Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH2:11]2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[NH:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[N:6]=[C:5]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:27]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=2)[CH2:11]1
Reactant: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3cnn(C4CCNCC4)c3)n2)C1

Procedure:
Crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277, 72 mg, 0.13 mmol) was treated with 2:1 DCM/TFA at RT for 1 hour and concentrated in vacuo to get (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide (278) TFA salt. It was dissolved in 4 mL NMP. To it were added DIEA (230 μL, 1.3 mmol) and cyclopropanecarbobyl chloride (41 mg, 0.39 mmol). The mixture was stirred at RT for 2 hours, acidified with 0.5 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (280) as HCl salt (32 mg, 47%). MS found for C25H36N10O3 as (M+H)+ 525.5, (M−H)− 523.3. UV: λ=253, 269, 298, 331, 374 nm.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[O:2].[CH3:13][Mg]Br>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH3:13]
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a −78° C. solution of methyl 6-formylnicotinate (0.300 g, 1.82 mmol) in tetrahydrofuran (6 mL) was added methylmagnesium bromide (0.787 mL, 3M in THF, 2.36 mmol) over 20 minutes. The solution was warmed to 0° C. and stirred for 2 hours. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC gave methyl 6-(1-hydroxyethyl)nicotinate (230 mg, 70%) as a red oil. 1H NMR (400 MHz, CD3OD, δ): 8.93 (m, 1H), 8.26-8.29 (m, 1H), 7.59 (d, 1H), 4.73-4.83 (m, 1H), 3.84 (s, 3H), 1.37 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:17]([OH:23])=[CH:16][C:15]=2[CH3:24])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]([CH3:24])=[CH:16][C:17]([O:23][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:18]3[C:22]=2[CH2:21][CH2:20][CH2:19]3)=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)c2c(c1Oc1ccc(OCc3ccccc3)c(Cc3ccc(F)cc3)c1)CCC2
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc(C)c(Oc2ccc(OCc3ccccc3)c(Cc3ccc(F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 11 using 7-[4-benzyloxy-3-(4-fluorobenzyl)phenoxy]-6-methylindan-4-ol instead of 2-hydroxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde and using ethyl bromoacetate instead of benzyl bromide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:30][C:28]1[CH:29]=[C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[C:15]=3[CH2:23]2)[CH:25]=[N:26][C:27]=1[O:31][CH3:32]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (766.2 mg, 1.66 mmol) was dissolved in a TFA/CH2Cl2 (1/2) solution and stirred at rt for 1 h. The reaction mixture was concentrated under vacuum, the residue was diluted with CH2Cl2, the organic layer washed with NaOH 1N then brine, dried over Na2SO4, filtered and evaporated to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine. LCMS: [M+H]+=362.1, Rt(3)=1.28 min.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.[OH-].[Na+]>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12.2 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of phenyl-acetic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo, and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-oxo-4-phenyl-butyronitrile in the amount of 4.0262 gms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([Br:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Yield: 107.5 %

