromo-3-chloropropane in 12 ml 2-butanone was heated under reflux for 64 hours. The reaction mixture was evaporated to dryness to give a light brown solid containing the desired product together with some starting material (0.58 g, 55%). This mixture was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH2:21][CH:13]([CH2:12][NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:14]2)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
369 mg (1.15 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl)indan was dissolved in 5 ml of methylene chloride, to which were added 460 mg (4.20 mmol) of anhydrous aluminum chloride under ice-cooling and then 302 mg (3.80 mmol) of acetyl chloride dropwise. After stirring for 30 minutes at the same temperature, the reaction solution was admixed with ice, and the organic phase was washed with water and saturated-aqueous sodium bicarbonate, dried and the solvent was removed. The residue was recrystallized from a solvent mixture of ethyl acetate and isopropylether to obtain 310 mg of colorless crystals. Yield: 75%
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:37][CH2:36][N:35]([C:21]3[C:34]4[C:25](=[CH:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:24]=[CH:23][CH:22]=3)[CH2:40][CH2:39]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: c1ccc2cc3c(N4CCNCC4)cccc3cc2c1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cccc3cc4ccccc4cc23)CC1
Yield: 62 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(1-anthryl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:21]([O:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate from step A (535 mg, 2.06 mmol) in DMF (8.2 mL) was carefully added sodium hydride (60% dispersion in mineral oil, 124 mg, 3.09 mmol). The mixture was stirred for 30 minutes at room temperature. Benzyl bromide (0.29 mL, 2.47 mmol) was added, and the reaction was stirred for another 30 minutes. Upon completion as monitored by TLC analysis, the reaction was quenched with 50 mL of 1:1 saturated aq. NH4Cl:water. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with MgSO4, and concentrated under vacuum. Silica gel chromatography (5-10% ethyl acetate:hexanes) provided the title compound as a clear oil (359 mg, 54% yield). MS (ES+) [M+H]+=340.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][N:19]([CH3:29])[NH:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(C3=NNN(C)N3)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242 in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to provide the title compound as a white solid (0.015 g); mass spectrum (m/e): 365.09 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1CCc2ccc(Br)cc21
Temperature: 120 °C

Procedure:
(Method 1): 6-Bromo-indan-1-one (0.23 mmol) and dimethyl-amine (0.71 mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.47 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover® equipped with a CEM Explorer® automated reaction handling module). The reaction mixture was heated for 5 min at 120° C. and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHCO3 The product was extracted with CH2Cl2 and washed with aqueous NaHCO3. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product (6-bromo-indan-1-yl)-dimethyl-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion™ system to yield the title compound (85%). MS [MH]+=240.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:18][C:19]([F:29])([F:30])[O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:25]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(OC(F)(F)F)cc2)N1

Procedure:
The same method but starting from racemic tryptophan ethyl ester and 4-trifluoromethoxybenzaldehyde gave cis and trans isomers of the title compound.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:6]1=[O:26].[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH2:34]>>[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH:34][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:6]1=[O:26]
Reactant: Nc1ccc(F)cc1F
Reactant: CC1(C)C(=O)N(c2ccc(Oc3ccccc3)cc2)C(=O)N1Cc1ccccc1Br
Product: CC1(C)C(=O)N(c2ccc(Oc3ccccc3)cc2)C(=O)N1Cc1ccccc1Nc1ccc(F)cc1F

