Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1F>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:11][CH:8]1[CH2:7][NH:6][CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[S:10][C:9]1=2
Reactant: Cc1cc2c(s1)C(O)CNC2
Reactant: Fc1ccccc1Br
Product: Cc1cc2c(s1)C(Oc1ccccc1Br)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: NC[C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CC(O)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:45][N:46]([CH:48]=O)[CH3:47]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:48][N:46]([CH3:45])[CH3:47])=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN(C)C=O
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (80 mg) was dissolved in DMF (5 mL) and treated with AcOH (10 □L), paraformaldehyde (48 mg), and sodium triacetoxyborohydride (125 mg) for 16 h. The reaction mixture was concentrated, and the crude residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, dried (MgSO4) and concentrated. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide. MS (Q1) 365.0 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:17]([O-])=O)[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:17][C:7]1[C:8]([O:15][CH3:16])=[C:9]([CH:14]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(C)(C)C)cc(N)c1OC
Reaction time: 12 h

Procedure:
2.7 g methyl 5-tert-butyl-2-methoxy-3-nitro-benzoate are dissolved in 120 ml of methanol, combined with 270 mg of 10% palladium on charcoal and hydrogenated for 12 hours at ambient temperature and 4 bar hydrogen pressure. Then the catalyst is filtered off, the solvents are eliminated in vacuo and the residue thus obtained is further reacted directly.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH3:12]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[NH:12])([O-:3])=[O:2]
Reactant: N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CO
Product: N=Cc1ccccc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
To a solution of 15.1 g (0.1 mole) of 2-nitro-benzaldehyde and 40 ml of methanol a methanolic solution of 1.7 g (0.1 mole) of ammonia is added dropwise under stirring. The reaction mixture is stirred at room temperature for 20 hours, then cooled, the precipitated product is filtered, washed with methanol and dried. Thus 11.3 g of trimeric 2-nitro-benzaldehyde-imine are obtained, yield 75.3%, m.p.: 117°-119° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[C:16](Cl)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
Triethylamine (0.65 ml, 4.65 mmol) was added to a solution of 200 mg (1.16 mmol) of 4-bromoaniline in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 5 min. Acetyl chloride (0.165 ml, 2.33 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution Was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 249 mg (yield 99%) of the title compound.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][S:29][CH2:30][CH2:31][NH2:32]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:32][CH2:31][CH2:30][S:29][CH3:28]
Reactant: CSCCN
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NCCSC)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 76 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (300 mg, 0.81 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 2-(methylthio) ethylamine instead of thiomorpholine to the title compound (273 mg, 76%) which was obtained as an off-white solid. MS: m/e=441.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:12][C:13]1[C:14]([C:34]2[CH:35]=[N:36][C:37](F)=[CH:38][CH:39]=2)=[CH:15][C:16]2[C:17]3[N:25]([C@H:26]4[CH2:29][C@@H:28]([O:30][CH3:31])[CH2:27]4)[C:24](=[O:32])[N:23]([CH3:33])[C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1>C1COCC1>[F:12][C:13]1[C:14]([C:34]2[CH:35]=[N:36][C:37]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:38][CH:39]=2)=[CH:15][C:16]2[C:17]3[N:25]([C@H:26]4[CH2:29][C@@H:28]([O:30][CH3:31])[CH2:27]4)[C:24](=[O:32])[N:23]([CH3:33])[C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1
Reactant: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4cc(F)c(-c5ccc(F)nc5)cc4c32)C1
Reactant: OCCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4cc(F)c(-c5ccc(OCCCN6CCCC6)nc5)cc4c32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(Pyrrolidin-1-yl)propan-1-ol (46.9 mg, 0.36 mmol) was added to sodium hydride (29.1 mg, 1.21 mmol) in THF (4 mL) at ambient temperature over a period of 20 minutes. 7-Fluoro-8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one (120 mg, 0.30 mmol) was added. The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water and the crude product purified by FCC, elution gradient 0 to 5% MeOH in DCM. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractious containing the desired compound were evaporated to dryness to afford the desired material (60.0 mg, 38.7%) as a off-white solid. NMR Spectrum: 1H NMR (300 MHz, MeOD) δ 1.90-2.00 (4H, m), 2.10-2.20 (2H, m), 2.81-3.00 (8H, m), 3.04-3.17 (2H, m), 3.28 (3H, s), 3.6 (3H, s), 3.85-3.96 (1H, m), 4.48 (2H, t), 5.00-5.13 (1H, m), 6.88 (1H, d), 7.82 (1H, d), 8.05 (1H, d), 8.43-8.50 (2H, m), 8.83 (1H, s) Mass Spectrum: m/z (ES+)[M+H]+=506.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[N:21][CH:22]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][O-].[Na+].CI.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([C:17]3[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH3:24])[CH:22]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Oc1ccc(-n2c(-c3cccc(F)c3)nc3cccnc32)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(-n2c(-c3cccc(F)c3)nc3cccnc32)ccc1=O
Yield: 61.2 %

