Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[CH:16]N(C)C)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[N:23][C:22]([NH2:24])=[N:21][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccc(Cl)nc1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 74.2 %

Procedure:
A suspension of 2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (7.49 g, 27.1 mmol), guanidine hydrochloride (7.7 g, 81.0 mmol) and potassium carbonate (22.4 g, 162 mmol) in N,N-dimethylformamide (105 ml) was stirred at 70° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with water. The resulting crystals were collected by filtration and washed with water, to give the title compound (5.48 g, 74%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:22])[C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:22][CH:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: CSc1ccc(C(C)Sc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1
Product: CSc1ccc(C(C)Sc2ncnc3c(N4CCS(=O)CC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(α-methyl-4-methylthiobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 200°-202° C.) and piperazine.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[CH2:13][OH:12])=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OC[C@H]1CCCN1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: OC[C@H]1CCCN1c1nnc2ccc(F)cn12
Temperature: 160 °C
Yield: 53.5 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (R)-(−)-2-(hydroxymethyl)-pyrrolidine (704 mg, 9.96 mmol) in NMP (6 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (75 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (220 mg, 53%). LCMS (Method 4): Rt 1.50, m/z 237 [MH+].
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[ClH:9].[CH3:10][NH:11][CH3:12].[CH2:13]=O>O>[ClH:9].[CH3:10][N:11]([CH2:13][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1)[CH3:12]
Reactant: CNC
Reactant: C=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Solvent: O
Product: CN(C)Cc1c[nH]c(=O)[nH]c1=O

Procedure:
Uracil (56.05 g, 0.50 mol) was refluxed with dimethylamine hydrochloride (81.55 g, 1.0 mol) and 37% aqueous formaldehyde (61 mL, 1.0 mol) in water (100 mL) for two days. The solvent was evaporated and the product triturated with methanol. After filtration and drying, the title compound was isolated (80.6 g, 78.3%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.C(N(CC)CC)C.[CH3:39][NH:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:50](=O)[O:51]C2C=CC=CC=2)=[CH:45][CH:44]=1)=[O:42].O>CN(C)C=O>[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:50](=[O:51])[NH:49][C:46]3[CH:45]=[CH:44][C:43]([C:41](=[O:42])[NH:40][CH3:39])=[CH:48][CH:47]=3)[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Reactant: CNC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)N2CCN(C(=O)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (60 mg) and triethylamine (48.3 mg) in N,N-dimethylformamide (0.6 ml) was added phenyl 4-(methylcarbamoyl)phenylcarbamate (33.8 mg), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[4-[4-(methylcarbamoyl)phenylcarbamoyl]piperazine-1-carbonyl]benzyloxy]-2-methylquinoline (61 mg) as colorless amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Yield: 67.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (180 mg, 0.4337 mmols), [3-(hydroxymethyl)phenyl]boronic acid (264 mg, 1.74 mmols), cesium carbonate (282 mg, 0.868 mmol), and Pd(PPh3)4 (22 mg, 0.021 mmol) in dioxane/water (2 mL/0.7 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (130 mg, 68%)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[S:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([NH:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[S:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CSc1c(NC(C)=O)cnc2ccccc12
Yield: 90 %

Procedure:
22.67 g (0.1 mole) of 3-amino-4-methylthio-quinoline-hydrochloride [or 19.02 g (0.1 mole) of the corresponding base] are dissolved in 125 ml of pyridine, whereupon 10.7 g (0.105 mole) of acetic anhydride are added at 10°-15° C. When the yellow colour of the solution has disappeared, the reaction mixture is poured into 1000 ml of water. The precipitated white crystals are filtered. Thus 20.9 g of 3-acetylamino-4-methylthio-quinoline are obtained, yield 90%, m.p.: 137°-138° C. (after crystallization from ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8]C(C)(C)C)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=[O:7]
Reactant: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86 g, 3.10 mmol) in CH2Cl2 (250 mL) was added TFA (15 mL) dropwise and the resulting solution was stirred at rt for 3 hours. The desired compound was then precipitated out of solution with a mixture of EtOAC:Hexanes (5:20), filtered off and dried under reduced pressure. (R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a white solid (0.59 g, 86%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32 Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m, 2H) 12.65 (s, 1H). LCMS: Anal. Calcd. for C11H14N2O3: 222.24; found: 223.21 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=0.75 min, 93% homogeneity index.
Reaction SMILES: [C:1](=[S:3])=[S:2].[C:4]1([CH:10]2[O:14][CH:13]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]>>[C:4]1([CH:10]2[O:14][CH:13]([C:15]([Cl:18])([Cl:17])[Cl:16])[N:12]([C:1]([S-:3])=[S:2])[CH2:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH2:19]([NH+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]
Reactant: ClC(Cl)(Cl)C1NCC(c2ccccc2)O1
Reactant: S=C=S
Reactant: CCN(CC)CC
Product: CC[NH+](CC)CC
Product: S=C([S-])N1CC(c2ccccc2)OC1C(Cl)(Cl)Cl

