Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[CH2:24]=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:24]
Reactant: Clc1ccc(CN2CCN=C2Cc2ccccc2)c(Cl)c1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C1=NCCN1Cc1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1-(2,4-Dichlorophenyl)methyl-4,5-dihydro-2-phenylmethylimidazole (3.19 g, 0.1 mol) was added to a slurry of sodium hydride (80% dispersion in mineral oil, 0.3 g, 0.01 mol) in dry dimethylformamide (15 ml) and the mixture was stirred at room temperature for 30 minutes. Paraformaldehyde (3 g, 0.01 mol) was added to the reaction mixture and the resulting mixture was heated at 70° C. for 6 hours. The reaction mixture was cooled, water was added and the resulting mixture was extracted with ether. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel in ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-(1-phenylethenyl)imidazole (2.6 g), (δ (CDC13) 3.3 (2H, t,J=6 Hz), 3.95 (2H, t,J=6 Hz), 4.1 (2H,s), 5.65 (1H, s), 5.8 (1H, s), and 7.0-7.5 (8H, m) p.p.m. having the formula ##STR25##
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.Cl.[C:32](N1C=CC=N1)(=[NH:34])[NH2:33].C(N(CC)CC)C>CO>[ClH:30].[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([C@H:6]3[CH2:7][CH2:8][C@@H:3]([NH:2][C:32]([NH2:34])=[NH:33])[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: N=C(N)n1cccn1
Reactant: N[C@H]1CC[C@@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(N)N[C@H]1CC[C@@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Yield: 161.6 %

Procedure:
A solution of 1-(cis-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg), 1-amidinopyrazole hydrochloride (47 mg) and triethylamine (100 mg) in methanol (10 ml)was stirred at room temperature for 1 day. The reaction solution was concentrated, and to the residue was added dichloromethane. The mixture was washed with 1 N sodium hydroxide aqueous solution, dried and concentrated. The residue was dissolved in ethyl acetate and transformed into hydrochloride with hydrochloric acid to give a colorless solid of the title compound (88 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].C([Li])CCC.[C:22](#[N:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[NH2:29][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]([NH:2][CH3:1])=[O:4]
Reactant: N#Cc1ccccc1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccccc2)noc1C=C(N)c1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A mixture of 100 grams (0.463 mole) of N,5-dimethyl-3-phenyl-isoxazole-4-carboxamide and 1000 milliliters of dry tetrahydrofuran is cooled to -5° C. While maintaining the temperature at -5° to 0° C., there is added over a period of 1 hour a solution of 435 grams (0.95 mole) of 15% n-butyllithium in hexane. The resulting mixture is stirred for 1 hour and while maintaining the temperature at -5° to 0° C. a solution of 50 grams (0.485 mole) of benzonitrile in 100 milliliters of dry tetrahydrofuran is added over a period of 1 hour. The resulting mixture is stirred for an additional hour at which time 100 milliliters of saturated ammonium chloride is added dropwise over a period of 15 to 20 minutes. The resulting solution is then mixed for 1 hour and 40 minutes and then diluted with 200 milliliters of water. The solids are then filtered off and washed three times with tetrahydrofuran/hexane. The solids are then dried under vacuum to give 94 grams of 5-(2-amino-2-phenylethenyl)-N-methyl-3-phenyl-isoxazole-4-carboxamide; m.p. 181° to 183° C. Further extraction from the mother liquors provide a total of 104 grams or 70.3% of the desired title compound. After further recrystallization from chloroform/methanol, the purified product has a melting point of 187° to 190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.4 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (49.9 mg, 42%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1[C:30]([OH:31])=[CH:29][C:28]([OH:32])=[N:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:32][C:28]3[N:27]=[CH:26][N:25]=[C:30]([OH:31])[CH:29]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Reactant: Oc1cc(O)ncn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3cc(O)ncn3)CC2)n1
Yield: 14.8 %

Procedure:
1.5 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (4.27 mmol), 0.72 g of pyrimidine-4,6-diol (6.4 mmol) and 1.31 g of triethylamine in 30 ml of dimethylformamide were stirred for 16 h at 80° C. The mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (1-10%). Fractions containing the product were combined. The solvents were evaporated and the oily residue was treated with acetonitrile. The precipitate was collected by filtration and dried to yield 0.27 g of the title compound.
Reaction SMILES: Cl.COC1C=C(C=CC=1OC)OC1C=CC(S([C:17]2(C(NO)=O)CC[N:20](CC#C)[CH2:19][CH2:18]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].CO[C:43]1[CH:44]=[C:45](O)[CH:46]=[CH:47][C:48]=1[O:49]C>CN(C)C=O>[O:49]([NH:20][CH2:19][C:18]#[CH:17])[C:48]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1ccc(O)cc1OC
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(OC)c(OC)c3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNOc1ccccc1
Yield: 90.9 %

