Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.ClC1N=C(Cl)C(Cl)=CN=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH2:7][N:8]([CH3:12])[C:9]2=[O:11]
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1CN(C)C2=O
Yield: 129.9 %

Procedure:
7-Amino-4-methoxy-2-methyl-2,3-dihydroisoindol-1-one (292 mg, 1.52 mmol) was combined with 2,4,5-trichloropyrimidine (279 mg, 1.52 mmol), and N,N-diisopropyethylamine (294 mg, 2.28 mmol) in isopropanol (5 mL) and microwaved at 120° C. for one hour. The yellow solid produced was isolated by filtration, was washed with clean isopropanol, and was dried in vacuo to afford 7-(2,5)-dichoropyrimidin-4-ylamino)-4-methoxy-2-methyl-2,3-dihydroisoindol-1-one (350 mg, 68%) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]1[CH2:11][CH2:10]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH:11]1([CH2:10][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:9][CH2:8]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (48.7 g) and (bromomethyl)cyclopropane (34.2 mL) were added to a solution of 4-methyl-3-nitrophenol (49.1 g) in DMF (320 mL) at room temperature, and the reaction mixture was stirred at 60° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether, and the solution was washed 3 times with water. The aqueous layer was extracted again with diethyl ether, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (66.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[O:15]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][C:28]=1[O:35][CH3:36])[C@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18].N1CCCCC1>CO>[C@@H:16]1([O:15][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[C:11]3[S:10][C:9](=[S:14])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[C:12]3=[O:13])=[CH:29][C:28]=2[O:35][CH3:36])[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C1CSC(=S)N1c1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1cc(C=C2SC(=S)N(c3ccc(O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
3-(4-Hydroxyphenyl)-2-thioxothiazolidin-4-one (0.23 g, 1.0 mmol) was added to a suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.32 g, 1.0 mmol) in methanol (20 ml) containing a drop of piperidine. The mixture, which rapidly turned yellow, was gently heated under reflux and deposited a thick precipitate after 30 min. The mixture was then cooled and filtered to give the required product (5c){0.12 g, 23%, m.p. decomp.>230° C., [α]D -34.4° (c 0.6, DMOS)}(Found: C, 53.04; H, 4.55; N, 2.81. C23H23NO9S2 requires C, 52.96; H, 4.44; N, 2.68%).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][C:11]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C@@H:2]3[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]4[CH2:17][CH2:16][C:13]5([CH2:15][CH2:14]5)[CH2:12][C:11]=4[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1=C(NC(=O)[C@H]2CCC(=O)C2)CCC2(CC2)C1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CC[C@@H](N3CCN(c4ccc(F)cc4)CC3)C2)CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of (S)-ethyl 6-(3-oxocyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylate (0.7 g, 2.23 mmol) in 1,2-dichloroethane (10 ml) were added 1-(4-fluorophenyl)piperazine (0.43 g, 2.40 mmol), glacial acetic acid (0.14 g, 2.40 mmol) and sodium triacetoxy borohydride (0.7 g, 3.44 mmol). The mixture was stirred at RT for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain a diastereomeric mixture (7:3) of title compound (0.9 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1Cl
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1
Yield: 94.8 %

Procedure:
Beginning with 0.50 gm (2.7 mMol) 6,7-dichloro-1H-indole and 0.66 mL (5.4 mMol) 1-methyl-4-piperidone, 0.72 gm (95%) of the title compound were recovered as a white solid.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:11]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[CH2:2]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCc2ccccc21
Reactant: BrC1CCCCC1
Product: O=C1CC(C2CCCCC2)c2ccccc21

