Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23]([Sn](CC)(CC)CC)[CH3:24]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:23][CH3:24])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(CC)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Yield: 66.8 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (100 mg, 0.26 mmol), tetraethyltin (106 μL, 0.52 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (19 mg, 0.03 mmol) in dimethylformamide (2.5 mL) was stirred at 130° C. for 1H before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (57 mg): MS: (+) m/z 328.99 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:30])([F:29])[F:31])[C:9]=4[CH:17]=3)[CH:19]=2)=[CH:35][CH:34]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1ccc(Cl)cc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.9 (M+H+); retention time=0.99 minutes.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C-:16]#[N:17].[Na+]>C(O)C>[C:16]([CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: CCOC(=O)C=Cc1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=Cc1ccccc1CC#N

Procedure:
Reagent XV is prepared from ethyl o-bromomethylcinnamate by the following series of reactions. (1) The starting ester is heated with a solution of sodium cyanide in ethanol to yield ethyl o-cyanomethylcinnamate. (2) This ester is hydrogenated over a Pt or Pd catalyst to afford ethyl o-cyanomethylhydrocinnamate. (3) This ester is reduced with sodium bis(2-methoxyethoxy)aluminum hydride in benzene to yield [2-(3-hydroxypropyl)phenyl]acetonitrile. (4) The nitrile is hydrolyzed by being heated with aqueous-ethanolic sodium hydroxide solution, and the acid is esterified (ethanol and mineral acid catalyst) to give ethyl [2-(3-hydroxypropyl)phenyl]acetate. (5) This hydroxyester is treated with phosphorous tribromide in ether to afford reagent XV.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:20]([C:19]([OH:22])=[O:21])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a round bottom flask containing 3-(4-fluorophenyl)-1H-indazole-5-carbonitrile (8.05 g, 0.034 mol) was added acetic acid (250 mL) and concentrated HCl (250 mL). The reaction was heated to reflux temperature for 7.5 hours and then 105° C. for two and one half-hours. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and a solid crashed out of solution. The solid was collected by filtration and dried in a low temperature oven to yield the title compound (7.5 g, 86% yield). 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 13.0 (br s, 1H), 8.64 (s, 1H), 8.0–7.9 (m, 3H), 7.68 (d, 1H), 7.42 (t, 2H); ES-MS (m/z) 301 [M+1]+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH2:14].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:8]1[CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]([NH2:14])=[C:4]([CH3:3])[CH:9]=1
Reactant: BrBr
Reactant: Cc1cccc(C(F)(F)F)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere a solution of 11.0 mL (214 mmol) bromine in 100 mL chloroform was added dropwise to a solution of 35.8 g (204 mmol) 2-methyl-6-trifluoromethyl-phenylamine in 350 mL chloroform and after the end of the addition the reaction mixture was stirred for 3 h at RT. Saturated NaHCO3 solution was added with stirring, the mixture was stirred for a further 20 min at RT, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the product was obtained as an oil, which was further reacted without purification.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]1[CH2:28][O:27][C:6]2([CH2:23][CH2:22][C@:21]34[O:24][C@:8]3([CH2:9][C@@H:10]([CH3:26])[C@@H:11]3[C:20]4=[CH:19][CH2:18][C@@:16]4([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]4[OH:25])[CH2:7]2)[O:5]1>C1COCC1.[Cl-].[NH4+].[Cu]Cl>[CH2:4]1[CH2:28][O:27][C:6]2([CH2:23][CH2:22][C:21]3[C@@:8]([OH:24])([CH2:9][C@@H:10]([CH3:26])[C@@H:11]4[C:20]=3[C@@H:19]([CH3:1])[CH2:18][C@@:16]3([CH3:17])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[OH:25])[CH2:7]2)[O:5]1
Reactant: C[Mg]Br
Reactant: C[C@@H]1C[C@@]23CC4(CC[C@@]2(O3)C2=CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21)OCCO4
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@]2(O)CC3(CCC2=C2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2C)OCCO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesiumbromide (1.4 M THF/toluene, 210 mL, 295 mmol) was added to THF (150 mL) and copper (I) chloride (2.92 g, 29.5 mmol) was added. After stirring at room temperature for ½ hr, a solution of the epoxide (Compound 5, 16.26 g 46.99 mmol) in THF (450 mL) was added dropwise over 5 min. The mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated ammonium chloride solution and air was bubbled through the mixture for ½ hr to oxidize Cu(I) to Cu(II). The aqueous mixture was extracted with ether (3×). The ether extracts were washed with water and brine, combined, and dried over sodium sulfate. Evaporation of the solvent gave 16.70 g of a yellow semi-solid. The material was triturated with ether and the solid was filtered to afford 8.86 g of a mixture of Grignard products (7α,11α-dimethyl and 7α,11β-dimethyl, referred to as Compounds 6a and 6b, respectively). Evaporation of the filtrate gave 7.4 g of a stable foam. Total amount was 16.26 g in quantitative yield.
Reaction SMILES: P(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][N+:7]=1[O-].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: O=[N+]([O-])c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
Phosphorus trichloride (4.2 mL, 48.7 mmol) was added to a solution of 2-chloro-4-nitro-pyridine-1-oxide (1.70 g, 9.74 mmol) in dry chloroform (25 mL) at r.t. The reaction mixture was then heated to reflux and maintained at this temperature overnight. The reaction was cooled to r.t. then poured onto ice, basified to between pH 7-8 with saturated aq. sodium bicarbonate solution and extracted with chloroform (×2). The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Drying under high vacuum afforded 2-chloro-4-nitro-pyridine (1.2 g, 78%) as a solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:18]=[C:17]2[C:8]([CH2:9][C:10]3([C:16]2=[O:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH2:21].C([O-])(=O)C.[Na+].O>CO>[N+:2]([C:5]1[CH:18]=[C:17]2[C:8]([CH2:9][C:10]3([C:16]2=[O:19])[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:12][CH2:11]3)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: C=Cc1ccccn1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC12CCNCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1c2cc([N+](=O)[O-])ccc2CC12CCN(CCc1ccccn1)CC2
Yield: 66 %

