Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]1=[O:25].[Cl-].[NH4+]>O1CCCC1.CCOCC>[OH:24][C:22]([CH3:1])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:7]1[C:8](=[O:17])[C:9]2[N:10]([CH2:14][CH2:15][CH3:16])[CH:11]=[N:12][C:13]=2[N:5]([CH3:4])[C:6]1=[O:25]
Reactant: C[Mg]Cl
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.4 g (0.3 mol) of methylmagnesium chloride in the form of a 20% strength solution in tetrahydrofuran are added dropwise with vigorous stirring at room temperature to a suspension of 61.3 g (0.2 mol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 2 l of anhydrous ether, the internal temperature rising to approximately 30° C. The mixture is then warmed with stirring and under reflux for 2 hours, treated with saturated aqueous ammonium chloride solution to decompose the alkoxide formed, and the organic phase is separated off and washed twice with 500 ml of water each time. The collected water phases are extracted thoroughly with dichloromethane again. The dichloromethane extract is combined with the ethereal phase, dried over sodium sulfate, filtered and evaporated under reduced pressure, 59.0 g of crude product (91.5% of theory) being obtained, which is purified by recrystallization from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)=[O:14].[H-].[Na+].CN(C)C=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([O:12][CH3:11])=[O:14])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
2,4-Dichlorobenzyl chloride (8.68 g) is added to a mixture of 5-methoxycarbonylindole (6.49 g), 60% sodium hydride (2.24 g) and N,N-dimethylformamide, while cooled in an ice-water bath. This is stirred at room temperature for 20 minutes, and water is added thereto. Then, this is extracted with ethyl acetate. After washed with water, the organic layer is dried, concentrated, purified through silica gel column chromatography (eluent: hexane/ethyl acetate=6/1), and finally recrystallized from ethyl acetate/hexane to obtain 1-(2,4-dichlorobenzyl)-5-methoxycarbonylindole (49) (6.59 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Yield: 100.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) and methanol (5 mL) was treated with 10% palladium on activated carbon (30 mg). The reaction mixture was shaken under 60 psi of hydrogen gas at 25° C. for 16 h. The catalyst was then removed by filtration through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (277.4 mg, quant) as a pale yellow glass: mp 65-68° C.; EI-HRMS m/e calcd for C21H25N3O3 (M+) 367.1893, found 367.1899.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:29][CH2:28]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(Cc3ccc(Cl)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-chloro-benzyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27ClN2O5 [M+H]+: 447.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[H-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C=O>[C:20]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:6]1)(=[O:22])[CH3:21]
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1cc(C2=CCN(C)CC2)c2cc(F)ccc21
Yield: 85.7 %