Procedure:
This compound was prepared according to the method described by B. M. Trost and L. H. Latimer in J. Org. Chem. 42 (1977) 3212. The starting compounds were 1-indanone and cyclohexyl bromide.
Reaction SMILES: C(#N)N(C)C.[CH3:6][O:7][C:8]([CH:10]1[CH2:16][CH:15]2[C:17](Br)=[CH:18][CH:11]1[C:12](=[O:33])[CH:13]([C:21]([C:23]1[C:24]([CH3:32])=[N:25][C:26]([CH:29]([F:31])[F:30])=[CH:27][CH:28]=1)=[O:22])[C:14]2=[O:20])=[O:9].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]([CH:10]1[CH2:16][CH:15]2[CH:17]=[CH:18][CH:11]1[C:12](=[O:33])[CH:13]([C:21]([C:23]1[C:24]([CH3:32])=[N:25][C:26]([CH:29]([F:30])[F:31])=[CH:27][CH:28]=1)=[O:22])[C:14]2=[O:20])=[O:9]
Reactant: COC(=O)C1CC2C(=O)C(C(=O)c3ccc(C(F)F)nc3C)C(=O)C1C=C2Br
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C#N
Product: COC(=O)C1CC2C=CC1C(=O)C(C(=O)c1ccc(C(F)F)nc1C)C2=O
Temperature: 80 °C

Procedure:
Catalytic amounts (10 mg) of azaisobutyronitrile are added to a solution of 0.10 g (0.24 mmol) of 8-bromo-3-(2-methyl-6-difluoromethyl-pyridine-3-carbonyl)-2,4-dioxo-bicyclo-[3.2.2]non-8-ene-6-carboxylic acid methyl ester (Example 1.1155) and 0.149 ml (0.48 mmol) of tris(trimethylsilyl)silane in 3.5 ml of toluene and the reaction mixture is stirred at a temperature of 80° C. 5 mg portions of fresh azaisobutyronitrile dissolved in a small amount of toluene are then added four times until, after 6 days, the reaction has come to a complete standstill (LC-MS monitoring). The solvent is then removed under reduced pressure and the residue is purified by silica gel chromatography (eluant: gradient mixture of ethyl acetate/tetrahydrofuran/hexane and 3% triethylamine). After removal of the solvents the triethyl-ammonium salt of 3-(2-methyl-6-difluoromethyl-pyridine-3-carbonyl)-2,4-dioxo-bicyclo-[3.2.2]non-8-ene-6-carboxylic acid methyl ester is obtained.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CCCCCC.C(OCC)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH:22]1[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1CCN(Cc2ccccc2)C(c2ccc(Br)cc2)C1
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 73.2 %