Procedure:
A solution of 0.150 g (0.53 mmole) 1,3-dihydro-6-nitro-1-oxospiro[2H-indene-2,4'-piperidine] hydrochloride, 0.116 g (1.1 mmoles) 2-vinylpyridine, and 0.090 g (1.1 mmoles) sodium acetate in 1.5 ml of 1:1 methanol: water was heated at reflux for 8 hours. Ethanol was removed in vacuo. The aqueous residue was diluted with 3 ml saturated sodium bicarbonate solution and extracted with 2×10 ml ethyl acetate. The combined extracts were washed with 3 ml water brine, dried, and the solvent was removed in vacuo to give 0.195 g crude product. This was recrystallized from ethyl acetate to give 0.123 g (66%) product, m.p. 142°-144° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:15])[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)=O.O.[NH2:17][NH2:18]>CO>[CH3:11][C:9]1([CH3:12])[CH2:10][C:5]([OH:15])([C:3]([NH:17][NH2:18])=[O:2])[CH2:6][C:7]([CH3:14])([CH3:13])[NH:8]1
Reactant: NN
Reactant: COC(=O)C1(O)CC(C)(C)NC(C)(C)C1
Solvent: CO
Solvent: O
Product: CC1(C)CC(O)(C(=O)NN)CC(C)(C)N1

