Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:39]=[C:38]([CH3:40])[C:29]3[NH:30][C:31]([CH:33]4[CH2:37][CH2:36][O:35][CH2:34]4)=[N:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:40][C:38]1[C:29]2[NH:30][C:31]([CH:33]3[CH2:37][CH2:36][O:35][CH2:34]3)=[N:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:39]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C3CCOC3)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C3CCOC3)[nH]c12
Temperature: 0 °C

Procedure:
138 mg (0.54 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 180 mg (0.54 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 280 μL (1.62 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 60° C. The reaction mixture was combined with ice water. The precipitate formed was suction filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH2:23][CH2:22][CH2:21][C:18]=3[CH:19]=2)[NH:14][C@@H:13]([CH3:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[CH2:36]([O:35][C:33]([N:14]1[C:15]2[C:20](=[CH:19][C:18]3[CH2:21][CH2:22][CH2:23][C:17]=3[CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:12][C@@H:13]1[CH3:24])=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc3c(cc2N1)CCC3
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-(2-methyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinolin-4-yl)-carbamic acid benzyl ester (Example 1A) (2.0 g, 5.9 mmol) in anhydrous dichloromethane (50 mL) was added pyridine (1.0 mL). The mixture was cooled to 0° C., and ethyl chloroformate (1.0 mL) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 4 h. The reaction mixture was washed twice with 25 mL of 2N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 15% ethyl acetate/hexanes as eluent afforded the title compound (500 mg). 1H NMR (CDCl3) δ1.1 (d, 3H), 1.2 (t, 3H), 4.2 (m, 2H), 5.2 (s, 2H), 7.0 (s, 1H), 7.3 (s, 1H), 7.4 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
To a solution of 4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (60 mg, 0.172 mmol) in 1:1 MeOH/THF (10 mL) at 0° C., was added NaBH4 (64 mg, 1.69 mmol). The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched by adding a few drops of acetone and concentrated to dryness. The crude solid was purified on HPLC to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol (18 mg, 30%); 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 5.67 (s, 1H), 5.83 (bs, 1H), 6.40 (bs, 1H), 7.13 (m, 2H), 7.55-7.53 (m, 3H), 7.79 (s, 2H), 8.57 (bs, 1H), 10.43 (s, 1H), 12.12 (bs, 1H); LC-MS (ESI) m/z 350 (M+H)−.
Reaction SMILES: C(C1C=CC(N)=CC=1)CC1C=CC(N)=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1C(O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(OC(N1C2C(=CC=CC=2)C=CC1)=O)C>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: CCOC(=O)N1CC=Cc2ccccc21
Agent: Nc1ccc(CCc2ccc(N)cc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 147.2 %

Procedure:
4,4′-Ethylenedianiline (2.98 g) and pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (7.09 g) were dissolved in DCM (90 mL), and 1-ethoxycarbonyl-1,2-dihydroquinoline (8.38 g) was added. The reaction mixture was stirred at ambient temperature for 3 hours and evaporated under vacuum. Oil was dissolved in ethyl acetate, forming a precipitate, which was collected by vacuum filtration and dried under vacuum, giving 2-[4-(2-{4-[(1-carboxylic acid tert-butyl ester-pyrrolidine-2-carbonyl)-amino]-phenyl}-ethyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (8.30 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1([N:24]([CH3:26])[CH3:25])[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Si]([Cl:31])(C)(C)C>C(OCC)(=O)C>[ClH:31].[CH2:1]([C:5]1([N:24]([CH3:26])[CH3:25])[CH2:6][CH2:7][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2CCCO)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
