Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=[O:42])[CH2:7][C:8]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([N:28]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH3:41])COCCOC)(=[O:27])=[O:26])=[CH:10][CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)([CH3:4])[CH3:3].[Si](Cl)(C)(C)C.[Na+].[I-].CCOC(C)=O>CC#N>[CH3:4][C:2]([NH:5][C:6](=[O:42])[CH2:7][C:8]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([NH:28][C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH3:41])(=[O:27])=[O:26])=[CH:10][CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)([CH3:1])[CH3:3]
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)NC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CC(=O)NC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the title compound of Step (D) (45 mg, 0.075 mmol) in 3 ml of CH3CN, Me3SiCl (41 mg, 0.38 mmol) was added and followed by NaI (57 mg, 0.38 mmol). The mixture was stirred at room temperature for 1.5 hrs. Additional Me3SiCl (32 mg, 0.3 mmol) and NaI (46 mg, 0.3 mmol) were added in twice after stirred for 30 min and 1 hr. 3 ml H2 O and 30 ml EtOAc were added. The organic layer was washed with sat. Na2S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 33% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 67% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (23 mg, 60%) as a white solid, m.p. 117°-123° C. (amorphous).
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][N:16]=2)[CH2:14][CH2:13]1.C(O)(=O)C.[OH-].[Na+]>CO>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][NH:16]2)[CH2:14][CH2:13]1
Reactant: COc1cc2c(cc1F)CCN=C2C1(c2ccccc2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(cc1F)CCNC2C1(c2ccccc2Cl)CC1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
Sodium cyanoborohydride (10.7 g) was added at 0° C. to a mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-3,4-dihydroisoquinoline (26.7 g, prepared in a similar manner to that described above), acetic acid (185 ml) and methanol (95 ml) under nitrogen. The mixture was allowed to reach ambient temperature and was stirred for 22 hours. The mixture was poured onto water, and solid sodium hydroxide (150 g) in ice-water (500 ml) was added. The product was extracted into ether and the solvent then removed in vacuo to yield 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-1,2,3,4-tetrahydroisoquinoline as a gum.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=O)[CH2:4][C:5]1([CH3:18])[C:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7][S:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>CCOCC>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1([CH3:18])[C:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7][S:6]1
Reactant: CN(C)C(=O)CC1(C)SCCC2=C1Cc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCC1(C)SCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The amide, N,N,1-trimethyl-1,3,4,9-tetrahydroindeno[2,1-c]thiopyran-1-acetamide (2.7 g), described in Example 196, in anhydrous ether (200 ml) is added dropwise to a stirred suspension of lithium alumimum hydride (1.0 g) in 100 ml of anhydrous ether. The mixture is stirred at room temperature for 30 min. Excess hydride is decomposed with water (4 ml). The mixture is filtered. The filtrate is dried (MgSO4) and concentrated to give the title compound, nmr (CDCl3), 1.45 (s, 3H), 3.50 (m, 2H), 7.32 (m, 4H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][C:10]([NH2:12])=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[S:4]
Reactant: NNC(N)=S
Reactant: NC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 75 %

Procedure:
Thiosemicarbazide (1.38 g, 15.1 mmol) was added to a solution of 4-oxo4-phenyl-butyramide (1.63 g, 9.22 mmol), prepared in the previous step, in 50 ml of methanol plus 2.5 ml of 1 N HCl plus 2.5 ml of water and the reaction stirred at room temperature for 28 hours. The solid formed was collected by filtration and dried to give 1.73 g of a purple solid. Recrystallization of the solid from methanol gave the title compound (1.34 g, 58%) as a purple solid, mp 186-188° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:27])C=CC=1)=O.II.OS([O-])=O.[Na+]>C(Cl)Cl>[I:27][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5]
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) (20 g, 97.4 mmol) in 1 L DCM was added bis(trifluoroacetoxy)iodobenzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at r.t. After 1 hour, 600 mL of saturated NaHSO3 was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (X) as a white solid (23.2 g, 70 mmol, 72% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(=O)Oc1ccc(OC(C)C)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(O)cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of acetic acid 3-bromo-4-isopropoxy-phenyl ester (1.44 g, 4.98 mmol, 1.00 eq.) in MeOH (20 mL), a solution of KOH (303 mg, 5.39 mmol, 1.08 eq.) in H2O (3 mL) was added. The resulting mixture was stirred at r.t. for 45 min. Water (5 mL) was added and the mixture was acidified with 2N aq. HCl soln. then extracted with DCM (3×). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a brown oil. The product was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:40]([O:39][C:37]([N:34]1[CH2:35][CH2:36][CH:31]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7]2)[CH2:32][CH2:33]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C=O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
A microwave vial was charged with 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (182 mg, 0.44 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (234 mg, 0.89 mmol), cesium carbonate (432 mg, 1.33 mmol) and DMF (2 ml). The vial was flushed with argon, sealed, and heated in a microwave reactor at 100° C. for 2 h. The reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc to give 108 mg (41%) of 4-{6-fluoro-3-[7-formyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as a light brown solid.
Reaction SMILES: [CH:1]12[CH:16]=[CH:15][CH:5]([O:6][N:7]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]2.[H][H]>[Ni]>[OH:6][C@@H:5]1[CH2:4][CH2:3][CH2:2][C@H:1]([NH:7][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1OC2C=CC1CCC2
Agent: [Ni]
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](O)CC1