Procedure:
Phenyl-acetic acid methyl ester (10 gm, 66.6 mmol) was taken in carbon tetrachloride (100 ml). N-Bromosuccinimide (13.05 gm, 73.33 mmol) was added in one lot followed by benzoyl peroxide (1.77 gm, 7.3 mmol) and refluxed for 3 hours. The reaction mixture was cooled to room temperature and filtered; filtrate was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide bromo-phenyl-acetic acid methyl ester (16.4 gm) as a gummy mass.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([Cl:37])[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:33]4[CH:32]=[C:31]([Cl:30])[CH:36]=[C:35]([Cl:37])[CH:34]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)cc(Cl)c4)c3O2)cc1
Yield: 14.7 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3,5-dichlorophenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.22 g (15%) of (±)-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.48 (silica, ethyl acetate:hexanes 1:3); mp 113-115° C.; Anal. calcd. for C22H18Cl2O4S: C, 58.8: H, 4.04. Found: C, 58.73; H, 3.77.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([CH3:11])[CH2:8][O:9][CH3:10].[OH2:21].C(Cl)(Cl)(Cl)Cl.CC#N>C(#N)C>[C:15]([O:14][C:13]([N:12]([CH3:20])[C@@H:6]([C@H:7]([CH3:11])[CH2:8][O:9][CH3:10])[C:2]([OH:1])=[O:21])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC[C@@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a suspension of NalO4 (0.83 g, 3.87 mmol, 6.0 equiv) in water/CCl4/acetonitrile (3/2/3, 17.9 mL) was added RuCl3 (45.0 mg, 0.22 mmol, 0.34 equiv) at room temperature. After stirring for 15 minutes, a solution of compound 2.1c (0.183 g, 0.65 mmol) in acetonitrile (2.0 mL) was added. After stirring for another 15 minutes, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.1b (0.17 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][CH:22]3[CH2:30]C4C(=CC=CC=4)[CH2:23]3)=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41].[CH3:43]C(C(OC(C)(C)C)=O)(C)N.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][C:22]([CH3:30])([CH3:23])[CH3:43])=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: CC(C)(NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)OC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of Intermediate 2 (180 mg, 0.489 mmol) in THF (3 ml) was added tert-butyl 2-methylalaninate (Intermediate 8) (117 mg, 0.73 mmol), stirred for 30 minutes, and then NaBH(OAc)3 (310 mg, 1.467 mmol). The reaction was stirred for 24 hours, diluted with EtOAc and the organics washed with sat NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound (Intermediate 15) (120 mg, 48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][CH:16]1[CH:23]2[CH2:24][C:19]3([C:26](O)=[O:27])[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2)=[O:14])(=[O:10])=[O:9].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:53]([NH:55][CH2:56][CH3:57])[CH3:54]>O.C(Cl)Cl>[CH2:53]([N:55]([CH2:56][CH3:57])[C:26]([C:19]12[CH2:18][CH:17]3[CH2:25][CH:21]([CH2:22][CH:23]([CH:16]3[NH:15][C:13](=[O:14])[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])([CH3:29])[CH3:30])[CH2:24]1)[CH2:20]2)=[O:27])[CH3:54]
Reactant: CCNCC
Reactant: CC(C)(NS(=O)(=O)c1ccccc1Cl)C(=O)NC1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)C12CC3CC(C1)C(NC(=O)C(C)(C)NS(=O)(=O)c1ccccc1Cl)C(C3)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
In a 25-mL flask, 4-[2-(2-chloro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid (100 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85 mg, 0.44 mmol), 1-hydroxybenzotriazol (60 mg, 0.44 mmol), and methylenechloride (10 mL) were charged, and stirred for 15 minutes at room temperature. Then, diethylamine (48 mg, 0.66 mmol) was added thereto, followed by stirring for 12 hours at room temperature. Purified water (5 mL) was added thereto, followed by stirring for 5 minutes. Then, the organic layer was separated, and added with magnesium sulfate (50 mg) so as to remove remaining moisture. The filtrate was concentrated and obtained as a residue. The mixture was purified with column chromatography (MC/MeOH=20:1) to obtain 4-[2-(2-chloro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid diethylamide (46 mg, 41.0%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][OH:11].C(Cl)Cl.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][O:11][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccoc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccoc1CCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of 2,3-di(2-hydroxyethyl)furan (23 mmol) in methylene chloride (114 mmol) is cooled to 0° C. and treated with triethylamine (69 mmol) followed by dropwise addition of methanesulfonyl chloride (50.4 mmol) over 10 minutes. After 1 hour the reaction mixture is transferred to a reparatory funnel and extracted with cold water, 10% citric acid, saturated aqueous NaHCO3, and brine. The organic layer is dried and concentrated twice with the aid of dioxane to produce 2,3-di(2-methanesulfonyloxy-ethyl)furan, which is used crude without further purification.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CCCN2CCCCC2)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCN3CCCCC3)C2)c2ccccc21
Yield: 14 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[3-[3-(piperidin-1-yl)propyl]-piperidin-1-yl]ethanamine in a yield of 14% of theory. Colourless amorphous substance, RF 0.13 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:4].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][NH:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:4]
Reactant: CNC(=O)N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)N[C@@H]1CCNC1
Temperature: 0 °C

