Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:26])[C:24]=1[F:25])[N:21]=[CH:20][C:19]([C:27](OCC)=[O:28])=[C:18]2[OH:32].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:27]([C:19]2[CH:20]=[N:21][C:22]3[C:17]([C:18]=2[OH:32])=[CH:16][C:15]([F:14])=[C:24]([F:25])[C:23]=3[F:26])=[O:28])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.45 mL) in 5 mL of toluene is added 1.84 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution is stirred for 5 min at 0° C. and then 0.20 g of ethyl 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate (Tetrahedron 48, 29 (1992)) is added. The solution is stirred at 0° C. for an additional 30 min and then it is stirred 18 h at 25° C. The mixture is poured onto a mixture of 50 mL of 3 M hydrochloric acid and 50 mL of crushed ice. The mixture is extracted with three successive 75 mL portions of ethyl acetate. The combined extracts are dried (MgSO4) and the solvent is evaporated at reduced pressure. The residue is dissolved in a small volume of ethyl acetate and hexanes is added until the solution becomes cloudy. The mixture is then allowed to stand for 1 h. Filtration of this mixture gives the desired amide as 0.25 g of a solid.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])(=O)=O.O>CS(C)=O>[CH2:30]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCCCCCCCCCS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a suspension of sodium theobromine (6.00 g, 30.0 mmol) in dimethylsulfoxide (60 mL) was added 12-methanesulfonyl-1-dodecene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (120 mL) and extracted with diethyl ether (2×100 mL). The organic portions were combined, dried using magnesium sulfate and evaporated to give a cream solid. Recrystallization from ethyl acetate/hexane 1:1 yields 6.97 g (67% yield) 1-(11-dodecenyl)-3,7-dimethylxanthine (inventive compound no. 2516) as a white solid.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][C:29]([S:33]([NH:36][CH2:37][CH2:38][CH2:39][N+:40]([CH3:43])([CH3:42])[CH3:41])(=[O:35])=[O:34])=[CH:28][C:27]=3[F:44])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:45][CH3:46].[C:47]([O-:50])([O-])=[O:48].[K+].[K+]>CN(C=O)C>[Cl-:2].[C:47]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:36]([CH2:37][CH2:38][CH2:39][N+:40]([CH3:41])([CH3:43])[CH3:42])[S:33]([C:29]2[CH:28]=[C:27]([F:44])[C:26]([CH2:25][S:24][C:15]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:12]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:45][CH3:46])[CH:5]=4)([CH3:10])[CH3:11])=[CH:13][N:14]=3)=[C:31]([F:32])[CH:30]=2)(=[O:35])=[O:34])=[CH:5][CH:4]=1)([OH:50])=[O:48]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCC[N+](C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)N(CCC[N+](C)(C)C)Cc4ccc(C(=O)O)cc4)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 24 h
Yield: 187.8 %

