Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCO.O.[NH3:16]>>[Cl:11][C:4]1[N:3]=[C:2]([NH2:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
2,6-Dichloro-3-nitropyridine 90 (10.0 g, 51.8 mmol) was dissolved in 37 ml of a 7N solution of NH3 in EtOH (0.26 mol, 5.0 eqv) and the solution was stirred at rt for 24 h. H2O (40 ml) was added and the resulting mixture was filtered to collect the crude yellow product. The solid material was dissolved in CH2Cl2 and then extracted with a 1N HCl solution. The aqueous extracts were combined and then neutralized with NaHCO3 before being re-extracted with CH2Cl2. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 8.0 g of a yellow solid (89%): 1H NMR (400 MHz, d6-DMSO) d 6.77 (d, J=8.8 Hz, 1H), 8.27 (s, 2H), 8.39 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 111.89, 126.02, 138.28, 153.36, 154.88; HRMS (EI) Calcd for C5H4ClN3O2: 172.9997. Found 172.9996.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]([C:19](O)=[O:20])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:28])[CH:15]=2)[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>C1COCC1.CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18]([C:19]([Cl:33])=[O:20])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:28])[CH:15]=2)[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1

Procedure:
2-Benzyloxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (240 mg) was dissolved in THF (4.8 ml), and oxalyl chloride (100 μl) and DMF (1 drop) were added at 0° C. with stirring. The mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times to give 2-benzyloxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CCCCCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of 30.9 g of 4-acetyl-4'-octylbiphenyl in 50 ml of acetic acid there are added 5.1 ml of bromine for one hour under stirring at the temperature of 50° C. The reaction mass is stirred for 1 hour at room temperature, poured into water, the organic layer is extracted with chloroform, the extract is washed with a 5% aqueous solution of soda, then with water and dried with sodium sulphate. Chloroform is distilled-off in vacuum and the residue is recrystallized from a minimum amount of ethanol to give 38 g of 4-bromoacetyl-4'-octylbiphenyl; from 19.6 g of the product and 16.5 g of benzaldehydeguanylhydrazone there is obtained, following the procedure of Example 1, 0.65 g of 1,1'-bisbenzylideneamino-4,4'-di-[4-(4-octylphenylene)-phenylene]-2,2'-azoimidazole (II /3/). The analysis data are shown in Table 1 hereinbelow.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[CH2:17][CH2:16][CH2:15][C:6]3=[N:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[C:9]([CH:10]=1)=[C:5]23.N([O-])=[O:19].[Na+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O.O>[OH:14][CH:12]([CH3:13])[CH2:11][N:8]1[C:9]2[CH:10]=[C:2]([OH:19])[CH:3]=[C:4]3[C:5]=2[C:6]([CH2:15][CH2:16][CH2:17]3)=[N:7]1
Reactant: O=N[O-]
Reactant: CC(O)Cn1nc2c3c(cc(N)cc31)CCC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(O)Cn1nc2c3c(cc(O)cc31)CCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
The product from Step D (1.90 g, 8.4 mmol) was dissolved in H2SO4/H2O (1:2, 60 mL) and cooled to 0° C. A solution of NaNO2 (0.64 g, 9.2 mmol) in H2O (2.0 mL) was added dropwise and the resultant dark solution was stirred for 2 h. Water (40 mL) was added to this solution and the mixture was heated to 110° C. for 2 h. After cooling the mixture to room temperature it was carefully neutralized with a saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 50% to 60% gradient of ethyl acetate in hexane) to give a solid (1.2 g, 83%): m.p: 153-155° C.; MS (ES) m/z 233(M+); 1H NMR (CDCl3) δ 9.39 (1H, s), 6.50 (1H, s), 6.34 (1H, s), 4.84 (1H, d, J=4.0 Hz), 4.00 (3H, m), 2.76 (2H, q, j=6.0 Hz), 2.01 (2H, m), 1.01 (3H, d, J=6.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[O:36](S(C)(=O)=O)[S:37]([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH3:40][S:37]([OH:39])(=[O:38])=[O:36].[OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(CO)n3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O