Procedure:
A solution of 250 mg of 5-[2-(3-fluorophenyl)-3H-imidazo [4,5-b]pyridin-3-yl]-2-pyridinol, 177 mg of sodium methoxide and 306 μL methyl iodide in a mixture (10 mL) of methanol and tetrahydrofuran in a ratio of 1/1 was stirred at room temperature for 1 day. Ethyl acetate and a saturated aqueous ammonium chloride solution were added thereto and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed once with brine and dried over magnesium sulfate followed by distilling the solvent away under reduced pressure, to give crude crystals. The resulting crude crystals were collected by filtration with diethyl ether, to give 160 mg of the title compound as brown crystals (61% y.).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[N:9]=[C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])[O:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:7][N:6]=[C:5]([CH2:4][O:3][CH3:2])[N:9]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(COC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (148 mg; compound B40) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C10) and HBTU (126 mg) in DCM (8 ml) in the presence of DIPEA (155 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/1.5 to 0/1 (v/v)] as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10](CO)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([S:24]([CH3:23])(=[O:26])=[O:25])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC12CC1CN(Cc1ccccc1)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C12CC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyl-1-hydroxymethyl-3-azabicyclo[3.1.0]hexane in ethyl acetate were added triethylamine (2.15 gm, 0.02125 mole) and methane sulphonylchloride (1.947 gm, 0.017 mole). The mixture was stirred at 0° C. for 1 hour. The reaction was quenched by the addition of saturated NaHCO3. The separated organic layer was washed with water, brine, dried and evaporated to give the crude product, which was used as such for further reaction.
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O=P(Cl)(Cl)[Cl:23]>>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[Cl:23])=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A 20 mL microwave vial was charged with 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester (1.711 g, 5.0 mmol) and POCl3 (phosphoryl chloride, 10.0 mL, 16.8 g, 109 mmol). The vial was capped and the mixture was microwave heated stepwise up to 180° C. (watching the pressure) over 5 min and then kept at 180° C. for 30 min Excess POCl3 was evaporated and the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL). The aqueous layer was extracted with CH2Cl2 (2×40 mL). The organic layers were combined, dried with Na2CO3 and evaporated. The residue was purified on column (silica gel, CH2Cl2 as eluent). Pure fractions were pooled, evaporated and the residue dried under vacuum to give 0.821 g (52%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. MS (ESI+) m/z 314, 316 (MH+).
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][CH2:25][CH2:26][N:27]=2)=[CH:19][CH:18]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:28]>C(O)(=O)C>[ClH:28].[ClH:28].[NH2:4][CH:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:27][CH2:26][CH2:25][N:24]=2)=[CH:21][CH:22]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccc(C2=NCCN2)cc1)(NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: NC(Cc1ccc(C2=NCCN2)cc1)C(=O)O

Procedure:
To 2-acetylamino-2-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl]-malonic acid, diethyl ester (3.0 g, 7.3 mmol) was added glacial acetic acid (50 mL) and 3N HCl (100 mL). The solution was heated to reflux for 3 hours, cooled and concentrated to a white solid which was recrystallized from methanol/ether (2.0 g, mp 270-272° C. dec.).
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](=[N+](C)C)[N:17](C)[CH3:18])C2C=CC=CC=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:46]=[N:45][C:44]([C:47](O)=[O:48])=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:16][N:17]([CH3:18])[C:47]([C:44]1[N:45]=[N:46][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:42][CH:43]=1)=[O:48]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU, 110 mg) was added to a solution of 6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylic acid (140 mg) and ethyl-diisopropyl-amine (60 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 20 min, before dimethylamine (2 mol/L in tetrahydrofuran, 300 μL) was added. After stirring the solution at room temperature for another 2 h, the solution was concentrated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 50 mg (34% of theory); Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.NC1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[NH:17][N:16]=1>C(O)(=O)C>[CH2:23]([O:22][C:20]([C:19]1[C:18]([CH3:25])=[N:17][N:16]2[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:13]=12)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1c(N)n[nH]c1C
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 9.09 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 2.54 g. of ethyl 3-amino-5-methylpyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 16 hours. The solvent is removed and the residue in dichloromethane is washed with saturated sodium bicarbonate solution. The dichloromethane solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 3.1 g. of the product of the example, m.p. 145°-146° C.
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5]1>>[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]([O-:9])=[O:1].[Na+:2]
Reactant: CN1CCCC1=O
Reactant: [OH-]
Agent: [Na+]
Product: CNCCCC(=O)[O-]
Reaction time: 5 h

