Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:18]=2[N:17]=1)[CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:24][C:18]=2[N:17]=1)[CH:10]([CH3:15])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(5-tert-butyl-1H-benzimidazol-2-yl)-2-methylpropanoate (Preparation 33, 7.25 g, 18.65 mmol) and lithium hydroxide (0.67 g, 27.95 mmol) in THF and water (100 mL/10 mL) was stirred at room temperature for 18 hours. The THF was evaporated and the remaining aqueous solution was diluted with water (100 mL). A solution of KHSO4 in water was added resulting in a white precipitate. The solid was filtered and dried to afford the title compound that was taken directly on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(N=C=S)c(Cl)c1
Yield: 46.6 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro-4-fluoro aniline (5.0 g, 34.48 mmol), thiophosgene (3.95 g, 34.34 mmol), N-ethyl di-isopropyl amine (8.80 g, 68.00 mmol) to afford 3.0 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 5-fluoro-3-iodo-pyridin-2-ylamine (4 g, 16.8 mmol) in THF (50 mL) and trimethylsilylacetylene (4.7 mL, 33.6 mmol) is treated with PdCl2(PPh3)4 (353 mg, 0.5 mmol), CuI (96 mg, 0.5 mmol) and triethylamine (7 mL, 50.4 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 10%-35% EtOAc in heptane to afford 5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.3 g, 94%). MS: 209 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.30 (m, 1H), 4.89 (s, NH2, 2H), 0.25 (s, 9H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:11](=O)[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:36][OH:37].N1C=CC=CC=1>C(O)C>[CH:1]1([NH:7][C:8]([C:10]2[C:11](=[N:36][OH:37])[C:12]3[C:17]([C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:13]=3)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NO
Reactant: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=NO
Temperature: 25 °C
Yield: 64.1 %

Procedure:
6-(2-Morpholine-4-ylethoxy)-1-oxo-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (130 mg, 0.28%) obtained in Step 4 was dissolved in ethanol (20 mL), and hydroxylamine hydrochloride (60 mg, 0.85 mmol) and pyridine (892 mg, 1.13 mmol) were added thereto. The mixture was refluxed for 1 hr, and cooled to RT, and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 86 mg of 1-hydroxyimino-6-(2-morpholine-4-yl-ethoxy)-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (yield: 64%). Subsequently, 1-hydroxyimino-6-(2-morpholine-4-yl-ethoxy)-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (80 mg, 0.17 mmol) thus obtained was dissolved in methanol (20 mL) and 10%-palladium (100 mg) was added thereto. The mixture was stirred for 15 hrs at RT while providing H2 gas thereto using a balloon, filtered through celite, and concentrated under a reduced pressure. Then, the resulting residue was purified by flash chromatography to obtain 14 mg of the titled compound (yield: 18%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([S:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[Na+]>CO>[Cl:1][CH2:2][C:3]([CH2:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:16])=[CH:8][CH:9]=1)(=[O:15])=[O:14])=[CH2:4]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=C(CCl)CCl
Agent: [Na+]
Solvent: CO
Product: C=C(CCl)CS(=O)(=O)c1ccc(C)cc1
Yield: 44.1 %

Procedure:
A solution of 2-(chloromethyl)-3-chloropropene (3.13 g, 25 mmol) and sodium p-toluenesulfmate (4.60 g, 25 mmol) in methanol (50 mL) was heated under reflux for 24 hours. The solvent was evaporated on a rotary evaporator and the residue was extracted between dichloromethane and water. The organic layer was dried (anhydrous MgSO4) and evaporated to give crude product (4.7 g) which, after purification by column chromatography on a silica-gel column using ethyl acetate/n-hexane 1:9 as eluent, gave pure product (2.7 g, 44% yield). 1H-NMR (CDCl3) δ (ppm): 2.46 (s, 3H, CH3Ar); 3.92 (s, 2H, CH2SO2); 4.19 (s, 2H, CH2Cl); 5.02 (s, 1H, vinylic-H); 5.45 (s, 1H, vinylic-H); 7.37 and 7.77 (2d, 4H, ArH).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]carbamate (82 mg, 0.18 mmol) was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) for 1 h at room temperature. The mixture was concentrated and used for next step without purification. MS calculated for C20H28F3N3O: (M+H) 383; found 383.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[CH:19][CH:18]=2)[S:22][CH:23]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)c2ccc(-c3cnc4ccc(Br)cn34)cc2)n1
Yield: 48.3 %