Procedure:
To a solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorphenylsulfonamido)-N,N,N-trimethylpropan-1-aminium chloride (96 mg, 0.13 mmol) in DMF (2 mL) was added K2CO3 (80 mg, 0.58 mmol) and methyl-(4-bromomethyl)-benzoate (40 mg, 0.18 mmol) at 25° C. and the resulting suspension was stirred for 24 h. The reaction mixture was quenched into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated to a colorless oil. The oil was reconstituted in THF (6 mL) and added to a solution of LiOH.H2O (420 mg) in water (10 mL) at 25° C. After 30 min the reaction was concentrated and adjusted to pH 1 with conc HCl. The aqueous layer was extracted with DCM, and combined extracts were dried (MgSO4) and concentrated to furnish the title product (104 mg, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=8.2 Hz, 2H), 7.62 (d, J=6.4 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.01 (t, J=8.7 Hz, 2H), 6.61 (dd, J=8.8, 4.9 Hz, 2H), 6.55 (d, J=1.8 Hz, 1H), 6.50 (dd, J=8.3, 1.9 Hz, 1H), 4.51 (s, 2H), 4.02 (s, 2H), 3.68 (s, 3H), 3.28-3.14 (m, 2H), 3.14-3.04 (m, 2H), 2.92 (s, 9H), 1.67 (d, J=8.3 Hz, 2H), 1.47 (s, 6H); MS (EI) m/z 815 (MH+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:31][CH:30]([CH2:32][C:33](OC)=[O:34])[CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH:30]5[CH2:31][O:28][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(=O)CC1COC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15.4 mg, 51.2%), MS (ISP) m/z=430.5 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and methyl 2-(oxetan-3-yl)acetate prepared from Oxetan-3-ylidene-acetic acid methyl ester as reported on WO2010031735. (example 47)
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.[CH:37]([NH:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][C:49]([CH:54]=[CH2:55])=[CH:48][C:47]=3[N:46]=[C:45]([NH2:56])[C:44]=2[N:43]=[C:42]1[CH2:57][CH2:58][CH3:59])([CH3:39])[CH3:38]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:37]([NH:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][C:49]([CH:54]=[CH:55][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[CH:48][C:47]=3[N:46]=[C:45]([NH2:56])[C:44]=2[N:43]=[C:42]1[CH2:57][CH2:58][CH3:59])([CH3:39])[CH3:38]
Reactant: C=Cc1ccc2c(c1)nc(N)c1nc(CCC)n(NC(C)C)c12
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cc(C=Cc4cccnc4)ccc3c2n1NC(C)C
Temperature: 120 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A suspension of palladium (II) acetate (0.067 g, 0.30 mmol) and tri-o-tolylphosphine (0.271 g, 0.891 mmol) in 10 mL of MeCN was placed in a 50 mL heavy wall glass pressure flask and placed under an atmosphere of nitrogen. The mixture was stirred until homogeneous. The mixture was treated with triethylamine (1.58 mL, 11.9 mmol), 3-bromopyridine (0.430 mL, 4.46 mmol) and N-isopropyl-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.92 g, 3.0 mmol). Nitrogen was bubbled through the mixture for 1 min and then the flask was sealed. The reaction was heated to 120° C. After 15 h, the homogenous orange solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between 75 mL of CHCl3 and 25 mL of 10% Na2CO3 solution. The phases were separated and the organic portion was washed with H2O (25 mL). The combined aqueous portions were back-extracted with CHCl3 (25 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange solid. The solid was purified by chromatography (SiO2, 20–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield N1-isopropyl-2-propyl-7-(2-pyridin-3-yl-vinyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.97 g) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[H-].[Na+].[CH2:21](I)[CH:22]=[CH2:23].O>C1COCC1>[CH2:23]([O:10][C@H:8]1[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C@H:5]([C:3]([N:2]([CH3:18])[CH3:1])=[O:4])[CH2:9]1)[CH:22]=[CH2:21]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCO[C@@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of 9.6 g of tert-butyl (2S,4R)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate in THF (100 ml) was added 937 mg of NaH and the reaction mixture was stirred at 60° C. for one hour. After returning to room temperature, 12.5 g of allyl iodide was added to the reaction solution, and the reaction mixture was refluxed for one hour. To the reaction solution was added water and the resulting mixture was extracted with EtOAc, then was washed with saturated brine. The organic layer was dried over Na2SO4, then the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=18/1 to 9/1; v/v) to obtain 6.70 g of the title compound (light brown oil).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>C1COCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.2 %

Procedure:
To a solution of 2-bromo-1-[3-(methyloxy)phenyl]ethanone (2.4 g, 10.5 mmol) in THF (80 mL) and water (20 mL) was added sodium azide (1.703 g, 26.2 mmol), and the reaction mixture was stirred at room temperature for 60 hours. Water (40 mL) was added, and the aqueous mixture was extracted with EtOAc (3×80 mL). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound (1.87 g) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 3.87 (s, 3H), 4.55 (s, 2H), 7.15-7.18 (m, 1H), 7.38-7.42 (m, 1H), 7.44-7.47 (m, 2H).
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1.Cl>O>[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([O:4][CH2:2][CH3:3])[N:7]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCO
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCOc1nc(N)nc2nc[nH]c12

Procedure:
Sodium (0.68 g, 29.5 mmol, Aldrich lot #9621CL) was added in portions to anhydrous ethanol (50 mL). Upon complete dissolution 2-amino-6-chloropurine (1 g, 5.9 mmol Sigma lot #69F4064) was added and the reaction heated at reflux for 96 hours. The reaction was cooled, diluted with 20 mL water, and neutralized with 1N HCl. The solvents were evaporated and the residue slurried in 100 mL water. The product was filtered off and air dried to give 0.95 g (5.3 mmol; 89.9%); mp=252-°253° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[CH3:24].CN(C)C=O.[H-].[Na+]>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOc1ccc(O)c(CC(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.4 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.72 g), methyl 2-(5-ethoxy-2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.08 g) under ice-cooling and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.56 g, 60%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15])(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:13]2[CH:8]([CH2:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:15])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C2=CC=CCC2C(C)CC1(C)C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C2=CC=C([N+](=O)[O-])CC2C(C)CC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
86.8 g of N-acetyl-2,2,4-trimethyltetrahydroquinoline are dissolved in 600 ml of acetic anhydride and the solution is cooled to 0° C. 28 g of fuming nitric acid in 50 ml of acetic anhydride are now added dropwise. The mixture is kept at 0° C. for a further 30 minutes and is then stirred overnight at room temperature. It is poured onto water and the precipitate is filtered off with suction. 89 g of 1-acetyl-2,2,4-trimethyl-6-nitrotetrahydroquinoline of melting point 91° C. are obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:9][CH:8]([CH3:10])[CH:7]([CH3:11])[O:6]1)[CH3:2].[N+:12]([C:15]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[N+:35]([O-:37])=[O:36])=[CH:23][C:16]=1[O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])([O-:14])=[O:13]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH:5]1[O:6][CH:7]([CH3:11])[CH:8]([CH3:10])[O:9]1)[C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[N+:35]([O-:37])=[O:36])[CH:25]=[CH:26][C:15]=1[N+:12]([O-:14])=[O:13])[CH3:22])[CH3:2]
Reactant: CCNCC1OC(C)C(C)O1
Reactant: CC(Oc1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CCN(CC1OC(C)C(C)O1)C(=O)C(C)Oc1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Temperature: -15 °C

