Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc[nH]1
Product: CCCCCC(=O)c1c[nH]c(C(=O)OCC)c1
Yield: 81.6 %

Procedure:
Starting with 2.0 g of ethyl pyrrole carboxylate (14 mmol) and 4.5 ml (30 mmol) of hexanoylchloride and following a procedure analogous to the one described above, 2.71 g (80% yield) of the desired product is obtained. 1H NMR (δ ppm, CDCl3): 10.70 (s, br, 1H, NH); 7.57 (dd, J=1.61, 3.35 Hz, 1H, α-pyrrolic); 7.29 (dd, J=1.61, 2.48, 1H ; β-pyrrolic); 4.32 (q, 2H, J=7.12 Hz, CO2Et); 2.74 (t, 2H, J=7.54, α-CO CH2); 1.68 (m, 2H, β-CO CH2); 1.34 (t, 3H, J=7.12, CO2Et); 1.31 (m, 4H, γ,δ-CO CH2); 0.87 (m, 3H, CH3). 13C NMR (CDCl3): 196.57; 161.32; 126.74; 126.65; 123.93; 114.91; 60.87; 39.60; 31.44; 24.28; 22.35; 14.17; 13.77. Exact mass calculated for C13H20NO3 (M+H)=238.144319, found=238.143749.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH:26]([CH3:28])[CH3:27])[C:19]2=[O:29].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C(O)(=O)C>ClCCl>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH:26]([CH3:27])[CH3:28])[C:19]3=[O:29])=[CH:33][CH:32]=1
Reactant: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1C(=O)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Sodium triacetoxyborohydride (1.03 g, 4.90 mmol) was added to a stirred solution of 5-amino-2-isopropyl-isoindole-1,3-dione (0.50 g, 2.69 mmol), 4-chlorobenzaldehyde (0.37 g, 2.69 mmol), and acetic acid (160 μl, 2.69 mmol) in anhydrous dichloromethane (10 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (5% methanol in dichloromethane) to afford the title compound as a light brown solid (160 mg, 20%). HPLC retention time 4.86 min. Mass spectrum (ES+) m/z 329 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]3[N:22]([C:18]([C:17]([F:34])([F:35])[F:16])=[N:19][N:20]=3)[N:23]=2)[CH2:28][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Product: FC(F)(F)c1nnc2ccc(N3CCC(Oc4cccc(OCc5ccccc5)c4)CC3)nn12
Yield: 40 %

Procedure:
Obtained in 40% yield by an analogous procedure to Example 430, preparation of starting materials, starting from 3-(benzyloxy)phenol and 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol.
Reaction SMILES: [CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)=[O:2].[CH2:27]([Mg]Br)[CH3:28].Cl>O1CCCC1.O>[OH:2][CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)[CH2:27][CH3:28]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Reactant: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Yield: 79 %

Procedure:
A solution of 0.2 g (0.56 mmol) of (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 1 in 15 mL of tetrahydrofuran (THF) was refrigerated at −78° C. and reacted at that temperature for 2 hours with ethyl magnesium bromide (0.22 mL, 1.2 eq) while stirring. After completion of the reaction, the reaction mixture was adjusted to pH 7 at 0° C. with 1N-HCl and concentrated in a vacuum. The residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to yield (E)-methyl 2-(2-((4-(1-hydroxypropyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.17 g, yield 79%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:2][N:3]([CH3:4])[S:16]([CH2:15][CH2:14][CH2:13][Cl:12])(=[O:18])=[O:17]
Reactant: CNC
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCCCl

Procedure:
To a suspension of dimethylamine hydrochloride (1.38 g) in dichloromethane (20 mL) was added triethylamine (2.52 mL) and then 3-chloropropanesulfonyl chloride (0.69 mL) and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×30 mL). The combined organics were washed with 1 M aqueous hydrochloric acid solution (40 mL) then saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and reduced in vacuo to give 3-chloro-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2]>C(O)(=O)C.O>[F:48][C:44]1[C:22]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)=[C:21]([C:19]2[N:20]=[C:15]([N:9]3[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)[CH:16]=[CH:17][CH:18]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of the title compound from Example 5 Step B (800 mg, 1.20 mmol) in acetic acid (4 mL) and water (1 mL) was stirred at 90° C. for 14 h. The reaction mixture was allowed to cool to ambient temperature and evaporated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 568.8 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Cl.Br[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:30][CH:31]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Brc1ccncc1
Agent: Cl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccncc2)cc1F