Procedure:
159 mg of 4-(6-bromoimidazo[1,2-a]pyridin-3-yl)benzoic acid (compound in Production Example 54), 58 mg of 2-amino-4-methyl-1,3-thiazole, 243 mg benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 83 μL triethylamine were reacted overnight in 4 mL dichloromethane. The reaction solution was purified by an NH silica gel column, to give 100 mg of the title compound (pale yellow crystals; recrystallization solvent, ethyl acetate-methanol).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br.N>C(Cl)(Cl)Cl.C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC(C2=C(Br)C(=O)CCC2)C1=O
Agent: Br
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCCCC(c2cccc(O)c2)C1=O
Reaction time: 4 h

Procedure:
A solution of 3-(2-bromo-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one (6 g) in chloroform (60 ml) was treated with 48% HBr in acetic acid (1 ml). After 4 hours, NMR indicated completion. Aqueous ammonia was added and the organic solvent removed under reduced pressure to yeild the title compound as a crystalline solid, m.p. 192°-3° (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccc(CN4CCOCC4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), morpholine (0.024 mL, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.409 mmol) in dichloroethane (1.4 mL) was shaken at ambient temperature for 16 h. Additional portions of morpholine (0.012 mL, 0.14 mmol), sodium triacetoxyborohydride (0.043 g, 0.20 mmol), and acetic acid (0.016 mL) were added and the reaction mixture was stirred at ambient temperature for 24 h. 1 N NaOH (1 mL) was added and the reaction mixture was filtered to afford a gray solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 10-60% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21-23 min was collected, concentrated, and lyopholized to afford N1-(4-{4-amino-1-[4-(morpholinomethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.007 g, 0.011 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.34-8.37 (2H, m), 8.14-8.18 (2H, m), 7.97-8.02 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.45-7.51 (2H, m), 7.44 (1H, s), 7.38-7.43 (1H, m), 3.41-3.59 (8H, m), and 3.36 (2H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.72 min. MS: MH+ 622.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18].[CH3:19][S-:20].[Na+]>CO>[CH3:18][C:3]1[C:4](=[O:17])[N:5]([CH2:14][C:15]#[CH:16])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]=1[S:20][CH3:19]
Reactant: C#CCn1c(-c2ccccc2)nc(Cl)c(C)c1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: C#CCn1c(-c2ccccc2)nc(SC)c(C)c1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 2.5 g (9.67 mmol) of 6-chloro-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 100 mL of methanol, was added 0.8 g (11.4 mmol) sodium thiomethoxide and the reaction was stirred at room temperature for 4 days. The methanol was evaporated and the residue was dissolved in 100 mL of ethyl acetate, then washed three times with 50 mL of 1M sodium hydroxide followed by one time with 50 mL of brine. The organic layer was dried over MgSO4 and concentrated to yield 2.6 g crude product. Flash column chromatography on silica gel (100% methylene chloride) afforded 5-methyl-2-phenyl-3-propargyl-6-thiomethyl-4(3H)-pyrimidinone (Compound 26) as a white solid. 1H-NMR (CDCl3) δ2.1 (3H, s); 2.35 (1H, t); 2.5 (3H, s); 4.55 (2H, d); 7.5 (3H, m); 7.7 (2H, m).
Reaction SMILES: [OH:1][C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][N:31]=2)[CH2:7][CH2:6][CH:5]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:10]2)[CH2:4][CH2:3]1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][N:31]=2)[CH2:7][CH2:6][CH:5]([N:8]([CH3:43])[C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:10]2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncco4)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C1CCC(O)(c2ccc(-c3ncco3)cn2)CC1)[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
N-{2-[(3S)-3-({4-Hydroxy-4-[5-(1,3-oxazol-2-yl)pyridin-2-yl]cyclohexyl}amino)pyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (45 mg, 0.081 mmol) and 37% aqueous formaldehyde (30 mg, 1.0 mmol) were dissolved in methylene chloride (5.6 mL). The mixture was evaporated to dryness. Then the residue was taken up in THF (1 mL) and sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to provide the title compound (27 mg). MS (M+H) 572.3.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[K+:33].CCCCCC>C(O)C>[K+:33].[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CCC(=O)O)cnc23)ccc(C(C)=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: CCCc1c(OCc2cccn3c(=O)c(CCC(=O)[O-])cnc23)ccc(C(C)=O)c1O
Yield: 73 %