Procedure:
To a mixture of 0.90 gm (3.94 mMol) 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 20 mL dimethylformamide were added 0.17 gm (4.3 mMol) sodium hydride (60% dispersion in mineral oil). The mixture was stirred for one hour at room temperature at which time 0.47 mL (5.0 mMol) acetic anhydride were added. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between chloroform and water. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromaography, eluting with chloroform containing 5% methanol. Fractions containing product were combined and concentrated under reduced pressure to give 0.92 gm (86%) of the title compound as a faintly yellow crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[N:12][C:11]2[NH:10][CH:9]([CH2:14][OH:15])[CH2:8][O:7][C:6]=2[CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:13]=[N:12][C:11]2[NH:10][CH:9]([CH2:14][OH:15])[CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)OCC(CO)N2
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)OCC(CO)N2
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Into a 500 mL round bottom flask were combined (7-nitro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)methanol (0.320 g, 0.00152 mol), 10%-palladium on carbon (0.06 g, 0.0005 mol) and methanol (50 mL). The apparatus was evacuated, then hydrogen was introduced and the mixture was allowed to stir overnight (at 1 atm presuure). The mixture was then filtered through Celite® and the filtrate was concentrated under vacuum to yield an oil (0.252 g, 89%) which was used directly in the next step without further purification. (0.252 g, 89%) LC-MS 0.29 min. M/Z=181.9(M+1).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28].[BH3-]C#N.[Na+]>CCO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15](=[CH:14][CH:13]=2)[CH:16]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH:18]=[CH:19]3)[CH2:9][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CS(=O)(=O)NC(=O)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(C)(=O)=O)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(methylsulfonyl)propanamide (239 mg, 1.19 mmol, 1.5 equiv) were dissolved in anhydrous EtOH. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by prep-TLC to give 3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(methylsulfonyl)propanamide as a white solid (65 mg, 14%), (mobile phase:CH3OH/DCM=1:10). ESI-MS (M+1)+: 461.2, HPLC: 96.38%. 1H NMR (400 MHz, DMSO-d6) δ: 7.93 (s, 1H), 7.85˜7.77 (m, 2H), 7.59˜7.49 (m, 1H), 7.43˜7.35 (m, 1H), 7.20˜7.11 (m, 1H), 4.45˜4.33 (m, 1H), 4.20 (s, 2H), 2.98 (t, 2H), 2.77 (s, 3H), 2.35 (t, 2H), 2.26˜2.14 (m, 2H), 1.86˜1.75 (m, 2H), 1.41˜1.30 (m, 2H), 1.27˜1.14 (m, 2H), 1.13˜1.02 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[C:36]([Cl:35])=[CH:41][CH:40]=[CH:39][C:38]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5c(Cl)cccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,6-dichloro-phenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[O:16][CH3:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccccc1C=CC(=O)O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3OC)nc2n(CC)c1=O
Yield: 23.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.48 g (13.9 mmol) of 2-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 990 mg (yield 24%) of Compound 108 as yellow grains.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:12][C:4]1[CH:5]=[N:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=1)[C:17]#[N:18]
Reactant: CC(C)Oc1ncc(O)cc1Cl
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1ncc(Oc2ccc(C#N)cc2Br)cc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chloro-6-isopropoxypyridin-3-ol (Preparation 35, 350 mg, 1.87 mmol) in dimethyl sulfoxide (2 mL) was added 3-bromo-4-fluorobenzonitrile (333 mg, 1.87 mmol) and potassium carbonate (386 mg, 2.80 mmol). The reaction was stirred at 50° C. for 4 hours and then partitioned between water (100 mL) and EtOAc. The aqueous phase was separated and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colourless oil which crystallised on standing (920 mg) and which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:50][CH2:49][C:48]2[C:51]3[CH2:57][CH2:56][CH2:55][CH2:54][C:52]=3[S:53][C:47]=2[C:46]1=[O:58])(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[CH2:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:35]4[C:30]([CH2:29][O:28][C:25](=[O:27])[CH3:26])=[C:31]([N:45]5[C:46](=[O:58])[C:47]6[S:53][C:52]7[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=7[C:48]=6[CH2:49][CH2:50]5)[CH:32]=[CH:33][CH:34]=4)[CH:3]=3)=[N:12][CH:13]=2)[CH2:18][CH2:19]1)[CH3:24]
Reactant: CCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCc6c(sc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 5-bromo-3-(5-(4-ethyl-piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 138c (250 mg, 0.637 mmol), boronic ester 111a (308 mg, 0.701 mmol), Pd(PPh3)4 (36.8 mg, 0.0319 mmol), Na2CO3 aqueous solution (1.0 N, 2.10 mL, 2.10 mmol), 1,2-dimethoxyethane (3.0 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 181a.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:16](#[N:19])[CH:17]=[CH2:18]>CN(C)C=O>[C:16]([CH2:17][CH2:18][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)#[N:19]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCCn1cnc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
4-Nitroimidazole (6.87 g, 60 mmol), triethylamine (18.2 g, 180 mmol) and acrylonitrile (9.55 g, 180 mmol) were dissolved in N,N-dimethylformamide (100 ml), and the solution was stirred at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and chloroform was added to the concentrate. Solids deposited were collected by filtration and dried to obtain 9.2 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:16][CH3:17])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18](OC(OCC)OCC)C>>[N:12]1([C@H:13]([CH2:16][CH3:17])[CH2:14][OH:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:18]1
Reactant: CC[C@H](CO)Nc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Product: CC[C@H](CO)n1cnc2cnc3ccccc3c21
Temperature: 145 °C

Procedure:
(2R)-2-[(3-Aminoquinolin-4-yl)amino]butan-1-ol (416.0 g, 1 eq.) and triethylorthoformate (1.2 L, 4 eq.) were combined and slowly heated to 145° C. Ethanol was distilled off as it formed during the reaction. After 500 mL of ethanol had been distilled off, the reaction mixture was allowed to cool to 50° C. under a nitrogen atmosphere. Excess triethyLorthoformate was removed under reduced pressure to provide crude (2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([C:18]2[C:19](=[O:39])[N:20]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:21][CH2:22][C:23]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[Cl:32])[CH3:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[Cl:32])[C:23]3[CH2:22][CH2:21][N:20]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:19](=[O:39])[C:18]=3[C:16]=2[CH3:17])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C1=C(Nc2ccc(F)cc2Cl)CCN(N2CCCCC2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1)CCN(N1CCCCC1)C2=O
Temperature: 100 °C