Procedure:
N-Ethyl-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-nitro-4-bromophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-ethyl-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-nitro-4-bromophenoxy)phenoxy]propionamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:26])[CH2:24]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CCOC(C)=O>C(OC(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:26])[CH2:24][NH:30][CH2:29][CH2:27][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(CCl)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Solvent: CC(=O)OC(C)C
Solvent: CCOC(C)=O
Product: O=C(CNCCO)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 55 °C

Procedure:
To a solution of the product from Step C (6.9165 g, 17.25 mmol) in 25 mL of isopropyl acetate was added ethanolamine (3.84 mL, 63.7 mmol). The reaction was warmed to 55° C. for 4 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:18](=[O:19])[CH:17]=[C:16]2[C:7](=[N:8][C:9]3[C:14]([S:15]2)=[CH:13][C:12]([O:20][CH3:21])=[CH:11][CH:10]=3)[CH:6]=1.CO>C(O)(=O)C>[Br:1][C:17]1[C:18](=[O:19])[C:5]([O:4][CH3:3])=[CH:6][C:7]2[C:16]=1[S:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([O:20][CH3:21])[CH:13]=1)[N:8]=2
Reactant: BrBr
Reactant: COc1ccc2nc3cc(OC)c(=O)cc-3sc2c1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of bromine (280 g) in acetic acid (2.8 l) was added over a period of 30 minutes to a suspension of 2,7-dimethoxy-3H-phenothiazin-3-one (250 g) (Step 3) in acetic acid (7.5 l) and the mixture was stirred for 2 hours. Methanol (12 l) was added over a period of 30 minutes to the reacting mixture and the black suspension was stirred until it became an orange suspension. Then, the precipitate was filtered, washed with methanol and air-dried to afford the desired compound (312 g), m.p. 260°-261° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2[CH2:27][CH2:28][CH2:29][CH2:30][C:22]1=2>C(O)(=O)C>[F:20][C:3]1[C:2]([N:1]2[C:24](=[O:25])[C:23]3[CH2:27][CH2:28][CH2:29][CH2:30][C:22]=3[C:21]2=[O:26])=[CH:19][C:6]2[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc2c(cc1F)OCC(=O)N2Cc1ccccn1
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1Cc1ccccn1
Yield: 80.5 %

Procedure:
A mixture of 6-amino-7-fluoro-4-(pyridin-2-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (2 g), 3,4,5,6-tetrahydrophthalic anhydride (1.2 g) and acetic acid (50 ml) was heated under reflux for 1 hour. The acetic acid was distilled off under a reduced pressure, and the residue was dissolved in toluene (100 ml), washed in a saturated aqueous solution of sodium bicarbonate and then in water, and dried over anhydrous sodium sulfate. The toluene was distilled off under a reduced pressure, and the resultant residue was recrystallized from ethanol, whereby the aimed product, namely, 7-fluoro-4-(pyridin-2-ylmethyl)-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (2.4 g) was obtained. m.p. 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([F:19])[CH:3]=1.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:10]1[CH:11]=[C:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2F)c(C)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
A solution of ethyl 3-(4-chloro-2-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (5.7 g, 20.2 mmol) in dry DMF (25 mL) was added dropwise to a cooled suspension of 60% NaH in mineral oil (0.89 g, 22.3 mmol) in dry DMF (25 mL). The mixture was stirred at 0° C. for 20 min, then benzylbromide (2.54 mL, 21.3 mmol) was added dropwise. The mixture was stirred for 10 min at 0° C., the cooling was removed and stirring was continued for 2 h at room temperature. The reaction was quenched by addition of saturated aqueous NH4Cl/ice (1:1, 150 mL) and the product was extracted with EtOAc (150 mL). The combined organic layers were dried on Na2SO4 and evaporated. The residual crude product purified using column chromatography (silica, heptane/EtOAc 2:1) to give the desired product (6.6 g, 88%) as an orange oil.