Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8]([NH2:11])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16](Cl)=[O:17])=[O:15]>>[CH2:1]([S:8]([NH:11][C:16](=[O:17])[C:14]([O:13][CH3:12])=[O:15])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)NS(=O)(=O)Cc1ccccc1

Procedure:
A mixture of benzylsulfonamide (16.7 g, 0.0975 mole) and methyloxalylchloride (38 ml, 0.41 mol) was heated at 100°-120° C. for 2 hours. Upon evaporation, there was obtained the title compound, 20.6 g, mp 119°-124° C.
Reaction SMILES: C(OC([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([C:38](=C=O)[O:39]OCC)[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=O)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[CH2:13]([O:28][C:29]([O:39][CH2:38][C@H:36]1[O:37][C@@H:29]([O:28][C:13]2[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=3)=[C:15]([CH3:16])[NH:11][N:12]=2)[C@H:30]([OH:31])[C@@H:32]([OH:33])[C@@H:34]1[OH:35])=[O:37])[CH3:14]
Reactant: CCOOC(=C=O)[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 150 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(6-O-ethoxy-carbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)-methyl]-5-methylpyrazole (0.17 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The resulting insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxy-phenyl)methyl]-5-methyl-1H-pyrazole (0.10 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C=C[N+](=O)[O-])cc1F

Procedure:
A solution of 3-fluoro-4-methoxybenzaldehyde [5.05 g, Intermediate (1)], nitromethane (5.3 mL) and ammonium acetate (6.3 g) in glacial acetic acid (60 mL) is heated at 110° C. for 16 hours, allowed to cool and poured into water (300 mL). The aqueous solution is extracted twice with EtOAc (200 mL). The combined extracts are washed with sodium bicarbonate solution (10%), with water, dried over sodium sulfate and evaporated affording 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene [4.2 g, Intermediate (2)]. MS: 198 (M+H); 1H NMR (CDCl3): δ 7.9 (1H, d, J=10 Hz); 7.5 (1H, d, 10 Hz); 7.3 (2H, m); 6.95-7.15 (1H, m); 4 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[C:13]([CH2:15][C:16](OCC)=[O:17])=O>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:13]([C:12]1[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=1[O:10][CH3:9])[CH:15]=[C:16]2[OH:17]
Reactant: CCOC(=O)CC(=O)c1ccccc1OC
Reactant: Nc1ccc(Cl)cc1
Product: COc1ccccc1-c1cc(O)c2cc(Cl)ccc2n1

Procedure:
Prepared according to procedure R using 4-chloroaniline (774.0 mg, 6.1 mmol), ethyl (2-methoxybenzoyl)acetate (2.0 mL, 10.3 mmol), and PPA (4.70 g, 47.0 mmol) to afford 6-chloro-2-(2-methoxyphenyl)quinolin-4-ol. Mass Spectrum (ESI) m/e=286.0 (M+1).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH:34]=[CH:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2cccc(N3CCNCC3)c2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4cccc(N5CCNCC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. LCMS calculated for C26H30N5O2(M+H)+: m/z=444.2. Found 444.2.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](O)=[O:21])(=[O:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]1[C:61]2([CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:60][NH:59]/[C:58]/1=[N:67]\[C:68]([C:70]1[C:75]([NH2:76])=[N:74][C:73]([NH2:77])=[C:72]([Cl:78])[N:71]=1)=[O:69]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([N:64]3[CH2:65][CH2:66][C:61]4([NH:57]/[C:58](=[N:67]/[C:68]([C:70]5[C:75]([NH2:76])=[N:74][C:73]([NH2:77])=[C:72]([Cl:78])[N:71]=5)=[O:69])/[NH:59][CH2:60]4)[CH2:62][CH2:63]3)=[O:21])[CH:18]=2)(=[O:15])=[O:16])[CH2:9][CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)O)c2)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(1-tert-butoxycarbonyl-cyclobutylmethyl)-sulfamoyl]-benzoic acid (Int. AC) (1.37 g, 3.71 mmol) in DMF (20 ml) was treated with N-methylmorpholine (1.631 ml, 14.83 mmol) and HATU (1.41 g, 3.71 mmol) followed by 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (1.27 g, 3.89 mmol). The reaction mixture was stirred at RT for 2 h and then partitioned between EtOAc and water. The organic portion was separated and washed with 0.5M aqueous 1,5,7-triazabicyclo[4.4.0]dec-5-ene solution, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 5-8% MeOH in iso-hexane afforded the title compound; LC-MS Rt 1.03 mins; 676.4 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][S:7]([C:10]1[N:14]=[CH:13][NH:12][N:11]=1)(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29].O>C(#N)C>[CH3:26][N:27]([CH3:32])[S:28]([N:12]1[CH:13]=[N:14][C:10]([S:7]([O:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=2)(=[O:8])=[O:9])=[N:11]1)(=[O:30])=[O:29]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=S(=O)(Oc1cccc(C(F)(F)F)c1)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)n1
Yield: 97.4 %

