Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[N:18]([CH3:22])[CH3:17])=[CH:4][C:3]=1[CH3:9]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)N(C)C)ccc1Br
Yield: 36.2 %

Procedure:
4-Bromo-3-methylaniline (5.00 g, 27 mmol), triethylamine (3.9 ml, 28 mmol), 4-(dimethylamino)pyridine (0.5 g, 4 mmol) and dimethylcarbamyl chloride (2.6 ml, 28 mmol) were mixed in dichloromethane (100 ml), and left to stand for 2 weeks. The solution was then washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated to give a solid. This was triturated with ether, and the solid was filtered off and dried, affording the title compound (2.51 g, 36%) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[C:8]([C:12]3[N:13]=[C:14]4[C:20]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]4=[N:16][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:3]1.[ClH:35]>CO>[Cl:35][CH2:3][CH:2]([OH:1])[CH2:5][NH:4][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[C:20]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CC(O)C4)c3)nc12
Reactant: Cl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(NCC(O)CCl)c3)nc12
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 1-[2-[3-(3-hydroxy-azetidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (36 mg, 0.075 mmol), in MeOH (1 ml), was treated with 18.5% HCl aq (1.75 ml). The reaction mixture was capped and heated to 90° C. for 1.5 hours. The reaction mixture was concentrated to dryness, and the resulting residue was taken up in 10 ml of EtOAc and 5 ml of sat. NaHCO3 aq. The reaction mixture was allowed to stir for 15 minutes and then extracted into EtOAc. The organic layers were collected, dried over MgSO4, filtered, concentrated. Silica gel chromatography using 0-10% MeOH in EtOAc as eluant gave 10 mg (35%) of 1-{2-[3-(3-chloro-2-hydroxy-propylamino)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a yellow solid. M+H=387.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7](COC(=O)C(C)(C)C)[C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[CH2:22][N:23]([C:27]1[CH:46]=[CH:45][C:30]([C:31](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:32])=[CH:29][CH:28]=1)[CH2:24][C:25]#[CH:26].[NH2:47][CH:48]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-:59])=[O:58])[CH:52]=1)[CH2:49][OH:50]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[CH2:22][N:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:47][CH:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-:59])=[O:58])[CH:52]=2)[CH2:49][OH:50])=[O:32])=[CH:45][CH:46]=1)[CH2:24][C:25]#[CH:26]
Reactant: NC(CO)c1cccc([N+](=O)[O-])c1
Reactant: C#CCN(Cc1cc2c(=O)n(COC(=O)C(C)(C)C)c(C)nc2cc1Br)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Product: C#CCN(Cc1cc2c(=O)[nH]c(C)nc2cc1Br)c1ccc(C(=O)NC(CO)c2cccc([N+](=O)[O-])c2)cc1
Yield: 61 %

Procedure:
Using an analogous procedure to that described in Example 19, pentafluorophenyl p-[N-(7-bromo-2-methyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoate was reacted with 2-amino-2-(3-nitrophenyl)ethanol and the pivaloyloxymethyl protecting group was removed from the resultant product to give p-[N-(7-bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-[2-hydroxy-1-(3-nitrophenyl)ethyl]benzamide (containing 0.25 equivalents of water) in 61% yield, m.p. 221°-232° C.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl-].[Mg+2].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].Cl>ClCCl.N1C=CC=CC=1>[C:2]([CH:3]([C:15](=[O:17])[CH3:16])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:1])[CH3:11]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(C(C)=O)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
34.2 ml (0.21 mol) of tert-butyl 3-oxobutanoate were dissolved in 300 ml of dichloromethane, and 20 g (0.21 mol, 1.0 eq.) of anhydrous magnesium chloride were added. At 0° C., 33.9 ml (0.42 mol, 2.0 eq.) of dry pyridine were added to the suspension, which was stirred vigorously. After 15 minutes, 14.3 ml (0.21 mol, 1.0 eq.) of acetyl chloride were added dropwise, and the mixture was stirred at RT for 1 hour. At 0° C., excess pyridine was neutralized with dilute hydrochloric acid (37 ml of conc. hydrochloric acid and 100 ml of water), and the organic phase was separated off. The aqueous phase was extracted with MTBE (3×100 ml), and the combined organic phases were washed with saturated NaCl solution and dried over MgSO4. Removal of the solvent gave 41.2 g (0.206 mol, 98%) of tert-butyl 2-acetyl-3-oxobutanoate in the form of a pale yellow oil.
Reaction SMILES: [CH:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16](C4C=CC=CC=4OC)[C:10]=3[S:9](=[O:26])(=[O:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>[Pd]>[CH:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=4)[C:10]=3[S:9](=[O:26])(=[O:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccccc1-c1cccc2c1S(=O)(=O)NC(C1CCCCC1)N2
Agent: [Pd]
Product: COc1cccc(-c2cccc3c2S(=O)(=O)NC(C2CCCCC2)N3)c1