Procedure:
16.2 parts of 2,2,6,6-tetramethyl-4-hydroxypiperidine-4-carboxylic acid methyl ester (according to German Patent No. 91,122), 5 parts of hydrazine hydrate and 20 parts of methanol are boiled under reflux for 10 hours and the methanol is subsequently distilled off. The residue is recrystallised from cyclohexane. Yield: 15.3 parts of 2,2,6,6-tetramethyl-4-hydroxypiperidine-4-carboxylic acid hydrazide melting at 121° to 123° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[N+:18]([O-])([OH:20])=[O:19].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)CC(=O)c1ccccc1O2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCC2(CC1)CC(=O)c1cc([N+](=O)[O-])ccc1O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Sulfuric acid (55 ml) was cooled to 0° C. and was stirred as 3,4-dihydro-1'-methyl-spiro[2H-1-benzopyran-2,4'-piperidin]-4-one (11.56 g, 0.05 mol) was added over 20 minutes. Some gum separated. A solution of 90% nitric acid (2.5 ml, 0.0525 mol) in sulfuric acid (5 ml) was added over 20 minutes. The mixture was stirred for 2 hours at 0° C. and then for 1 hour at room temperature. A solution resulted but nitration was not complete. 90% Nitric acid (0.3 ml, 0.007 mol) was added and stirring was continued for 1 1/2 hours at room temperature. The reaction solution was poured into a mixture of ice, ethyl acetate, and sodium bicarbonate (210 g). The basic mixture was filtered, the ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (150 ml). The combined ethyl acetate extracts were washed with saturated NaCl, dried, filtered and concentrated in vacuo to yield 10.6 g (77%) of product
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:11]([OH:30])[CH:10]=1)=[O:8].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[C:11]([O:30][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])[CH:10]=1)=[O:8]
Reactant: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)CCCC(=O)OC)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 111.3 %

Procedure:
Under the conditions of example 1A, 420 mg of 5-(3-hydroxy-4-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl}-5-oxopentanoic acid methyl ester is reacted with 167 mg of bromoacetic acid ethyl ester in 4 ml of dimethylformamide in the presence of 650 mg of cesium carbonate and worked up. 562 mg of 5-{3-(1-ethoxycarbonylmethoxy)-4-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl}-5-oxo-pentanoic acid methyl ester is obtained as colorless oil.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:20]([CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:16]([O:18][CH3:19])=[O:17])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(COS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
3-Carbomethoxy-5-nitrobenzyl methanesulfonate (300.0 g, 1.04 mol) and sodium azide (81.0 g, 1.25 mol) were suspended in DMF (1700 ml) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (2000 ml), washed with 1000 ml portions of H2O (2×) and saturated NaCl (1×), dried (MgSO4), and concentrated under reduced pressure. The resulting amber syrup was dried under vacuum at 40° C. to yield the title compound as a tan solid (226.5 g, 92%). 1H NMR (CDCl3): 8.60 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 4.52 (s, 2H), 3.88 (s, 3H); MP=44°-46° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2].O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)CCN1CCC(O)CC1
Product: CCOC(=O)CCN1CCC(OC(=O)c2cc3cc(C#N)ccc3o2)CC1
Yield: 37.1 %

Procedure:
In the same manner as in Example 75 (2), 5-cyano-2-benzofurancarboxylic acid (1.00 g, 5.34 mmol) was converted a corresponding acid chloride and reacted with ethyl 3-(4-hydroxypiperidino)propionate (1.08 g, 5.77 mmol). The reaction mixture Was purified by silica gel column chromatography (chloroform) to give 733 mg of ethyl 3-[4-[(5-cyano-2-benzofuranyl)carbonyloxy]piperidino]propionate as a colorless solid (33%).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH:15]4[CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH:16]4[CH2:20]3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), and DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and methanesulfonyl chloride (13.0 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 13-1 as a pale yellow oil. MS m/z (M+H): calculated=407.2113; observed=407.2115.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)C(CC1CCCCC1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC2CCCCC2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 38 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (118.9 mg) and ethyl 4-aminophenylacetate hydrochloride (88.98 mg) were condensed in THF (3 ml) in the presence of triethylamine (135.67 mg) and pivaloyl chloride (66.33 mg), and then the resulting crude product was purified by column chromatography (silica gel 20 g, hexane/ethyl acetate=3/1) to obtain as a colorless oil (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (66.2 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)C.[H][H]>C1(C)C=CC=CC=1.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 4 h
Yield: 108.8 %