Procedure:
In run 2, the aqueous NaOH and 12.5 gallons of NMP were charged to a separate stirred vessel (vessel 1) and contacted at 121° C. for 5 hours to form sodium N-methyl-4-aminobutyrate. The aqueous NaSH was then charged to the stirred vessel and the contents held for 30 minutes at 121° C. to form the polymerizable complex. The liquid mixture was then transferred to the polymerization reactor containing 6 gallons of NMP and 23 lb (0.28 lb-mole) of NaOAc through a Cuno Inc., Process Filtration Products 316 SS porous metal cartridge filter having nominal openings of five microns to remove metal impurities. The stirred vessel was then flushed with 17.7 gallons of NMP through the filter to the polymerization reactor.
Reaction SMILES: [C:1]1([C:7]([Mg]Br)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:15]1[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)[O:21][C:19]=2[N:20]=1)(=O)=O.[Cl-].[Li+].C(OCC)(=O)C>O1CCCC1>[C:1]1([C:7]([C:15]2[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)[O:21][C:19]=3[N:20]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Reactant: C=C([Mg]Br)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1nc(OCCC)c2nc(-c3cccc(C)c3)oc2n1
Reaction time: 1 h

Procedure:
298 mg of 1-phenyl-vinylmagnesium bromide were added to a solution of 500 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine (example 5, step (f)) and 61 mg of lithium chloride in 20 ml of tetrahydrofuran. The reaction mixture was stirred for 1 h. Then 100 ml of ethyl acetate were added. The solution was extracted with 1 N hydrochloric acid, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC21CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC21CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.7 %

Procedure:
To a solution of 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyrimidine (Intermediate 161, 255 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (234 mg, 4.25 mmol) and then ammonium chloride (227 mg, 4.25 mmol) were added and the reaction mixture was stirred for 48 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 4:6 as eluents affording the title compound (52 mg) as a light orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].Cl.[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])[C:23]([CH3:31])=[CH:22][C:21]=3[F:32])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([NH:8][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:10]([O:33][CH3:34])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)c(OC)cc23)c(F)cc1C
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc2ncnc(Nc3cc(OC(=O)OC)c(C)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
Methoxyacetyl chloride (62 μl, 0.68 mmol) was added dropwise to a solution of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (215 mg, 0.52 mmol) in methylene chloride (5 ml) and pyridine (l.5 ml) at 0° C. and the mixture stirred for 2 hours at 0° C. Further methoxyacetyl chloride (14 μl, 0.15 mmol) was added and the mixture stirred for 20 minutes at 0° C. The reaction mixture was partitioned between ethyl acetate and water and the aqueous layer adjusted to pH9 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60138/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-methoxyacetamidoquinazoline (1 75 mg, 75%) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[N:17]=3)[N:14]=2)O1.[Cl:23][C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][C:29]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[NH4+].[Cl-].O>[Cl:23][C:24]1[N:25]=[N:26][C:27]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[N:17]=3)[N:14]=2)=[CH:28][C:29]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)(=[O:32])=[O:33]
Reactant: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: O=S(=O)(Nc1cc(Cl)nnc1Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cn2nc(-c3cc(NS(=O)(=O)c4ccc(F)cc4)c(Cl)nn3)ccc2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
To a 50 mL round-bottomed flask was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (100 mg, 331 μmol), N-(3,6-dichloropyridazin-4-yl)-4-fluorobenzenesulfonamide (107 mg, 331 μmol), cesium carbonate (216 mg, 662 μmol), 662 μmol), dioxane (3 mL), water (0.5 mL). The reaction mixture was stirred at 90° C. for 2 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with satd NH4Cl (2 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with satd NaCl (2 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography (15% MeOH/CH2Cl2) to give N-(6-(6-chloro-5-(4-fluorophenylsulfonamido)pyridazin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (21 mg, 14% yield). MS (ESI positive ion) m/z: 461 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.13 (s, 3H) 7.36 (t, J=8.70 Hz, 3H) 7.53 (d, J=8.18 Hz, 1H) 7.82-8.00 (m, J=6.14 Hz, 2H) 8.05 (d, J=9.35 Hz, 1H) 8.29 (s, 1H)