Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.I.CS[C:11]1[NH:12][CH2:13][CH2:14][N:15]=1.[NH2:16][C:17]1[C:38]([Cl:39])=[CH:37][C:20]([C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:27][CH2:26]2)=[O:22])=[C:19]([O:40][CH3:41])[CH:18]=1.[OH-].[Na+]>CO>[NH2:16][C:17]1[C:38]([Cl:39])=[CH:37][C:20]([C:21]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[CH2:29][CH2:30]2)=[O:22])=[C:19]([O:40][CH3:41])[CH:18]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: CSC1=NCCN1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC2=NCCN2)CC1
Yield: 47.5 %

Procedure:
Triethylamine (0.59 g) and 2-methylthio-2-imidazoline hydroiodide (1.4 g) were added to a solution of 4-amino-N-((1-(5-aminopentyl)-piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.5 g) in methanol (20 ml), and the mixture was stirred at refluxing temperature for 4 hr. A 10% aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 0.84 g of 4-amino-5-chloro-N-((1-(5-(imidazolin-2-ylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: COCCCN
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: COCCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 3-methoxypropylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 160-175° C.; LC-MS: 444 (MH+); HPLC RT: 3.92 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of 4-amino-6-(4-nitrophenoxy)pyrimidine (560 mg, 2.41 mmol) and DIPEA (630 μL, 3.62 mmol) in DCM (15 mL) under nitrogen at 0° C. was added 2-methoxyacetyl chloride (330 μL, 3.62 mmol) dropwise over 5 min. The mixture was warmed to RT for 1 hr and the reaction was quenched by addition of a 1% solution of NH3 in MeOH (10 mL) and then evaporated in vacuo. The residue was partitioned between DCM (50 mL) and water (25 mL) and the organic layer was separated and washed with brine (25 mL) and was then dried (MgSO4). Evaporation of the volatiles in vacuo gave the title compound as a beige solid (730 mg, 97%): Rt 1.87 min (Method 2); m/z 305 (M−H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([CH2:42]O)[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(Cl)Cl>[Cl:30][C:27]1[S:26][C:25]([S:22]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:44])[CH:37]=3)[N:12]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: CN(C)CCOc1cccc(CO)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(OCCN(C)C)c1
Temperature: 65 °C
Yield: 70 %

Procedure:
A mixture of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (150 mg, 0.28 mmol), (3-{[2-(dimethylamino)ethyl]oxy}phenyl)methanol (73 mg, 0.37 mmol), triphenylphosphine (113 mg, 0.43 mmol) and di-tert-butyl azodicarboxylate (132 mg, 0.57 mmol) in THF (15 mL) was heated to 65° C. O/N. The mixture was evaporated under reduced pressure, the residue was dissolved in MeOH, and then loaded on a SCX-2 ion-exchange cartridge (20 g) and eluted with sequential solvents methanol, 2M ammonia in methanol. The appropriate fractions were combined and evaporated in vacuo to give the crude product. This was dissolved in DCM and purified by chromatography on silica (20 g cartridge) on Flashmaster using a 0-15% methanol (containing 1% Et3N)-dichloromethane over 20 min. The appropriate fraction was evaporated in vacuo to give the title product (140 mg, 70%) as a white foam. LCMS (System F) RT=1.27 min, ES+ve m/z 701/703 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.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:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[CH:35][C:34]([CH3:38])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(Br)cc21
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(C)cc21
Temperature: 25 °C
Yield: 43.8 %

Procedure:
Purge a mixture of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.400 g, 0.672 mmol), trimethylboroxine (0.084 g, 0.672 mmol), and potassium carbonate (0.279 g, 2.02 mmol) in anhydrous tetrahydrofuran (5 mL) with nitrogen, then add tetrakis(triphenylphosphine)palladium (0) (0.077 g, 0.067 mmol) and stir at reflux for 1 h. Cool the mixture to room temperature and dilute with ethyl acetate (30 mL) and wash with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 3:1), to provide the title compound as a white solid (0.156 g, 44%): ESI MS 531 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:26][CH3:27])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[C:11]2[NH:17][C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=1[Cl:25].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[NH:17][C:11]1[C:10]2[C:15](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:7]([O:26][CH3:27])=[CH:8][CH:9]=2)[NH:14][C:13](=[O:16])[CH:12]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCN1CCOCC1