Procedure:
Synthesis as for compound 80 (using 3-methoxyphenylboronic acid for the Pd-cat. cross coupling). M.p. 108–115° C.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10](O[C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[NH2:15][NH2:16].Cl>C(O)(C)C>[OH:14][C:13]1[C:3]2[C:4](=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:1][CH:2]=2)[C:10]([OH:11])=[N:16][N:15]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NN
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1ccc2c(O)nnc(O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of 1,2,4 benzenetricarboxylic anhydride (5 g, 0.026 mol) and anhydrous hydrazine (1.67 g, 0.052 mol) in isopropyl alcohol (50 mL) was refluxed for 5 hours. The resulting mixture was neutralized with concentrated HCl and stirred at room temperature for an additional 1 hour. The mixture was filtered and the white residue washed with isopropyl alcohol to provide 1,4-dihydroxy-phthalazine-6-carboxylic acid (5.1 g, 95%) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:8](=[O:9])[N:7]2[CH2:10][C@H:3]1[CH2:4][CH2:5][C@H:6]2[C:11]([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:12].[S:28](=[O:31])(=[O:30])=[O:29].N1C=CC=CC=1>N1C=CC=CC=1>[O:9]=[C:8]1[N:7]2[CH2:10][C@@H:3]([CH2:4][CH2:5][C@H:6]2[C:11]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:12])[N:2]1[O:1][S:28]([OH:31])(=[O:30])=[O:29]
Reactant: O=S(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)CC1
Reaction time: 8 h

Procedure:
To a solution of the product of Step 2 (50 mg, 0.13 mmol) in dry pyridine (1 mL) was added pyridine sulfur trioxide (104 mg, 0.652 mmol) at room temperature under nitrogen. The reaction mixture was stirred overnight then filtered (collected solid was washed well with dichloromethane). The filtrate was concentrated under vacuum to afford the title compound which was used without purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:21]=1)([O-:3])=[O:2].[OH:22]O>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:22])[C:12]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:21]=1)([O-:3])=[O:2]
Reactant: OO
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccc([N+](=O)[O-])cc1C=C2