Procedure:
1.0 g of 3-(3-trifluoromethylphenoxysulfonyl)-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 1 was dissolved in 10 ml of acetonitrile. Then, 0.57 g of potassium carbonate was added, and 0.59 g of dimethylsulfamoylchloride was gradually added at room temperature while stirring them. Then, they were refluxed for one hour, and the reactant solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvent was removed by distillation and the residue was purified by silica gel chromatography. As a result, 1.33 g of the titled compound was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=2)=[N:14][CH:15]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:11]=1
Reactant: CCCCCCOc1ccc(-c2ncc(-c3ccc(O)c(F)c3F)cn2)cn1
Reactant: CCCCCCCCBr
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCC)nc3)nc2)c(F)c1F
Yield: 61 %

Procedure:
The etherification of 12 mmol of 5-(2,3-difluoro-4-hydroxyphenyl)-2-(6-hexyloxypyridin-3-yl)pyrimidine using 13.2 mmol of 1-bromooctane in 100 ml of DMF is carried out analogously to the procedure indicated for Example 3. The crude product is chromatographed on silica gel 60 using dichloromethane as eluent and is recrystallized from n-heptane and toluene, giving 3.6 g (61%) of colorless crystals, whose analytical data correspond to those of the compound obtained as described in 1a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: ClCc1ccccc1OCc1ccccc1
Product: COc1ccc(C2=NN(Cc3ccccc3OCc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-benzyloxybenzylchloride as described for component 78. Purified by chromatography [ethyl acetate/petroleum ether (60°-80° C.), 1:3]. M.p. colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC=CC=1.[ClH:28]>O>[ClH:28].[ClH:28].[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
10.00 kg (52.84 mol) 1-benzylpiperidone (K) were taken and 9.21 kg (105.68 mol) morpholine (L) as well as 50.0 L toluene were added. Then the reaction mixture obtained was heated to reflux temperature using the water separator (110° C.) and stirred until no more water separated off. Then the mixture was hydrogenated at 4 bar and an internal temperature of 60° C. in the presence of 0.50 kg Raney nickel catalyst in 6 L ethanol. The catalyst was separated off and washed with 20 L ethanol. Then the solvent was distilled off completely in vacuo. Then 80.0 L ethanol were added and at 50° C. 16.05 kg (132.10 mol) hydrochloric acid (30%) were metered in. The resulting suspension was cooled to 20° C. and stirred for 30 minutes at 20° C. The product was centrifuged off and dried.
Reaction SMILES: [CH2:1]([S:8]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)SC)=[O:21]>CO.C(O)(=O)C>[CH2:1]([S:8]([C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:23]([NH:22][C:20](=[O:21])[O:19][CH3:18])=[N:17][C:12]=2[CH:11]=1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)Cc2ccccc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)Cc3ccccc3)ccc2[nH]1

