Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14](Br)=[C:13]([C:17]([O:19]CC)=[O:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[OH-].[Na+].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>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1cc(-c2ccnc(NC(C)=O)c2)oc1Br
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: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2cc(C(=O)O)c(-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a solution of ethyl 5-[2-(acetylamino)pyridin-4-yl]-2-bromo-3-furoate (0.030 g, 0.09 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.0088 mmol), (2-chlorophenyl)boronic acid (0.018 g, 0.11 mmol), and cesium carbonate (0.087 g, 0.27 mmol). The reaction mixture was subjected to microwave irradiation at 130° C. for 20 min. The reaction mixture was then diluted with water (2 mL) and 1N aqueous sodium hydroxide (0.25 mL) was added. The mixture was allowed to stir at rt overnight. The reaction mixture was extracted with EtOAc and the organic solutions were combined and concentrated. The residue was purified by column chromatography to give 5-[2-(acetylamino)pyridin-4-yl]-2-(2-chlorophenyl)-3-furoic acid (0.015 g, 50%) as a white solid. LCMS (FA): m/z=357.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:33][CH3:34])=[CH:7][CH:6]=2.C(OCC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:33][CH3:34])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of 2.6 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)-piperidine-4-carboxylate in 40 cm3 of dioxane, to which was added 14 cm3 of 4 N hydrochloric dioxane, was stirred for 16 hours at a temperature in the region of 20° C. The suspension obtained was diluted by addition of 100 cm3 of diethyl ether, stirred at about 20° C. for 1 hour and then filtered. The cake was washed with twice 40 cm3 of diethyl ether and then dried in a desiccator under reduced pressure (5 kPa). 1.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate were obtained in the form of a white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH3:18])[C:14]=1[C:15]([NH2:17])=[O:16])(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[S:11][C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:13]([CH3:18])[C:14]=1[C:15](=[O:16])[NH2:17])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1scc(C)c1C(N)=O
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1sc(S(=O)(=O)Cl)c(C)c1C(N)=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Neat ClSO3H (6.7 mL, 100 mmol) is cooled to 0° C. 2-acetylamino-4-methyl-thiophene-3-carboxylic acid amide (1.98 g, 10 mmol) is added in portions over a period of 15 min, and the mixture is stirred at 40° C. for 3 h. The mixture is cooled down to room temperature and poured slowly onto ice cold water. The resulting suspension is washed twice with EtOAc, the combined organic fractions are dried over MgSO4, filtered and evaporated to yield the desired product which is used as such.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:17])=[CH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)CC>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(O)ccnc2c1
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: Cc1noc(C)c1-c1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 125 °C
Yield: 75 %

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-4-quinolinol (for a preparation see Intermediate 11, 8.5 g, 35 mmol) in propanoic acid (442 ml) was added nitric acid (7 ml) at room temperature, followed by heating the reaction mixture to 125° C. for 2 h. After cooling, the mixture was filtered, washed with isopropyl ether to give the title compound as a yellow solid (7.5 g, 75%). [APCI-MS] m/z: 283 [M−H]−, Rt 2.41 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22]OS(C)(=O)=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Na+].[I-:29]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][I:29])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A stirred solution of methanesulfonic acid 5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester (8.80 g, 0.0206 mol) and NaI (4.64 g, 0.0309 mol) in acetone (175 mL) was refluxed for 90 min. The thick reaction slurry was cooled to rt, quenched with H2O (200 mL) and extracted with EtOAc (3×75 mL). The organic layer was dried with Na2SO4, filtered and concentrated to a dark oil. The crude oil was purified by column chromatography (silica gel, 85:15 hexane/EtOAc) to obtain 9.15 g (97%) of the title compound after two steps. HPLC: Rt=11.03 (Method E). MS (ES+): mass calculated for C17H13Cl2IN2O, 459.10; m/z found 460.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.37 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.95 (dd, J=6.3, 2.0 Hz, 1H), 6.88 (d, J=9.1 Hz, 2H), 6.55 (s, 1H), 4.47 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](N)[CH:3]=1.N([O-])=O.[Na+].[ClH:16]>>[Cl:16][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cn1
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To 4-chloro-5-nitropyridine-2-amine (Method 92, 4.40 g, 21.0 mmol) in concentrated HCl (70 ml) was added sodium nitrite (4.36 g, 63.1 mmol) potion wise at 0-5° C. After 1 hour at 0-5° C., the reaction was warmed to room temperature and stirred for 50 hours. Ice (100 g) was added and the mixture was extracted with ether (2×50 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-DCM=1:5) to give the title compound as a white solid (1.47 g, 33%). 1H NMR (400 MHz) 9.18 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(F)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (6 g, 28 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one (5 g, 16 mmol) prepared in Example 85 in dichloromethane (200 mL) were added triethyl amine (15 mL, 109 mmol) and AgF (2.7 g, 218 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (33 g, 130 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel 120 g, 10-40% EtOAc in hexanes) to give as rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a light yellow solid (1.5 g, 18%)
Reaction SMILES: [H][H].[CH:3]([C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)=[CH:4][CH3:5]>C1COCC1.[Pd]>[CH2:3]([C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CC=Cc1cccc(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cccc(F)c1F
Reaction time: 3 h

