Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH:25]([CH3:27])[CH3:26])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:25]([C@@H:4]1[CH2:3][C:2](=[O:1])[CH2:7][CH2:6][C@@H:5]1[N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:24])([CH3:27])[CH3:26]
Reactant: CC(C)[C@@H]1C[C@H](O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.7 %

Procedure:
Benzyl (S)-1-((1S,2S,4R)-4-hydroxy-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (333 mg) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. prior to the addition of Dess-Martin reagent (678.9 mg). This solution was warmed to rt over 1 h, and then was cooled to 0° C. prior to the addition of more Dess-Martin reagent (260 mg). After 1 h at rt, the reaction was quenched with Et2O and 1N NaOH. The organic extracts were combined, washed with saturated Na2S2O3 and NaHCO3 solutions, dried (MgSO4), filtered, and concentrated to afford benzyl (S)-1-((1S,2S)-2-isopropyl-4-oxocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (350 mg). MS found: (M+H)+=373.4.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].[C:10]([O:13]C(=O)C)(=O)[CH3:11].Cl>N1C=CC=CC=1>[C:10]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:13])[CH3:11]
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of 0.50 g of 1,2-dimethyl-3-nitroisothiourea and 10 ml of pyridine was dropwise added 1.03 g of acetic anhydride at room temperature. The mixture was stirred at room temperature for 1 hour, and then poured onto 150 ml of 2N hydrochloric acid followed by extraction with 100 ml of chloroform. The chloroform layer was washed with 50 ml of 2N hydrochloric acid and then concentrated to give 0.60 g of 1-acetyl-1,2-dimethyl-3-nitroisothiourea as pale yellow liquid. NMR (CDCl3):2.23(3H, s), 2.52(3H, s), 3.17(3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Yield: 96.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.260 g, 0.98 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.360 g, 1.42 mmol), KI (37 mg, 0.22 mmol), and DIPEA (0.35 mL, 2.01 mmol) in DMF (5 mL) was heated at 60° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 415 mg (96%) of 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester as a tan solid. To a cold (0° C.) solution of 5-Cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.409 g, 0.937 mmol) in THF (4.5 mL) and MeOH (9 mL) was added LiBH4 (229 mg, 10.52 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was diluted with 1.0 N NaOH (10 mL) and extracted with CH2Cl2 (5×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.332 g (87%) of COMPOUND 56 as a white foam. 1H NMR (CDCl3) δ 1.61-1.77 (m, 3H), 2.05-2.14 (m, 1H), 2.30-2.44 (m, 2H), 2.51 (s, 6H), 3.71 (s, 2H), 4.11 (d, 2H, J=10.8 Hz), 4.46 (s, 2H), 4.94 (br s, 1H), 6.87-6.96 (m, 4H), 7.22-7.27 (m, 3H), 8.21 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 19.35, 25.70, 28.19, 51.31, 62.24, 67.36, 109.58, 119.48, 122.56, 129.25, 130.02, 132.00, 132.24, 138.53, 139.79, 145.29, 146.76, 159.25; ES-MS m/z 413 (M+H). Anal. Calcd. For C26H28N4O.1.0H2O2: C, 72.53; H, 7.02; N, 13.01. Found: C, 72.46; H, 6.73; N, 12.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:17]=1)=[N:10][CH:11]=2.[CH3:40][S:41]([CH2:44][CH2:45]Br)(=[O:43])=[O:42]>>[CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:45][CH2:44][S:41]([CH3:40])(=[O:43])=[O:42])[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:17]=1)=[N:10][CH:11]=2
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)nc32)c(OC)c1
Reactant: CS(=O)(=O)CCBr
Product: COc1ccc(Cn2c(=O)n(CCS(C)(=O)=O)c3cnc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)nc32)c(OC)c1

Procedure:
300 mg (0.567 mmol) of the compound from example 93A were reacted in analogy to the method in example 83A with 2-bromoethyl methyl sulfone. 490 mg (100% of theory, 73% purity) of the title compound were obtained.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].C1COCC1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][CH2:3][CH:2]=[CH2:1])=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a 2M solution of allylmagnesium chloride in THF (24 mL, 48.00 mmol, 1.5 equiv) at 0° C. was added, under an atmosphere of N2, 4-bromobenzyl bromide (8.00 g, 32.01 mmol, 1.0 equiv) neat in 10 portions over a period of 5 min. The mixture was stirred for 1 h at 0° C. and then at rt for 28 h. The mixture was carefully quenched with water (100 mL) and then extracted with ethyl acetate (3×150 mL). The combined extracts were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated. High-vacuum drying gave 11a (6.51 g, 30.84 mmol, 96%) as a clear oil: Rf=0.94 (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 2.32-2.38 (m, 2H), 2.67 (t, J=7.8 Hz, 2H), 4.98-5.06 (m, 2H), 5.78-5.86 (m, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 34.9, 35.4, 115.4, 119.7, 130.4, 131.5, 137.7, 140.9; HRMS (EI) Calcd. for C10H11Br: 210.0044 (M+). Found: 210.0053.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[F:44][C:45]1[CH:46]=[C:47]([NH2:53])[CH:48]=[N:49][C:50]=1[O:51][CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:19]=[N:20][C:21]=3[NH:53][C:47]3[CH:48]=[N:49][C:50]([O:51][CH3:52])=[C:45]([F:44])[CH:46]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Tert-butyl 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2-methylpropanoate (185 mg, 0.315 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Aldrich; 67.1 mg, 0.472 mmol) were dissolved in tetrahydrofuran (3.1 mL) and the resulting mixture was cooled to −60° C. and sodium bis(trimethylsilyl)amide, 1 M in THF (Aldrich; 944 μL, 0.944 mmol) was added. The resulting mixture was stirred at −60° C. for 1 h, and the reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel) with 100% hexanes to 50% EtOAc/hexanes to give the title compound (11% yield) as a yellow oil. m/z (ESI, +ve) 709.8 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:6]=1[NH:13][CH3:14])C.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[Cl:11][C:9]1[CH:8]=[C:7]([F:12])[C:6]([NH:13][CH3:14])=[C:5]([CH:10]=1)[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)c1cc(Cl)cc(F)c1NC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CNc1c(F)cc(Cl)cc1C(=O)O
Yield: 93.2 %

