Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:15].Cl([O-])=O.[Na+].Cl[O-].[Na+].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC1(C)N([O])C(C)(C)CCC1.C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCOCc1ccccc1
Reactant: O=P([O-])([O-])[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)CCCOCc1ccccc1
Temperature: 35 °C
Reaction time: 5.5 h
Yield: 102 %

Procedure:
3.0 g of 4-benyloxybutanol and 182 mg of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, radical) were dissolved in a mixture composed of 60 ml of acetonitrile and 60 ml of phosphate buffer (pH 6.7). To this reaction mixture were added 20 ml of an aqueous solution of sodium chlorite (NaClO2) (3.8 g) and 0.5 ml of a 5% aqueous solution of sodium hypochlorite (NaClO), followed by stirring at 35° C. for 5.5 hours. The reaction mixture was adjusted to pH 8.0 by the addition of a 2M aqueous solution of sodium hydroxide, and stirred for 20 minutes. Thereafter, 84 ml of an aqueous solution of sodium sulfate (5.1 g) was added thereto under cooling with ice so that its internal temperature would not exceed 20° C. , followed by stirring for 30 minutes. After the reaction mixture was washed with 50 ml of t-butylmethyl ether, the aqueous solution was adjusted to pH 3–4 by the addition of 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.3 g (102% yield) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([CH2:29][C@H:30]1[O:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:31][C@H:30]([OH:32])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(NCc1ccccc1)CCCC2
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCCC2
Reaction time: 3 h
Yield: 66.2 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amine (187 mg) and (2S)-1-phenoxy-2,3-epoxypropane (100 mg) in dichloromethane (10 ml) was added yetterbium(III) trifluoromethanesulfonate (50 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amino]-3-phenoxy-2-propanol (190 mg).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][C:38]=4[O:39][CH3:40])[CH:31]=3)[N:26](COCC[Si](C)(C)C)[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(O)C>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][C:38]=4[O:39][CH3:40])[CH:31]=3)[NH:26][N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CN4CCOCC4)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1ccncc1-c1ccc2[nH]nc(Nc3nc4cc(CN5CCOCC5)ccc4n3C3CCCCC3)c2c1
Temperature: 78 °C

Procedure:
A mixture of (1-cyclohexyl-5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-[5-(4-methoxy-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-amine (15 mg, 0.000022 mol), hydrogen chloride (300 uL, 0.01 mol) and ethanol (1.2 mL, 0.020 mol) in a 5 mL test tube with a septum cover was heated at 78° C. for 2 hours. The reaction mixture was concentrated and purified by HPLC to yield 1.5 mg after lyopholizaion.
Reaction SMILES: [OH:1][C:2]1([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CC#CC2(O)CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCCC2(O)CCCCC2)cc1

Procedure:
4-{3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl}benzoic Acid (4.0 g., 0.01 mole) is dissolved in ethyl acetate (45 ml.) and hydrogenated at 25° C. and one atmosphere pressure over 1.0 g. of a 5% palladium on charcoal catalyst. When 0.01 mole of hydrogen is absorbed (2 hours), uptake of hydrogen becomes very slow. An additional 1.5 g. of catalyst is added and hydrogenation continued for 70 hours until 0.02 mole of hydrogen has been absorbed. The catalyst is removed by filtration and the solvent evaporated. The residual oil is chromatographed on silica gel with elution by 2% methanol in chloroform. The chromatographed product crystalizes when triturated with ether. There is obtained 1.2 g. of the title product, m.p. 118°-121° C.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=c1cc(OCc2ccc(Br)cn2)cn[nH]1
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Br)cn2)cc1=O
Yield: 90 %

Procedure:
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:5][O:6][P:7]([C:20]1[CH:39]=[CH:38][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[CH:33]=2)[C:28]([OH:30])=O)=[CH:22][CH:21]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=1)=[O:8].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH2:10][O:9][P:7]([C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[C:27]([C:28](=[O:30])[NH:45][C:46]3[S:47][CH:48]=[CH:49][N:50]=3)[CH:31]=[C:32]([O:34][CH:35]([CH3:36])[CH3:37])[CH:33]=2)=[CH:38][CH:39]=1)(=[O:8])[O:6][CH2:5][C:4]1[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)O)c3)cc2)cc1F
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)Nc4nccs4)c3)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a solution of 3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoic acid (350 mg, 0.557 mmol) in DMF (6 mL) was added 2-aminothiazole (70 mg, 0.696 mmol), HATU (265 mg, 0.696 mmol), and diisopropylethylamine (368 μL, 2.23 mmol). Stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with H2O (2×) and brine (2×). Dried with MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel using an ethyl acetate-hexanes gradient to provide 164 mg (42%) of the title compound: 1H NMR (300 MHz, DMSO-d6): δ 12.68 (bs, 1H), 7.75 (dd, J=13, 9 Hz, 2H), 7.55 (d, J=4 Hz, 2H), 7.35 (s, 1H), 7.16 (m, 9H), 6.91 (s, 1H), 4.97 (dd, J=8, 2 Hz, 4H), 4.76 (m, 1H), 3.82 (s, 6H), 1.30 (d, J=6 Hz, 6H); LCMS m/z=711.6 [C35H33F2N2O8PS+H]+: Anal. Calcd. for (C35H33F2N2O8PS+1.2H2O): C, 57.41; H, 4.87; N, 3.83. Found: C, 57.06; H, 4.24; N, 3.91.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:17])(=O)=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6]([Cl:17])=[O:7])([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 2-nitro-5-chlorobenzoic acid (200 mg) in sulfonylchloride (20 ml) was stirred for 4 hours at 99° C. in a stream of argon. After leaving to cool, the solution was concentrated under the reduced pressure to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:38]/[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:55](N2C=NC=C2)=[O:56])C=1>C(Cl)(Cl)Cl>[C:33]([O:32][C:31]([NH:30][CH2:29][CH2:28][N:27]1[CH2:26][CH2:25][N:24]([CH2:23][C@@H:19]2[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:38]\[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:12]3[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[S:10][CH:11]=3)[C:21](=[O:22])[NH:20]2)[C:55]1=[O:56])=[O:37])([CH3:35])([CH3:36])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCNCCNC[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCN1CCN(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C1=O