Procedure:
0.50 g (1.18 mmoles) of 3-[9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3yl]propionic acid was suspended in 20 ml of ethanol, and 3.90 ml (1.18 mmoles) of a 2% ethanolic solution of potassium hydroxide was added thereto. This suspension was stirred until a clear solution was obtained. To the resulting reaction solution was added a small amount of n-hexane. The solid matter which separated out was collected by filtration and then dried to obtain 0.40 g (73% yield) of 3-[9-(4-acetyl-3-hydroxy-2-n-propyl-phenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]propionic acid potassium salt in the form of white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:32])[CH2:30][O:31][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](CC(O)CO)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H](CC(O)COS(C)(=O)=O)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-(2,3-dihydroxypropyl)succinate from step 1j (2.917 g, 5.47 mmol) was dissolved in pyridine (10 mL), cooled to 0° C. and MsCl (0.444 mL, 5.74 mmol) was added. The solution was stirred at 0° C. for 4 hours and diluted by 10% citric acid. The reaction mixture was extracted with EtOAc three times. The combined organic solution was washed by 10% citric acid three times, then brine, dried with MgSO4 and concentrated, the residue was purified on silica gel using 50% EtOAc/Hexane as elution to provide of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate (2.696g, 81%). MS (ESI): 612.1.1 (M+H+).
Reaction SMILES: ClC1C=CC2N(C(C(C3C=[C:15]4[C:19](=CC=3F)[N:18]([CH3:23])[N:17]=[CH:16]4)=O)=CN=2)N=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([C:34]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][C:45]=3[F:46])[N:42]([CH3:47])[N:41]=[CH:40]4)(O)[CH3:35])=[CH:32][N:33]=2)[N:30]=1.C[Mg]Br>C1COCC1.CCOC(C)=O>[F:46][C:45]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH3:47])=[CH:38][C:37]=1[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:15]3[CH:16]=[N:17][N:18]([CH3:23])[CH:19]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1)[CH3:35]
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethanol (6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanone (Stage 278.3, 3.7 g, 11.22 mmol) was dissolved in THF (250 mL) with heating under Argon. The solution was let to cool down and methylmagnesium bromide (3 M, 7.48 mL) was added. The mixture was stirred at rt for 1 h. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 120 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 20 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound (tR 1.14 min (conditions 2), MH+=346)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)[N:3]=[C:2]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: OB(O)c1ccccc1
Product: COc1cccc2c(-c3ccccc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and phenylboronic acid to give (5-Methoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:20][CH2:17][C:18]#[CH:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C#CCN
Product: C#CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 131° C. and MS: m/e=249 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and prop-2-ynylamine.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[H-].[Na+].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(#N)C>[C:4]1(=[O:25])[N:5]([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])[CH:15]=3)[N:10]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[CH:9]=2)[C:1](=[O:30])[C:2]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3C(=O)c4ccccc4C3=O)c3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a solution of 3-(2-phthalimidoethyl)-5-trifluoromethanesulfonyloxy-1H-indole (Example 10) (0.640 g, 1.46 mmol) in anhydrous acetonitrile (15 mL) was added sodium hydride (60% dispersion in mineral oil, 0.335 g, 23.3 mmol) and the resulting mixture was stirred at room temperature under argon for 5 minutes. p-Toluenesulfonyl chloride (0.333 g, 1.75 mmol) was then added and the mixture stirred at room temperature for 2 hours. After quenching with water (20 mL), the mixture was extracted with ethyl acetate (2×20 mL) and the organic phase dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using hexane/ethyl acetate (4:1 and 2:1) to provide the title compound (0.520 g, 60%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ: 8.03 (d, J=9.0 Hz, 1H), 7.86-7.83 (A2 of A2B2 system, 2H), 7.75-7.72 (B2 of A2B2 system and A2' of A2'B2' system, 4H), 7.58 (s, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.26-7.21 (B2' of A2'B2' system, 2H), 7.20 (dd, J=2.4 and 9.0 Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 3.05 (t, J-7.3 Hz, 2H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([C@H:8]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH3:9])[CH2:4][CH2:3]1)(=[O:28])=[O:27]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cis-(R)-tert-butyl 1-(4-hydroxycyclohexyl)ethylcarbamate (575 mg, 2.363 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. under nitrogen. Triethylamine (478.2 mg, 658.7 μL, 4.726 mmol) followed by methanesulfonylchloride (284.2 mg, 192.0 μL, 2.481 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The crude mixture was washed with 1M HCl, water and a saturated aqueous solution of sodium bicarbonate. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the compound as a white solid (706 mg, 93% yield).
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:10]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9]3)=[O:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C2(c3ccccc3)CC2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 1-phenylcyclopropanecarboxylic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%.