Procedure:
tert-Butyl [4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (20.36 g, 43.6 mmol) was slurried in toluene (450 mL) and added to a Parr vessel charged with 5% platinum on carbon (4.3 g) and a small amount of toluene. 2-Propanol (50 mL) was added, and the vessel was charged with hydrogen (30 psi, 2.1×105 Pa). The hydrogen was replaced three times. After 4 hours, the catalyst was removed by filtration through a layer of CELITE filter aid, and the filter cake was rinsed with toluene (0.5 L), 50% toluene/2-propanol (0.5 L), and 2-propanol (0.25 L). The filtrate was concentrated under reduced pressure, and the residue was mixed with toluene and concentrated under reduced pressure to provide 20.7 g of tert-butyl [4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]carbamate as a viscous, black oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:17]([O:19][C:20](=[O:39])[C:21]([N:23]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:39])[C:21]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=2)=[CH:34][CH:33]=1)=[O:22])[CH3:18]
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(CN(Cc3ccccc3)C(=O)C(=O)OCC)cc2)cc1
Yield: 58 %

Procedure:
The same procedure as employed in the preparation of Example 15, step d but using 4-hexyloxy-benzoyl chloride and ethyl[(4-aminobenzyl)(benzyl)amino](oxo)acetate gave the title compound as a colorless oil (58%). M−(ESI): 515.2. HPLC (Condition A), Rt: 6.0 min (HPLC purity: 94.9%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1([C:22]#[N:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To 4-cyano-4-(2,4-dichlorophenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.620 g, 1.74 mmol) in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.442 g (99%) of 4-(2,4-dichlorophenyl)-piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[C:9]([CH3:22])=[C:8]1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[NH:14][C:15](=[O:17])[C:16]2[N:7]([CH3:6])[C:8]([CH3:23])=[C:9]([CH3:22])[C:10]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CCl
Reaction time: 2 h

Procedure:
A solution of 21 of chloroacetyl chloride in 10 ml of toluene is added dropwise to 31 g of 1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5-]benzodiazepin-10-one, 6 g of anhydrous potassium carbonate, 40 ml of dioxane and 20 ml of toluene in the course of 30 minutes at 70° to 80° C., and the thus-prepared mixture is stirred at this temperature for a further 2 hours. The mixture is concentrated to dryness, the residue is boiled 3 times with 25 ml of chloroform each time, and the filtrate is concentrated to dryness. 3.6 g of the title compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:7]([C:8]([Cl:16])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: O=S(Cl)Cl
Product: CSc1nc(Cl)c(C(=O)Cl)c(Cl)n1
Reaction time: 18 h
Yield: 100 %

Procedure:
10 g of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid (41.83 mmol) are placed in 61 ml of thionyl chloride (836.54 mmol) with stirring. After 18 hours at 80° C., the thionyl chloride is evaporated off and the residue is taken up twice with 15 ml of toluene and concentrated to give 10.77 g of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:14][CH:15]([F:27])N1C=C2C(C=C(N)C=C2C)=N1>>[F:14][CH:15]([F:27])[N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([NH2:11])[CH:8]=2)[CH:4]=[N:5]1
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ncc12
Reactant: Cc1cc(N)cc2nn(C(F)F)cc12
Product: Cc1cc(N)cc2c1cnn2C(F)F

Procedure:
In accordance with Example 24 (Steps 1 and 2), 4-methyl-6-nitro-1H-indazole (934 mg) was used instead of 6-nitro-1H-indazole to obtain 1-(difluoromethyl)-4-methyl-1H-indazol-6-amine (112 mg) and 2-(difluoromethyl)-4-methyl-2H-indazol-6-amine.