Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:8])(C)(C)C.Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[CH:15][CH:16]=2)[CH2:9][NH:7][CH3:8])=[CH:23][CH:22]=1
Reactant: Clc1cnccn1
Reactant: CN(CC(c1ccc(O)cc1)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNCC(c1ccc(Br)cc1)c1ccc(Oc2cnccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
A solution of [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (125 mg, 0.31 mmol), 2-chloropyrazine (35.2 mg, 0.31 mmol) and K2CO3 (213 mg, 1.54 mmol) in dimethylformamide (8 ml) was heated to 100° C. for 17 hours. Upon cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was then treated with saturated HCl in diethyl ether (15 ml) and stirred at room temperature for 72 hours. The solvent was then removed under reduced pressure and the crude product was purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product (82 mg). LC/MS: (PS-B3) Rt 3.17 [M+H]+ 384.
Reaction SMILES: [N+:1]([C:4]([CH3:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.N1C=CC=CC=1.[Pd]>[N+:1]([C:4]([CH3:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([NH:15][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: CC(C)(Cc1c[nH]c2c([N+](=O)[O-])cccc12)[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(Cc1c[nH]c2c(NS(=O)(=O)c3ccccc3)cccc12)[N+](=O)[O-]
Temperature: 0 °C
Yield: 71 %

Procedure:
3-(2-Nitro-2-methylpropyl)-7-nitroindole (1.89 g, 7.2 mmol) is dissolved in ethyl acetate (75 mL) and 10% Pd/C is added (750 mg). The mixture is stirred under a balloon of nitrogen for 2–3 hours. The mixture is filtered to remove the Pd/C, and the filtrate is evaporated to give a crude oil. This crude 3-(2-nitro-2-methylpropyl)-7-aminoindole is immediately dissolved in pyridine (100 mL) and the solution is cooled with an ice bath to 0° C. Benzenesulfonyl chloride is added slowly, and the mixture is stirred for 5 minutes at this temperature before removing the ice bath. The reaction mixture is stirred overnight before being quenched by addition of 1N HCl and ethyl acetate. The aqueous layer is extracted with ethyl acetate several times and the combined organic extracts are washed twice with brine and dried over Na2SO4 to give a crude oil. The crude material is purified by flash chromatography (25% ethyl acetate/hexanes) to provide 1.9 g of 3-(2-nitro-2-methylpropyl)-7-benzenesulfonamidyl-indole (71%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8]([CH:10]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]1=O)=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:10]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: CCOC(=O)C(=O)C1CCC(C)(C)C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCC2(C)C
Yield: 70.9 %

Procedure:
Hydrazine hydrate (0.229 mL, 4.71 mmol) was added to a stirring room temperature solution of 1 (0.9961 g, 4.71 mmol) in EtOH (4.7 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (2 h). The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH). Only pure fractions were combined and concentrated to obtain 0.6955 g (71.2%) of 2. 1H (CDCl3, 400 MHz): δ 11.04 (1H, broad s), 4.33 (2H, q, J=7.3 Hz), 2.76 (2H, t, J=6.8 Hz), 2.26 (2H, t, J=6.8 Hz), 1.33 (3H, t, J=7.3 Hz), 1.31 (6H, s) ppm. 13C (CDCl3, 100 MHz): δ 168.08, 160.61, 128.73, 127.27, 61.15, 47.22, 38.64, 27.57, 22.00, 14.48 ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(F)cc1N

Procedure:
4,5-Difluoro-2-nitro-phenylamine is a known compound.8 It was reduced with tin (II) chloride dihydrate in ethanol to give the 4,5-difluoro-benzene-1,2-diamine. The diamine was reacted with hexaketocyclohexane octahydrate to give [(HATNA)F6]. The product was purified by train purification (sublimation). The compound is yellow needle like crystal. It is slightly soluble in chloroform. It is very soluble in chloroform/TFA (3:1) mixture.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].[CH3:37]I.O>COCCOC>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH3:37])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
8-(3,5-Bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (253 mg) was suspended in 1,2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60%) was added with stirring at room temperature. After 15 minutes methyliodide (78 mg) was added and stirring was continued overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. Chromatography on silica gel (hexane/ethylacetate=1:1) yielded the desired product (152 mg, 59%), MS: m/e=520.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>O1CCCC1>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:29](=[O:30])[NH:28][CH2:26][CH3:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(1-Ethylpiperazin-4-yl)-3-(4-hydroxyphenyl)isoquinoline (333 mg) was dissolved in tetrahydrofuran (5 ml), ethyl isocyanate (800 ml) was added thereto, and then the mixture was stirred at room temperature for 3 hr. The reaction mixture was evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), and then recrystallized from ethyl acetate/hexane, to give the free compound of the title compound. The free compound was converted into a hydrochloride in a conventional manner, which was then recrystallized (from ethanol/isopropyl ether), to give the hydrochloride of the title compound as yellow crystals (313 mg, yield; 70%).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([N:11]1[CH2:15][CH:14]([N:16]2C(=O)[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13][N:12]1[CH2:27][CH3:28])[CH3:10].[F:29]C1C=CC(C(Cl)=O)=CC=1>>[F:29][C:23]1[CH:22]=[CH:19][C:18]([C:17]([NH:16][CH:14]2[CH2:15][N:11]([CH2:9][CH3:10])[N:12]([CH2:27][CH3:28])[CH2:13]2)=[O:26])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CC(N2C(=O)c3ccccc3C2=O)CN1CC
Agent: O=C(O)/C=C\C(=O)O
Product: CCN1CC(NC(=O)c2ccc(F)cc2)CN1CC