Procedure:
To a solution of 5-chloro-3-fluoro-2-methylaminobenzoic acid ethyl ester (135 mg, 0.58 mmol) in MeOH was added 1N NaOH (1165 μl, 1.17 mmol) and the reaction mixture was refluxed for 2 h. The reaction mixture was diluted with ethyl acetate and water and then extracted. The aqueous layer was acidified to pH3 using 1N HCl and the aqueous layer was extracted with EtOAc (2×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (110 mg, 93%) which did not require further purification. MS (ISP) 202.1 (M−H)−.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH2:11]1)=[O:7])(C)(C)C.[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[O:20])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCNC(=O)c2ccncc2)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccncc2)C1

Procedure:
N-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-4-pyridinecarboxamide (0.90 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(4-pyridinecarbonylamino)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[O:3]1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:28]1[CH2:27][CH:26]1[CH2:24][O:22][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[CH:11][C:2]([CH3:23])([CH3:1])[O:3]2)=[CH:8][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Yield: 86 %

Procedure:
2,2-Dimethyl-4-(1-naphthyl)-2H-chromen-7-ol (7.92g, 0.026 moles) and epichlorohydrin (28.5ml) were dissolved in acetone (50ml). Potassium carbonate (6.3g) was added and the mixture refluxed for 6 hours, allowed to cool and filtered. The acetone was removed in vacuo and the residue dissolved in ether, washed with water and dried. Removal of solvent gave the title product as an orange oil (8.1g, 86%) which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[N+:69]([CH3:72])([O-:71])=[O:70]>>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:72][N+:69]([O-:71])=[O:70])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)/C=C/C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C[N+](=O)[O-])C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Temperature: 0 °C
Yield: 97.2 %

Procedure:
A 31.07 g (82.75 mmol) portion of ethyl (E)-3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]acrylate was dissolved in 300 ml of nitromethane to which, while cooling in an ice bath with stirring, was subsequently added dropwise 13.37 ml (82.75 mmol) of diazabicycloundecene. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, the reaction solution was acidified by gradually adding 10% citric acid aqueous solution and then mixed with ethyl acetate to effect separation of layers. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and then with saturated brine. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure to give 35.12 g (97.2%) of the title compound. This compound was used in the following reaction without purification.
Reaction SMILES: [OH:1][CH:2]([CH2:9][OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:11](C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC(OC)=CC=1.O>N1C=CC=CC=1>[OH:10][CH2:9][CH:2]([O:1][CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCC(O)CO
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCCCCC(CO)OC
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of 45 g of 7,8-dihydroxy-1-octene and 101.2 g of p-anisylchlorodiphenylmethane in 200 ml of pyridine was allowed to stand at 10° C. for 48 hours. The mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was dissolved in 300 ml of dimethylformamide containing 83.1 ml of methyl iodide and this solution was added dropwise to a suspension of 17.75 g of 60t sodium hydride in 500 ml of dimethylformamide over a 2 hour period. After stirring an additional 13 hours the mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was dissolved in 400 ml of methanol and stirred with 35 g of Amberlyst 15 resin. The solution was filtered and solvent was removed. The residue was purified by chromatography giving 22.6 g of 8-hydroxy-7-methoxy-1-octene as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2c([N+](=O)[O-])cccc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A mixture of 4-nitroindazole (2.0 g, 12 mmol) and potassium carbonate (5.1 g 37 mmol) in DMF (40 mL) was stirred for 30 minutes, after which 2-(dimethylamino)ethylchloride hydrochloride (2.7 g 18 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by Flash Chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.6g, 50% yield). 1H NMR (300 MHz, DMSO-d6) ppm 2.74(t, J=6.44, 2H), 3.31 (s, 6H), 4.63 (t, J=6.44, 2H), 7.64 (m, 1H), 8.16 (m, 1H), 8.30 (m, 1H), 8.51(m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[N:12][C:13](=[O:16])[NH:14][CH:15]=1.Cl[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][CH2:20][N:12]2[CH:11]=[C:10]([C:9]([F:17])([F:8])[F:18])[CH:15]=[N:14][C:13]2=[O:16])=[CH:24][CH:25]=1
Reactant: ClCOCc1ccc(Cl)cc1
Reactant: O=c1ncc(C(F)(F)F)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(C(F)(F)F)cn1COCc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Triethylamine (1 mmol) was added to a mixture of 5-trifluoromethyl pyrimidin-2-one (see Preparation 11 of European Patent Publication Ser. No. 0 056 319) (1 mmol) in dichloromethane (10 ml) and the solution stirred for 5 minutes before 4-chlorobenzyl chloromethyl ether (see Preparation 5a and 5b) (1 mmol) in dichloromethane (2 ml) was added. The mixture was stirred at room temperature overnight and at 40° C. for 3 hours before the solvent was distilled off and the residue triturated with water. The product was extracted into chloroform, dried (MgSO4) and evaporated. The residue was washed with ether and dried; yield 91%, m.p. 120° C. 1H NMR (CDCl3): δ4.64 (CH2Ph), 5.38 (NCH2), 7.24 (Ph), 8.11 (H-4, J 3 Hz), 8.74 (H-6, J 3 Hz). IR (KBr): 1680 cm-1 (CO).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CCOc1ccccc1C=O
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1C=[N+]([O-])C(C)(C)C
Temperature: 25 °C
Reaction time: 70 h
Yield: 78 %

