Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([O:34]C)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])(=[O:22])=[O:21])=[CH:17][C:12]2[N:13]=[C:14]([CH3:16])[NH:15][C:11]=2[CH:10]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])(=[O:21])=[O:22])=[CH:17][C:12]2[N:13]=[C:14]([CH3:16])[NH:15][C:11]=2[CH:10]=1
Reactant: COC(=O)Cc1ccc(Oc2cc3[nH]c(C)nc3cc2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2cc(NS(=O)(=O)c3ccc(Cl)cc3Cl)c(Oc3ccc(CC(=O)O)cc3Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(6-(2,4-dichlorophenylsulfonamido)-2-methyl-3H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.138 g, 0.248 mmol) was dissolved in THF (2.5 mL), and 1N LiOH (2.5 mL) was added. The reaction was allowed to stir at room temperature for 2.5 h. The reaction was brought to pH 5 with 1N HCl and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with an ethyl acetate/hexanes mixture and the product was collected by filtration. LC-MS ESI (pos.) m/z: 541.9 (M+H). 1H NMR (400 MHz) (DMSOd-6) δ 7.76 (d, J=8.5 Hz, 1H); 7.64 (d, J=1.8 Hz, 1H); 7.62 (s, 1H), 7.43-7.40 (m, 2H); 7.10 (d, J=8.2 Hz, 1H); 6.77 (s, 1H); 6.57 (d, J=8.3 Hz, 1H); 3.59 (s, 2H); 2.61 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][C:34]([CH2:39]O)([CH2:37][OH:38])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][CH2:39][C:34]([NH2:33])([CH2:37][OH:38])[CH2:35][OH:36])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NC(CO)(CO)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)OCC(N)(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 7 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 2-amino-2-[hydroxymethyl]-1,3-propandiol as for example 34. After stirring at RT for 60 h, a precipitate had formed. The solid was isolated by filtration and further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 2-amino-3-hydroxy-2-(hydroxymethyl)propyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (7%) as a white solid; m.p. (EtOAc/Hexane) 117-122° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2CO] δ 9.44 (br s, 1H), 8.61 (s, 1H), 7.67 (dd, J=9.9, 1.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.35 (dt, J=8.4, 2.4 Hz, 1H), 5.62 (dd, J=6.3, 1.2 Hz, 1H), 4.26 (s, 2H), 3.56 (d, J=1.8 Hz, 4H), 3.49 (s, 3H). HRMS (FAB+) calcd for C17H20FIN3O5 492.0432 (M+), found 492.0450. HPLC 88.9% (254 nm).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH2:29][CH2:30][C:31](OCC)=[O:32].CN(C)C=O>[Cl-].[Na+]>[O:32]=[C:31]1[CH2:30][CH2:29][S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CCOC(=O)CCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NC(=O)CCS1)OCO3
Temperature: 85 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
A mixture of 2.00 g (5.20 mmol) of the starting material I, 1.89 g (10.44 mmol) of ethyl 3-bromopropionate and 20 ml of dimethylformamide was stirred at 80-90° C. for 3 h. The reaction mixture was diluted with 25% sodium chloride solution and extracted with dichloromethane. After drying and concentration the crude product was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of ethyl acetate-methanol (2:1) as eluent to yield 1.34 g (59%) of the title compound; Mp.: 220-221° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[N:7]1[O:8][N:9]=[C:5]2[CH:4]=[C:3]([CH2:2][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]4([C:40]5[C:31](=[CH:32][C:33]6[O:38][CH2:37][CH2:36][O:35][C:34]=6[CH:39]=5)[O:30][CH2:29]4)[C:21]3=[O:41])[CH:11]=[CH:10][C:6]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc3nonc3c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(bromomethyl)-2,1,3-benzooxadiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ7.86 (d, J=9.3 Hz, 1H), 7.75 (s, 1H), 7.43-7.37 (m, 1H), 7.25-7.19 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.23 (s, 1H), 5.13 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.94 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.24-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 149.0, 148.7, 144.8, 141.4, 139.7, 138.4, 132.0, 131.4, 129.0, 124.3, 124.0, 120.6, 117.8, 113.9, 111.4, 108.8, 99.6, 80.1, 64.5, 63.9, 58.0, 44.0; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[CH:29][C:30]#[N:31]>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Reactant: N#CC=Cc1ccccn1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, mp. 278-280° C., MS m/e (%): 288 (M+H+, 100), was prepared in accordance with the general method of example 22 from 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and 3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])[O:9][CH2:8][CH2:7][O:6]1.S(OC)(O[CH3:22])(=O)=O>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:22])[O:9][CH2:8][CH2:7][O:6]1
Reactant: Oc1ccc(Cl)cc1C1(CCCCl)OCCO1
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C1(CCCCl)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 4-chloro-1-(5-chloro-2-hydroxyphenyl)-1,1-ethylenedioxybutane (0.86 g, 2.5 mmol) sodium hydride (0.18 g, 4.5 mmol in mineral oil) and DMF (3 mL) was stirred 30 minutes. The mixture was cooled to approximately 0° C. and dimethyl sulfate (0.44 g, 3.5 mmol) was added. The mixture was heated 4 hours with stirring at approximately 25° C. and then poured into ice cold water. The mixture was extracted with ether/pentane (7:3) and the extract concentrated to give 4-chloro-1-(5-chloro-2-methoxyphenyl)-1,1-ethylenedioxybutane (0.85 g, 2.4 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:10]([C:20]3[C:21]([F:41])=[C:22]([N:26](COC)[S:27]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].Cl.[O:43]1CCOCC1>O.[OH-].[Na+]>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:41])=[C:20]([C:10]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:43])[CH:8]=3)=[CH:13][N:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:29])=[O:28]
Reactant: C1COCCO1
Reactant: COCN(c1cccc(-c2nn(C3CCOCC3)cc2-c2ccnc(C#N)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(-c2cn(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{3-[4-(2-cyano-pyridin-4-yl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (60 mg, 0.103 mmol) in dioxane (2 mL) concentrated HCl was added (0.5 mL) and the mixture was stirred at room temperature overnight. After two more additions of concentrated HCl (0.5 mL each) and 5 more hours of stirring, the reaction mixture was diluted with water and neutralized with 32% NaOH. It was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure, A 1.1 mixture of the title product and 4-[3-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxamide was obtained. The two products were separated by flash chromatography on silica gel (gradient cyclohexane/AcOEt 2:8 to pure AcOEt), giving 21 mg of the title compound and 15 mg of 4-[3-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxamide as white solids. HPLC (254 nm): Rt: 6.26 min; 1H NMR (DMSO-d6) Shift: 10.67 (s, 1H), 8.59 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.80 (s, 1H), 7.62-7.51 (m, 1H), 7.51-7.43 (m, 1H), 7.43-7.31 (m, 3H), 7.31-7.22 (m, 2H), 4.58-4.36 (m, 1H), 3.98 (dd, J=3.0, 11.7 Hz, 2H), 3.58-3.41 (m, 2H), 2.16-2.04 (m, 2H), 2.04-1.84 (m, 2H); HRMS (ESI) calcd for C26H21F3N5O3S [M+H]+ 540.1312. found 540.1332.
Reaction SMILES: Cl[C:2]1[CH:3]=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CC(O)C>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH:2]([CH3:3])[CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(C(=O)OC(C)C)c(Sc3ccc(Cl)cc3)c2c1
Yield: 58 %