Procedure:
To prepare the compound of example 49, the procedure may be according to process “A”. Analogously to the process described in example 1.2, 49.2 and 2,4-difluoroaniline were reacted. 49: Molecular weight 513.18 (C30H25F2N3O3); retention time Rt=2.41 min. [B]; MS (ESI): 514.23 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:8]O)=[C:5]([Cl:7])[N:6]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:8][C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[Cl:7]
Reactant: BrP(Br)Br
Reactant: OCc1sc(Cl)nc1Cl
Solvent: ClCCl
Product: Clc1nc(Cl)c(CBr)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2,4-dichloro-1,3-thiazol-5-yl)methanol (850 mg, 4.6 mmol) in anhydrous dichloromethane (40 mL) was added dropwise phosphorus tribromide (850 μL, 9.2 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-2,4-dichloro-1,3-thiazole. The product was used without further purification.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>CN(C)C=O>[CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)occ1O
Solvent: CN(C)C=O
Product: O=c1cc(CCl)occ1O
Temperature: 10 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
50 g(351.8 mmol) of kojic acid was dissolved in 250 ml of N,N-dimethylformamide. The resulting solution was cooled in a ice bath of 10° C. and 30 ml(411.3 mmole) of thionyl chloride was added dropwise thereto. The mixture was stirred at a room temperature for 2 hours and 2000 ml of ice water was added. The precipitates were filtered and dissolved into 1000 ml of ethyl acetate. The reaction product was dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated and hexane was added to give crystals, which was then dried under vacuum to give 37.5 g(66.83%) of the desired chlorokojic acid as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C@H:18]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH3:19])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:16])([C@H:18]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH3:19])[CH2:17][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(Cl)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
1H-1,2,4-Triazole (42.1 g) was added portionwise to a dispersion of 60% sodium hydride in oil (22.2 g) in dimethylformamide (300 ml) under ice-cooling, followed by stirring for 15 minutes. To the mixture was added a solution of the crude product of 2-(4-chlorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (52 g) in dimethylformamide (50 ml), followed by stirring for 4 hours at 80° C. After cooling, the reaction mixture was poured into ice water (400 ml) and extracted three times with ethyl acetate (200 ml). The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=3:2→ethyl acetate/acetone=4:1) to give (3R)-2-(4-chlorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (53 g) as a colorless amorphous substance.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][C:3]([C:4]=23)=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][C:3]([C:4]=23)=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CI
Reactant: CCOC(=O)c1[nH]c2cccc3c2c1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c3c(cccc3n1C)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 1,3,4,5-tetrahydro-benz[cd]indole-2-carboxylate (1.00 g , 4.36 mmol) in N,N-dimethylformamide (20 ml) was added 60% sodium hydride (0.19 g, 4.80 mmol), followed by stirring at room temperature for 30 minutes. Then, methyl iodide (1.86 g, 13.1 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was poured into ice water, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1.5/98.5) to obtain ethyl 1,3,4,5-tetrahydro-1-methyl-benz[cd]indole-2-carboxylate (1.03 g).
Reaction SMILES: C([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][Cl:26])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[C:21]([O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:25][Cl:26])[C:12]2[C:27]3[C:32]([C:9]([OH:8])=[CH:10][C:11]1=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C1CCCN(CCl)c2c1cc(OCc1ccccc1)c1ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCCN(CCl)c2c1cc(O)c1ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 86 (0.043 g, 0.095 mmol, 1 equiv) in THF (1.5 mL) was treated with 10% Pd—C (0.020 g, 0.019 mmol, 0.2 equiv) followed by aqueous HCO2NH4 (0.5 mL, 25% w/v, 1.98 mmol, 21 equiv) and the resulting black suspension was stirred rapidly at 25° C. for 2.5 h. The crude mixture was filtered through a plug of Celite to afford a biphasic filtrate which was partitioned. The aqueous portion was extracted with EtOAc (2×1 mL) and the combined organic portions were dried (MgSO4), filtered, and concentrated to provide 87 as an analytically pure white solid (0.032 g, 0.034 g theoretical, 94%). Recrystallization from 10% EtOAc-hexane gave colorless plates suitable for X-ray analysis:24 mp 157-159° C.; 1H NMR (400 MHz, CDCl3) major rotamer δ 7.98-7.94 (m, 1H), 7.37-7.32 (m, 1H), 7.22-7.19 (m, 1H), 6.96-6.90 (m, 1H), 6.47 (s, 1H), 4.41-4.26 (m, 1H), 4.19-4.07 (m, 1H), 3.89-3.81 (m, 2H), 2.88-2.78 (m, 1H), 2.51-2.46 (m, 1H), 2.18-2.05 (m, 1H), 1.71-1.67 (m. 2H), 1.40 (s, 9H); 1H NMR 400 MHz, acetone-d6) major rotamer δ 9.17 (s, 1H), 8.27 (d, J=8.1 Hz, 1H), 8.19-8.17 (m, 1H), 7.59-7.54 (m, 1H), 7.50-7.46 (m, 1H), 6.75 (s, 1H), 4.39-4.36 (m, 1H), 4.19-4.15 (m, 1H), 3.92-3.87 (m, 1H), 3.75-3.63 (m, 1H), 2.75-2.68 (m, 1H), 2.37-2.33 (m, 1H), 2.06-2.04 (m, 1H), 1.69-1.67 (m, 2H), 1.40 (s, 9H); 13C NMR(100 MHz, CDCl3)major rotamer δ 155.8, 152.9, 151.6, 139.3, 132.3, 126.5, 124.9, 124.7, 123.5, 122.4, 109.4, 81.5, 48.9, 44.6, 38.6, 28.4 (3C), 26.3, 24.2; IR (film) νmax 3287, 2965, 2915, 2844, 1693, 1663 cm−1; FABHRMS (NBA-NaI) m/z 384.1352 (M+Na+, C20H24CINO3 requires 384.1342).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:22]([O:23][CH3:24])=[CH:21][C:6]2[S:7][C:8]([CH:19]=O)=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]1[C:22]([O:23][CH3:24])=[CH:21][C:6]2[S:7][C:8](/[CH:19]=[C:31](\[C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc(Oc2c(C=O)sc3cc(OC)c(OC)cc23)cc1
Reactant: CCOC(=O)Cc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(=C/c1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1)c1ccncc1
Temperature: 100 °C