Procedure:
To 3.34 g (14.5 mMol) of 4-(benzyl)sulfinyl-1,2-diaminobenzene in 35 ml methanol and 0.84 ml acetic acid is added 3.11 g (16 mMol) 1,3-bis(methoxycarbonyl)-S-methyl isothiourea, and the resulting solution heated to reflux for 3 hours. The solvent is removed in vacuo, the solid digested with water and filtered and washed with ether. The resulting solid is recrystallized from ethanol to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[C:16]3[CH:17]=[C:18]([F:27])[CH:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]=3[N:14]=[CH:13]1)[C:6]([CH3:28])=[C:5]2[C:29]([O:31]C)=[O:30]>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[C:16]3[CH:17]=[C:18]([F:27])[CH:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]=3[N:14]=[CH:13]1)[C:6]([CH3:28])=[C:5]2[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1c(C)c(-n2cnc3c(-c4ccccc4)cc(F)cc32)nc2ccc(F)cc12
Solvent: CCCCO
Product: Cc1c(-n2cnc3c(-c4ccccc4)cc(F)cc32)nc2ccc(F)cc2c1C(=O)O
Temperature: 25 °C
Yield: 3.7 %

Procedure:
Methyl 6-fluoro-3-methyl-2-(6-fluoro-4-phenyl-1-benzimidazolyl)quinoline-4-carboxylate: A mixture of 2-bromo-4-carbomethoxy-6-fluoro-3-methylquinoline,obtained in Example 1D, (2.53 g, 8.48 mmol) and the product of example 68C (1.80 g, 8.48 mmol) in n-butanol (12 mL) was heated at reflux for 18 h. The reaction was allowed to cool to room temperature and solvent was removed. The residue was chromatographed (1:1 hexanes-ethyl acetate) to provide the desired product (0,135 g, 0.31 mmol) in 3.7% yield as a tan solid, mp=208-210° C.; NMR(CDCl3): 8.27 (s, 1H), 8.13 (dd, 1H), 8.01 (d, 2H), 7.41-7.62 (m, 5H), 7.30 (dd, 1H), 7.06 (dd, 1H), 4.16 (s, 3H), 2.40 (s, 3H); IR(KBr): 1734; Mass spectrum: m/z 430.0 (M+H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:29][C:30](=[N:36][OH:37])[CH2:31][NH:32][C:33](=[O:35])[O-:34]>>[C:11]([O:35][C:33](=[O:34])[NH:32][CH2:31][C:30]1[N:29]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:37][N:36]=1)([CH3:26])([CH3:12])[CH3:10]
Reactant: NC(CNC(=O)[O-])=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)(C)OC(=O)NCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
161 mg (0.40 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 83 mg (0.44 mmol, 1.1 eq.) of tert-butyl[(2-amino-2-(hydroxyimino)ethyl]carbamate were reacted according to the General Method 1. Yield: 127 mg (57% of theory)
Reaction SMILES: [C-:1]#[N:2].[Na+].[N+:4]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22]Cl)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].O>CS(C)=O>[N+:4]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:1]#[N:2])=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C(NCCc1ccccc1CCl)c1ccc([N+](=O)[O-])cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccccc1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 74.5 %

Procedure:
Sodium cyanide (2.9 g) was dissolved in 100 ml of dimethylsulfoxide, and with stirring at room temperature, 15.5 g of 1-(4-nitrobenzoyl)amino-2-(2-chloromethylphenyl)ethane was gradually added. The reaction was performed at room temperature for 10 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from ethanol to afford 11.2 g of 1-(4-nitrobenzoyl)amino-2-(2-cyanomethylphenyl)ethane having a melting point of 118.6° to 119.1° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.I[CH3:14]>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: Brc1ccc2c(c1)CNCC2
Agent: Cl
Product: CN1CCc2ccc(Br)cc2C1