Procedure:
Prepared in analogous manner to example 3 step 3, using tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-(11,11-dimethyl-9-oxo-10-oxa-2,5,8-triazadodecyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (135 mg, 0.189 mmol), CDI (46.1 mg, 0.284 mmol), TEA (132 μl, 0.947 mmol) and chloroform (1.9 mL). The crude residue was used as such in the following step. LC/MS: R=1.02 min, m/z=739.4 (M+1) Method 2m_acidic.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Yield: 64.3 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (30 mg, 0.072 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.150 mmol) to afford the desired product (22.3 mg, 64%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.10-7.95 (m, 2H), 7.55-7.46 (m, 1H), 7.42 (dd, J=11.7, 2.3 Hz, 1H); 3.53 (d, J=12.7 Hz, 2H), 3.22 (t, J=11.6 Hz, 2H), 2.61 (d, J=6.6 Hz, 2H), 2.59-2.51 (m, 1H), 2.48 (s, 6H), 1.96 (d, J=10.0 Hz, 3H), 1.69-1.56 (m, 2H), 1.35-1.28 (m, 2H), 1.28-1.16 (m, 2H); ESI MS m/z 482 [C27H29ClFN3O2+H]+; HPLC 98.0% (AUC), tR=10.47 min.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([I:22])[CH:21]=1)[C:16]([OH:18])=[O:17].[C:23](O)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([I:22])[CH:21]=1)[C:16]([O:18][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Reaction time: 0.25 h

Procedure:
To a vigirously stirred suspension of poudered MgSO4 (7.36 g) in dichloromethane (50 mL) was added sulfuric acid (0.758 mL) at room temperature. After stirring for 15 minutes, to the mixture was added 3-bromo-5-iodobenzoic acid (5.00 g) followed by tert-butanol (7.31 mL). The mixture was stirred for 3 days at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHCO3 and brine, dried over MgSO4, and evaporated to give tert-butyl 3-bromo-5-iodobenzoate as pale purple crystals (4.44 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:35][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:32][N:31]([CH3:33])[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:18]2[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:35][C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:1][N:36]6[CH2:40][CH2:39][CH2:38][CH2:37]6)=[CH:8][CH:7]=5)=[CH:10][C:11]=34)=[CH:21][N:20]([CH3:22])[N:19]=2)=[CH:24][CH:25]=1)=[O:34]
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4ccc(C=O)cc4)cc23)cc1
Reactant: C1CCNC1
Product: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{4-[2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-methyl-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and pyrrolidine provided the title compound. ESMS [M+H]+: 520.4.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CNC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CN(C(=O)c1ccccc1)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Yield: 54.1 %

Procedure:
A solution of 3-benzyl-7-chloro-2-[1-(2,2-dimethoxy-ethylamino)-2-methyl-propyl]-3H-quinazolin-4-one (505 mg, 1.17 mmol), benzoyl chloride (247 mg, 1.76 mmol), and triethylamine (179 mg, 1.76 mmol) in methylene chloride (10 mL) was stirred at room temperature for 18 h. The reaction was washed sequentially with 0.5 N HCl, water. 5% NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated to yield the title compound as an orange oil (338 mg, 54%). MS(ES+) m/e 534 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:11])=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[CH:15][CH:16]=O>C(O)C.C(O)(=O)C>[C:1]([C:5]1[C:6]([NH2:11])=[N:7][N:8]2[CH:16]=[CH:15][CH:14]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)n[nH]c1N
Reactant: CN(C)C=CC=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1c(N)nn2cccnc12
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture from Example 105A (2.61 g, 16.9 mmol), 3-dimethylaminoacrylaldehyde (2.0 mL, 20.0 mmol) and acetic acid (25 μL, 0.44 mmol) in ethanol (18 mL) was heated by microwave to 150° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (EtOAc, Rf=0.39) afforded 2.34 g (43%) of the title compound. MS (DCI) m/z 191 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(NC1CC1)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and cyclopropanamine (0.34 g, 92%); MS: 201.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([C:10]2[C:14]([CH3:15])=[C:13]([S:16][CH3:17])[N:12]([CH3:18])[N:11]=2)=[C:4]([F:19])[CH:3]=1.[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:10]2[C:14]([CH3:15])=[C:13]([S:16][CH3:17])[N:12]([CH3:18])[N:11]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COc1cc(-c2nn(C)c(SC)c2C)c(F)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CSc1c(C)c(-c2cc(O)c(Cl)cc2F)nn1C
Temperature: 22 °C
Reaction time: 60 h