Procedure:
Part C: To a solution of the propargyl amine of part B (8 g, 22.63 mmol) and powdered K2CO3 (8.8 g, 56.6 mmol) in N,N-dimethylformamide (150 mL) was added 3,4-dimethoxyphenol (6.98 g, 45 mmol) at ambient temperature. The composition was heated to 90 degrees Celsius for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography (on silica, ethyl acetate/hexane) provided phenoxy propargyl amine as light yellow gel (10 g, 90.9%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)NCC[C@H](C)N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 56.3 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (27 mg, 0.060 mmol) and free based [(3S)-3-aminobutyl](1-methylethyl)amine (67 mg, 0.51 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (18 mg, 56%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (15 mg, >1.00%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.94-2.03 (m, 1H), 2.71-2.76 (m, 1H), 2.82-2.88 (m, 1H), 3.13-3.16 (m, 1H), 4.16-4.19 (m, 1H), 4.30-4.33 (m, 1H), 4.48 (m, 1H), 4.55-4.65 (m, 2H), 4.97-5.00 (m, 1H), 6.97-7.01 (m, 2H), 7.30-7.34 (m, 2H), 8.28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES+ MS: 443 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH2:32]([O:34][C:35]1[C:36]([F:45])=[C:37](B(O)O)[C:38]([F:41])=[CH:39][CH:40]=1)[CH3:33]>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[C:38]([F:41])=[CH:39][CH:40]=[C:35]([O:34][CH2:32][CH3:33])[C:36]=3[F:45])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Product: CCOc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c1F

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-ethoxy-2,6-difluorophenyl)boronic acid gave 285. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.63 (s, 1H), 7.79 (s, 1H), 7.39 (td, J=9.3, 5.2 Hz, 1H), 7.24 (td, J=9.6, 1.9 Hz, 1H), 4.80 (dd, J=11.0, 3.6 Hz, 1H), 4.49-4.25 (m, 1H), 4.16 (q, J=6.9 Hz, 3H), 4.08-3.90 (m, 1H), 3.78 (s, 3H), 3.29-3.18 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 1H), 1.74-1.64 (m, 2H), 1.36 (t, J=6.9 Hz, 3H). LCMS (ES+) m/z 496 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=2[C:18]([F:21])([F:20])[F:19])[CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:18]([F:19])([F:21])[F:20])[CH:2]=1
Reactant: COC(=O)c1ccc(Oc2cccnc2)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Oc2cccnc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
0.9 g of methyl 4-(3-pyridyloxy)-3-trifluoromethylbenzoate was dissolved in 10 ml of THF and 235 mg of LiAlH4 were added at 0° C. The mixture was stirred at RT for 3 h, poured onto 50 ml of 1N Na2 CO3 and extracted 3 times with 50 ml of EA. It was dried over Na2SO4 and the solvent was removed in vacuo. 780 mg of a white solid were obtained, which was used without further purification.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])N>>[CH3:33][C:34]([OH:36])([CH3:37])[CH2:35][N:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[N:2]1
Reactant: CC(C)(O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(C)(O)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Hydrazino-2-methyl-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=5.8 Hz, 2 H), 8.24 (d, J=8.3 Hz, 1 H), 8.09 (d, J=9.1 Hz, 1 H), 7.87 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.76 (m, 1 H), 7.72 (m, 1H), 7.17 (m, 4 H), 7.00 (d, J=6.2 Hz, 2H), 5.42 (s, 2H) 3.89 (s, 2H), 1.04 (s, 6H); MS: (M+H m/z=451.2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][N:33]2[CH:38]=[C:37]([C:39]3[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=3[F:46])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49][CH:48]=3)=[N:35][C:34]=12)=[O:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][N:33]2[CH:38]=[C:37]([C:39]3[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=3[F:45])[C:36]([C:47]3[CH:48]=[CH:49][C:50]([CH2:53][N:16]4[CH2:17][CH2:18][CH:13]([C:11]5[N:12]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=6)[NH:9][N:10]=5)[CH2:14][CH2:15]4)=[CH:51][CH:52]=3)=[N:35][C:34]=12)=[O:29]
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(CN4CCC(c5n[nH]c(-c6cccc(C)n6)n5)CC4)cc3)nc12
Reaction time: 1 h