Procedure:
A solution of 355.6g (3.56 moles) triethylamine, 203.6 g (2.68 moles) carbon disulfide, and 474 g (1.78 moles) 5-phenyl-2-trichloromethyloxazolidine (prepared from 2-amino-1-phenyl-ethanol and chloral; m.p. 67°-9°) was stirred for nine days at ambient temperatures. The solution was removed of volatiles under reduced pressures to leave a residual viscous oil which was extracted with ethyl ether (10 × 200 ml). The combined ether extracts were removed of solvent under reduced pressures to yield 330 g of the crude, liquid triethylammonium 5-phenyl-2-trichloromethyl-3-oxazolidinecarbodithioate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([Cl:17])=[CH:6][CH:5]=2.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23]>O.CN(C)C=O.C1(C)C=CC=CC=1>[C:22]([CH2:21][N:3]1[C:4]2[C:9](=[CH:8][C:7]([Cl:17])=[CH:6][CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[CH3:1])(=[O:23])[NH2:24]
Reactant: NC(=O)CCl
Reactant: Cc1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)c2cc(Cl)ccc2n1CC(N)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 3 g. of 2-methyl-3-phenyl-5-chloro-indole in a solvent mixture 7 ml. of toluene and 5 ml. of dimethylformamide is added to a suspension of 0.6 g. of 50% sodium hydride (in paraffin) in 5 ml. of toluene at 20° C. After the reaction mixture is stirred at 20° C. for one hour, a solution of 1.1 g. of chloroacetamide in 20 ml. of dimethylformamide is added thereto at 20° C., and the reaction mixture is stirred under reflux for 5 hours. The resultant mixture is diluted with water and is extracted with benzene. The organic layer is washed with water and dried over sodium sulfate. The solvent is removed to a residue, which is recrystallized from ethanol to give 1-carbamoylmethyl-2-methyl-3-phenyl-5-chloroindole, m.p. 223°-224° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C@H:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:19]=O>[Pd].CO>[CH3:19][N:13]1[CH2:14][CH2:15][C@H:10]([CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C@@H:12]1[C:16]([NH2:18])=[O:17]
Reactant: C=O
Reactant: CCOP(=O)(C[C@H]1CCN[C@@H](C(N)=O)C1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(C[C@H]1CCN(C)[C@@H](C(N)=O)C1)OCC
Reaction time: 16 h

Procedure:
A mixture of 500 mg of cis-4-diethylphosphonomethyl-2-piperidinecarboxamide, 3 ml of 37% aqueous formaldehyde, 50 ml of methanol and 500 mg of 10% palladium on carbon catalyst is hydrogenated at 3 atmospheres pressure for 16 hours. The solvent is removed and the residue chromatographed on silica gel with 10% methanol/methylene chloride as the eluant to afford cis-1-methyl-4-diethylphosphonomethyl-2-piperidinecarboxamide. This product is refluxed for 16 hours in 6N hydrochloric acid followed by treatment with propylene oxide to yield cis 1-methyl-4-phosphonomethyl-2-piperidinecarboxylic acid, m.p. 256°-260°.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1C=CN=C1)=[S:16].N>ClCCl.CO.C(OC(=O)C)C>[CH2:1]([C:8]1[CH:9]=[C:10]([NH:11][C:15]([NH2:17])=[S:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(Cc2ccccc2)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: NC(=S)Nc1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-benzylaniline (183 mg, 1 mmol) and 1,1′-thiocarbonyldiimidazole (197 mg, 1.1 mmol) in dichloromethane (5 ml) is stirred at room temperature for 1.5 hours. 2 M ammonia in methanol (2.5 ml) is added to the solution and the mixture is stirred at room temperature overnight. The solution is diluted with ethylacetate, and the organic layer is washed with 5% HCl, saturated NaHCO3, and brine, and dried (anhydrous Na2SO4). The crude product is recrystallized from ethylacetate and petroleum ether to give the desired product as a white powder. 1H NMR (300 Hz, CDCl3) δ 7.93 (br s, 1H, NH), 7.73-7.02 (m, 9H, Aryl H), 6.06 (br s, 2H, NH2), 3.98 (s, 2H, CH2). MS (APCI) m/z 243 [M+H]±.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C)C=O>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([CH:37]([CH3:39])[CH3:38])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)Br
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N4CCOCC4)CC3)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a brown oil (88%).
Reaction SMILES: [CH3:1][O:2][C@:3]1([C:10]2[S:14][C:13]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)=[N:12][CH:11]=2)[CH2:8][CH2:7][O:6][C@@H:5]([CH3:9])[CH2:4]1.Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C@:3]1([C:10]2[S:14][C:13]([S:15][C:16]3[CH:21]=[CH:20][C:19](/[C:22](=[N:26]/[OH:27])/[CH3:23])=[CH:18][CH:17]=3)=[N:12][CH:11]=2)[CH2:8][CH2:7][O:6][C@@H:5]([CH3:9])[CH2:4]1
Reactant: NO
Reactant: CO[C@]1(c2cnc(Sc3ccc(C(C)=O)cc3)s2)CCO[C@@H](C)C1
Agent: Cl
Product: CO[C@]1(c2cnc(Sc3ccc(/C(C)=N/O)cc3)s2)CCO[C@@H](C)C1
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-{5-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]thiazol-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]thiazol-2-ylthio}acetophenone oxime in 84% yield as a foam.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][O:5]CC1.Cl[C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10].[NH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[NH:19][N:18]=1>C1COCC1>[CH2:12]([O:11][C:9]([NH:2][C@H:7]([C:6]([NH:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[NH:19][N:18]=1)=[O:5])[CH:27]([CH3:32])[CH3:28])=[O:10])[C:13]1[CH:15]=[CH:20][CH:25]=[CH:24][CH:14]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CN1CCOCC1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 5, 386 mg (1.53 mmol) of N-benzyloxycarbonyl-(D,L)valine in 3.2 ml of THF and 337 μl (3.07 mmol) of NMM are activated with 219 μl (1.68 mmol) of isobutyl chloroformate and then reacted with 400 mg (1.53 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6). The reaction mixture is concentrated by evaporation; ethyl acetate is added to the residue and the ethyl acetate suspension is washed with 2N HCl solution, sat. NaHCO3 solution and brine and finally the insoluble crude product is filtered off. Crystallization from a hot mixture of 1.1 ml of DMSO and 10 ml of ethanol yields rac.-3-([N-benzyloxycarbonyl-valyl]-amino)-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=1 4.9; FAB-MS: (M+H)+=494.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CCO.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCc1ccc(C(N)=O)cc1
Reaction time: 4 h