Procedure:
A mixture of 15 g (0.05 mol) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-4-methyl-5-(methylthio)-1-methyl-[1H]-pyrazole (Example P7) and 10.6 g (0.25 mol) of lithium chloride in 100 ml of N,N-dimethylformamide is stirred at 22° C. in an argon atomsphere for 2.5 days. The solution is cooled and poured into 0.5 liter of ice-water and 15 ml of 37% hydrochloric acid and extracted with tert-butyl methyl ether (MTBE). The organic phase is extracted with a dilute sodium hydroxide solution, and the aqueous phase is separated off and again acidified and extracted with MTBE. AFter concentration by evaporation and recrystallisation in diethyl ether, 4.8 g (33.5% of the threoretical yield) of the desired product are obtained in the form of crystals having a melting point of 136-138° C. and 7.6 g of crude product of the desired compound in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:11]=1Cl)=[O:5])[CH3:2].C(OC(C1C=CN2N=CC=C2N=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(-c3cccc(Cl)c3)cnn2c1Cl
Agent: CCOC(=O)c1ccn2nccc2n1
Product: CCOC(=O)c1cnc2c(-c3cccc(Cl)c3)cnn2c1

Procedure:
This compound was synthesized from 3-(3-chlorophenyl)-7-chloro-pyrazolo-[1,5-a]-pyrimidine-6-carboxylic acid ethyl ester, according to the process for synthesizing the foregoing pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester. mp: 135.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:19][CH:20]=1.Cl.O>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:4][C:5]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Reactant: Clc1ncc(Br)c(NCC2CC2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(NCC3CC3)n2)cn1

Procedure:
263 mg (1.0 mmol) of (5-bromo-2-chloro-pyrimidin-4-yl)-cyclopropylmethyl-amine is dissolved in 2 ml of acetonitrile and added to a suspension of 172 mg (1.0 mmol) of 5-amino-pyridine-2-sulfonic acid amide (representation according to W. T. Caldwell, E. C. Kornfeld J. Am. Chem. Soc. 1942, 64, 1695-1698) in 1 ml of acetonitrile, 0.25 ml of a 4 molar solution of hydrochloric acid in 1,4-dioxane as well as 0.25 ml of water. The reaction mixture is stirred under reflux overnight. After cooling, the precipitate that is formed is filtered off and washed with warm water. After drying, 286 mg (0.72 mmol, 72% of theory) of the product 5-[5-bromo-4-(cyclopropylmethyl-amino)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(-c3cccnc3)cnn12
Yield: 81.7 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (306 mg, 82%). MS (ISP) 375.3 [(M+H)+]; mp 188° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31]C1C2C(=O)NC([C@H]3[C@H](C)CNC3)=NC=2N(C2CCOCC2)N=1>>[CH3:31][C:23]1[C:18]2[C:17](=[O:30])[NH:16][C:15]([C@H:3]3[C@H:2]([CH3:1])[CH2:6][N:5]([CH2:7][C:8]4[CH:13]=[N:12][C:11]([CH3:14])=[N:10][CH:9]=4)[CH2:4]3)=[N:20][C:19]=2[N:21]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=1
Reactant: Cc1nn(C2CCOCC2)c2nc([C@@H]3CNC[C@H]3C)[nH]c(=O)c12
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(c(C)nn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 3-methyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.63 (s, 2H), 4.74-4.68 (m, 1H), 4.11-4.08 (m, 2H), 3.74-3.63 (m, 2H), 3.60-3.52 (m, 2H), 3.28 (t, J=8.3 Hz, 1H), 3.03 (d, J=9.5 Hz, 1H), 2.85-2.83 (m, 1H), 2.71 (s, 3H), 2.65-2.61 (m, 1H), 2.53 (s, 3H), 2.48-2.29 (m, 2H), 1.98 (t, J=8.7 Hz, 1H), 1.87-1.80 (m, 3H), 1.19 (d, J=7.1 Hz, 3H). MS: (M+H m/z 424.2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)=[O:4].Cl[Sn]Cl>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1

Procedure:
4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester was reduced using SnCl2 using the procedure of step 4 of preparation 6 to afford 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=242.