Procedure:
2-Ethoxybenzaldehyde (12.0 g, 79.90 mmol) and N-tert-butylhydroxylamine (10.69 g, 119.86 mmol) were mixed in chloroform with molecular sieves (50 g, 4A) and silica gel (10 g). The mixture was sealed under argon gas and stirred for 70 h at room temperature. The mixture was then filtered and the solid washed with ethyl acetate and the combined solution was rotary evaporated. Pentane (50 mL) was added to the liquid residue and isolation of the resulting solid afforded 13.79 g (78.0% yield) of the title compound as white crystals, m.p. 58.3° C. (Rf=0.55 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18](=[O:19])[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[BH4-].[Na+]>C(O)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([OH:19])[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH2:14][CH2:15][OH:16])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1nc2c(n1CCO)C=Cc1cc(Cl)ccc1C2O

Procedure:
A mixture of the product of step (i) (0.79 g) in ethanol (100 ml) was treated with sodium borohydride (0.207 g) followed by heating at reflux for 4 hours. The mixture was treated with a few drops of acetone and then concentrated under reduced pressure to dryness. Used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24]N3CCCCC3)=[CH:5][C:4]=2[N:3]=1.C(O[C:35](=[O:37])[CH3:36])(=O)C>ClCCl>[C:35]([N:3]1[CH2:4][CH2:9][CH2:10][CH2:11][CH:2]1[O:24][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCc1nc2c(N)nc3cc(ON4CCCCC4)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OC4CCCCN4C(C)=O)ccc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
1-[4-Amino-2-(ethoxymethyl)-7-(piperidinyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (from Part A) was slurried in dichloromethane (11 mL). Acetic anhydride (0.105 mL, 1.03 mmol) was added and the reaction was stirred for 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The resulting solid was covered with diethyl ether for one week. Filtration of the solid provided 0.130 g of 1-[7-[(1-acetylpiperidinyl)oxy]-4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as red-tan crystals, mp 162-164° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:25][C:24]=1[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:25][C:24]=1[N:35]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C)c(OC(F)(F)F)cc1NC(=O)OC(C)(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(OC(F)(F)F)c(C)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
Add methyl 4-bromobutyrate (1.1 g, 6.0 mmol) and cesium carbonate (3.9 g, 12.0 mmol) to a DMF solution of 2-(tert-butoxycarbonylamino)-5-methyl-4-trifluoromethoxy-benzoic acid methyl ester (1.4 g, 4.0 mmol) under nitrogen. After stirring at 60° C. for 5 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate (150 mL). Wash the organics with water (2×150 mL) followed by brine (100 mL), dry over sodium sulfate, and filter. Remove the solvent under vacuum and chromatograph the crude product over silica gel using ethyl acetate/hexane (5-30%) to elute. This provides the title compound (1.1 g, 61%) as an oil: H NMR (CDCl3, 400 MHz) δ 1.28 (s, 6H), 1.49 (s, 3H), 1.91 (m, 2H), 2.33 (m, 5H), 3.39 (m, 1H), 3.63 (s, 3H), 3.77 (m, 1H), 3.86 (bs, 3H), 7.06 (m, 1H), 7.80 (m, 1H). MS (ES+): 350 (M+H-100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([CH2:43][C:44]([NH2:46])=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][N:37]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:38][CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 2-piperazin-1-yl-acetamide (Matrix) in an analogous manner as described in example 25. LR-MS: 647.2 [(M+H)+]