Procedure:
A solution containing 6 mmol of the product obtained in Step E, 30 mmol of ethyl 4-pyridylacetate and 5 ml of acetic anhydride is maintained at 100° C. for 18 hours. After returning to room temperature, the reaction mixture is hydrolysed by a saturated NaHCO3 solution and extracted with ethyl acetate. The organic phases are then washed with water and then with an NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 98/2) enables the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:28][C:26]1[N:25]=[C:24]([O:30][C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)[CH:23]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:27]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)nc(OC)n3)CC1)C(=O)N2

Procedure:
45 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.15 mmol) 6-(6-chloro-2-methoxypyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL (0.57 mmol) DIPEA in 1.0 mL DMF were stirred for 3 h at 90° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:15])=O.[Br-].[CH2:17]([O:19][C:20]([CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:3]([CH:1]=[CH:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])=[C:4]([OH:15])[CH:5]=[CH:6]2)#[N:14]
Reactant: N#Cc1ccc2c(C=O)c(O)ccc2c1
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)C=Cc1c(O)ccc2cc(C#N)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
A solution prepared by dissolving 19.3 g of 1-formyl-6-cyano-2-naphthol and 42.1 g of ethoxycarbonylmethyltriphenylphosphonium bromide in 140 ml of DMF was added dropwise to a solution comprising 13.6 g of anhydrous potassium carbonate and 250 ml of anhydrous methanol, followed by stirring for 3 hours under cooling with ice in a nitrogen stream and 24 hours at room temperature. The precipitate was filtered, and 2.7 liters of water was added to the filtrate, followed by stirring for 2 hours. Then, the precipitate was collected by filtration and washed with 90 ml of methanol to obtain 12.6 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.[C:10](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)cs1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COC(=O)c1cc(O)cs1

Procedure:
50.0 g (0.347 mol) of 4-hydroxy-2-thiophenecarboxylic acid and 58.3 g (0.694 mol) of sodium carbonate are heated to the boiling point in 990 ml of absolute 2-butanone under nitrogen, and 43.7 g (0.347 mol) of dimethyl sulfate are added dropwise in the course of 20 minutes. The mixture is heated under reflux for a further 2.5 hours. It is then evaporated in vacuo and the residue is partitioned between saturated sodium carbonate solution and ether. The aqueous phase is extracted five more times with 80 ml of ether each time. The combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:7]=1[NH2:26].Cl.[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:26][N:28]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(3-chloro-propoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.66 g, 4.25 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.3 g, 4.4 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.6 g, 4 mmoles).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2C=C[CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.[C:41](O)([C:43](F)(F)F)=O>C(Cl)Cl>[F:22][C:17]1[CH:18]=[CH:19][CH:43]=[CH:41][C:16]=1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:29]=3)[CH2:25][C:24](=[O:39])[NH:23][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(C#Cc3ccccc3F)cc2N1

Procedure:
Prepared from {4-(2-fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K38) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (99 mg).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.Cl.O1CCOCC1>>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 49.5 %

Procedure:
Following the general procedure for Example 18, the product from step 1 (0.80 g 1.99 mmol) was treated with a 1:1 mixture of concentrated HCl/dioxane (36 mL) to afford the title compound (0.21 g, 26%) as a white solid.