Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:9](=[O:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.FC1C=C[C:38]([C:39](Cl)=[O:40])=CC=1.C(Cl)(=O)C>>[C:39]([O:11][CH2:10][C:9]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23](=[O:32])[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C@@H:15]([CH3:33])[CH2:14]1)=[O:12])(=[O:40])[CH3:38]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CO)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CC(=O)Cl
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1

Procedure:
N-(4-chlorophenyl)-2-hydroxy-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was made following general procedure G, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. Procedure A was followed further substituting acetoxyacetylchloride for acetyl chloride in the last step to yield 2-{(4-chlorophenyl)[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH3:4]>CC(C)=O>[I-:2].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[C:13]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH3:4]
Reactant: CI
Reactant: CCOCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(3-(2-ethoxyethoxy)-1,2,5-thiadiazol-4-yl)pyridine (4 mmol) in acetone (3 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 1.45 g (92%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:29])=O>>[Cl:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1O
Reaction time: 3 h
Yield: 100 %

Procedure:
7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (10.1 g) was suspended in thionyl chloride (200 ml) then dimethylformamide (0.5 ml) added and the resultant mixture heated to 80° C. and stirred for 3 hours. The reaction mixture was evaporated and azeotroped with toluene to yield 4-chloro-7-hydroxy-6-methoxyquinazoline as a solid (12.1 g, 100%); NMR: 4.88 (s, 3H), 5.25 (s, 2H), 7.44 (s, 1H), 7.49 (s, 1H), 7.32-7.52 (m, 5H), 8.83 (s, 1H); m/s: M+H+ 283.
Reaction SMILES: [O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C.C1COCC1>[F:20][C:18]1[CH:19]=[CH:12][C:13]([C:14]#[N:15])=[C:16]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][S:2]2(=[O:8])=[O:1])[CH:17]=1
Reactant: O=S1(=O)CCCCN1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1N1CCCCS1(=O)=O
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of 1,1-dioxo[1,2]thiazinane (8.84 g, 65.4 mmol) in DMF (20 mL) and THF (10 mL) was added portion-wise sodium hydride (1.65 g, 65.5 mmol, 95%). After stirring for 30 min, 2,4-difluorobenzonitrile (10.0 g, 72 mmol) was added and the mixture was stirred at 90° C. for 2.5 h. The mixture was cooled and concentrated and the residue was purified by flash chromatography eluting with 0%-10% EtOAc/hexane to give the title compound as white needles (1.37 g, 8% yield). 1H-NMR (500 MHz, CDCl3) δ: 7.70 (1H, dd, J=8.8, 5.8 Hz), 7.30 (1H, dd, J=8.8, 2.4 Hz), 7.15-7.12 (1H, m), 3.72 (2H, t, J=5.3 Hz), 3.33 (2H, t, J=6.1 Hz), 2.40-2.35 (2H, m), 2.05-2.01 (2H, m). LCMS [M+H]+ calcd for C11H12N2FO2S: 255.06; found: 255.19.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:26]([NH:30][S:31]([C:34]1[S:38][C:37]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[C:5]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 90 °C
Yield: 43.5 %

Procedure:
A mixture of 2-bromo-5-((tert-butyldimethylsilyloxy)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (210 mg, 0.49 mmol, 1.0 equiv.), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (260.4 mg, 0.99 mmol, 2 equiv.), PdCl2(dppf)CH2Cl2 (120.0 mg, 0.15 mmol, 0.3 equiv.), K2CO3 (236.67 mg, 1.72 mmol, 3.5 equiv.) in dioxane (10 mL) and water (2 mL) was heated for 12 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=5:12:1 as eluant) to give N-tert-butyl-5-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (120.0 mg, 43.5%) as white solid. LC-MS (m/z)=563.1 [M+H]+;
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1.[Cl-].[Na+]>CN(C)C=O.O1CCCC1>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][O:16][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[CH:25][N:26]=3)[N:23]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: Clc1ccc2ncnn2n1
Reactant: CN1CCN(S(=O)(=O)CCCO)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)CCCOc2ccc3ncnn3n2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.6 %