Procedure:
Following the method used to prepare 24a, 1b (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with 2-propanol (2 mL) provided 44 mg (58%) of product 12 as a white solid, mp 172-174° C. 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.24 (m, 6H), 2.35 (s, 3H), 5.09-5.12 (m, 1H), 7.04 (dd, J=2, 9 Hz, 2H), 7.19 (d, J=8, 1H), 7.25-7.30 (m, 3H), 7.46 (dd, J=2, 9 Hz, 1H), 12.34 (s, 1H). LC-MS (CI): m/z 360.0 [(M+H)+ C19H18ClNO2S requires 359.07]. Purity (100%). Calcd for C19H18ClNO2S: C, 63.41; H, 5.04; N, 3.89; S, 8.91; Cl, 9.85. Found: C, 63.59; H, 4.97; N, 3.90; S, 9.04; Cl, 9.85.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1nccc(Cl)n1
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-chloro-2-methylpyrimidine in Step 4. LC-MS Method 2 tR=1.196, m/z=446; 1H NMR (CD3OD) 0.92 (s, 3H), 1.27 (s, 3H), 1.58 (d, 3H), 2.12 (s, 2H), 2.23 (m, 1H), 2.51-2.66 (m, 2H), 2.70 (s, 3H), 3.07 (m, 1H), 5.59 (m, 1H), 7.09 (d, 2H), 7.16-7.42 (m, 5H), 7.65 (d, 1H), 7.89 (d, 2H), 8.61 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cl
Reaction time: 0.05 h
Yield: 72.1 %

Procedure:
To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give a residue which is crystallized from methylene chloride to give 525 mg of the desired product as a white crystalline stalline solid, m.p. 228°-230° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:29])[O:4][C:5]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([CH3:23])=[N:19][O:20][C:21]=3[CH3:22])=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]2[N:38]=[C:39]([SH:41])[N:40]=[C:33]2[N:32]=1>>[CH:24]1([C:5]2([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:18]([CH3:23])=[N:19][O:20][C:21]=4[CH3:22])=[CH:13][CH:12]=3)[O:4][C:3](=[O:29])[C:2]([S:41][C:39]3[N:40]=[C:33]4[N:32]=[C:31]([CH3:30])[CH:36]=[C:35]([CH3:37])[N:34]4[N:38]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: Cc1noc(C)c1-c1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCc4ccc(-c5c(C)noc5C)cc4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared from 3-Chloro-6-cyclopentyl-6{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-one from Step 2 and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the coupling method described in Example C(4).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].C[O:8][C:9]([CH:11]1[CH2:13][CH2:12]1)=O.C[O-].[Na+]>CS(C)=O>[CH:11]1([C:9](=[O:8])[CH2:1][C:2]([CH:4]2[CH2:6][CH2:5]2)=[O:3])[CH2:13][CH2:12]1
Reactant: COC(=O)C1CC1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 52.5 °C