Procedure:
3-{2-[4-(tert-Butyldimethylsilanyloxy)phenyl]-1-methyl-2-oxo-ethyl} -4-(2-chloro-4-fluorophenylamino)-5,6,3′,4′,5′,6′-hexahydro-2′H-[1,1′]bipyridinyl-2-one (1.135 g, 1.94 mmol) was suspended in toluene (5 ml) and toluene-4-sulfonic acid (0.037 g, 0.19 mmol) was added. The reaction mixture was heated in a microwave oven at 100° C. for 30 min. Water/toluene were added to the reaction mixture and the phases separated. The organic phase was washed with water, dried (MgSO4), filtered and evaporated to yield the crude product (crude 0.929 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:6]=1[C:18]1[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:6]=2[C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH2:27][CH2:26]1
Reactant: CCCCC(=O)Nc1ccc(OCCCl)c(-c2ccnn2C)c1
Reactant: OC1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCC(=O)Nc1ccc(OCCN2CCC(O)CC2)c(-c2ccnn2C)c1
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of pentanoic acid [4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (50 mg, 0.15 mmol), 4-hydroxypiperidine (18 mg, 0.18 mmol), potassium carbonate (31 mg, 0.225 mmol) and catalytic amount of tetrabutyl ammonium iodide in DMF (1 mL) was heated with microwaves at 100° C. for 2.5 hours. The crude was purified by HPLC to provide the title compound as a sticky solid (51 mg, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 0.89 (t, J=7.33 Hz, 3H), 1.30 (guar, J=7.58 Hz, 2H), 1.40-1.48 (m, 1H), 1.54 (quin, J=7.58 Hz, 2H), 1.66-1.82 (m, 2H), 2.28 (t, J=7.33 Hz, 2H), 2.82-2.89 (m, 1H), 3.05-3.09 (m, 2H), 3.19-3.22 (m, 1H), 3.39-3.45 (m, 2H), 3.64 (d, J=2.53 Hz, 3H), 3.85 (s, 1H), 4.11-4.18 (m, 4H), 6.25 (dd, J=2.02, 5.05 Hz, 1H), 7.16 (d, J=9.09 Hz, 1H), 7.45 (dd, J=2.02, 5.31 Hz, 1H), 7.55 (d, J=2.78 Hz, 1H), 7.66 (dd, J=2.53, 9.09 Hz, 1H), 9.23 (s, br, 1H), 9.91 (s, 1H). Exact mass calculated for C22H32N4O3 400.2, found 401.3 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10](=[O:15])[CH2:11][S:12]([CH3:14])=[O:13].[N:16]([O-])=O.[Na+]>O>[Cl:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[NH:2][N:16]=[C:11]([S:12]([CH3:14])=[O:13])[C:10]2=[O:15]
Reactant: O=N[O-]
Reactant: CS(=O)CC(=O)c1cc(Cl)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)c1n[nH]c2ccc(Cl)cc2c1=O

Procedure:
500 ml of 3N HCl was chilled to 0° in an ice-salt bath, and 10 g of 2'-amino-5'-chloro-2-(methylsulfinyl)acetophenone was added. The mixture was stirred until a clear solution was obtained, and a solution of 3.45 g of NaNO2 in 20 ml of H2O was added with stirring at ca. 0°-3°. The solution became first orange colored, and then a yellow precipitate formed. The ice bath was removed, and the mixture was stirred until room temperature was attained. The precipitate was filtered off, washed with H2O, and recrystallized from dimethylformamide, mp. 267°-72°; yield 5 g (44%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COCOc1cc(OCc2ccccc2)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)cc1OCOC
Yield: 99.3 %

Procedure:
To a suspension of 55% sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes at 0° C. under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0° C. with stirring, and the resulting mixture was stirred for 2 hours at 0° C. under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml×2). The organic layer was washed successively with water (100 ml×1) and saturated aqueous sodium chloride solution (100 ml×1), dried-over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to afford the title compound (9.32 g, yield: 99%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:20])[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7]2)[CH2:5][CH2:4]1.Cl>CO>[CH:3]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:20])[C:8]([C:21]([OH:23])=[O:22])=[CH:7]2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 5 h
Yield: 76.8 %

Procedure:
10 ml of a 4% w/v aqueous solution of sodium hydroxide were added to a solution of 0.48 g (0.0015 mole) of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XXXII) (prepared as described in Preparation 3) in 20 ml of methanol, and the mixture was allowed to stand at room temperature for 5 hours. The reaction mixture was then acidified by adding concentrated hydrochloric acid to precipitate a crystalline substance, which was collected by filtration to afford 0.34 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIC) as colorless powdery crystals melting at 184°-185° C.