Procedure:
In 10 ml of dimethylformamide was suspended 0.21 g of 60% sodium hydride in oil followed by addition of 1.12 g of 3-(1-methyl-4-piperazinylsulfonyl)-1-propanol and the mixture was stirred under reduced pressure at room temperature for 75 minutes. Then, 0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 40 ml of ice water, the reaction mixture was saturated with sodium chloride. The aqueous layer was extrated with tetrahydrofuran and the extrat was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (10:1). The fractions containing the desired product were pooled and concentrated to provide 1.032 g of the title compound. m.p. 140°-141° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:17]([C:23]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[O:24])=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.Cl>O.C(Cl)(Cl)Cl.CN(C)C=O>[Cl:22][C:19]1[N:18]=[C:17]([C:23]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[O:24])[C:16]([S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Cc1nsc(NC(=O)c2nc(Cl)ccc2Cl)n1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nsc(NC(=O)c2nc(Cl)ccc2Sc2ccc(O)cc2)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
12 g of 4-hydroxythiophenol and 16 g of potassium carbonate were added to a dimethylformamide (150 ml) solution of 15 g of 3,6-dichloro-N-(3-methyl-1,2,4-thiadiazol-5-yl)pyridine-2-carboxamide, and stirred at 50° C. for 1.5 hours. At room temperature, chloroform and water were added to it, and its pH was controlled to 3 with aqueous 2 N hydrochloric acid solution added thereto. This was extracted with chloroform, the organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, 300 ml of t-butyl methyl ether was added to the residue, and the resulting solid was taken out through filtration to obtain 14.1 g of the entitled compound as a yellow solid.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=1)#N.C[OH:14]>>[CH2:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([OH:14])=[O:1])[CH3:12]
Reactant: CO
Reactant: CCc1cccc(C#N)c1
Reactant: [OH-]
Agent: [Na+]
Product: CCc1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 28 %

Procedure:
6 M Sodium hydroxide (25 ml) was added to 1-cyano-3-ethylbenzene (1 g, 7.62 mmol) in methanol (25 ml) and then heated at 100° C. overnight. After concentrating the reaction mixture, the aqueous layer was washed with dichloromethane (2×), then acidified pH about 3 with 12 M HCl. The precipitate was extracted with ethyl acetate then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 3-ethylbenzoic acid as a colorless oil; 0.770 g (28% yield over 2 steps). 1H NMR (CDCl3), δ (ppm): 7.76 (d, 2H), 7.43 (m, 2H), 2.67 (m, 2H), 1.19 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH2:10])=[N:6]1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:6]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cn1nnc(N)n1
Product: COC(=O)Cn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 168-169° and MS: (neg. ions): m/e=350.2 (M+−H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetic acid methyl ester and diphenylacetyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18](OC)=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].N=C1C=CC2C(=O)N[C:29](=[O:36])C=2C1.COC1C=C(B(O)O)C=CC=1[F:45].O.C(O)(=O)C=O>>[O:36]=[C:29]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([F:45])=[C:17]([O:23][CH3:24])[CH:16]=3)[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[C:1](=[O:3])[NH:2]1
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: COc1cc(B(O)O)ccc1F
Reactant: N=C1C=CC2=C(C1)C(=O)NC2=O
Agent: O=CC(=O)O
Solvent: O
Product: COc1cc(C(Nc2ccc3c(c2)C(=O)NC3=O)C(=O)O)ccc1F
Yield: 17 %

Procedure:
43A was prepared in a procedure similar to that of 1A using 5-iminoisoindoline-1,3-dione, 7C and glyoxylic acid monohydrate. Yield: 17%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.87 (s, 3H) 5.21 (s, 1H) 6.90 (dd, J=8.35, 2.20 Hz, 1H) 6.99 (d, J=1.76 Hz, 1H) 7.06-7.12 (m, 2H) 7.28 (d, J=8.79 Hz, 1H) 7.51 (d, J=8.35 Hz, 1H), LCMS: 345 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:33])=[C:15]([CH3:32])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=1)=[O:18].Cl[S:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=1)(=[O:37])=[O:36]>>[CH3:32][C:15]1[C:16]([C:17]([C:19]2[CH:20]=[C:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:28][S:35]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=3)(=[O:37])=[O:36])=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:24]=2)=[O:18])=[C:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:13][C:14]=1[CH3:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.681 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.209 g, 0.885 mmol). Purification on Dynamax C18 (80% CH3CN/H2O) gave 0.240 g (55%) of the title compound as a yellow solid, mp 130-135° C. 1H NMR (DMSO-d6) δ1.03 (d, 12 H), 1.83 (s, 3 H), 2.20 (s, 3 H), 3.09 (septet, 2 H), 4.01 (s, 2 H), 7.18 (d, 1 H), 7.43-7.48 (m, 5 H), 7.51 (s, 2 H), 7.77-7.79 (m, 2 H). 7.82-7.86 (m, 1 H), 8.05 (d, 1 H). IR (KBr) 3400, 2950, 1700, 1375 and 1190 cm−1. mass spectrum (−ESI) m/z 639 (M−H). Anal. Calcd. for C37H36O8S: C, 69.36; H, 5.66; N, 0.00. Found: C, 69.04; H, 5.77; N, 0.04.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1([C:52]([C:54]2[N:55]=[C:56]([C:63]([F:66])([F:65])[F:64])[N:57]3[CH2:62][CH2:61][NH:60][CH2:59][C:58]=23)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:60]1[CH2:61][CH2:62][N:57]2[C:56]([C:63]([F:66])([F:64])[F:65])=[N:55][C:54]([C:52]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:53])=[C:58]2[CH2:59]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1
Reaction time: 12 h
Yield: 18.8 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (417 mg, 1.40 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1 g, 2.80 mmol), crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (400 mg, 1.40 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.20 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of H2O, extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 18 (150 mg, yield 18.0%) as a light yellow solid.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[K+]>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:19][CH2:3][CH2:2][CH2:1][OH:4]
Reactant: CC1CO1
Reactant: CCCCCCCCCCCCCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
Propylene oxide was bubbled into 685 g of myristyl alcohol in the presence of potassium hydroxide catalyst until three moles of propylene oxide were added per mole of myristyl alcohol, thus obtaining a pale, yellow liquid (PPG-3 myristyl ether) as the major product.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:12]=1[CH2:13][N:14]1[CH2:17][CH2:16][CH:15]1C(OC(C)(C)C)=O.[O:33]1CCCC1>>[CH3:9][O:10][C:11]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:12]=1[CH2:13][N:14]1[CH2:17][CH2:16][C:15]1=[O:33]
Reactant: COc1cc(OC)c(CN2CCC2C(=O)OC(C)(C)C)c(OC)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc(OC)c(CN2CCC2=O)c(OC)c1
Reaction time: 1 h
Yield: 56 %