Procedure:
Following the procedure described for Intermediate 3 using 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride and iodomethane provided the title compound. ESMS [M+H]+: 226.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1ccc(F)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nccc(C(F)(F)F)n2)cc1Br
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To 3-bromo-4-fluoroaniline (0.76 g, 4.0 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (0.73 g, 4.0 mmol) was added dioxane (13.33 mL) and p-TSA (0.761 g, 4.0 mmol). The reaction was sealed and was heated at reflux overnight. The reaction was cooled to room temperature and was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and the organic was dried over sodium sulfate and filtered before concentration. The crude product was purified by flash chromatography (25:75 ethyl acetate:hexanes) to afford N-(3-bromo-4-fluorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (1.2 g, 3.57 mmol, 89%) as a pale yellowish solid. 1H NMR (500 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H); 7.99-7.96 (m, 1H); 7.51 (d, J=8.4 Hz, 1H); 7.29 (s, 1H); 7.14 (t, J=8.5 Hz, 1H); 7.10 (d, J=4.9 Hz, 1H). rhSYK activity=+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:4]1[N:3]=[C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN1CCNCC1
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(Cl)cc3ccccc23)CC1
Yield: 98.8 %

Procedure:
1,3-Dichloroisoquinoline (9.30 g), N-ethylpiperazine (5.90 g) and potassium carbonate (10.0 g) were reacted in dimethylformamide (70 ml) at 70° C. for 5 hr. The reaction solution was evaporated and partitioned between ethyl acetate and water. The resulting organic phase was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 12.80 g of the title compound as a pale brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[C:13]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:13]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)c1n[nH]c2ccccc12

Procedure:
This compound is synthesized in a manner similar to the procedure described in Example 2 by coupling indazole-3-carboxylic acid and N-phenyl-1,4-phenylenediamine on the scale of 1 mmol, but using dicyclohexylcarbodiimide (DCC) as coupling reagent. The crude product obtained after extraction is taken up in CHCl3. The insoluble matter is filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][O:12][C:22]([Cl:21])=[O:23])([O-:3])=[O:2]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 2-(2-nitrophenyl)propanol (500 mg, 2.76 mmol) and Et3N (279 mg, 0.385 ml, 2.76 mmol, dist. over KOH) in THF (6.75 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (655 mg, 3.3 mmol) in THF (6.75 ml, see above). It was stirred for 1 h while being cooled in an ice bath and stirred for 1 h at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-nitrophenyl)propoxycarbonyl chloride (644 mg, 96%) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][S:11][C:10]=3[CH2:14][OH:15].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][S:11][C:10]=3[CH2:14][O:15][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: OCc1scc2c1-c1ccccc1Oc1ccc(Cl)cc1-2
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOCc1scc2c1-c1ccccc1Oc1ccc(Cl)cc1-2

Procedure:
Starting from the alcohol 13 (0.29 mmole) and 2-dimethylaminoethylchloride-hydrochloride (2.9 mmoles), an oily product was obtained.
Reaction SMILES: [ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[NH:6])#[N:3].C([OH:18])(C)C>>[ClH:1].[ClH:1].[C:2]([NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[NH:6])(=[O:18])[NH2:3]
Reactant: N#CNC(=N)NCc1ccccn1
Reactant: CC(C)O
Agent: Cl
Product: N=C(NCc1ccccn1)NC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated HCl (15.4 ml) is added to a stirred solution of 1-cyano-3-(2-pyridylmethyl)guanidine (4.50 g) in 310 ml of isopropanol. The reaction mixture is stirred at room temperature overnight. The solvent is concentrated in vacuo and the residue treated with 1.8 liters of boiling ethanol. The resulting suspension is stirred and heated while adding small portions of water until most of the solid has dissolved. The solution is filtered through Celite, diluted to 2 liters with absolute ethanol and concentrated on a hot plate and cooled. The first crop of crystals, MP 214°-215° C. w/dec, and the second crop of crystals, MP 215°-216° C. w/dec, obtained by concentration of the filtrate, were combined to give 2.60 g of the carbamoyl guanidine as a grey-green solid. The grey-green solid is dissolved in boiling ethanol, treated with Darco G-60 and filtered. The filtrate is boiled down on a hotplate and the white crystalline precipitate is collected, washed with absolute ethanol and dried in air yielding 1.77 g of the desired product MP 214°-216° C. w/dec.