Procedure:
To a suspension of 6-hydroxymethyl-4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (38.5 mmol) in CH2Cl2 (175 mL) and Et3N (50 mmoles) at 8° C. is added a solution of (CH3SO2)2O (48 mmol) in 50 mL of CH2Cl2 over 10-15 minutes. The reaction mixture is then extracted with cold water, dried over Mg2SO4, filtered, and concentrated under high vacuum nearly to dryness. The residue is treated with ethyl acetate, and the desired product is collected by filtration, washed with ethyl acetate, and dried under vacuum.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N:14]([CH:24]2[CH2:29][CH2:28][P:27]([O:31][CH3:32])(=[O:30])[CH2:26][CH2:25]2)[C:15]([CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C[C@H]1CC[C@H](C(Cl)=O)CC1>C1COCC1>[CH3:33][C:2]([CH3:1])([CH3:34])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N:14]([CH:24]2[CH2:29][CH2:28][P:27]([O:31][CH3:32])(=[O:30])[CH2:26][CH2:25]2)[C:15]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCP(=O)(OC)CC1
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCP(=O)(OC)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Methyl 5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5phosphinan-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (420 mg, 1.1 mmol) was dissolved in 2 mL of THF and cooled to −78° C. with a dry ice-acetone bath. A solution of KHMDS (2.6 mL, 0.5 M in toluene) was added slowly, and the mixture was stirred for 5 min. Trans-4-methylcyclohexanecarbonyl chloride (210 mg, 1.3 mmol) was added dropwise and stirring was continued at −78° C. for a further 5 min. The mixture was then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl, and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10% MeOH in EtOAc Hexanes as eluent and then further purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid), resulting in the title compound (37 mg) and recovered starting material (210 mg). MS (m/z): 508.2 [M+H]+; HPLC retention time: 4.949 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)C(C)C)(C)C>C1COCC1>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol) in THF (1.88 mL) was added acetyl chloride (26 μL, 0.36 mmol) and N,N-diisopropylethylamine (170 μL, 0.98 mmol). The reaction was stirred at rt for 17 h. The mixture was partitioned between EtOAc (25 mL) and H2O (25 mL). The layers were separated and the organic phase was washed with H2O (20 mL), brine, dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 0 to 10% MeOH in EtOAc. The isolated compound was crystallized from EtOAc/hexanes to afford 64 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.28-7.38 (m, 5 H), 7.13 (dd, 1 H), 6.59 (s, 1 H), 5.64 (s, 2 H), 4.48 (d, 1 H) 3.89 (s, 1 H), 3.32-3.41 (m, 3 H), 3.19 (s, 1 H), 2.67 (d, 1 H), 1.98-2.07 (m, 3 H), 1.66 (d, 1 H), 1.51 (s, 1 H); ES-MS m/z 466.4 [M+H]+, HPLC RT (min) 2.49.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:24]>CO>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]=1[NH2:24])=[O:15])[CH3:18]
Reactant: [NH4+]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CN(Cc2ccccc2)CC1

Procedure:
Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (25 g, 83.96 mM) and ammonium acetate (32.36 g, 419.79 mM) in MeOH (250 mL) were agitated overnight. The mixture was concentrated, the crude product was dissolved in methylene chloride and washed sequentially with aqueous saturated potassium carbonate solution and water. The organic was dried and reduced in vacuo to yield the title compound (24.0 g, 110%, higher yield possibly due to accluded solvents) as an oil which solidified on standing.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[N:7]([CH2:15][CH2:16][C:17]#[C:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:18]#[C:17][CH2:16][CH2:15][N:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=[N:6]2)[N:24]=1)[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cccc(C#CCCn2nc3ccccc3n2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of methanesulfonyl chloride (98 mg, 0.85 mmol) in DCM was added to a solution of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (100 mg, 0.38 mmol, Example 169(A)) and Et3N (0.12 mL, 0.85 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 140 mg (0.33 mmol, 88%) of N-methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamide as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:21])=[CH:6]1)(=[O:4])=[O:3].[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[NH:25]([N:26]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:21])[C:8]1=2)[C:22]([NH2:24])=[NH:23]
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Reaction time: 12 h
Yield: 46.7 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.41 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.068 ml), water (0.068 ml) and ethanol (30 ml) was refluxed for 20 minutes. The reaction solution was allowed to stand in a refrigerator for 12 hours, and precipitated crystals were filtered, which were washed with ethanol and recrystallized from water to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 13) (0.25 g) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18])[CH3:5].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH:4]([N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH3:5])[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(CCBr)N1c2cccc3cccc(c23)S1(=O)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCN1CCN(c2ccc(F)cc2)CC1)N1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Yield: 17.9 %

Procedure:
The experiment is carried out as in Example 56, starting with 2-(4-bromo-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.2 g), triethylamine (2.1 cc) and 4-(4-fluorophenyl)piperazine (2.8 g) in toluene (200 cc). The mixture is heated at boiling point for 8 hours and then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (90-10 vol) as eluant, crystallization from isopropyl oxide (30 cc) and recrystallization from boiling acetonitrile (10 cc), 2-{4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g) is obtained, m.p. 116° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1ccc2c(Cl)nc(Cl)nc21
Product: CC(C)n1ccc2c(NCCc3ccc(O)cc3)nc(Cl)nc21