Procedure:
400 ml of a 1.2M solution of n-BuLi in hexane were added dropwise within 45 minutes to a solution, cooled to -70° C., of 112.5 g (0.48 mol) of 1,4-dibromobenzene in 1200 ml of diethyl ether in such a manner that the temperature did not rise above -60° C. After completion of the addition the mixture was stirred at -70° C. for 2.5 hours. Thereafter, a solution of 90.84 g (0.48 mol) of 1-benzyl-4-piperidone in 300 ml of ether was added dropwise at -70 to -65° C. during one hour. After the dropwise addition the mixture was stirred at -70° C. for 2 hours. For the working-up, the cold reaction mixture was poured into 1200 ml of a 15% ammonium chloride solution, the mixture was transferred to a separating funnel and the organic phase was separated. The aqueous phase was extracted twice with ether and subsequently the combined organic phases were extracted twice with water and saturated sodium chloride solution. Then, the organic phase was dried over magnesium sulphate evaporated under reduced pressure, with the crude product separating as a yellowish solid. For purification, this was dissolved in hot methylene chloride, the solution was treated with hexane until turbidity began and cooled to room temperature while stirring. The resulting precipitate was filtered off under suction and dried. There were obtained 121.65 g (73% of theory) of 1-benzyl-(4-bromo-phenyl)-piperidin-4-ol as a yellowish solid; m.p.: 106° C., MS: 346, 348 (M+H)+.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C=O)C>[OH:9]/[N:8]=[C:1](\[Cl:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1ccccc1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of (E)- and/or (Z)-benzaldehyde-oxime (5.27 g, 44 mmol) in DMF (44 mL) was added N-chlorosuccinimide (5.81 g, 44 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature overnight. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to afford the title compound (5.91 g, 87%) which was obtained as a light yellow solid. MS m/e (EI): 155.0 [M].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CCCCNC(=O)C(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7.23 g of 3,4,5-trimethoxycinnamoyl chloride is added with stirring at room temperature to a solution of 5.00 g of 1-[1-(butylaminocarbonyl)ethyl]piperazine in 80 ml of chloroform, and the resulting solution is stirred at room temperature for 15 minutes.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)CC(C)OB([C:17]([C:19]([F:22])([F:21])[F:20])=[CH2:18])O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:17]([C:19]([F:22])([F:21])[F:20])=[CH2:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: Clc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=C(c1ncccc1Cl)C(F)(F)F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 2-bromo-3-chloropyridine (Matrix, 1.651 g, 8.58 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (Frontier, 2.0 g, 9.01 mmol), and potassium carbonate (4.74 g, 34.3 mmol) in degassed 1,2-dimethoxyethane (50 mL) and water (25 mL) was added tetrakis(triphenylphosphine)palladium (496 mg, 0.429 mmol). The reaction mixture was refluxed for 8 hours, cooled to ambient temperature, diluted with water (200 mL), extracted twice with diethyl ether (200 mL), washed with brine, dried (Na2SO4) and concentrated to a yellow liquid. The residue was purified by silica gel chromatography (AnaLogix® SF25-40G; 50 micron silica; elution with 0-20% ethyl acetate in hexane at 30 mL/min) to provide the title compound (1.530 g, 7.37 mmol, 86% yield) as a colorless liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (dd, J=4.6, 1.4, 1H), 8.10 (dd, J=8.2, 1.4, 1H), 7.53 (dd, J=8.3, 4.6, 1H), 6.51-6.46 (m, 1H), 6.13-6.10 (m, 1H); MS (EI) m/e 207 (M)+.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH3:31])[CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(=O)=O.Br[C:33]1SC(C(C2C3C(=C(CSC)C=CC=3)NC=2)CCC#N)=C[N:37]=1>CS(C)=O>[CH3:31][CH:7]([CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:6][C:33]#[N:37]
Reactant: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)COS(C)(=O)=O)c[nH]c12
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)CC#N)c[nH]c12