Procedure:
In analogy to example 57.1 (RS)-N-(4-cyano-benzyl)-2-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methoxy-acetamide (example 73.1) was reacted with 4-bromopyridine, hydrochloride to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-pyridin-4-yl-phenyl)-2-methoxy-acetamide. Light brown amorphous solid. MS 376.3 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14]Br)[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].[P:20]([O:29]C(C)C)([O:25][CH:26]([CH3:28])[CH3:27])[O:21][CH:22]([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][P:20]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:29])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Product: CCOC(=O)C(C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 19 h

Procedure:
8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropyl phosphite (90%) are heated to from 80° to 90° C. and stirred for 19 hours under a pressure of approximately 100 mbar. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethanol (9: 1) as eluants. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: C(B1O[C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])O1)(C)=C.C(=O)([O-])[O-].[K+].[K+].ClC1C=[C:22]([C:35]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:36]=2)[C:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:24]C=1>O1CCOCC1.O>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][N:42]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=2)[C:37]2[N:36]=[C:35]([C:22]3[C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[N:24][CH:11]=[C:9]([C:6]([CH3:7])=[CH2:8])[CH:10]=3)[N:40]=[C:39]([CH3:41])[N:38]=2)=[CH:49][CH:48]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Yield: 91.5 %

Procedure:
A mixture of isopropenylboronic acid pinacol ester (0.119 mL, 0.633 mmol, Aldrich, St. Louis, Mo.), potassium carbonate (0.175 g, 1.267 mmol), (Amphos)2PdCl2 (0.022 g, 0.032 mmol) and 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 155, 0.185 g, 0.317 mmol) in 4:1 dioxane/water (2.5 mL) was heated in a sealed tube for 24 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol, 92% yield) as an orange solid. m/z (ESI, +ve ion) 590 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.71 (br. s., 1H); 8.94 (s, 1H); 8.44 (d, J=2.5 Hz, 1H); 8.27 (d, J=2.3 Hz, 1H); 7.91 (br. s., 1H); 7.22 range (m, 4H); 6.86 range (m, 4H); 6.73 (d, J=9.0 Hz, 1H); 5.33 (s, 1H); 5.01 (s, 1H); 4.89 (s, 2H); 4.82 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 2.59 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([CH:37]([O:44][C:45](=[O:64])[C:46]([C:50]2[CH:55]=[CH:54][C:53]([O:56][C:57](=[O:59])[CH3:58])=[C:52]([O:60][C:61](=[O:63])[CH3:62])[CH:51]=2)([O:48][NH2:49])[CH3:47])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:49]/[O:48][C:46]([C:45]([O:44][CH:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:64])([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57](=[O:59])[CH3:58])=[C:52]([O:60][C:61](=[O:63])[CH3:62])[CH:51]=3)[CH3:47])/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Oc1ccc(C(C)(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Product: CC(=O)Oc1ccc(C(C)(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
To a solution of (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (0.49 g) in methanol (25 ml) was added dropwise a solution of the product obtained in Step 3 (0.61 g) in methanol (10 ml). The mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving 0.8 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]1[CH3:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:17]([CH3:22])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(Cl)nn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A mixture of 3,6-dichloropyridazine (298 mg, 2 mmol) and (R)-1-N-Boc-2-methyl piperazine (401 mg, 2.0 mmol) in N,N-diisopropylethylamine (0.7 mL, 4 mmol) was stirred at 120° C. for 5 h. The reaction mixture was diluted with ethyl acetate and washed with brine (2×), then dried over MgSO4. The salts were removed by filtration and the filtrate was concentrated and the residue was purified by chromatography on silica gel eluting with 20% to 80% ethyl acetate in hexane to give compound 11 as a light yellow solid (511 mg, 82%). 1H NMR (500 MHz, CD3OD) δ 7.24 (1H, d, J=10 Hz), 6.88 (1H, d, J=10 Hz), 4.38 (1H, br s), 4.17 (1H, d, J=10 Hz), 4.05-3.97 (2H, m), 3.39 (1H, dd, J=15 Hz, J=5 Hz), 3.29 (1H, ddd, J=15 Hz, J=10 Hz, J=5 Hz), 1.51 (9H, s), 1.21 (3H, d, J=10 Hz) ppm; LCMS-ESI (POS), M/Z, M+1: Found 313.1, Calculated 313.1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)=O.[CH3:24][NH:25][NH2:26].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=4)[CH:13]=3)=[N:26][N:25]2[CH3:24])=[CH:4][CH:5]=1
Reactant: CNN
Reactant: COc1ccc(C(=O)c2ccc3cc(OC)ccc3c2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2cc(-c3nn(C)c4cc(OC)ccc34)ccc2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
A mixture of (2-fluoro-4-methoxyphenyl)(6-methoxy-2-naphthyl)methanone (1.0 g, 3.22 mmol), 1-methylhydrazine (0.74 g, 16.1 mmol), pyridine (10 mL), and 4-dimethylaminopyridine (0.39 g, 3.22 mmol) was stirred at 100° C. for 12 h. The mixture poured in the water, extracted with ethyl ether, washed with HCl (2N), and dried over MgSO4. Evaporation and crystallization from ethyl ether/hexanes gave an off-white solid (0.82 g, 80% yield, m.p. 166-168° C.); MS m/e 319 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12](=[O:14])[CH3:13])[N:4]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27]([N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][C:5]([C:12](=[O:14])[CH3:13])=[C:6]2[CH2:11]1)=[O:28])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 76 %