Procedure:
tert-Butyl-(3R)-3-{[(methylamino)carbonyl]amino}pyrrolidine-1-carboxylate 6-3 (2.174 g, 8.93 mmol) was dissolved in 3 mL CH2Cl2 and the solution was cooled to 0° C. 4.0M HCl in dioxane (33.50 mL, 134.0 mmol) was added and the solution was allowed to warm to room temperature. After 4.5 hours the reaction was concentrated in vacuo to afford N-methyl-N′-[(3R)-pyrrolidin-3-yl]urea 6-4 as an off-white solid. HCl salt: 1H NMR (DMSO-d6) δ 9.13 (bs, 2H), 4.15 (m, 1H), 3.10-3.3.29 (m, 3H), 2.96-2.87 (m, 1H), 2.54 (s, 3H), 2.13-2.01 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)=O)C.[OH-].[NH4+:16]>C(O)C>[C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)(=[O:3])[NH2:16]
Reactant: CCOC(=O)Cn1ccn2nccc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-ethoxycarbonylmethyl-1H-imidazo-[1,2-b]pyrazole (35 g) in ethanol (180 ml) was added 28% ammonium hydroxide solution {110 ml). The mixture was stirred at room temperature for two hours. The resultant precipitate was collected by filtration, washed with isopropyl ether and dried to give 1-carbamoylmethyl-1H-imidazo[1,2-b]pyrazole [18.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14]Br)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:19](CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][C:17]#[N:19])=[CH:12][CH:13]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CBr)o1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(CC#N)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
The tert-butyl((5-(bromomethyl)furan-2-yl)methyl)carbamate (5.8 g, 20 mmol) obtained above and 50 mL of acetonitrile were added into a flask. Triethylamine (2.3 g, 22 mmol) was added thereto dropwise and the reaction mixture was stirred at room temperature for 6 h. After the completion of the reaction, the reaction mixture was washed successively with water and saturated brine. The organic layer was dried, concentrated, and crude product was purified by column chromatograph to give 3.9 g (83.3% yield) of 5-(tert-butoxycarbonylaminomethyl)-furan-2-acetonitrile.
Reaction SMILES: C(Cl)Cl.B(Cl)(Cl)Cl.[CH:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[S:20][C:21]([CH3:26])=[CH:22][C:23]=3[O:24]C)=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.O>C(Cl)Cl>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]([C:19]3[S:20][C:21]([CH3:26])=[CH:22][C:23]=3[OH:24])=[O:18])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COc1cc(C)sc1C(=O)c1ccc(C2CC2)cc1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)c(C(=O)c2ccc(C3CC3)cc2)s1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In a nitrogen stream, a boron trichloride methylene chloride solution (1.0 M, 6.4 mL, 6.4 mmol) was added to a solution of (4-cyclopropylphenyl)-(3-methoxy-5-methylthiophen-2-yl)methanone (582 mg, 2.14 mmol) in methylene chloride (12 mL) at −15° C. and the reaction mixture was stirred for one hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methanol:methylene chloride (1:100)] to obtain the title compound (497 mg, 90%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[C:14]=1[N+:23]([O-:25])=[O:24])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 4.3 g (13 mmol) N-ethoxalyl-3,5-bistrifluoromethylaniline in 15 ml concentrated sulfuric acid was added at 0° C. 1.5 g (15 mmol) potassium nitrate. Stirring was continued at 0° C. for 90 min., and then at 25° C. for 120 min. The reaction mixture was poured into 100 ml ice-water and the precipitate was filtered off. The crude product was purified by column chromatography on silica gel with toluene/ethylacetate 5:1 as eluent, to give 0.44 g (9%) of N-ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline. M.p. 115.0° C.
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([C:12]1[C:13]([CH3:21])=[N:14][C:15]([CH3:20])=[C:16]([CH2:18]Cl)[CH:17]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na].[CH3:23][OH:24]>>[CH3:1][C@H:2]([NH:9][C:10]([C:12]1[C:13]([CH3:21])=[N:14][C:15]([CH3:20])=[C:16]([CH2:18][O:24][CH3:23])[CH:17]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: Cc1nc(C)c(C(=O)N[C@@H](C)c2ccccc2)cc1CCl
Agent: [Na]
Product: COCc1cc(C(=O)N[C@@H](C)c2ccccc2)c(C)nc1C

Procedure:
In a 250 ml round-bottomed flask, (S)-3-[N-(α-methylbenzyl)-carbamoyl]-5-chloromethyl-2,6-dimethylpyridine (21 g), the preparation of which is described in Example 6, is introduced into anhydrous methanol (50 ml). After dissolution, a solution of sodium (5.00 g) in methanol (50 ml) is run in.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Cl[CH2:10][CH2:11][OH:12].[OH-].[Na+]>>[OH:12][CH2:11][CH2:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCCO)cc1

Procedure:
p-Cresol may be reacted with excess 2-chloroethanol in the presence of sodium hydroxide to give 4-(2-hydroxyethoxy)toluene which may be purified by conventional techniques.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:8])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: Cc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 1,3-difluoro-2-methylbenzene (15 g, 0.12 mol) in H2SO4 (100 mL) was treated dropwise with HNO3 (65%, 11.4 g, 0.12 mol) at −10° C. The resultant mixture was stirred for about 30 min. The mixture was poured into ice-water and extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried (NaSO4) and concentrated in vacuo to give 1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 6.8-7.1 (m, 1H), 2.30 (s, 3H).