Procedure:
402 mg (1.27 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 10 mL NMP. After addition of 0.43 mL triethylamine the reaction mixture is stirred for one hour. 500 mg (1.27 mmol) 6-(2,6-Difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester and 0.13 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 296.3 mg (1.40 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. After treatment of the reaction mixture with saturated NaHCO3 the precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 368.6 mg (44.4%) of the desired product are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[C:27]([CH3:34])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:31]([C:28]3[C:27]([CH3:34])=[N:26][N:25]([CH3:24])[C:29]=3[CH3:30])=[O:32])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Product: Cc1nn(C)c(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.71 min; [M+H]+=469.2.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCC1.[C:68]([O:72][C:73](=[O:83])[N:74](C1C=CC=C(N)C=1)[CH3:75])([CH3:71])([CH3:70])[CH3:69].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:68]([O:72][C:73](=[O:83])[N:74]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:75])([CH3:71])([CH3:70])[CH3:69]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCC2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 9, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. The product was characterised as the hydrochloride salt. 1H NMR (DMSO-d6) 9.89 (1H, br s), 7.84-7.40 (6H, m), 7.20 (1H, m), 6.66 (1H, m), 4.78 (2H, m), 3.98 (1H, m), 3.68 (1H, m), 3.35 (1H, m), 2.73 (3H, s), 1.85-1.33 (8H, m), 1.13 (9H, s).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].Br[C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=[CH:45][CH:44]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:19][C:18]([C:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:46]=[CH:45][CH:44]=4)=[N:17][C:16]=3[CH:15]=2)[CH2:11][CH2:12]1)([CH3:6])[C:3]([NH2:5])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Brc1ccnc2ccccc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4ccnc5ccccc45)nc(N4CCOCC4)c3s2)CC1
Yield: 28.7 %

Procedure:
To a degassed mixture of 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide (235 mg, 0.339 mmol), 4-bromoquinoline (60 mg, 0.288 mmol), copper(I) thiophene-2-carboxylate (55 mg, 0.228 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (17 mg, 0.014 mmol). The reaction mixture was reacted in the CEM microwave at 140° C. for 30 min. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH, eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 171 (44 mg, 29%). LCMS: M+H+=532.2. 1H-NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 9.04 (s, 1H), 8.86 (d, 1H), 8.22 (d, 1H), 7.84 (t, 1H), 7.73 (t, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 3.97 (m, 4H), 3.88 (s, 2H), 3.68 (m, 4H), 2.54-2.67 (m, 8H), 1.09 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12]CC2C=CC=CC=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(COCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CO)CC1

Procedure:
4-Benzyloxymethyl-cyclohexanecarboxylic acid methyl ester (340 mg, 1.30 mmol) is dissolved in MeOH (15 mL). In presence of catalytic amount of 10% Pd/C, the reaction mixture is stirred for 3 hours under hydrogen (10 bar). After removing 10% Pd/C, solvent is evaporated to obtain trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester as colorless oil (160 mg, 72%) after purification. 1H-NMR (400 MHz, CDCl3), δ (ppm): 0.99 (m, 2H), 1.47 (m, 3H), 1.88 (m, 2H), 2.02 (m, 2H), 2.23 (m, 1H), 3.46 (d, 2H), 3.66 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[N:15](CC)[N:16]=[CH:17][C:5]=12)[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[NH:15][N:16]=[CH:17][C:5]=12)[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Temperature: 20 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
A mixture of Intermediate 35 (1.0 g, 3.8 mmol) and N-bromosuccinimide (1.49 g, 8.4 mmol) in carbon tetrachloride (35 ml) was heated at reflux for 3 hours. The reaction mixture was cooled in an ice-bath and the precipitate filtered. The filtrate was concentrated in vacuo and the residue dissolved in tetrahydrofuran (12.5 ml). Water (3.5 ml) and saturated sodium carbonate solution (3 ml) were added and the mixture stirred at 20° C. for 18 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined organic phases were dried Na2SO4) and evaporated in vacuo. The residue was purified on an SPE cartridge (silica, 20 g) eluting with dichloromethane, chloroform, then chloroform:methanol (99:1, 49:1, 19:1 then 9:1). Appropriate fractions were combined and evaporated in vacuo to afford Intermediate 36 as an off-white solid (0.45 g). LCMS showed MH++236, TRET=2.46 min.