Procedure:
A Parr bottle was charged with Raney Nickel (ca. 1 g). The catalyst was washed with ethanol and suspended in ethanol (30 mL). The starting material, 23A (1.0 g, 4.44 mmol) was added and the reaction pressurized with hydrogen. After hours, TLC analysis suggests good conversion to desired product. The reaction was flushed with nitrogen and filtered through a pad of magnesium sulfate. The filter cake was rinsed well with ethanol. The ethanol solution was evaporated. The isolated material was dissolved in tetrahydrofuran to give a cloudy solution. The liquid was passed through a PTFE filter and then evaporated. The crude product was crystallized from ether-hexanes. The crystalline material was filtered off and rinsed with hexanes. Residual solvent was removed under vacuum to give 23B (780 mg, 3.40 mmol, 77% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.76 (d, 1H, J=7.6 Hz); 4.36 (d, 1H, J=4.0 Hz); 3.51-3.73 (m, 1H); 3.37 (br. s, 1H); 1.69-1.91 (m, 2H); 1.45-1.66 (m, 5H); 1.37 (s, 9H); 1.06-1.34 (m, 3H).
Reaction SMILES: [Cl:1]C1C=C([C@H]2[C@@H](C3C=CC=CC=3)CCNC2)C=CC=1.[C:20]1([S:26](N2CC[C@H](C3C=CC=CC=3)[C@H](C3C=CC=C(Cl)C=3)C2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([Cl:1])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Reactant: Clc1cccc([C@@H]2CNCC[C@@H]2c2ccccc2)c1
Product: O=S(=O)(Cl)c1ccccc1

Procedure:
In analogy to Example 38, from rac-cis-3-(m-chlorophenyl)-4-phenylpiperidine (CAS Reg. No.: [735259-16-2]) and benzenesulfonyl chloride was prepared cis-1-benzenesulfonyl-3-(3-chloro-phenyl)-4-phenyl-piperidine as colorless oil, MS: 412.2 (M+H, 1Cl)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[Br:21][C:22]1[CH:23]=[C:24]([NH2:34])[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([NH:34][C:2]2[C:11]3[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:20])[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:27]=1
Reactant: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Cl
Reactant: Nc1cc(Br)cnc1N1CCOCC1
Product: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1

Procedure:
Prepared according to the acid catalyzed Procedure K, Method 2 using 4-chloro-5,8-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (300 mg, 1.03 mmol) and 5-bromo-2-morpholinopyridin-3-amine to give N-(5-bromo-2-morpholinopyridin-3-yl)-5,8-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=512.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12]C=CC=2)=[C:7](F)[CH:8]=1.[CH2:19](O)C>>[OH:18][C:16]([CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:10][CH:11]([CH3:12])[CH3:19])=[CH:5][CH:4]=1)[CH3:1])=[O:17]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCO
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 60 °C

Procedure:
Three grams of flurbiprofen and 30 g of poloxamer 237 were heated at 110° C. for 10 minutes to obtain a liquified mixture and cooled to 60° C. Into this mixture, 5 g of polyethylene glycol 300, 10 g of ethanol and 52 g of pH 4 buffer solution were added at 60° C. to obtain an ibuprofen gel.
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:22]([NH:23][CH3:24])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 66 %

Procedure:
A solution of 1-benzyl-3-butyl-6-hydrazinouracil (4.0 g, 13.9 mM) and methyl isothiocyanate (2.85 ml, 41.7 mM) in DMF (50 ml) was stirred at 120° C. for 20 hours. To the solution was added methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (3.0 g, 66%), m.p. 282°-284° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CCO
Product: CCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 133° C. and MS: m/e=284.2 (M+H+) was prepared in accordance with the general method of example 1 from diphenyl-acetyl isocyanate and ethanol.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[C:9]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[NH2:21].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9]1[N:10]([CH3:11])[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:18]([CH3:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Cn1c(-c2ccco2)cc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccco5)n(C)c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (92 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 3.5 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL×2), and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (105 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([NH:21][C:22]([C:24]2([CH3:27])[CH2:26][O:25]2)=[O:23])[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]>>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:14]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:12]([CH3:11])[CH:13]=2)=[O:23])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(C#N)c(Cl)c2)ccc1[N+](=O)[O-]