3-(2-(4-Butyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)propan-1-ol (more polar diastereomer) (54 mg, 0.15 mmol) was dissolved in ethyl acetate (5 ml). Me3SiCl (38 μl, 0.3 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×3 ml) and then dried. Example 181 (57 mg, m.p. 128-132° C., 95%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:37])[C:5]([NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][CH:11]([S:13][C:14](=O)C)[CH3:12])=[O:8].CI.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:17]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH:11]([S:13][CH3:14])[CH3:12])[C:5]([NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=2)=[O:20])=[C:4]([CH3:37])[CH:3]=1
Reactant: CC(=O)SC(C)CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CI
Product: CSC(C)CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 2.3 g (4.0 mmol) thioacetic acid S-[2-(5-chloro-2-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-3-methyl-benzoylamino)-1-methyl-ethyl]ester in 100 ml MeOH is added 1 ml MeI at a temperature of 5° C., followed by a solution of 0.8 g NaOH in 15 ml H2O. After 30 minutes, the clear solution is evaporated. The residue is triturated with 300 ml water (pH brought to 5 by adding HCl 1N). The crystals are filtered and washed with water and hexane (2.0 g, 92%, m.p.: 140-145° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][CH3:18])[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:20]1[S:24][N:23]=[C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[N:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([C:20]4[S:24][N:23]=[C:22]([N:25]5[CH:29]=[CH:28][N:27]=[CH:26]5)[N:21]=4)[CH3:18])[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1nc(-n2ccnc2)ns1
Reactant: CNCC1CCN(Cc2ccc3c(c2)OCO3)C1
Product: CN(CC1CCN(Cc2ccc3c(c2)OCO3)C1)c1nc(-n2ccnc2)ns1

Procedure:
(1-Benzo[1,3]dioxol-5-ylmethyl-pyrrolidin-3-ylmethyl)-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-methyl-amine was prepared following the procedures described in the preparation of Example 23 in Step 3 using (1-benzo[1,3]dioxol-5-ylmethyl-pyrrolidin-3-ylmethyl)-methyl-amine and 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole. [M+H]+ 398.99; 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.63 (s, 1H), 7.06 (s, 1H), 6.81 (s, 1H), 6.70-6.67 (m, 2H), 5.89 (s, 2H), 3.14 (s, 2H), 2.92 (s, 2H), 2.90 (m, 2H), 2.65-2.47 (m, 2H), 2.58 (s, 3H), 2.00 (m, 2H), 1.72 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][P:9]([O-:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23]CC)(=[O:22])[CH:20]=[CH2:21].C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[CH2:11]([O:10][P:9]([CH2:21][CH2:20][C:19]([OH:23])=[O:22])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC(=O)OCC
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of dibenzylphosphite (2.6 mmol) in 10 mL of THF was added ethyl acrylate (3.0 mmol), K2CO3 (16 mmol), and 0.3 mL of (Bn4NH)2SO4 50% w/w. The reaction mixture was stirred at 45° C. overnight. Water was added. The aqueous layer was extracted with ethyl acetate. Organic layer was collected and dried with MgSO4. Solvent was removed to afford a clear oil 3-bis(benzyloxy)phosphorylpropanoic acid in 90% yield. 1H-NMR (CDCl3, 400 MHz): 7.33 (m, 10H), 4.90-5.10 (m, 4H), 3.61 (s, 3H), 2.50-2.60 (m, 2H), 2.00-2.15 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:20](Cl)(=[S:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[O:21]([C:20]([O:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1)=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Reactant: S=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(=S)Oc3ccccc3)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S, 6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (4.5 g) in pyridine (10 mL), was added O-phenyl chlorothiocarbonate (3.15 g). The mixture was then stirred at room temperature for 3 hrs. The resulting mixture was evaporated in vacuo. To the residue, water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed successively with diluted hydrochloric acid, sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the target compound (5.22 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:40]5[S:39][CH:43]=[CH:42][CH:41]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCN4CCCC4)c3)n2)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCN4CCCC4)c3)n2)c1