Procedure:
1-(3-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-ethanone 27g (192 mg, 0.72 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (0.24 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.4 mL, 2.88 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.275 g, 1.08 mmol) was then added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 27h (0.3 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[CH:41]1[CH:40]=[CH:39][N:31]2[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:43][CH:42]=3)=[O:27])[CH2:29][C:30]=12
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a stirred solution of 0,440 g of 3-chlorobenzo[b]thiophen-2-carbonyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0,485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.49 g of solid, m.p. 220°-222° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH2:24])=[CH:9][CH:8]=1)[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH:24][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(Br)cc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccc(Br)cc3c(=O)c12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
1-[[2-(Diethylamino)ethyl]amino]-4-(aminomethyl)-7-bromothioxanthen-9-one (1 g, 2.3 mmol) in 11.5 mL of dry pyridine under nitrogen was stirred in an ice bath for 15 min and 0.2 mL (2.6 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred at room temperature. The reaction mixture was poured into 200 mL of water, added 0.19 g of sodium hydroxide in ice/water, and extracted into chloroform. The organic layer was washed with water (2×) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated in vacuo and the residue was stirred in ether, filtered, and dried to afford 1.02 g of N-[[1-[[2-(diethylamino) ethyl]amino]-7-bromo-9-oxothioxanthen-4-yl]methyl]methanesulfonamide, m.p. 134°-139° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9](OC)=[O:10].OC1C=CC=CC=1/[C:23](=[N:28]/OC)/C(OC)=O.CN.CO>O1CCCC1>[CH3:23][NH:28][C:9](=[O:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[N:13][O:14][CH3:15]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1O
Reactant: CON=C(C(=O)OC)c1ccccc1O
Agent: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
0.5 g (0.0013 mol) of methyl 2-(2-hydroxyphenyl)-2-methoxyimino-acetate (in particular Example II-Id from process step 4; HPLC: 54.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39 is disolved in 6 ml of tetrahydrofuran and cooled to 10° C. With cooling, methylamine is introduced. After about 30 minutes, 2 ml of methanol are added, the solution is saturated with methylamine and the mixture is allowed to stand at 10° C. overnight. The solvents are distilled off under reduced pressure and the residue is mixed with a mixture of 5 ml of 2 N hydrochloric acid and 5 ml of saturated sodium chloride solution and extracted three times with 10 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure, giving 0.6 g of crude product. This crude product is chromatographed with a mixture of 7 parts of n-hexane and 3 parts of acetone on silica gel. This gives 0.4 g of product which, according to HPLC, contains 99.2% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28](=[O:31])[CH2:29]Br)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28](=[O:31])[CH2:29][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1COCCN1
Reactant: CCCCOc1ncc(C(=O)CBr)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ncc(C(=O)CN2CCOCC2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
Triphenylphosphine (110 mg, 0.42 mmol) in dichloromethane (1 mL) was added slowly to an ice cooled solution of 5-(2-butoxy-5-glycoloyl-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 33) (150 mg, 0.35 mmol) and carbon tetrabromide (140 mg, 0.42 mmol) in dichloromethane (3 mL). The solution was allowed to warm to room temperature. After 2 h further carbon tetrabromide (25 mg, 0.075 mmol) and triphenylphosphine were added and stirring continued for 2 h. Concentration and purification of the product by flash column chromatography (gradient elution with ethyl acetate/pentane (10:90-70:30) gave 5-[2-butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one which was used without any further purification (slight contamination with triphenylphosphine oxide). 5-[2-Butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (205 mg, 0.42 mmol) was dissolved in dichloromethane and the solution cooled to 0° C. Morpholine (54 mg, 0.62 mmol) and triethylamine (84 mg, 0.83 mmol) were added and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water (twice), saturated sodium bicarbonate (twice) and brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution 20% ethyl acetate/pentane:100% ethyl acetate:3% methanol/methyl acetate) gave 70 mg product.