Procedure:
In a 50 ml round bottom 3-neck flask was prepared a solution of 1.2 mmol lithium diisopropylamide in ca. 10 ml tetrahydrofuran. To this clear, practically colorless solution cooled to -78°, was added 0.34 g (1 mmol) N-(2,4,6-trimethoxybenzyl)-2-carbo-tert-butoxyazetidine dissolved in 3 ml tetrahydrofuran. After stirring for 1 hour at this temperature, the golden-orange solution was silylated and photooxygenated in the usual manner. The resulting pink solution was then concentrated in vacuo and the residue applied to a 10×2 cm silica gel (Woelm) column. Elution with chloroform gave 0.14 g (56%) of pale yellow liquid, which by NMR analysis was greater than 90% pure: IR (liquid film) cm-1 1745, 1600, 1230, 1210, 1150, 1060, 1050, 950, 820; NMR (CDCl3) delta 6.09 (2H, s), 4.36 (2H, s), 3.79 (6H, s), 3.75 (3H, s), 2.98 (2H, t, J=4 Hz), 2.74 (2H, t, J=4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.41 g, 3.19 mmol) in DMF (50 mL) was added 2-aminothiazole (479 mg, 4.78 mmol), HBTU (1.33 g, 3.51 mmol) and Et3N (0.90 mL, 6.38 mmol). The reaction mixture was stirred at room temperature for 18 hours before was concentrated and applied to flash chromatography to afford the titled compound 0.99 g (60%). LC-MS m/z 525 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])[CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(Cc2ccccc2)sn1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(Cc2ccccc2)sn1

Procedure:
The 5-Benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)isothiazole-3-carboxamide is prepared following method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride, 5-benzylisothiazole-3-carboxylic acid (which can be prepared by procedures known to the skilled in the art), HATU and N,N-diisopropylethylamine in DMF.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1>CN(C=O)C>[CH3:45][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[CH:37][C:38]=1[C:46]([F:47])([F:49])[F:48])(=[O:44])=[O:43]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (12.8 g, 62.8 mmol) in dry DMF (200 ml) under an inert atmosphere of Argon is added dropwise, BEMP (19.9 ml, 69.1 mmol) over five minutes. After stirring at room temperature for 1 hour, the resulting solution is added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/acetone (15:1). The crude is further purified by dissolving in hot ethyl acetate and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the solvent is removed in vacuo. The resulting solid is re-crystallized from ethyl acetate/iso-hexane to yield the titled product as a white solid. (MH+ 441)
Reaction SMILES: [C:1]([CH:6]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[O-]CC.[Na+].[C:32]1([CH2:38][CH2:39][CH2:40][CH2:41]I)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:41][CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: ICCCCc1ccccc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CCCCc1ccccc1)(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Ethyl 2-carboethoxy-4[4'-(4"-chlorophenyl) phenyl]-4-oxobutanoate (0.40 g, 1.02 mmol) was added in one portion at rt to a solution of sodium ethoxide (0.08 g, 1.12 mmol) in DME (1 mL). After 15 min, 4-phenyl-1-iodobutane (0.24 g, 0.93 mmol) in DME (3 mL) was added. The resulting solution was stirred for 18 h. The solvent was concentrated in vacuo and the resulting oil dissolved in CH2Cl2 (100 mL) and washed with water (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (10% to 25% ethyl acetate) as the eluent to afford a crystalline solid which was recrystallized with hexane and ethyl acetate to afford 1-[4'-(4"-chlorophenyl)phenyl]-3,3-dicarboethoxy-1-oxo-7-phenylheptane (0.272 g, 28%).