Procedure:
Hydrogen is introduced at room temperature until saturation into a solution of 0.13 mol of 3-propenyl-1,2-difluorobenzene (obtainable according to Example 11) in 100 ml of THF containing 5 g of suspended Pd/C. Customary working up is carried out after stirring for 3 hours, b.p.30 : 72° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:31][CH2:32][CH3:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:34](Cl)([Cl:36])=[O:35]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:34]([Cl:36])=[O:35])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:31][CH2:32][CH3:33])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]3[CH3:20])=[C:10]3[CH:21]=[N:22][CH:23]=[CH:24][C:9]=23)=[C:4]([F:25])[CH:3]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:42])[CH2:16][C@H:15]3[CH3:20])=[C:10]3[CH:21]=[N:22][CH:23]=[CH:24][C:9]=23)=[C:4]([F:25])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccc(Cl)cc2F)c2ccncc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(Cl)cc2F)c2ccncc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(4-chloro-2-fluorophenyl)-4-((R)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine (118 mg, 330 μmol) was dissolved in Hünig's base 13 (0.200 ml, 1148 μmol) and DMF (2 ml). Benzoyl chloride (0.0478 ml, 412 μmol) was added and the solution stirred at RT for 2 days. The reaction was then taken up in ethyl acetate (30 ml) and washed with aqueous K2CO3 (10%), water, and brine. The organic phase was dried (MgSO4) and evaporated to give an orange oil. Chromatography of the residue over silica with a gradient of hexane to 100% ethyl acetate gave ((R)-4-(1-(4-chloro-2-fluorophenyl)pyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 14 as a yellow solid. LC/MS m/z=462 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[CH2:13]([N:20]1[C:28]2[C:27](Cl)=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.O>[CH2:13]([N:20]1[C:28]2[C:27]([O:12][C:5]3[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=3[CH3:3])=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(Oc2nc(N)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a stirred suspension of NaH (56 mg, 2.33 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl phenol (317 mg, 2.33 mmol). The mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (200 mg, 0.78 mmol) in dry NMP (1.5 mL) and the resulting solution was heated at 90° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3:1) to give the product as a white solid (140 mg, 50%).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[O:20]1[C:25]2([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH2:24][NH:23][CH2:22][CH2:21]1.[CH3:38][C:39]1[S:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:38][C:39]1[S:40][CH:41]=[C:42]([C:44]([N:23]2[CH2:24][C:25]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[O:20][CH2:21][CH2:22]2)=[O:45])[N:43]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Reaction time: 16 h

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.57M solution in THF, 4.18 mL) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.92 g), 2-methylthiazole-4-carboxylic acid (0.94 g) and triethylamine (5.48 mL) in DMF (70 mL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solutions were washed with water (2×100 mL) and brine (100 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate to give the subtitled compound as a clear oil. Yield 2.30 g.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1C=CN=C1)=[S:2].N1CC[O:16][CH2:15]C1>C1COCC1>[N:8]1([C:1](=[S:2])[NH2:3])[CH2:12][CH2:11][O:16][CH2:15][CH2:9]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: NC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.1 %

Procedure:
To a stirred solution of 1,1′-thiocarbonyldiimidazole (10.0 g, 56.1 mmol) in THF (150 mL) was added morpholine (4.24 g, 4.2 mL, 48.7 mmol). The reaction was stirred for 72 h at r.t. and then concentrated in vacuo to 30 mL. Ammonia (60 mL, 2.0M in MeOH) was added to the reaction mixture, which was then stirred at r.t. in a sealed flask overnight. The reaction mixture was filtered and the solid washed with Et2O to give the title compound (2.0 g, 28%) as a white solid. δH (DMSO-d6) 7.46 (2H, bs), 3.80-3.60 (4H, m), 3.60-3.50 (4H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:17])[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:11][C:3]=12.Cl.Cl.[CH2:20]([C:22]1[N:23]=[C:24]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1)[CH3:21].C(N(C(C)C)CC)(C)C>CO>[CH2:20]([C:22]1[N:23]=[C:24]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[N:7]=[CH:6][N:5]=[C:4]4[NH:8][C:9](=[O:17])[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:11][C:3]=34)[CH2:34][CH2:35]2)[N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1)[CH3:21]
Reactant: CCc1cn(CCO)c(C2CCNCC2)n1
Reactant: O=C1Nc2ncnc(Cl)c2CN1CC(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(CCO)c(C2CCN(c3ncnc4c3CN(CC(F)(F)F)C(=O)N4)CC2)n1
Temperature: 150 °C
Yield: 140.7 %

