Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29]C(=O)OCC1C=CC=CC=1)[CH2:25][CH:26]([CH3:28])[CH3:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCOC(C)=O>[Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH2:29])[CH2:25][CH:26]([CH3:27])[CH3:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](N)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A flask containing a solution of the Cbz-protected amine 11b (460 mg, 0.846 mmol) in a 5:1 MeOH/EtOAc mixture (12 mL) was purged and filled 3 times with argon, then 10% Pd/C (50 mg) was added. The flask was purged and filled 3 times with H2, and the resulting black suspension was stirred at rt under H2 (1 atm). Since the reaction did not reach completion after 3 h, an additional amount of 10% Pd/C (30 mg) was added and stirring under H2 was continued for 5 h. The reaction mixture was then filtered through a pad of Celite, the Celite washed with MeOH and AcOEt, and the solution concentrated in vacuo to yield 317 mg (92%) of the crude title compound as a pale yellow oil, that was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[CH:38][CH:39]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
(3S)-4-{2-Chloro-6-[(phenylsulfonyl)methyl]pyrimidin-4-yl}-3-methylmorpholine (3.2 g, 8.70 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (36 mL). Tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (4.16 g, 13.05 mmol), 2M sodium carbonate solution (8 mL) and dichlorobis(triphenylphosphine) palladium catalyst (306 mg, 0.43 mmol) were then added and the reaction refluxed at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-30% ethyl acetate in DCM to give the desired material as a beige solid (3.1 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10]2)=[O:6].Cl>CO>[CH2:16]([N:12]1[C:13]2[C:9](=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCn1ccc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCn1ccc2cc(C(=O)O)ccc21
Reaction time: 4 h

Procedure:
Aqueous sodium hydroxide (1N, 3.4 mL, 3.4 mmol) was added to a solution of 1-pentyl-1H-indole-5-carboxylic acid methyl ester (0.79 g, 3.09 mmol) in methanol (30 mL). The resultant solution was heated at reflux for 4 hours. Additional aqueous sodium hydroxide (3.4 mL) was added and heating was continued for 4 hours. The solution was cooled, neutralized with 1N hydrochloric acid. The solvent was evaporated in vacuo. The residue was partitioned between water dichloromethane. The organic solution was dried over sodium sulfate and the solvent was evaporated in vacuo, to give the product, 0.715 g (100%). MS: m/z 232 (MH+). 1H NMR (CDCl3): 0.88 (t, 3 H), 1.24-1.42 (m, 4 H), 1.80-1.89 (m, 2 H), 4.14 (t, 2 H), 6.61 (d, 1 H), 7.16 (d, 1 H), 7.36 (d, 1 H), 7.99 (d of d, 1 H) and 8.50 (s, 1 H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.N(O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Li+]>CC(O)CC>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: COc1cccc(NC(=N)N)c1
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: COc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (2.22 g, 10.5 mmol), 3-methoxy-phenyl-guanidine nitrite (2.40 g, 10.5 mmol), lithium hydroxide (350 mg, 14.5 mmol) in 2-butanol (25 mL) is heated to reflux for 8 hours. The reaction mixture is cooled to room temperature, concentrated and water (60 mL) is added. The resultant solid is collected by filtration and washed with water, isopropanol and dried to give N-[3-methoxy-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (2.81 g); ESI-MS (m/z): 313 (M++H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([N+:24]([O-])=O)[C:6]=2[N:5]=1)[CH3:3].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:3][CH:2]([C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:22]=[C:23]([NH2:24])[C:6]=2[N:5]=1)[CH3:1]
Reactant: CC(C)c1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
TiCl3 (16.3 mL) was added to a solution of 2-(1-methylethyl)-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-4-nitro-1H-benzimidazole (1.6 g) and NH4OAc (4 g) in MeOH (40 mL). After stirring for 4 h at room temperature, TLC showed no starting material. The pH of the mixture was made basic by adding Na2CO3 aqueous solution. The solvent was evaporated off under reduced pressure and the residue was extracted with DCM (250 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the desired product as a white solid (1.2 g, 81%). LC-MS: m/e=401 [M+1]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:34]1[N:35]=[C:36]([NH:39]N)[S:37][CH:38]=1>>[F:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:34]1[N:35]=[C:36]([N:39]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[S:37][CH:38]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: COc1ccc(-c2csc(NN)n2)c(F)c1
Product: COc1ccc(-c2csc(-n3nccc3-c3nn(-c4cccc(S(C)(=O)=O)c4)ccc3=O)n2)c(F)c1
Yield: 41 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and [4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-hydrazine according to the method described for Example 91 in 41% yield.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[C:11]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=[C:8]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:7]=1>CO>[CH3:4][O:5][C:6]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[C:8]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:7]=1
Reactant: COc1nc(OCC(F)(F)F)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: COc1nc(OCC(F)(F)F)ccc1CN
Temperature: 50 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
Hydrazine hydrate (0.13 mL) is added to a solution of 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.83 mmol) in methanol (20 mL) and stirred for 20 hours at 50° C. After removal of the solvent, the residue is poured into 2N sodium hydroxide (10 mL) and extracted with dichloromethane (30 mL×3) and dried over sodium sulfate, and concentrated in vacuo to give 0.41 g (95% yield) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].Cl.[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1>>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH:22][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Product: O=C(O)c1ccc(C(=O)NC2CCC(F)(F)CC2)nc1

