Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([O:13][C:14](=[O:53])[C:15]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[O:39][C:38]=3[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.C(Br)C1C=CC=CC=1.Cl>O.O1CCCC1>[CH2:46]([C:38]1[O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:37]=1[C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][C:15]([CH3:23])([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:14]([OH:53])=[O:13])=[CH:26][CH:27]=2)=[CH:36][CH:35]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Agent: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccccc1)(Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Temperature: -45 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M, 1.68 mL, 1.68 mmol) was added dropwise into a cold (−78° C.) mixture of 2-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yloxy]-2-methyl-3-phenyl-propionic acid ethyl ester (0.8 g, 1.68 mmol), and tetrahydrofuran (8.0 mL). The mixture was allowed to gradually warm up to −45° C., and stirred for 2 hours. Benzyl bromide (0.29 mL, 2.52 mmol) was added into the reaction mixture. The temperature was gradually raised to room temperature and the reaction was stirred for 15 hours. The mixture was then poured in to water, acidified with HCl (2 N) to pH=5, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtAOc 5:1) gave an clear oil (0.43 g). The product was saponified according to Example 1 step h, to give a white solid (0.32 g, 34% yield for two steps): MS m/e 538 (M+);
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].[C-]#N>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:16][C:17](=[O:18])[N:7]([OH:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:15])[CH3:14]
Reactant: ONc1ccccc1
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Agent: [C-]#N
Solvent: c1ccccc1
Product: CC(C)(NC(=O)N(O)c1ccccc1)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A solution of 2.2 g of N-phenylhydroxylamine in 10 ml of benzene was added to a solution of 0.02 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as in Synthesis Example 1) in 10 ml of benzene. The mixture was stirred well and allowed to stand overnight. The precipitated crystals were filtered off and washed with n-hexane to yield 5.7 g of 3-(m-chloro-α,α-dimethylbenzyl)-1-hydroxy-1-phenylurea. To 3.1 g of the urea was added a solution of 550 mg of sodium methoxide in 10 ml of methanol. The mixture was made homogeneous by stirring and 1.5 g of methyl iodide was added thereto. The mixture was then heated under reflux for 2 hours. The solvent was evaporated off and the residue was extracted with benzene and water was added. The benzene layer was dried over sodium sulfate and the solvent was distilled off to give crystals, which were recrystallized from a mixture of n-hexane and benzene to obtain 2.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].C([C:12]1[CH2:13][S:14][CH2:15][CH2:16][CH:17]=1)=O.S1CCCCC1C([O-])=O>N1CCCCC1.C(O)(=O)C.C(Cl)Cl>[S:14]1[CH2:15][CH2:16][CH2:17][CH2:12][C:13]1=[C:4]([C:5](=[O:6])[CH2:7][Cl:8])[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)CC(=O)CCl
Reactant: O=CC1=CCCSC1
Agent: O=C([O-])C1CCCCS1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(C(=O)CCl)=C1CCCCS1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyl-4-chloroacetoacetate (0.45g) in dry methlene dichlorode (5 ml) containing 4A molecular sieve (3g) was treated with tetrahydrothiapyran-2-carboxylate (0.4g) and then piperidine (2 drops) and acetic acid (2 drops). The mixture was stirred at room temperature for 45 min. The solution was diluted with methylene dichloride and the organic solution washed with water and brine. After drying over anhydrous magnesium sulphate the solvent was evaporated. Chromatography of the residue on silica gel using ethyl acetate-hexane (1:5) as eluant gave the title product as a 2:1 (Z/E) mixture of isomers (0.43g). νmax (CHCl3) 1710 and 1625 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:11]([Si:15]([CH3:17])([CH3:16])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
4-Nitrophenol (5.6 g, 40 mmol) was dissolved in CH2Cl2 (200 ml) and stirred at room temperature in the presence of tertbutyldimethyl-silyl chloride (7.8 g, 52 mmol), 4-dimethylaminopyridine (0.1 g, 0.8 mmol) and triethylamine (7.2 ml, 52 mmol). After 30 minutes at room temperature, the reaction mixture was washed with H2O (2×200 ml) and the resulting aqueous phases were extracted with CH2Cl2 (100 ml). The combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ether 9:1) to provide tert-Butyl-dimethyl-(4-nitro-phenoxy)-silane (10 g, 100%) as a yellow solid, m.p. 36°-38° C. and MS: m/e=253 (M+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:9]([F:22])[CH:8]=1.[C:23](=[O:25])=[O:24].Cl>C1COCC1>[F:22][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:13][C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:23]([OH:25])=[O:24]
Reactant: CCCCCC[C@@H](C)Oc1ccc(Br)cc1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)Oc1ccc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium (2.5M, 17.2 ml, 0.043 mol) in hexanes was added, dropwise, to a cooled (-78° C.), stirred solution of compound 35 (10.00 g, 0.033 mol) in dry THF (100 ml) under a dry nitrogen atmosphere and left to stir for 20 min. The resultant solution was poured into a slush of solid carbon dioxide and dry THF. This was left overnight at room temperature and then acidified with dilute hydrochloric acid. The TBF/water azeotrope was evaporated off in vacuo and the residue was dissolved in diethyl ether, washed with water and then extracted with 5% sodium hydroxide solution which was acidified with dilute hydrochloric acid. The product was extracted with diethyl ether and the ethereal solution was washed with water until acid-free, dried (MgSO4) and evaporated in vacuo to leave an off-white, semi-solid.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:12]Br>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([OH:1])=[C:7]([Br:12])[N:6]=1)=[O:9]
Reactant: BrBr
Reactant: COC(=O)c1cnc(O)cn1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnc(O)c(Br)n1