Yield: 71 %

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-chloro-3-{[2-(1-pyrrolidinyl)ethyl]oxy}phenyl)-2-pyrimidinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F, and purification via column chromatography using a 0-20% gradient of EtOAc/MeOH w/NH4OH to generate the product in 71% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.7 (s, 4H) 3.8 (s, 3H) 4.0 (s, 3H) 6.5 (s, 1H) 6.9 (d, J=4.4 Hz, 2H) 7.1 (t, J=6.9 Hz, 2H) 7.2 (t, J=9.0 Hz, 2H) 7.4 (m, 3H) 7.5 (m, 2H) 7.7 (s, 2H) 7.9 (s, 1H) 8.2 (d, J=0.9 Hz, 1H) 8.4 (s, 1H) 8.8 (d, J=1.3 Hz, 1H) 9.7 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 650 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:15]([OH:17])=O)=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:24][C:23]([CH2:35][CH2:36][NH2:37])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:24][C:23]([CH2:35][CH2:36][NH:37][C:15]([C:6]2[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:14][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:17])=[CH:22][CH:21]=1
Reactant: CC(=O)Oc1cc2ccccc2cc1C(=O)O
Reactant: COc1ccc(CCN)cc1-c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(CCNC(=O)c2cc3ccccc3cc2OC(C)=O)cc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Acetic acid 3-[2-(6-methoxy-4′-nitro-biphenyl-3-yl)-ethylcarbamoyl]-naphthalen-2-yl ester (108 mg) was prepared from 3-Acetoxy-naphthalene-2-carboxylic acid (58 mg, 0.25 mmol) and 2-(6-Methoxy-4′-nitro-biphenyl-3-yl)-ethylamine (68 mg, 0.25 mmol following the general procedure A.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23][CH3:24])=[N:19][CH:20]=2)[N:15]([CH2:25][CH3:26])[C:14]1=[O:27].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23]([CH3:24])=[O:36])=[N:19][CH:20]=2)[N:15]([CH2:25][CH3:26])[C:14]1=[O:27]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(SC)nc21
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reaction time: 8 h

Procedure:
A solution of 4.23 g (10.67 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one in 90 mL of chloroform was treated with 3.35 g (12.80 mmol) of 3-phenyl-2-(phenylsulfonyl)-oxaziridine and stirred at room temp. under N2 atmosphere overnight. Crude product was purified by medium-pressure chromatography eluting with straight ethyl acetate and a gradient of 1% to 3% MeOH in chloroform to give 4.45 g (quantitative) title compound. MS (APCI) (m+1)/z 413.1.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:13]=1)=[O:11].B(Br)(Br)Br.C(Cl)Cl>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:13]=1)=[O:11]
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 49.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (2.82 g, 6.03 mmol) and 1M boron tribromide/CH2Cl2 (18.7 mL) in CH2Cl1. Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/pet. ether step gradient gave 1.36 g (50%) of the title compound. (DMSO-d6) δ1.42-1.44 (m, 2 H), 1.58-1.72 (m, 4 H), 1.79 (s, 3 H), 1.87-1.92 (m, 2 H), 2.16 (s, 3 H), 3.17 (quintet, 1 H), 3.92 (s, 2 H), 6.85 (d, 1 H), 7.12-7.17 (m, 2 H), 7.29 (t, 1 H), 7.45 (dd, 1 H), 7.50-7.52 (m, 2 H), 10.31 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][CH2:2][C:3]([NH:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([OH:10])=[O:9])=[O:4])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(-c2ccccc2)cc1)Nc1ccccc1C(=O)O