Procedure:
The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 4,4-difluorocyclohexylamine hydrochlorid, and the second as described for Intermediate example I-98 at 55° C., starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 65%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (dd, 1 H), 8.89 (d, 1 H), 8.43 (dd, 1 H), 8.13 (dd, 1 H), 3.95-4.07 (m, 1 H), 1.68-2.11 (m, 8 H); MS (ESI) m/z 285[M+H+], m/z 283[M−H+];
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[CH3:35][S:36]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)(=[O:38])=[O:37]
Reactant: OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 84.0 g of N-triphenylmethyl-4-piperidinemethanol and 36.2 ml of triethylamine in 420 ml of dried tetrahydrofuran, 18.3 ml of methanesulfonyl chloride was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was added with waiter and extracted with diethyl ether. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting residue was added with a mixture of isopropanol and methanol, and the precipitated crystals were collected by filtration and washed with methanol to give 90.4 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless prisms having the melting point of from 129.5 to 134° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20]>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:15]([CH:16]([CH2:17][CH2:18][C:19](=[O:21])[NH2:20])[C:22]([OH:24])=[O:23])[C:7]2=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 87.5 °C
Yield: 72.6 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.5 g, 7.8 mmol) and L-glutamine (1.14 g, 7.8 mmol) in DMF (15 mL) is heated at 85-90° C. for 4 hours. The mixture is concentrated in vacuo and the residue is slurried with water (30 mL). The resulting slurry is filtered and the solid is washed with water (10 mL), dried (60° C., <1 mm Hg) to give 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (1.82 g, 73%); mp 182-184° C.; 1H NMR (DMSO-d6) δ8.33 (d, J=7.7 Hz, 1H), 8.22 (d, J=7.0 Hz, 1H), 8.11 (t, J=7.8 Hz, 1H), 7.19 (s, 1H), 6.73 (s, 1H), 4.82-4.77 (dd, J=4.6 and 9.8 Hz, 1H), 2.36-2.11 (m, 4H); 13C NMR (DMSO-d6) δ173.21, 170.03, 165.43, 162.75, 144.45, 136.70, 132.98, 128.83, 127.25, 122.52, 51.87, 31.31, 23.87; Anal. Calcd. For C13H11N3O7: C, 48.60; H, 3.45; N, 13.08. Found: C, 48.52; H, 3.28; N, 13.05.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][NH:12][CH3:13].[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][N:12]([CH3:13])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:18]2[NH:17][C:16](=[O:30])[C:15]([CH3:14])([CH3:31])[O:20][C:19]=2[CH:21]=1
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Reactant: CNCc1oc2ccccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of (3-chloro-benzofuran-2-ylmethyl)-methyl-amine (151 mg, 0.77 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (174 mg, 0.7 mmol), 1-hydroxybenzotriazole (107 mg, 0.77 mmol), diisopropylethylamine (366 uL, 2.1 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (154 mg, 0.77 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (218 mg, 73%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.53-7.67 (m, 3H), 7.40-7.44 (m, 3H), 4.89-5.11 (m, 2H), 2.97-3.23 (m, 3H), 1.46 (s, 6H); MS (ESI) m/e 426 (C22H20ClN3O4+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[C:20]([S:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29](F)[CH:28]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1>C(OCC)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[C:20]([S:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:28]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(F)c2)c1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N3CCN(C)CC3)c2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
N-Methylpiperazine (2.0 mL) was added to N-(3,5-dimethylphenyl)-2-(2-fluoropyridin-4-ylmethylthio)pyridine-3-carboxamide (Reference compound No. 3-1, 100 mg, 0.27 mmol) at room temperature, then the vessel was sealed and the reaction mixture was stirred for 3 hours at 150° C. The mixture was cooled to room temperature, ethyl acetate (20 mL) was added to the reaction mixture, and then the whole was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting solid was filtered off with ethyl acetate to give 39 mg of the target compound as a colorless crystal. (Yield 32%)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[CH2:37]1>>[C:41]([CH:38]1[CH2:39][CH2:40][N:36]([C:29](=[O:30])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37]1)#[N:42]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: N#CC1CCNC1
Agent: Cl
Product: CC(C(=O)N1CCC(C#N)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and pyrrolidine-3-carbonitrile hydrochloride (Tyger and Cat. No. P76159). LCMS (M+H)+: m/z=552.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CN
Reactant: N#Cc1cccc(CBr)c1
Product: CNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of methylamine (40% in water, 200 mL) under N2, was added 3-(bromomethyl)benzonitrile (10 g, 51 mmol) slowly in portions over 10 minutes at 0° C. After being stirred at RT for 3 hours, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid (6.1 g, 82%). 1H NMR (DMSO-d6, 400 MHz) δ 7.74 (s, 1H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1H), 3.66 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.C1COCC1>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(CO)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Reaction time: 1.5 h