Procedure:
Cyclopropyl methyl ketone (10.8 g; 0.2 mol) and MCPC (40 mL; 0.4 mol; 2 equiv) were dissolved in DMSO (100 mL) and sodium methoxide (21.6 g; 0.4 mol; 2 equiv) was added. The resulting mixture was heated to 50-55° C. for 4-6 h and then cooled overnight to room temperature, The reaction mixture was quenched into 100 mL of 18% HCl. Water (50 mL) and toluene (50 mL) were added. The layers were thoroughly mixed and allowed to settle. The lower aqueous layer was removed and extracted with a second portion of toluene (25 mL). The combined toluene solution was washed with water (50 mL), dried with sodium sulfate, and concentrated. The residue was vacuum distilled to afford two fractions which were 92 and 99.5% pure 10, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(#N)C.CN1CCCC1=O>[Cl:16][C:17]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:18]=1[C:19]([NH:21][C:22]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[O:14][CH3:15])=[O:23])=[O:20]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1N
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 28.4 %

Procedure:
100 mg (0.53 mmol) of 7-amino-6-methoxy-1H-quinazoline-2,4-dione were suspended in 20 ml of acetonitrile and 2 ml of N-methyl-2-pyrrolidinone, and 200 mg (0.97 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate (example 1a) were added. The reaction mixture was heated to boiling and then quenched with methanol and concentrated in vacuo. The residue was stirred with acetonitrile, and the resulting precipitate was filtered off. 64 mg (30%) of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][OH:13]>CC(N(C)C)=O.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:10]([CH2:12][OH:13])[CH2:5]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CO
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1
Yield: 29 %

Procedure:
A brown solution of Intermediate 24b (565 mg, 3.29 mmol) and R-3-hydroxymethyl piperidine (Chess GmbH, 948 mg, 8.23 mmol) in DMA (10 mL) was irradiated at 175° C. for 3 h in the microwave. The cooled solution was concentrated in vacuo, suspended in water (10 mL) and brine (10 mL), and then extracted with DCM (2×20 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. FCC, using 4-5% MeOH in DCM, gave the title compound as a viscous yellow oil (237 mg, 29%). LCMS (Method 3): Rt 2.11 min, m/z 251 [MH+].
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.C([Li])CCC.C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#C[C@H]1CC[C@H](CCCCC)CC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of 84.5 g of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane in 800 ml of absolute tetrahydrofuran was cooled to -75° C. under nitrogen gasification and treated dropwise within 30 minutes with 400 ml of an about 1.6M solution of butyl lithium in hexane. The mixture was subsequently stirred at -70° C. for a further 2 hour, then poured into 5.5 l of 2% (wt./vol.) sodium hydrogen carbonate solution and extracted with 1 l of hexane. The aqueous phase was back-extracted with 700 ml of hexane. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting light yellow oil in a high vacuum gave in the main run 40.6 g (91.1%) of trans-1-ethynyl-4-pentylcyclohexane as a colourless liquid which still contained cis-isomer; b.p. 52°-54° C./0.02 Torr. By recrystallization from ethanol at -25° C. and drying up to constant weight at 30° C. in a vacuum drying oven there could be obtained 20.4 g of product free from cis-isomer. From the mother liquor there could be isolated according to the same method a further 6.5 g of product which was almost free from cis-isomer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[C:36]1([C@@H:42]2[CH2:44][C@H:43]2[C:45](Cl)=[O:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:45]([C@@H:43]4[CH2:44][C@H:42]4[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:46])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a mixture of benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.0 g, 0.0063 mol) in pyridine (100 mL) was added racemic trans-2-phenyl-cyclopropane carbonyl chloride (1.163 g, 0.007 mol) at −5° C. The mixture was stirred at −5° C. for 10 minutes then warmed up to room temperature and stirred for 1.5 hours. The mixture was quenched with an aqueous 1N solution of sodium hydroxide. Organic solvents were removed under reduced pressure. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with a 5% aqueous solution of citric acid (3×100 mL), 1 N aqueous solution of hydrochloride (3×100 mL), water, saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure to give trans benzyl 4-[4-amino-3-(3-methoxy-4-{[(2-phenylcyclopropyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.47 g, 0.006 mol).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-fluorophenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (35%).