Procedure:
3-(3-Chloro-4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 4-amino-2-chlorobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.52 (3H, s), 3.27 (1H, dd, J=13.8 Hz, J=5.5 Hz), 3.55 (1H, dd, J=13.8 Hz, J=6.9 Hz), 6.12 (1H, s), 6.72 (1H, dd, J=8.8 Hz, J=2.2 Hz), 6.90 (1H, d, J=2.2 Hz), 6.95-6.98 (1H, m), 7.46 (1H, d, J=8.7 Hz), 7.80 (1H, dd, J=8.9 Hz, J=2.3 Hz), 7.83 (1H, d, J=2.0 Hz), 8.02 (1H, d, J=8.9 Hz), 10.05 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O.CO>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:5]4[CH2:6][CH2:7][CH:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CN(C)C1CCNC1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCC(N(C)C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
N,N-dimethylpyrrolidin-3-amine (114 mg, 1.00 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C. The resulting solution was stirred at room temperature for 20 mins. The reaction mixture was diluted with methanol (5.00 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a brown oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (130 mg, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[F:16].O1CCOCC1.[NH3:23]>O>[NH2:23][C:4]1[C:3]([F:16])=[C:2]([NH2:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: N
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Reaction time: 1.33 h
Yield: 100.1 %

Procedure:
To a stirred solution of methyl 4-amino-2,3-difluoro-5-nitrobenzoate (4) (33.0 g, 142.15 mmol) in 1,4-dioxane (165 mL, 1.93 moles), in a 250 mL glass pressure vessel, was added an aqueous solution of ammonia (39 g, 711 mmol, 42.9 mL, 16.5 M). The vessel was then heated in an immersion bath at a bath temperature between 79 and 105° C., for 80 minutes, over which time the internal pressure ranged between 0.2 and 2.7 bar. The pressure was then released slowly and the mixture was treated with water (330 mL, 10 vol). The resultant suspension was stirred for 20 minutes and then filtered under vacuum, and the solid was washed with water (33 mL, 1 vol). The solid was sucked dry, then dried in a vacuum oven at 50° C. to provide methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (32.6 g, 92% yield) as a yellow solid. 1H NMR (500 MHz, d6 DMSO) δ 3.83, (3H, s, OMe), 7.20 (2H, br, NH2), 7.37 (2H, br, NH2), 8.47 (1H, s, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 52 (CH3), 101 (C), 122 (C), 126 (CH), 134 (C), 137 (C), 142 (C), 166 (C═O). νmax/cm−1 3474, 3358, 1697, 1633, 1528, 1435, 1317, 1285.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH2:29][CH:30]=O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(OC(=O)C)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH2:29][CH2:30][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(Br)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(CCCNc2ccc(Br)cc2C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
2-Methyl-4-bromo-aniline (1.68 g, 9.05 mmol, 1 eq) was dissolved in 1,2-dichloroethane (95 mL). A solution of 4-(3-Oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.8 g, 9.05 mmol, 1 eq) in 95 mL of 1,2-dichloroethane was added to the previous solution followed by glacial acetic anhydride (1.74 g, 28.05 mol, 3.1 eq) and NaBH(OAc)3 (5.76 g, 27.15 mmol, 3 eq). The reaction mixture was stirred for 48 h, quenched with 200 mL of water, transferred to a separatory funnel and extracted with dichloromethane (2×100 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (200 g column, 25% EtOAc in heptanes; 50 mL/min). This gave 3.78 g (86%) of the title compound as a beige gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([C:6]2[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Cc1cc(C(=O)Cc2ccccc2)cc(C)n1
Product: Cc1cc(C(=O)C(Cc2ccc(Br)cc2)c2ccccc2)cc(C)n1

Procedure:
In analogy to example 43, step 1, from 1-(2,6-dimethyl-pyridin-4-yl)-2-phenyl-ethanone and 4-bromobenzylbromide was prepared the title compound as a yellow oil, MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17]
Reactant: Nc1cc(S(N)(=O)=O)ccc1Cl
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(S(N)(=O)=O)ccc1Cl

Procedure:
To 3-amino-4-chlorobenzenesulfonamide (420 mg) in tetrahydrofuran (2 ml) solution, ethylisocyanate (180 μl) was added and the mixture was stirred under heating and reflux for 15 hours. The reaction solution was concentrated, then the residue was recrystallized from chloroform/methanol to obtain the title compound as a crude product (550 mg).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:16][CH3:17])([O:14][CH3:15])[CH:10]([OH:18])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH:10]([O:18][CH3:21])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(Cc2ccccc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b, 5.5 g, 22 mmol) from Example 1 in 30 ml of dimethylformamide was added slowly to a stirred suspension of sodium hydride (0.81 g, 27 mmol, 80% oil suspension) in 100 ml of dimethylformamide. The reaction mixture was warmed to 60° C. for 2 hours, then cooled to 0° C. whereupon methyl iodide (3.8 g, 27 mmol) was slowly added to the mixture. The reaction mixture was stirred overnight at room temperature then quenched with 10 ml of 10% sodium hydroxide solution. The reaction mixture was concentrated under vacuum, the residue slurried in 300 ml of water and the aqueous mixture extracted with 3×100 ml of ether. The combined organic layers were dried over magnesium sulfate, concentrated under vacuum, then purified by column chromatography (alumina; ethyl acetate/hexane; 2.5:1) to yield the intermediate 1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 3.77 g, 64.6%, Rf 0.63).