Procedure:
To a solution of compound 62.2 (18.5 mmol) in dichloromethane is added molecular sieves (4.0 g) and PDC (39.0 mmol) at room temperature (THF is added to help dissolve the starting material). After 1.5 hours, an additional equivalent of PDC is added and the reaction is stirred for 5.5 hours. The reaction mixture is poured directly onto a silica gel column and is eluted with a gradient of 100% dichloromethane to 100% EtOAc. Fractions containing the desired product are pooled and concentrated to afford (5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (compound 62.3).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][O:8][C@H:9]1[O:13][C@@H:12]([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH:11]=[CH:10]1)([O:5][CH3:6])=[O:4].[Cl:22]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH3:6][O:5][P:3]([CH2:7][O:8][C@H:9]1[O:13][C@@H:12]([N:14]2[CH:21]=[C:20]([Cl:22])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH:11]=[CH:10]1)([O:2][CH3:1])=[O:4]
Reactant: COP(=O)(CO[C@@H]1C=C[C@H](n2ccc(=O)[nH]c2=O)O1)OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: COP(=O)(CO[C@@H]1C=C[C@H](n2cc(Cl)c(=O)[nH]c2=O)O1)OC
Yield: 85.1 %

Procedure:
To a solution of the product of Example 57 (400 mg, 1.3 mmol) in pyridine (15 mL) was added N-chlorosuccinimide (200 mg, 1.5 mmol) and the solution was heated at 90°-95° C. for 30 min under nitrogen. All volatiles were removed in vacuo and the oily residue was chromatographed on silica gel using CH2Cl2 /3% MeOH as eluent to give the product (390 mg, 87%) as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:24]2[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[N:34]([C@@H:37]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C:38]([O:40][CH3:41])=[O:39])=[C:35]=[O:36]>>[CH3:41][O:40][C:38](=[O:39])[CH:37]([NH:34][C:35]([N:14]1[CH2:15][CH2:16][C:11]2([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([CH:24]3[CH2:26][CH2:25]3)[CH2:10]2)[CH2:12][CH2:13]1)=[O:36])[CH:42]([CH3:45])[CH2:43][CH3:44]
Reactant: CC[C@H](C)[C@H](N=C=O)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1CC1)C2c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(NC(=O)N1CCC2(CC1)CN(C1CC1)C2c1ccc(Cl)cc1)C(=O)OC

Procedure:
Treat the compound from Example 2 with TFA according to the procedure of step D in Example 1 and treat the resultant product from this reaction with (2S,3S)-2-isocyanato-3-methylvaleric acid, methyl ester according to the procedure Example 1 step E to give the title compound which is characterized by LCMS. (MWT 448).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18]O)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2.S(Cl)(Cl)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2
Reactant: C1CCNC1
Reactant: OCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CN3CCCC3)c[nH]c1=S)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A solution of (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-hydroxymethyl-1,3-dihydroimidazole-2-thione (140 mg, 0.47 mmol), prepared as in Example 18, in 20 mL of THP and 1 drop of DMF was cooled to between 0° and 5° C. and thionyl chloride (13.7M, 109 μL, 1.49 mmol) was added drop-wise under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 hours, under reflux for 0.5 hours and again at room temperature for 0.5 hours. The mixture then was cooled to between 0° and 5° C. and pyrrolidine (12.0M, 818 μL, 9.8 mmol) was added drop-wise. The mixture was stirred under reflux for 1.5 hours. The solvents were removed by evaporation and the residue was diluted with water. Ethyl acetate was added to the dilution and the mixture was adjusted to pH 7. The ethyl acetate layer was dried and concentrated by evaporation. Purification of the residue by column chromatography gave (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrrolidin-1-ylmethyl)-imidazole-2-thione (100 mg, 0.29 mmol). [α]D25 =-10.96° (c=1.3, DMSO).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9](OCC)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(OC)c(OCc2c(C)cccc2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1OCc1c(C)cccc1C
Reaction time: 4 h

Procedure:
To a solution of Ethyl 3-(2,6-dimethylbenzyloxy)-4-methoxybenzoate (Step B, 6.04 g, 19.23 mmol) in dry THF (30 ml) was added drop wise LiAlH4 (1M in THF, 0.803 g, 21.16 mmol) at 0° C. under argon. The reaction mixture was stirred for 4 hours or until all the starting material is consumed, then quenched slowly with 1N HCl, EtOAc (20 ml) was added to the reaction mixture. The reaction mixture was filtered and precipitate was washed with EtOAc (25 ml×2). The combined organic layer was washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.