Procedure:
The title compound was prepared starting from 620 mg (1.32 mmol) of the compound from Example 70A in analogy to the synthesis of the compound from Example 53 but with dimethyl sulfoxide as solvent. 492 mg (93% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH2:33][C@@H:32]([N:35]([CH3:37])[CH3:36])[CH2:31]2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C.CN(C=O)C>[CH3:37][N:35]([CH3:36])[C@@H:32]1[CH2:33][CH2:34][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[CH2:20][N:16]3[CH2:15][CH2:14][CH:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:18][CH2:17]3)=[CH:25][CH:26]=2)[CH2:31]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CN3CCC(c4ccccc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added to a solution of (R)-2-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the mixture was kept at 65° C. for 12 hours. The mixture was freed of volatile fractions and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:32][CH2:33][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].[CH2:24]1[O:26][CH2:25]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:24][CH2:25][OH:26])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Reactant: C1CO1
Solvent: CCO
Product: COc1ccc(C2=C(CC(C)N(CCO)C(C)C)C(=O)NCCC2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The mixture of 6.3 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 20 ml of ethylene oxide and 25 ml of absolute ethanol is stirred in a sealed vessel at room temperature for 5 days. The resulting solution is evaporated, the residue crystallized from petroleum ether and recrystallized from ethyl acetate-hexane, to yield the 3-[2-(N-isopropyl-N-hydroxyethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 109°-111°.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[C:13]([NH:14][C@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][OH:17])=[N:12][C:11]([SH:22])=[N:10][C:9]=2[N:23]=1.[ClH:24]>O.CC#N>[Cl:24][C:6]1[S:7][C:8]2[C:13]([NH:14][C@H:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][OH:17])=[N:12][C:11]([S:22][S:22][C:11]3[N:12]=[C:13]([NH:14][C@@H:15]([CH2:16][OH:17])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:8]4[S:7][C:6]([Cl:24])=[N:23][C:9]=4[N:10]=3)=[N:10][C:9]=2[N:23]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CC(C)C)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Temperature: 2.5 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Sodium nitrite (5.19 g, 75 mmol) in water (25 mL) was added dropwise at 0° C. to (2R)-2-[[2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentan-1-ol (7.50 g, 25 mmol) in conc. HCl (150 mL) and CH3CN (150 mL). The reaction mixture was stirred for 18 h at 0-5° C., and then poured onto ice (500 mL), and extracted with EtOAc. Any remaining solid was filtered off. The combined organic phases were washed sequentially with saturated NaCl solution and saturated aqueous NaHCO3 solution. The organic phase was dried and evaporated and the solid previously filtered off was added to this. The total solid was slurried in EtOAc, which after filtration provided the title compound (6.3 g, 80% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19].O>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1nc2cc(Br)ccc2[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2cc(Br)c([N+](=O)[O-])cc2[nH]c1=O
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 7-bromo-3,4-dihydro-3-oxoquinoxaline-2-carboxylate (2.60 g, 8.75 mmol) in acetic acid (35 ml) was added dropwise fuming nitric acid (1.40 ml, 31.5 mmol) at 60° C., and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water (300 ml). The precipitate was collected by filtration, washed with water, and then air-dried to obtain 2.79 g of the title compound as yellow powder. Yield 93%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N+:23]([CH3:25])=[CH2:24].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:22][N:23]([CH2:25][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:2]=1[CH3:1])[CH3:24]
Reactant: COC(=O)c1ccc(Cn2c(C)cc3ccccc32)cc1
Reactant: C=[N+](C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C)c(CN(C)C)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
Methyl 4-((2-methyl-1H-indol-1-yl)methyl)benzoate 3 (0.500 g, 1.90 mmol) and dimethylformiminium chloride (0.200 g, 2.15 mmol) were heated to reflux in a solution of DCM (5 mL) and DMF (2 mL) for 20 h. The reaction was then cooled to RT and DCM (50 mL) was added along with sat. NaHCO3 (20 mL). The organic fraction was isolated and the aqueous solution was further extracted with DCM (2×20 mL). The combined organic fractions were washed with H2O (20 mL), brine (20 mL), dried with Na2SO4 and concentrated in vacuo. The desired product was purified via automated column chromatography method 2 (0.221 g, 37%). 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.1 Hz, 2H), 7.69 (m, 1H), 7.14 (m, 3H), 7.02 (d, J=8.0 Hz, 2H), 5.38 (s, 2H), 3.90 (s, 3H), 3.62 (s, 2H), 2.35 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1.[Cu][C:24]#[N:25].O>CN(C=O)C>[C:24]([C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1)#[N:25]
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2coc3cc(OC)cc(Br)c3c2=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(OC)cc(C#N)c3c2=O)cc1
Temperature: 120 °C
Yield: 98.7 %

Procedure:
A suspension of 5-bromo-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1 benzopyran (150 mg), copper(I) cyanide (55.5 mg) in DMF (4 mL) was heated at 120° C. for 3 h. The mixture was cooled, poured into cold water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried over MgSO4. Evaporation of the solvents afforded the title compound (126 mg) as a white solid. 1H NMR (DMSO-d6): 8.52 (s, 1H), 7.67 (d, 1H, J=2.7 Hz), 7.54 (m, 3H), 7.01 (d, 2H, J=8.7 Hz), 3.97 (s, 3H), 3.80 (s, 3H); MS: 308 (MH+); HPLC tR: 2.29 min.