Procedure:
Pd/C (11 mg, 0.11 mmol) was added to a solution of 4-(2-azidoethyl)benzamide (200 mg, 1.05 mmol) in EtOH (4 mL). A hydrogen balloon was placed over the reaction and it stirred for about four hours. The crude reaction was filtered through a pad of celite and concentrated to give 4-(2-aminoethyl)benzamide which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[ClH:19]>CCOC(C)=O.CCOCC.O1CCOCC1.[Pd]>[ClH:19].[C:13]1([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[N:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cccc2c1cnn2-c1ccccc1
Reaction time: 2 h

Procedure:
4-Nitro-1-phenyl-1H-indazole (Intermediate 7) was dissolved in EtOAc (200 mL) then 10% Pd/C (500 mg) was added and the mixture was stirred under a hydrogen atmosphere for 2 hours. Filtration through Celite and concentration of the filtrate gave a yellow oil which was dissolved in ether (100 mL). A solution of 4N HCl in dioxan (10 mL) was added slowly resulting in a yellow precipitate which was filtered off to give the title compound as a yellow solid (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][NH:23][CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][N:23]([C:5]4[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccc(Cl)nn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 3 with 3,6-dichloropyridazine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine. mp (.HCl) 265–270° C. 13C NMR (base, CDCl3): δ 26.8, 29.0, 36.4, 45.1, 50.4, 54.4, 58.6, 60.3, 71.5, 115.2, 115.3, 115.4, 115.6, 115.9, 128.7, 146.7, 155.0, 155.6, 158.76, 158.82. HRMS calcd for C19H22ClFN4O: 376.1461; found: 376.1453.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][C:16]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(CCl)NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1NCC(=O)NCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of N-benzyl-2-chloro-acetamide (20 g) in DMF (200 mL) were added 4-fluoro-2-methylaniline (13.3 mL) and N,N-diisopropylethylamine (22.2 mL). The reaction mixture was heated to 100° C. over night, cooled to room temperature, and the mixture was diluted with ethyl acetate and washed with water. The combined inorganic phases were extracted with ethyl acetate and the combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by chromatography (SiO2, n-heptane/ethyl acetate 1:2) to give N-benzyl-2-(4-fluoro-2-methyl-phenylamino)-acetamide (20 g) as grey solid, MS: 273.0 ([M+H]+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: CS(=O)(=O)N1CCNCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A suspension of 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 9.8 mmol) and cyclohexane (30 ml) in ethanol (70 ml) containing 20% palladium hydroxide on carbon (500 mg) was stirred at 80° C. for 4 hours. The mixture was cooled, filtered and the filtrate was evaporated to give 1-methylsulfonylpiperazine (1.58 g, 98%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[I:10]I>[OH-].[Na+].ClCCl>[I:10][C:6]1[NH:5][C:4]([CH2:3][O:2][CH3:1])=[N:8][C:7]=1[CH3:9]
Reactant: II
Reactant: COCc1nc(C)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCc1nc(C)c(I)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.2, 1.9 g, 15.06 mmol) in sodium hydroxide aqueous solution (30 mL, 2M). This was followed by the addition of a solution of iodine (7.7 g, 30.34 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 1 h at room temperature. The aqueous phase was collected and the pH was adjusted to 4 with hydrogen chloride (2M). The reaction mixture was extracted with 4×30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium sulfite (sat.) and 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 1.2 g (32%) of the title compound as a yellow solid.