Procedure:
A mixture of 2 g (13 mmol) methyl 5-hydroxypyrazine-2-carboxylate (commercially available), 0.192 g (0.65 mmol) FeBr3, 0.7 mL (14 mmol) Br2 in 20 mL CHCl3 was refluxed for 16 h. After evaporation of all volatiles the residue was used without further purification in the consecutive step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][C:28]1[C:36]2[C:31](=[N:32][C:33]([F:37])=[CH:34][CH:35]=2)[N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:29]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:41]([O:40][C:38]([N:30]1[C:31]2=[N:32][C:33]([F:37])=[CH:34][CH:35]=[C:36]2[C:28]([CH2:27][O:17][C:15]2[CH:14]=[C:13]([F:18])[C:12]([Cl:19])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[CH:16]=2)=[N:29]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(F)c2Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)n1nc(COc2cc(F)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, 3-chloro-5-(2-chloro-3-fluoro-5-hydroxyphenoxy)benzonitrile (50-5) (150 mg, 0.503 mmol) was dissolved in NMP (4 mL, 0.1 M). Next, Cs2CO3 (164 mg, 0.503 mmol) was added and the reaction was allowed to stir at room temperature for 15 minutes. Then, tert-butyl-3-(bromomethyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (37-5) (166 mg, 0.503 mmol, prepared using the procedure set forth in Example 37) was added to the reaction. The reaction was stirred at room temperature for 2 hours. It was then diluted with EtOAc (4 mL). It was partitioned with water (3 mL) and then extracted with EtOAc (3×4 mL). The organic extracts were then washed with water (3×4 mL) and brine (1×4 mL), dried over sodium sulfate and concentrated. Silica gel chromatography (1%-20% EtOAc/Hexanes) gave tert-butyl3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)-5-fluorophenoxy]-methyl}-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (50-6) (230 mg, 85%). LCMS (ES) m/z 446.9 (M-BOC)+.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](C=O)=[CH:4][C:3]=1[CH3:11].C1C=C(Cl)C=C([C:19]([O:21]O)=[O:20])C=1>C(Cl)Cl>[F:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([O:21][CH:19]=[O:20])=[CH:8][C:9]=1[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C=O)cc(C)c1F
Solvent: ClCCl
Product: Cc1cc(OC=O)cc(C)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-fluoro-3,5-dimethyl-benzaldehyde (1.0 g, 6.4 mmol) in 20 mL DCM was added mCPBA (1.2 g, 7.6 mmol) at 25° C. After being stirred for 20 h at 25° C., the reaction was quenched by the addition of 40 mL of 5% aqueous potassium carbonate. The mixture was extracted DCM (3×30 mL) and the combined DCM layer was washed with brine (2×30 mL). The solution was dried over Na2SO4 before being concentrated under reduced pressure. The crude product was used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-cyano-p-toluenesulfonanilide (1153 g (4.23 mol) in acetic anhydride (2306 ml), fuming nitric acid (294.3 g (4.53 mol) was added dropwise, keeping the temperature at 50° C. with stirring, over a period of 100 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 1.5 hours. Then, 1.75 ml (0.042 mol) of fuming nitric acid was further added and stirring was continued for another one hour at 50° C. To the resulting mixture, after being left to cool to room temperature, water (7000 ml) was then added to make crystals to deposite. After stirring under cooling with ice for one hour, the crystals were filtered and washed with water to give 1305 g (97%) of 4′-cyano-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [Na].[CH2:2]([C:9]#[N:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[C:3]1([C:2](=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]#[N:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC=O
Reactant: N#CCc1ccccc1
Agent: [Na]
Solvent: CO
Product: CCCCCC=C(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
Sodium (27.6 g, 1.2 mol) is dissolved in methanol (550 ml) and benzyl cyanide (140.4 g, 1.2 mol) is added, followed by dropwise addition over 45 min. of hexanal (164.2 g, 1.44 mol), keeping the inside temperature between 20-25° C. The mixture is further stirred during 90 min. at room temperature, and then extracted 3 times with hexane. The organic layers are washed with water, 2 N aq. HCl-solution, then brine. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.04 mbar. The fraction distilling at 114-121° C. is collected (172 g) and subjected to a fine distillation over a Widmer-column to yield olfactorily pure 2-phenyl-oct-2-ene nitrile (113 g, 44%) as a colourless oil (b.p. 113-115° C./0.03 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][S:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:41][CH:40]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CSc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (112 mg, 0.3 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (45.5 mg, 0.45 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-methylsulfanyl-benzene (59.4 mg, 0.36 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide as a white solid (Yield 0.13 g, 80%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1>>[CH3:15][C:16]1[C:17]([N:23]2[CH2:24][CH2:25][N:26]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=3)=[O:12])[CH2:27][CH2:28]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CC(=O)NCc1ccc(C(=O)O)cc1
Product: CC(=O)NCc1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 70.9 %