Procedure:
Following the procedure of Example 128b, 2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (b) (0.278 g, 1.21 mmol) was reacted with tyramine. The crude residue was purified by silica gel chromatography (25 to 75% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 331.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].C(OO)(=O)C1C(=CC=CC=1)C(O)=[O:36].[Mg]>CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:16][CH2:15][S:14](=[O:36])[CH2:13][CH2:12]1)=[O:4]
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1
Agent: [Mg]
Solvent: CCO
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCS(=O)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (57 mg, 0.124 mmol)in EtOH (1.2 mL) from step 2 was added magnesium monoperoxyphthalic acid (29.6 mg, 0.06 mmol) in one portion, stirred for 24 h. Reaction mixture was diluted with water, extracted with EtOAc. The combined organic solution was washed with brine, dried, and concentrated. Purification of the residue on Preparative TLC using 5% MeOH-DCM gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-oxo-tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 51%). NMR 1H (CDCl3, 400 MHz, For major isomer): 7.66-7.6 (m, 2H), 7.5-7.4 (m, 3H), 7.09 (s, 1H), 4.84-4.76 (t, 1H), 3.85 (s, 3H), 3.4-1.2 (m), 0.772 (d, J=6.6, 3H), 0.74-0.56 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:14]([NH2:16])=[O:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:9]2[NH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:14]([NH2:16])=[O:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: NC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (0.040 g, 0.13 mmol) was dissolved in methanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (20 mg, 0.2 mmol). The reaction vessel was charged to 50 PSI with hydrogen and shaken for 2 h. The reaction mixture was then filtered and concentrated to give crude 5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide as a glass (0.040 g. 100%). LCMS calculated for C14H15N4O2 (M+H)+: m/z=271.1. found: 271.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1.C(O)(=O)C>O1CCOCC1>[CH:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]3[CH:14]=[C:15]([C:20]4[S:24][C:23]([C:25]5([OH:29])[CH2:28][CH2:27][CH2:26]5)=[N:22][CH:21]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)[N:7]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Clc1nccc(C2CCC2)n1
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C3CCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
2-Chloro-4-cyclobutylpyrimidine (65 mg, 0.39 mmol), Intermediate 15 (100 mg, 0.39 mmol), and acetic acid (22 μL, 0.39 mmol) were combined in dioxane (1.9 mL) and the mixture was stirred at 120° C. for 3 h. The mixture was cooled to room temperature and directly purified by Combiflash chromatography on silica gel, eluting with ethyl acetate/isohexane to provide 66 mg (0.17 mmol, 44%) of 1-(5-{3-[(4-cyclobutylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol. MS ESI: [M+H]+ m/z 393.2. 1H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.33 (d, J=4.8, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 6.68 (d, J=5.4, 1H), 6.46 (s, 1H), 3.53-3.50 (m, 1H), 2.52-2.46 (m, 2H), 2.33-2.22 (m, 9H), 1.99 (m, 1H), 1.87-1.83 (m, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1F.[OH2:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[NH:9][CH2:8][CH2:7][O:20][CH2:5][CH2:6][OH:18]
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: O
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(NCCOCCO)cc2c1=O
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (10 g, 0.035 mol) in 1-methyl-2-pirolidone (70 mL) 2-(2-amino-ethoxy)-ethanol (18 mL, 0.18 mol, 5 eq.) was added, the reaction mixture was stirred at 110° C. for 24 hours. Then was diluted with water (200 mL) and CH2Cl2 (60 mL) and the pH was adjusted to 10. The aqueous layer was extracted with CH2Cl2 (5×50 mL) and then the pH was adjusted to 6.7. After 10 minutes first product precipitated. Filtrated off yielding 2.7 g of crude 7-chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. (according to LC-MS 100% pure Intermediate 6B) Over night second product precipitated. Filtrated off yielding 7.7 g of yellow product (according to LC-MS a mixture of Intermediate 6A and Intermediate 6B in a 1:1 ratio).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:46]([O:53][C:54](=[O:57])[CH2:55][NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH2:46]([O:53][C:54](=[O:57])[CH2:55][NH:56][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 91.9 %

Procedure:
13.3 g (50 mmoles) of tert.-butoxycarbonyl-D-phenylalanine and 5.6 ml (50 mmoles) of N-methylmorpholine are dissolved in 50 ml of dimethyl formamide. The solution is cooled to -10° C., and 6.6 ml (50 mmoles) of isobutyl chloroformate are added with stirring. After 10 minutes the mixture is cooled to -20° C., and a solution of 18.6 g (55 mmoles) of glycine benzyl ester p-toluenesulfonate and 6.1 ml (55 mmoles) of N-methylmorpholine in 80 ml of dimethyl formamide, cooled to -20° C., is added. The reaction mixture is stirred at -10° C. for 10 minutes, at 0° C., for one hour, and then at room temperature overnight. The mixture is filtered and evaporated under reduced pressure. The residue is dissolved in a mixture of 300 ml of ethyl acetate and 100 ml of water. The ethyl acetate phase is separated and washed successively with 5% aqueous sodium hydrocarbonate solution (2×60 ml), water (2×60 ml), 1 n aqueous hydrochloric acid cooled with ice water (2×60 ml) and with water (2×60 ml) again, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is suspended in a 1:1 mixture of diethyl ether and n-hexane, the solid is filtered off, washed with the above solvent mixture and dried in a vacuum desiccator. 18.95 g (91.9%) of tert.-butoxycarbonyl-D-phenylalanyl-glycine benzyl ester are obtained; m.p.: 133°-134° C., Rf14 =0.28-0.38, [α]D20 =+8° (c=1%, in dimethyl formamide).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:27])[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:27][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1cccs1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccs1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-thiophen-2-yl-methylamine (CA [5693-42-5]).