Procedure:
The title compound was prepared from 8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one and morpholine following the procedure outlined in Example 18, Step 2. 1H NMR (400 MHz, DMSO-d6, HCl salt): δ 10.58 (br, 1H), 10.44 (s, 1H), 8.94 (s, 1H), 8.77 (s, 2H), 7.93 (d, 1H), 7.09 (d, 1H), 4.82 (s, 1H), 4.02 (t, 2H), 3.98 (m, 2H), 3.93 (s, 3H), 3.76 (t, 2H), 3.46 (d, 2H), 3.33 (m, 2H), 3.10 (m, 2H), 2.22 (m, 2H); MS (ESI): 479.3.
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([S:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:14])[CH2:11]3)[C:8]=2[C:15]([O:17]CC2C=CC([N+]([O-])=O)=CC=2)=[O:16])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:34]>O1CCOCC1.O.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:14])[CH2:11]3)[C:8]=2[C:15]([O-:17])=[O:16])=[CH:28][CH:29]=1.[Na+:34]
Reactant: Cc1ccc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(SC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1

Procedure:
A mixture of a solution of 70 mg of 4-nitrobenzyl 3-(4-methylthiophenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 13 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 35° for 60 minutes.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH3:20])[CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[S:35]([CH3:34])(=[O:37])=[O:36])[CH3:20])=[CH:9][C:7]=2[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrrolidin-2-ylmethyl-amine hydrochloride salt (380 mg) in dichloromethane (10 mL) was added triethylamine (0.30 mL) and methane sulfonyl chloride (71 μL). The mixture was stirred at room temperature for 2 h and then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organics were washed with brine (20 mL), dried, reduced in vacuo and purified by column chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methanesulfonyl-pyrrolidin-2-ylmethyl)-methyl-amine as an off-white solid (124 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:29])[C:25]([OH:28])([CH3:27])[CH3:26])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:29])[C:25]([CH3:27])([OH:28])[CH3:26])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(O)C(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.52 g), ammonium acetate (0.37 g) and acetic acid (4 mL) was stirred at 90° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.28 g, yield 56%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 531 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:28]=2)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1cc(Br)c(C#N)n1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)c(C#N)n1N
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a stirred solution of ethyl 1-amino-4-bromo-5-cyano-1H-pyrrole-2-carboxylate (1.43 g, 5.55 mmol), 4-benzyloxybenzeneboronic acid (3.80 g, 16.7 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) complex with dichloromethane (453 mg, 0.56 mmol) in degassed DME (41 mL) was added aqueous Na2CO3 solution (2 M, 8.3 mL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The reaction was filtered through a pad of Celite® and the filter cake was rinsed well with ethyl acetate. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The organic phase was further washed with water (75 mL), brine, was dried (Na2SO4), and concentrated. The crude material was purified by flash chromatography on silica gel using a gradient of 10 to 20% ethyl acetate in hexanes to afford 1.0 g (50%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.43 (m, 2 H), 7.41-7.25 (m, 6 H), 7.18 (s, 1 H), 7.02-6.97 (m, 1 H), 6.55 (s, 2 H), 5.15 (s, 2 H), 4.31 (q, 2 H), 1.33 (t, 3 H); ES-MS m/z 362.02 [M+H]+, HPLC RT (min) 3.38.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>N1C=CC=CC=1>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:31][CH2:30][CH2:29][O:28][CH3:27])[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Reactant: COCCN
Solvent: c1ccncc1
Product: COCCNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 120 °C
Yield: 47.8 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (0.2 g, 0.444 mmol) and dry pyridine were added into a microwave vial under nitrogen atmosphere. 2-methoxyethylamine (0.193 ml, 2.219 mmol) was added and the mixture was heated with microwaves at 120° C. for 10 h. Afterwards a total of 0.232 ml of 2-methoxyethylamine was added and the mixture was heated for another 10 h. The product was purified by Flash-chromatography. Yield 47.8%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 3.41 (s, 3H), 3.44 (m, 2H), 3.57 (m, 2H), 4.29 (dd, 1H), 4.40 (dd, 1H), 4.54 (m, 1H), 5.39 (t, 1H), 6.62 (d, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 7.68 (dd, 1H), 7.69 (d, 1H), 7.83 (dd, 1H), 7.98 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:11]([C:8]1[C:7](=[O:14])[N:6]2[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:13])[CH2:29][CH3:30]
Reactant: CCCN
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2ccc(C)cn2c1=O
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at -18° C. during 20 minutes. After stirring for 5 minutes, 5.2 (0.088 mol) of propylamine dissolved in 80 ml of chloroform are dropped to the above solution at -18° C. during 60 minutes. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 17.5 g (89.2%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 126°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:23])[O:14][CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:33]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH3:33])[C:18]3=[O:23])[O:14][CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN2CCCNC2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCN(C[C@H]2OCCN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-[(2-oxotetrahydropyrimidin-1(2H)-yl)methyl]-1,4-oxazepane-4-carboxylate (300 mg) in DMF (3 mL) was added sodium hydride (60% in oil, 31 mg), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added dropwise methyl iodide (190 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (180 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][CH2:3][CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1onc2n1C(CCCO)CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1onc2n1C(CCCBr)CCCC2
Reaction time: 2 h