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-aminobiphenyl (13.12 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2 N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. The resulting air-sensitive material was triturated with ethyl acetate (100 mL), filtered, and rinsed with ethyl acetate (2×25 mL) to yield, after drying, 8.18 g (76%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.4 (broad s, 1H), 12.05 (s, 1H), 8.75 (d, J=8.4, 1H), 7.95 (dd, J=7.4, J=1.2, 1H), 7.60 (td, J=7.2, J=1.2, 1H), 7.54 (d, J=7.6, 2H), 7.45 (d, J=8.8, 2H), 7.37 (t, J=7.6, 2H), 7.22 (t, J=7.6, 1H), 7.13 (t, J=7.6, 1H), 6.69 (d, J=8.4, 2H), 6.7 (broad s, 1H), 3.90 (s, 2H); 13C NMR (DMSO-d6) δ 170.74, 169.12, 147.71, 140.60, 140.36, 134.20, 131.14, 128.87, 128.74, 127.28, 125.96, 125.55, 122.69, 119.40, 115.97, 112.85, 48.87; MS (EI, m/z) 328 (M-H2O+).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C:16]3[C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]([O:26][CH3:27])=[C:18]([O:28][CH3:29])[C:17]=3[O:30][CH3:31])[C:5]([C:12]([O:14]C)=[O:13])=[CH:6][C:7]=2[O:10][CH3:11])[O:2]1.[OH-].[K+].Cl>O1CCOCC1>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([O:26][CH3:27])=[C:18]([O:28][CH3:29])[C:17]=3[O:30][CH3:31])[C:5]([C:12]([OH:14])=[O:13])=[CH:6][C:7]=2[O:10][CH3:11])[O:2]1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1-c1c(C(=O)OC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)c(-c2c(C(=O)O)cc(OC)c3c2OCO3)c(OC)c1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
In 50 ml of dioxane was dissolved 1.3 g of dimethyl 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'-dicarboxylate obtained in Example 2, and 10 mg of 5% potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight. When the pH value of the mixture was adjusted to 1 by 3N hydrochloric acid, crystals were precipitated. The precipitated crystals were recovered by filtration and recrystallized from ethanol to obtain 1.12 g of 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:41](=[O:42])[CH2:40][C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2)[CH3:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc(CC(C)N)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CC(C)NC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
2.30 g (8.48 mmol) of crude 2-(4-benzyloxy-3-methoxyphenyl)-1-methylethylamine, 1.03 g (10.2 mmol) of triethylamine and 25 ml of tetrahydrofuran were mixed and cooled to about 0° C. and then 1.42 g (8.48 mmol) of (4-methylphenyl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 2.40 g of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-2-(4-methylphenyl) acetamide.
Reaction SMILES: O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=2)=[N:17][CH:18]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:39]=2)O1.ClCCl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N:42]1([CH2:41][CH2:40][N:38]2[CH:39]=[C:35]([C:13]3[CH:14]=[N:15][C:16]([C:19]4[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=4)=[N:17][CH:18]=3)[CH:36]=[N:37]2)[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
7.2 4.25 g (20.0 mmol) of tripotassium phosphate trihydrate and 842 mg (1.2 mmol) of bis(triphenylphosphine)palladium chloride are added to a solution, kept under nitrogen, of 2.65 g (1.0.0 mol) of [3-(5-bromopyrimidin-2-yl)-phenyl]methanol and 3.38 g (11.0 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl}morpholine in 50 ml of 1,2-dimethoxyethane, and the mixture is stirred at 80° C. for 18 hours. Dichloromethane and water are added to the reaction mixture, which is then filtered through kieselguhr, and the residue is washed with dichloromethane. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is recrystallised from 2-propanot, giving (3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}phenyl)methanol as yellowish crystals; ESI 366. 7.3 A solution, kept under nitrogen, of 324 mg (0.70 mmol) of (3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}phenyl)methanol, 131 mg (0.91 mmol) of 6-isopropyl-2H-pyridazin-3-one and 278 mg (1.05 mmol) of triphenylphosphine in 1.4 ml of THF is cooled in an ice bath, and 217 μl (1.056 mmol) of diisopropyl azodicarboxylate are added dropwise. After the reaction mixture has been stirred at room temperature for 2 hours, it is evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 6-isopropyl-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one (“A13”) as yellowish crystals; ESI 486;