Procedure:
Using 4-(acetylaminomethyl)benzoic acid (116 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (115 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (156 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18].Cl>O.O1CCCC1>[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:24])(=[O:19])[CH3:18]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NCc1ccc(C(=O)O)cc1
Yield: 32.6 %

Procedure:
4-Aminomethylbenzoic acid (1.50 g) and sodium hydrogen carbonate (1.68 g) are suspended in water (20 ml), and thereto is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (2.86 g) in tetrahydrofuran (6 ml) with vigorously stirring. After the reaction is completed, the reaction mixture is acidified with hydrochloric acid and is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol to give the title compound (1.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-])=O>CO>[CH3:10][C:5]1[C:4]([NH:1][NH:1][C:4]2[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1ccccc1NNc1ccccc1C
Yield: 54 %

Procedure:
The identical reduction of o-nitrotoluene as described in example 5 was carried out except 68 g of absolute methanol was used in place of the 95% ethanol. The reduction products were isolated using the same procedures and a 54% yield of o-hydrazotoluene was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH2:36][OH:37]>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][N:18]([CH2:35][CH2:36][OH:37])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: OCCI
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCO)CC1
Temperature: 80 °C

Procedure:
3.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate and 2.07 g of potassium carbonate were added to a solution of 1.17 cm3 of 2-iodoethanol in 80 cm3 of acetonitrile, at a temperature in the region of 20° C. with stirring and under an inert atmosphere. After heating for 23 hours at a temperature in the region of 80° C., a further 1.17 cm3 of 2-iodoethanol were added. After heating for 40 hours at a temperature in the region of 80° C., the reaction mixture was cooled to about 20° C., filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained was purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 40-60μ; diameter 4 cm; height 60 cm), eluting with a dichloromethane/methanol/aqueous ammonia mixture (89/10/1 by volume) and collecting 50-cm3 fractions. Fractions 14 to 17 were combined and then concentrated as previously. 1.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[CH:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:33][CH2:32][C:31]2[CH:30]=[CH:29][N:28]=[C:27]3[NH:23][CH:24]=[CH:25][C:26]=23)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccnc3[nH]ccc23)cc1

Procedure:
The titled compound was prepared from N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 400 (M+H). Calc'd. for C24H25N5O—399.50.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)=[O:13])[CH3:10].CI>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH3:2])[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of LDA (7.0 mL, 14 mmol, 2M solution in THF/ethylbenzene) in THF (10 mL) was added a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (Compound 282H, 2.14 g, 9.99 mmol) in THF (5 mL) at −78° C. under nitrogen. The resulting mixture was stirred at this temperature for 30 min, then a solution of methyl iodide (1.98 g, 14.0 mmol) in THF (5 mL) was added. The resulting mixture was slowly warmed to rt overnight. The reaction was quenched with sat. aq. NH4Cl (20 mL) and diluted with EtOAc (50 mL). The organic layer was washed with brine (30 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure to give the desired compound as a light-yellow oil, 2.30 g, 100% yield. The material was used in next step without further purification. 1H NMR (CDCl3): 1.20 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.52-1.68 (m, 6H), 2.12-2.17 (m, 2H), 3.94 (s, 4H), 4.15 (q, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])[CH2:21][CH:20]3[OH:32])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]=1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])[CH2:21][C:20]3=[O:32])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])[CH:3]=1
Reactant: Cc1cc(C(=O)NC2(C(=O)NC3CCN(c4ccccc4N)CC3O)CCCCC2)no1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(C(=O)NC2(C(=O)NC3CCN(c4ccccc4N)CC3=O)CCCCC2)no1
Temperature: 0 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To the solution of 4-[N-[1-[N-(5-methyl-isoxazol-3-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-aminophenyl)piperidin-3-ol (1.1 g) obtained in Step 1 in 5 ml of dimethyl sulfoxide, was added 1.2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.9 g) was added to the reaction mixture, which was then stirred for about 4 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 820 mg of the titled compound as white color.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CN1C(=O)CCC1.C(N(CC)CC)C.F[C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([C:29]=1[F:30])[NH2:28]>O>[F:30][C:29]1[C:23]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:24][CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[C:27]=1[NH2:28]
Reactant: CN1CCNCC1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5,6-difluoro-2-nitroaniline (1.0 eq) were heated at 90° C. for 1 hour. The reaction was allowed to cool to room temperature and then poured into water and let stand for 1 hour. The resulting solid was collected and dried and utilized without further purification. MH+=255.3