Procedure:
To a solution of the product of Example 11 in methylene chloride at 0° C. is added carbon tetrabromide and triphenylphosphine. The reaction is stirred for 2 hours and the solvent is removed under reduced pressure. The crude product is dissolved in an eluting solvent system and chromatographed to afford the title compound.
Reaction SMILES: CO[C:3](=[NH:18])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1.[N:19]#[C:20][NH2:21]>CO>[C:20]([NH:21][C:3](=[NH:18])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1)#[N:19]
Reactant: COC(=N)CCSCc1cc(CN(C)C)ccn1
Reactant: N#CN
Solvent: CO
Product: CN(C)Cc1ccnc(CSCCC(=N)NC#N)c1
Reaction time: 8 h

Procedure:
Methyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate is added to a methanol solution of cyanamide. After standing overnight N-cyano-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionamidine is obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:33][C:29]1[CH:30]=[N:31][CH:32]=[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:28]=1)=[C:3]([CH3:20])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[N:5]2
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (44.0 mg, 0.130 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.93 (2H, dd, J=4.3, 2.3 Hz), 7.43 (1H, ddd, J=9.5, 2.5, 1.3 Hz), 7.36 (1H, d, J=14.5 Hz), 6.99 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.64 (1H, t, J=2.2 Hz), 4.16 (2H, br. s.), 3.77-3.89 (4H, m), 3.20-3.30 (4H, m), 2.60 (2H, t, J=7.9 Hz), 2.27 (2H, qd, J=7.5, 7.3 Hz), 2.01 (3H, s). Mass Spectrum (ESI) m/e=440.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]1=[O:24].Cl[C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:32][C:31]1[C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([N:16]4[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]4=[O:24])=[C:2]([F:1])[CH:7]=3)=[O:9])[CH2:11][CH2:12]2)=[N:27][CH:28]=[C:29]([Cl:33])[CH:30]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1F
Temperature: 100 °C
Yield: 48.8 %

Procedure:
(R)-3-[2-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (343 mg) described in Preparation Example 94 was dissolve in N,N-dimethylformamide (2 mL), 2,3,5-trichloropyridine (275 mg) and potassium carbonate (562 mg) were added and the mixture was stirred at 100° C. To the reaction mixture was added ethyl acetate under ice-cooling and insoluble materials were filtered off. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (240 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O.C(N(CC)CC)C.CS([Cl:36])(=O)=O>ClCCl>[Cl:36][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH2:5][O:4][CH2:3][C:2]([F:24])([F:23])[F:1]
Reactant: OCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)COCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Temperature: 25 °C

Procedure:
422 mg [4-(2,2,2-Trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol were dissolved in 5 ml dichloromethane and cooled in an ice bath. 247 μl triethylamine were added, followed by the addition of 110 μl methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. 50 ml dichloromethane were added and the reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 509 mg 5-chloromethyl-4-(2,2,2-trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazole as an oil which was used without further purification.