Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CCO>[C:21]([O:20][C:19](=[O:25])[NH:18][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][NH:10][C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:17][CH2:16]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Cl)CC1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a solution of the above 5-chloro-2,4-dichloropyrimidine (73 mg, 0.4 mmol) in EtOH (2 mL) were added tert-butyl trans-4-aminomethylcyclohexylcarbamate (100 mg, 0.44 mmol) and DIPEA (77 μL, 0.44 mmol). The reaction mixture was heated at 40° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The solution was washed with brine. The aqueous layer was re-extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield 148 mg (99%) of {4-[(2,5-dichloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].[Cl-].[Na+]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:11]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of (2-aminoethyl)carbamic acid tert-butyl ester (from Step 6 below) (4.2 g, 26.3 mmol) in methylene chloride (50 mL) was added triethylamine (4.4 mL, 31.4 mmol) and methyl bromoacetate (2.4 mL, 26.3 mmol). The reaction was stirred overnight at room temperature. A saturated aqueous solution of sodium chloride (100 mL) was then added, and the organic layer was separated dried over MgSO4, filtered and concentrated. The residue was taken up in diethyl ether, and a saturated solution of HCl in diethyl ether was added to precipitate the product, which was filtered, and dried. It was recrystallized in ethanol/ethyl acetate, to give a white solid; 1.39 g (20% yield). MS-APCI: M+1=233.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:78][N:79]([CH3:83])[CH2:80][CH2:81][NH2:82]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:82][CH2:81][CH2:80][N:79]([CH3:83])[CH3:78])=[O:28])=[CH:24][C:23]=4[C:31]([F:34])([F:32])[F:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN(C)CCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a mixture of 0.125 g (0.257 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 9 mL of dimethylformamide was added 0.0521 g (0.386 mmole) of 1-hydroxybenzotriazole, 0.146 g (0.385 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.140 g (1.081 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.034 g (0.385 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.1188 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-trifluoromethyl-benzamide (I-208) as a white solid.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[C:18]1([CH2:24][CH2:25][CH2:26]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:4]([CH3:7])([CH2:5][CH3:6])[C:3](=[O:9])[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])=[O:1]
Reactant: OCCCc1ccccc1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OCCCc1ccccc1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (600 mg; 2.49 mmol), 3-phenyl-1-propanol (508 mg; 3.73 mmol), dicyclohexylcarbodiimide (822 mg; 3.98 mmol), camphorsulfonic acid (190 mg; 0.8 mmol) and 4-dimethylaminopyridine (100 mg; 0.8 mmol) in methylene chloride (20 ml) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of Example 1 as a colorless oil. 1H NMR (CDCl3): d 0.84 (t, 3H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H); 2.22 (m, 1H); 2.64 (m, 2H); 3.47 (m, 2H); 4.14 (m, 2H); 4.51 (d, 1H); 7.16 (m, 3H); 7.26 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2Cl.[CH3:17][N:18]([CH3:27])[CH:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[N:24]1[CH2:25][CH2:26][CH:21]([CH:19]([N:18]([CH3:17])[CH3:27])[CH3:20])[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C1CCNCC1)N(C)C
Product: CC(C1CCN(c2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1)N(C)C
Yield: 67.9 %

Procedure:
Following general procedure B, 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (100 mg, 0.311 mmol) was reacted with N,N-dimethyl-1-(piperidin-4-yl)ethanamine (229 mg, 1.00 mmol) to afford the desired product (93 mg, 68%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.11-7.93 (m, 2H), 3.67-3.55 (m, 2H), 3.44 (s, 3H), 3.34 (s, 2H), 2.75-2.62 (m, 1H), 2.46 (s, 6H), 2.07-1.96 (m, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.73-1.53 (m, 2H), 1.15 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[F:16][C:17]([F:30])([F:29])[C:18]1[N:23]=[CH:22][C:21]([O:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1>>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:26](=[O:27])[CH2:25][O:24][C:21]1[CH:22]=[N:23][C:18]([C:17]([F:16])([F:29])[F:30])=[CH:19][CH:20]=1
Reactant: O=C(O)COc1ccc(C(F)(F)F)nc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)COc2ccc(C(F)(F)F)nc2)cc1F