Procedure:
Add 5-chloro-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.28 g, 1.05 mmol), 2-(4-ethyl-2-(piperidin-4-yl)-1H-imidazol-1-yl)ethanol dihydrochloride (0.38 g, 1.3 eq), methanol (15 mL) and diisopropylethylamine (0.91 mL, 5.0 eq) into a 20 mL microwave vial. Seal the tube and heat in a microwave reactor to 150° C., for 1 hour. Filter through silica gel, eluting with 10% ammonia-methanol/dichloromethane. Concentrate the filtrate in vacuo. Purify by silica gel chromatography, eluting with 3:1 ethyl acetate/methanol, to give the title compound as a yellow foam (0.67 g, 70%). MS (ES) m/z=454 [M]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](Cl)=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:9])[C:4]=1[Cl:8])=[O:21])[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1sc(Cl)c(Cl)c1Cl
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)c1sc(Cl)c(Cl)c1Cl
Temperature: -18 °C
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
To tetrachlorothiophene (2.0 g, 9.0 mmol) in an oven dried 50 mL flask, evacuated and flushed with nitrogen, was added anhydrous diethyl ether (12 ml). The resulting solution was cooled to −18° C., then n-butyllithium (1.6 M in hexane) (5.6 ml, 9.0 mmol) was added dropwise via a syringe. After stirring for 10 min at −18° C., diethyl oxalate (1.4 ml, 9.9 mmol) was added dropwise. Stirring was continued for 30 min, then the reaction mixture was quenched with 1N HCl. The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. Purification was performed by column chromatography using hexane/ethyl acetate (20:1) to provide (3,4,5-trichlorothiophen-2-yl)-oxo-acetic acid ethyl ester as a yellow solid (0.93 g, 47%). MS (M+H)+: 288.92; 1H NMR (300 MHz, CDCl3) δ4.44 (2H, q, J=7.1 Hz), 1.43 (3H, t, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ173.72, 161.82, 136.83, 133.16, 127.30, 126.53, 63.76, 14.11.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.C(OCC)C.O>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[CH3:7])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(CCCO)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(C)NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-4-(p-nitrobenzyloxycarbonyl)aminopentanol (1.63 g) and p-toluenesulfonyl chloride (2.3 g) in pyridine (17 ml) was allowed to stand at 5° C. overnight. The reaction mixture was diluted with diethyl ether and water, washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to give 5-p-toluenesulfonyloxy-2-methyl-2-(p-nitrobenzyloxycarbonyl)aminopentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)([CH3:25])[CH3:24]>>[C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[N:30]=1)([CH3:25])([CH3:22])[CH3:24]
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)(C)c1nc(CN)cs1
Product: CC(C)(C)c1nc(CNC(=O)c2ccc(OCC3CC3)c(-c3ccc(Cl)cc3)n2)cs1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAN 937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 456.0 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:21])[C@@H:4]([NH:9][C:10](=[O:20])[CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:5][CH2:6][S:7][CH3:8].[ClH:22]>O1CCOCC1>[ClH:22].[NH2:12][CH2:11][C:10]([NH:9][C@@H:4]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([NH:2][OH:1])=[O:21])=[O:20]
Reactant: CSCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NO
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)CN)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-tert-butyl 2-(1-(hydroxyamino)-4-(methylthio)-1-oxobutan-2-ylamino)-2-oxoethylcarbamate (200 mg, 0.62 mmol) was added 4N HCl in dioxane (1 mL). The mixture was stirred at rt for 1 h, concentrated and triturated with ether to give (S)-2-(2-aminoacetamido)-N-hydroxy-4-(methylthio)butanamide hydrochloride as a white solid after drying under vacuum (0.12 g, 75%). MS calcd for (C7H16N3O3S—H)+: 220.1; MS found: (M+H)+=220.0.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH:35]=[CH:34]3)=[CH:27][C:17]=1[CH2:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl.C(O)(=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][N:19]([CH2:18][C:17]2[CH:27]=[C:28]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]=[CH:34]4)[CH:29]=[CH:30][C:16]=2[F:15])[CH:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)=[CH:43][CH:42]=1
Reactant: CN1CCC(NCc2cc(-c3ccc4[nH]ccc4c3)ccc2F)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N(Cc2ccc(F)cc2)Cc2cc(-c3ccc4[nH]ccc4c3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Sodium triacetoxyborohydride (470 mg, 2.23 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of [2-fluoro-5-(1H-indol-5-yl)-benzyl]-(1-methyl-piperidin-4-yl)-amine (250 mg, 0.74 mmol) and 4-fluorobenzaldehyde (183 mg, 1.48 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and neutralized with the careful addition of saturated sodium bicarbonate solution. The organic phase was separated and dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/ethyl acetate) provided 232 mg of product. LC/MS (long run): Retention time, 6.12 min; (M+H)=446.