Procedure:
The title compound was prepared as described in Example 2 of U.S. Pat. No. 4,207,327 from 1,2-diethyl-4-phthalimidopyrazolidine maleate and p-fluorobenzoyl chloride, m.p. 114°-116° C.
Reaction SMILES: O1C2(CC[CH:8]([CH2:11]OC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7]C2)OCC1.[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([O:38][C:39]3[C:51](Cl)=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[C:41]([F:53])[CH:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([O:38][C:39]3[C:51]([CH:11]4[CH2:8][CH2:7]4)=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[C:41]([F:53])[CH:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)OCCO3)cc1F

Procedure:
Following the procedure as described in Example 305/306, Step 2 and making variations as required to replace tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a yellowish oil (0.557 g, 79%): 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J=8.4 Hz, 1H), 6.53 (d, J=13.2 Hz, 1H), 4.54-4.39 (m, 1H), 3.97-3.93 (m, 4H), 2.07-1.58 (m, 9H), 1.55 (s, 9H), 0.92-0.82 (m, 2H), 0.63-0.57 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.Cl.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH2:30][NH2:31])[N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:31][CH2:30][C:22]2[N:21]=[CH:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1cc2ccccc2cn1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2cc3ccccc3cn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-isoquinolin-3-yl-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69.9 %