Yield: 12.8 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (270 mg, 1.00 mmol) was reacted with (6-trifluoromethyl-pyridin-3-yloxy)-acetic acid (221 mg) to give N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-(6-trifluoromethyl-pyridin-3-yloxy)-acetamide (54 mg, 88%) after recrystallization from Hex/EtOAc.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][CH:5]([C:8]2[S:22][C:11]3[N:12]=[C:13]([CH3:21])[N:14]=[C:15]([C:16]([O:18]CC)=[O:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:23])[CH2:3][CH2:4][CH:5]([C:8]2[S:22][C:11]3[N:12]=[C:13]([CH3:21])[N:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C(=O)O)c2cc(C3CCC(C)(C)CC3)sc2n1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixture of ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (1.0 g) and EtOH (10 mL) was added a 1 M aqueous NaOH solution (3.9 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added thereto, followed by stirring for 30 minutes. The precipitate was collected by filtration, washed with water and then with hexane, dried by flowing air, and then dried under reduced pressure to obtain 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (900 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CN1CCOCC1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[C:28]([O:27][CH3:26])=[O:35])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1-c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(O)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 4-hydroxy-2-(4-fluorophenyl)benzoic acid (4.5 g; 0.019 mol) in DMF (90 ml) cooled to 0° C. under an argon atmosphere was added in sequence NMM (6.4 ml; 0.058 mol), L-methionine methyl ester hydrochloride (4.0 g; 0.020 mol), EDC (4.47 g; 0.023 mol) and HOBT (2.7 g; 0.020 mol) and the reaction warmed to ambient temperature and stirred for 3 hours. The DMF was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, filtered through PSI filter paper and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography eluting with ethyl acetate/iso-hexane (1:1) gave methyl (2S)-2-[4-hydroxy-2-(4-fluorophenyl)benzoylamino]-4-methylsulfanylbutyrate as a white foam (5.7 g).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([Cl:26])=[CH:10][C:11]([F:25])=[C:12]([N:14]2[C:22](=[O:23])[C:17]3=[CH:18][CH2:19][CH2:20][CH2:21][N:16]3[C:15]2=[O:24])[CH:13]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(OCC)(=O)C>[Cl:26][C:9]1[C:8]([NH:7][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:13][C:12]([N:14]2[C:22](=[O:23])[C:17]3=[CH:18][CH2:19][CH2:20][CH2:21][N:16]3[C:15]2=[O:24])=[C:11]([F:25])[CH:10]=1
Reactant: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(N3C(=O)C4=CCCCN4C3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
To a pyridine (5 mL) solution of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1, 3[2H, 7H]-dione (0.35 g, 1.2 mmol) was dropwise added p-toluenesulfonyl chloride (0.25 g, 1.3 mmol) under cooling in an ice-water bath, and the mixture was stirred for 2.5 hours at the ambient temperature. 1N Hydrochloric acid (60 mL) and ethyl acetate (40 mL) were added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (20 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (100 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain a white solid of 2-[4-chloro-2-fluoro-5-(p-toluenesulfonylamino)phenyl]-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.32 g, yield:59.3%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([OH:19])[CH:7]=2.[C:20](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>>[CH3:1][N:2]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([O:19][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=2
Reactant: Cn1c2c(c3cc(O)ccc31)CSc1ccccc1-2
Reactant: CC(C)(C)C(=O)Cl
Product: Cn1c2c(c3cc(OC(=O)C(C)(C)C)ccc31)CSc1ccccc1-2

Procedure:
Following the procedure in Example 80, using 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (105 mg, 0.393 mmol) and PivCl (71 mg, 0.59 mmol) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])=[O:12])[CH2:4][O:3]1.[CH3:29][NH:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=1)=[O:32]>>[CH3:1][C:2]1([CH3:28])[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]([CH2:47][C:44]3[CH:43]=[CH:42][C:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[CH2:34][NH:33][C:31]([NH:30][CH3:29])=[O:32])=[CH:46][CH:45]=3)[C:15]2=[O:25])=[O:12])[CH2:4][O:3]1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC[C@H]1COC(C)(C)O1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H]3COC(C)(C)O3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[[2,2-dimethyl-1,3-dioxolan-4(S)-yl]-methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step B) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H.1H NMR (200 MHz, CD3OD): δ 1.14 (s, 6H), 1.28 (s, 3H), 1.34 (s, 3H), 2.07 (m, 1H), 2.20-2.42 (m, 3H), 2.48-2.76 (m, 4H), 2.64 (s, 3H), 3.64 dd; 8, 6 Hz; 1H), 4.05 (dd; 8, 6 Hz; 1H), 4.14 (s, 2H), 4.20 (m, 1H), 4.40 (dd; 12, 8 Hz; 1H), 4.94 (d, 15 Hz, 1H), 5.27 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H). FAB-MS: calculated for C37H46N5O5 641; found 642 (M+H, 80%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]=[O:29]>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]([OH:29])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccccc1)N(O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1,3-difluoro-2-nitrosobenzene (143 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [Li].C([Li])CCC.[CH:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:18](=[O:20])[CH3:19]>CCCCCC.C(NC(C)C)(C)C>[OH:20][CH:18]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:19]
Reactant: CCOC(=O)C1CCCCC1
Reactant: CC=O
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1(C(C)O)CCCCC1

Procedure:
A solution of lithium isopropylamidide was prepared from 300 cm3 butyl lithium 1.5 M in hexane and 52 g of diisopropylamine. At -40° C. 62.4 g (0.4 mole) of ethyl cyclohexyl-carboxylate were added, then at -80° C. 17.6 g of acetaldehyde were also added. The solvent was evaporated off and the mixture was poured into acid ice water. After extraction with benzene the ether was distilled off and a colourless liquid was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:29]1
Reactant: OB(O)c1ccoc1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccoc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-furanboronic acid in General Procedure A. Purification on silica yielded 231. NMR (CDCl3): 2.66-2.68 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.28-3.31 (m, 4H, 2×CH2), 3.86-3.88 (m, 6H, 3×CH2), 3.98-4.01 (m, 4H, 2×CH2), 7.04 (d, H, ArH, J=1.65 Hz), 7.26 (ms, H, ArH—part under CDCl3), 7.46 (ms, H, ArH), 8.18 (s, H, ArH). MS: (ESI+): MH+464.16
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)=[CH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#[N:2].COC(OC)[N:23]([CH3:25])C>C(Cl)Cl>[CH3:11][C:3]1[CH:1]=[C:25]([CH:6]=[C:5]([CH3:10])[CH:4]=1)[NH:23][C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[CH:1][N:2]=1
Reactant: N#CC(=Cc1ccncc1)c1ccccc1C(=O)O
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: Cc1cc(C)cc(Nc2ncc(Cc3ccncc3)c3ccccc23)c1
Reaction time: 22 h

Procedure:
With the exclusion of moisture, 211 g (0.843 mol) of 2-[(1-cyano-2-(pyridin-4-yl)-vinyl]-benzoic acid are suspended in 3.3 liters of CH2Cl2; 169 ml (=90%, 1.1 mol) of dimethylformamide dimethylacetal (Fluka, Buchs, Switzerland) are added at room temperature, and stirring is carried out for 22 hours to complete the reaction. The reaction mixture is filtered, and the residue is washed thoroughly with CH2Cl2 and discarded. Concentration of the filtrate by evaporation, chromatography (SiO2; ethyl acetate) and crystallisation from ethyl acetate/hexane yield the title compound: m.p. 102-104° C.; FAB-MS: (M+H)+=265; 1H NMR (DMSO-d6) 8.76 (d, 2H), 7.97 (d, 1H), 7.76 (m, 3H), 7.65 (m, 2H), 7.60 (s, 1H), 3.86 (s, 3H); Anal. calc. (C16H12N2O2) C 72.72%, H 4.58%, N 10.60%; found C 72.7%, H 4.8%, N 10.5%.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([I:11])[C:8]([F:12])=[CH:7][C:6]=1[O:13][CH3:14])(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[F:12][C:8]1[C:9]([I:11])=[CH:10][C:5]([OH:4])=[C:6]([O:13][CH3:14])[CH:7]=1
Reactant: COc1cc(F)c(I)cc1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c(I)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 64B (680 mg, 2.19 mmol) in THF (3.0 mL) and MeOH (1.0 mL) was added 1.0 N NaOH (2.74 mL, 2.74 mmol). The reaction was stirred at rt for 2.0 h before it was acidified by addition of 5% citric acid. The mixture was extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, 64C (586 mg, 100% yield) was obtained as a solid and used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3H) 6.62 (d, J=8.79 Hz, 1H) 7.21 (d, J=6.15 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4]([CH3:12])[CH:3]=1.Cl.[N:14](OCCC(C)C)=[O:15]>C(OCC)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:14][OH:15])[C:8]2=[O:11])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(F)cc2c1CCC2=O
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(F)cc2c1CC(=NO)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a stirred solution of 6-fluoro-4-methyl-2,3-dihydro-1H-inden-1-one (1 g, 6.09 mmol) in a mixture of diethyl ether (10 mL) and concentrated HCl (10 mL) was added isopentyl nitrite (0.73 mL, 5.47 mmol) and stirred at RT for 3 h. The precipitated solid was collected by filtration and washed with MeOH to obtain 6-fluoro-2-(hydroxyimino)-4-methyl-2,3-dihydro-1H-inden-1-one as a brown solid (800 mg, 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([O:19]C(=O)C)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:23])[CH:14]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Cl>CO>[C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([OH:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:23])[CH:14]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1c(C)c(CC(=O)OC(C)(C)C)cc2ccc(F)cc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1c(CC(=O)OC(C)(C)C)cc2ccc(F)cc2c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
To a mixture of the above prepared (4-acetoxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid tert-butyl ester (28.4 g, 85.44 mmol) in 140 mL of methanol was added sodium methoxide (25% solution in methanol, 23.44 mL, 102.5 mmol) rapidly dropwise. The resulting reaction mixture was stirred at room temperature for 20 minutes, when HPLC analysis indicated a completed reaction. The mixture was cooled to 0° C., and then acidified to pH 2 with 1N hydrochloric acid solution (111.1 mL, 111.1 mmol). The mixture was then stirred at 0-5° C. for an additional 30 minutes. The resulting solid was filtered, and washed with water (2×40 mL), then dried under vacuum overnight (40° C.), to produce 23.7 g of a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.09 (s, 1H), 7.76-7.86 (m, 2H), 7.26-7.35 (m, 2H), 3.71 (s, 2H), 2.23 (s, 3H), 1.41 (s, 9H).