Procedure:
400 Mg. 8-nitrodibenzo[b,f]thiepin-3-carboxylic acid is stirred for 24 hours in 200 cc. acetic acid and 1.5 cc. 30% hydrogen peroxide. The product is filtered, washed with water and dried to yield 315 mg. (74%) of pure product, m.p. 278°-281° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:14]([OH:17])(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][C:4]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Biphenyl (46.3 g, 0.3 mol) was dissolved in 500 ml of chloroform. The solution was cooled in an ice/water bath. Chlorosulfonic acid (19.9 ml, 1 eq) was added dropwise over 30 min. The ice/water bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solid was washed with CHCl3 to provide 41.2 g of biphenyl-4-sulfonic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[S:25]([CH2:32][C:33](Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:33]2[CH2:32][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CSc1ccccc1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(CSc2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) was added thiophenoxyacetyl chloride (102 mg, 0.545 mmol). The mixture was stirred at room temperature for 3 h, then irradiated (uwave) at 90° C. for 15 min. The mixture was quenched with methanol, concentrated, and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenylthio)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (20 mg, 15%); LC/MS: MS (ES+) m/e 499 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 3.52-3.59 (m, 4H), 3.62-3.73 (m, 4H), 4.18 (s, 2H), 5.59 (s, 2H), 6.52 (d, J=7.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.21-7.42 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[N:34]1([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidine. ES-MS m/e (%): 426 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[C:26]([O:30][C:31](=[O:32])[NH:33][C@H:34]([CH:38]([CH3:39])[CH3:40])[C:35]([NH:23][NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]1[CH:16]=[N:17][C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[N:14]1)=[O:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.05 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.038 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.16 mL, 2 eq.) was added dropwise followed by DIPEA (0.095 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (R,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.017 g, yield: 26%). In a 10 mL round-bottom flask, (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.2 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.02 g), which was triturated with petroleum ether and dried under reduced pressure to yield (R,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.007 g, yield: 35%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:19](=[O:20])[O:21][CH2:22][CH3:23])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liter of dichloromethane was added 4.7 ml of ethyl chloroformate and 8.9 ml of diisopropylethylamine. The mixture was stirred for 3 hours at room temperature, concentrated in vacuo to a volume of 500 ml, filtered and the solid washed with 200 ml of dichloromethane to give a tan powder, 11.4 g, mp 232°-235° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][O:16][C:14]([C:8]1([CH2:7][C:6]([OH:18])=[O:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:15]
Reactant: COC(=O)C1(CC(=O)OC(C)(C)C)CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CC(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
To a solution of methyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.1 g, 4.26 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL) and the resulting solution was stirred at rt for 5 h. The mixture was concentrated under reduced pressure to afford [4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (900 mg, 94%), which was used in the next step without further purification. LC-MS ret. time 0.93 min, m/z 202.9 (MH+); 1H NMR (300 MHz, DMSO-d6), 1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.68 (s, 2H), 3.62-3.71 (m, 2H), 3.72 (s, 3H), 3.79-3.86 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[CH2:29][CH2:28][N:27]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:14])[CH2:26][CH2:25]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C(=O)c2cnoc2-c2ccc(C)cc2)CC1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 4-(2-methoxyphenyl)piperidine (9.5 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H24N2O3: 376.1787, found 376.1790.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1ccc2ncc(Cl)n2n1
Product: Clc1cnc2ccc(NCc3ccccn3)nn12
Yield: 27 %

Procedure:
Prepared from 3,6-dichloroimidazo[1,2-b]pyridazine and 2-(aminomethyl)pyridine according to general procedure 3 providing the title compound (56 mg, 27%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.50 (d, J=4.9 Hz, 1H), 7.79 (dt, J=1.7, 9.4, Hz, 1H), 7.61 (d, J=9.7 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J=5.3, 6.5 Hz, 1H), 6.81 (d, J=9.7 Hz, 1H), 4.68 (s, 1H); 13C NMR (75 MHz, CD3OD) δ 159.7, 155.5, 149.7, 138.7, 127.9, 126.1, 123.7, 123.6, 115.7, 114.6 (one carbon overlapping with solvent); HPLC tR=8.8 min (Synergi), 98.8 %; ES-MS: (M+H)=260 m/z.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][CH:13]=1)(=[O:5])[CH3:4]>CC(O)=O>[C:3]([O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][C:13]=1[Br:1])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc(CCOC(C)=O)cs1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCOC(C)=O)c(Br)s1
Yield: 75.1 %