Procedure:
(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (300 mg, 1 mmol), K2CO3 (170 mg, 1.2 mmol), and 4-methoxybenzyl chloride (170 mg, 1.1 mmol) in DMF (25 mL) was heated to 60° C. for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over MgSO4 and concentrated to give a crude white wax. Further purification by flash chromatography (SiO2, 25% EtOAc/hexanes) afforded the titled compound (297 mg) as a white solid in 70% yield. [α]D=+44.2 (c 1.00, MeOH); MS (ESI), (M−H)−422.9; 1H NMR (CDCl3) δ7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H , J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd,2H, J=50, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].Cl[C:9]1[C:10]([F:45])=[C:11]([C@@H:15]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:44])[NH:31][CH:32]([CH2:36][C@H:37]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38]3)[CH2:33][NH:34][CH3:35])[CH2:25]2)[O:16][CH2:17][CH2:18][NH:19][C:20](=[O:23])[O:21][CH3:22])[CH:12]=[CH:13][CH:14]=1>CO.[Pd]>[F:45][C:10]1[CH:9]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@H:15]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:44])[NH:31][CH:32]([CH2:36][C@H:37]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38]2)[CH2:33][NH:34][CH3:35])[CH2:25]1)[O:16][CH2:17][CH2:18][NH:19][C:20](=[O:23])[O:21][CH3:22].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CNCC(C[C@H]1CCCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2F)C1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNCC(C[C@H]1CCCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((1R)-(3-chloro-2-fluorophenyl)((3R)-1-(1-(methylamino)-3-((R)-oxepan-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate TFA salt (12 mg, 0.018 mmol) in MeOH (5 mL) was added HCO2NH4 (1.2 g) and 10% Pd/C (50 mg). The mixture was stirred for 1 h at rt. The catalyst was filtered off and concentrated, the residue was purified on preparative HPLC to give methyl 2-((1R)-(2-fluorophenyl)((3R)-1-(1-(methylamino)-3-((R)-oxepan-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate as a TFA salt (1.84 mg, 16%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C=O.[CH:30](O)=O>O1CCOCC1>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@H:17]3[CH2:21][CH2:20][N:19]([CH3:30])[CH2:18]3)(=[O:15])=[O:16])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@H]3CCNC3)ccc21
Reactant: O=CO
Agent: C=O
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@H]3CCN(C)C3)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To solution of (S)—N,N-dimethyl-2-(2-neopentyl-5-(pyrrolidin-3-ylsulfonyl)-1H-benzo[d]imidazol-1-yl)ethanamine (STEP F, 776 mg, 1.98 mmol) in 1,4-dioxane (5 mL) were added 37% formalin (588 microL, 7.31 mmol) and formic acid (379 microL, 9.88 mmol). The mixture was stirred at 60° C. for 1 h. The mixture was concentrated in vacuo. The residue was diluted with saturated sodium bicarbonate aqueous solution (4 mL) and extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The resulting solution was concentrated in vacuo and residue was purified by amine gel column chromatography (dichloromethane-ethyl acetate, gradient) to give the title compound (704 mg, 87%) as clear grease.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (15.47 g, 37.3 mmol) in 150 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 15.12 g, 61.3 mmol). After stirring for 1.5 h, the reaction mixture was treated with water (100 mL) and CHCl3 (50 mL) and the layers were separated. The organic portion was washed with 2% Na2CO3 solution (2×), H2O and brine then dried over Na2SO4 and concentrated to give 16.06 g of tert-butyl 2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[CH:61]=[C:60]([C:65]1[CH:66]=[C:67]([NH2:71])[CH:68]=[CH:69][CH:70]=1)[CH:59]=[CH:58]2>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[CH:61]=[C:60]([C:65]1[CH:66]=[C:67]([NH:71][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:68]=[CH:69][CH:70]=1)[CH:59]=[CH:58]2
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(OC(F)(F)F)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
DIEA (0.0115 mL, 0.067 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.06 mmol) and HATU (0.025 g, 0.067 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.015 g of product in 49% yield: LCMS (ESI) m/z 506 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:35]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: COCC(=O)Cl
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A175) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1OCCOCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
To 1 mL of DMF/H2O (v/v=9/1) was added 2-(2-(2-bromoethoxy)ethoxy)isoindoline-1,3-dione (50 mg, 0.17 mmol) and sodium azide (16.6 mg, 0.26 mmol). The mixture was heated to 80° C. overnight. Then it was allowed to cool down to room temperature and was extracted with ethyl acetate for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (hexanes: ethyl acetate 2:1) to afford 2-(2-(2-azidoethoxy)ethoxy)isoindoline-1,3-dione (44 mg, 0.17 mmol, 100%) as colorless oil. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.28 (t, J=4.7 Hz, 2H), 3.64 (t, J=4.8 Hz, 2H), 3.84 (t, J=3.8 Hz, 2H), 4.34 (t, J=3.9 Hz, 2H), 7.71 (dd, J=2.6, 4.7 Hz, 2H), 7.79 (dd, J=3.2, 5.0 Hz, 2H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30]P(=O)(OCC)OCC)=[N:27]2)=[CH:22][CH:21]=1.C=O>O1CCCC1>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH2:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)NC(C)C
Reactant: CCOP(=O)(Cc1ccc2ccc(Cl)cc2n1)OCC
Agent: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2ccc(Cl)cc2n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A stirred solution of diisopropylamine (2.24 ml, 15.97 mmol) in tetrahydrofuran (15.0 ml) at −10° C. under nitrogen was treated dropwise with a 2.5 M solution of n-butyllithium in hexane (6.4 ml, 15.97 mmol). After stirring below 0° C. for 30 min the pale yellow solution was cooled to −20° C. and a solution of diethyl 7-chloro-2-quinolylmethylphosphonate (5.0 g, 15.97 mmol) in tetrahydrofuran was added dropwise. The resulting dark green solution was stirred below 0° C. for 1 h, cooled to −10° C. and treated with paraformaldehyde (0.53 g, 17.57 mmol) in portions. Stirred cold for 15 min after which the cooling bath was removed and the mixture was stirred at 25° C. for 90 min. Quenched with brine (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (3×200 ml), dried (Na2SO4) and the solvent was removed in vacuo to give a dark brown solid. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:19) provided the title compound (1.80 g, 59%) as pale yellow crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40-60° C.) as cream crystals, m.p. 79.7-80° C. (Found: C, 69.84; H, 4.15; N; 7.25; Cl, 18.91. C11H8ClN requires C, 69.67; H, 4.25; N, 7.39; Cl, 18.69%); νmax (nujol)/cm−1 1628, 1609; δH (270 MHz) 5.67 (1H, dd, 2′-H, 3J2′,1′=10.89, 2J2′,2″=1.0 Hz); 6.29 (1H, dd, 2″-H, 3J2″,1′=17.7, 2J2″,2′=0.8 Hz); 7.02 (1H, dd, 1′-H, 3J1′,2″=17.5, 3J1′,2′=10.9 Hz); 7.42 (1H, dd, 7-H, Jo=8.8, Jm=2.1 Hz); 7.53 (1H, d, 3-H, Jo=8.9 Hz); 7.66 (1H, d, 5-H, Jo=8.9 Hz); 8.03 (1H, d, 4-H, Jo=8.3 Hz); 8.05 (1H, s, 8-H). δc (67.8 MHz) 118.6 (2′-C); 120.5 (3-C); 125.7 (4a-C); 135.3 (7-C); 136.0 (4-C); 137.5 (1′-C); 148.3 (8a-C); 156.9 (2-C). Remaining signals fall in the range 127.1-128.5 ppm; m/z 191.0, 189.0 (33.48, 100, M+), 165.0, 163.0 (21.89, 65.87), 154.0 (5.13), 128.1 (9.14).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Brc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a solution of 2-bromophenol (1 g, 5.84 mmol), phenylboronic acid (1.42 g, 11.69 mmol) and TEA (2.95 g, 29.2 mmol) in DCM (30 mL) was added Cu(OAc)2 (1.05 g, 5.84 mmol) and 4 Å molecular sieves (500 mg). The reaction mixture was stirred at room temperature over air with a dry tube attached for 16 h. The mixture was filtered and the filtrate was washed by water (50 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated with the residue purified by column chromatography to give 612 mg of the desired product.