Procedure:
Br2 (0.46 g, 2.9 mmol) was dropped into 2-(2-acetamidothiazol-4-yl)ethyl acetate (0.60 g, 2.6 mmol) in 20 mL AcOH. The reaction was instantaneous. Acetic acid was evaporated from the reaction and saturated sodium bicarbonate was slowly added to the residue. The resulting mixture was extracted twice with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. 2-(2-Acetamido-5-bromothiazol-4-yl)ethyl acetate (0.6 g, yield=74.3%) was obtained as a white solid. LCMS (API-ES) m/z (%): 309.0 (100%, M++H).
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: [H][H]
Reactant: O=C1CCN(CCCN(Cc2ccccc2)Cc2ccccc2)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: NCCCN1CCC(=O)NC1=O
Yield: 90 %

Procedure:
A mixture of intermediate (53) (0.010 mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator. The residue was dried over the weekend under a gentle stream of nitrogen. Toluene was added and azeotroped on the rotary evaporator. The residue was stirred in DCM (50 ml). NaOCH3 (0.504 g) was added and the reaction mixture was stirred for one hour under nitrogen. More methanol (25 ml) was added and the mixture was stirred for 30 minutes. The precipitate was filtered off and the filtrate was evaporated in vacuo, yielding 1.54 g of 1-(3-aminopropyl)dihydro-2,4(1H,3H)-pyrimidinedione (intermediate 54).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:22][CH:23]=4)[N:15]=[CH:16][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:14]3[N:15]=[CH:16][C:11]4[S:10][CH:9]=[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:33]([CH:30]6[CH2:32][CH2:31]6)=[O:34])[CH:7]=[CH:6][CH:5]=5)[C:12]=4[N:13]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26]1
Reactant: Nc1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1)C1CC1
Yield: 91.5 %

Procedure:
N-(3-(2-(6-Morpholinopyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)cyclopropanecarboxamide (16 mg, 91% yield) was prepared in the same manner as Step 7 of Example 1 using 7-(3-aminophenyl)-N-(6-morpholino pyridin-3-yl)thieno[3,2-d]pyrimidin-2-amine (15 mg, 0.037 mmol) and cyclopropanecarbonyl chloride (5 mg, 0.044 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[NH:30][C:29]2=[O:39])=[C:24]([F:40])[C:23]=1[CH:41]=[N:42][O:43][CH3:44]>C(OCC)(=O)C>[NH2:7][N:30]1[C:31]([C:35]([F:36])([F:37])[F:38])=[CH:32][C:33](=[O:34])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([CH:41]=[N:42][O:43][CH3:44])[C:24]=2[F:40])[C:29]1=[O:39]
Reactant: CON=Cc1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1F
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CON=Cc1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c1F
Temperature: 50 °C
Reaction time: 10 h

Procedure:
Potassium carbonate (132 g) and 2,4-dinitrophenoxyamine (104 g) were added to a solution of 3-(4-chloro-2-fluoro-3-methoxyiminomethylphenyl)-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine (175 g) in 1 l of ethyl acetate, after which the reaction mixture was stirred for 10 hours at 50° C. and then cooled. The resulting solid portion was separated off and washed with diisopropyl ether. After combining the clear reaction solution and the ether phase, the mixture was washed once with water, dried over sodium sulfate and concentrated. The crude product was recrystallized from 200 ml of diisopropyl ether. Yield: 150 g.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[C:12](=[NH:13])[O:18][NH:17][C:14]3=[NH:15])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: N#CC(C#N)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: c1ccncc1
Product: N=C1NOC(=N)C1C1CCC2(CC1)OCCO2
Temperature: 100 °C

Procedure:
A solution of 2-(1,4-dioxa-spiro[4.5]dec-8-yl)-malononitrile (as prepared in the previous step, 0.207 g, 1.00 mmol) and hydroxylamine hydrochloride (Aldrich, 0.107 g, 1.54 mmol) in anhydrous pyridine (5 mL) were heated to 100° C. under a reflux condenser for 18 h. After cooling to ambient temperature and evaporation of the solvent in vacuo, the crude product was purified by thin layer chromatography on silica gel (10% methanol in dichloromethane) giving the title compound as an orange solid.