Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:41](=[O:43])[CH3:42])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N(C(C)=O)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol), triethylamine (1 mL) and acetyl chloride (116 μL, 1.64 mmol) in 1,4-dioxane (10 mL). The title compound was obtained as a white solid (69 mg, 31.8%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cn2)cc1
Temperature: 170 °C

Procedure:
2,5-dichloropyridine (1.48 g; 10 mmol), 4-methylsulfonylphenol (1.89 g; 11 mmol) and Cs2CO3 (4.24 g; 13 mmol) was slurried in 75 mL of NMP. The slurry was heated to approx 170° C. over night. After cooling the Cs2CO3 was filtered off and the solvent was extracted between H2O and EtOAc. The organic phase was dried over Na2SO4 and evaporated. Heptane:EtOAc 2:1 was added to the residue and the crystals was filtered off. 1.42 g (50%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[CH2:5]Br.[CH2:11]([Mg]Cl)[CH:12]=[CH2:13]>O1CCCC1>[C:4]1([C:5]#[C:11][C:12]2[CH:13]=[CH:8][CH:9]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 177.5 %

Procedure:
To a dry, round bottom flask was charged 0.43 mol 3,5-difluorobenzyl-bromide and 300 ml anhydrous tetrahydrofuran. The mixture was cooled under nitrogen atmosphere to 0° C. at which time a solution of 0.54 mol allylmagnesiumchloride in 270 ml tetrahydrofuran was slowly added keeping the temperature at 0° C. After allowing to warm to room temperature and stirring until completion (20 hours), the reaction was quenched with an excess of diluted hydrochloric acid. The organic layer was separated, and the aqueous layer extracted twice with petroleum spirits (2×75 ml). The organic layers were combined, washed with water (2×75 ml) and dried over anhydrous sodium sulphate. Removal of the solvent yielded 68 g of the title compound as a pale oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1Cl
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-chlorophenol and 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:61](Cl)(=[O:63])[CH3:62]>ClC(Cl)C>[C:61]([N:11]([CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][S:2](=[O:51])(=[O:1])[CH2:7][CH2:6]1)[C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)(=[O:63])[CH3:62]
Reactant: CC(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(N(CCN3CCS(=O)(=O)CC3)C(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.05 g, 0.071 mmol) in dichloroethane (1 mL) and Hunig's base (0.062 mL, 0.355 mmol) was added acetyl chloride (0.020 mL, 0.284 mmol). The mixture was heated to 50° C. After heating the mixture for 71.25 h, the mixture was cooled to rt and was directly loaded onto a 12 g Thomson silica gel column and was purified by Biotage flash chromatography using a 0-5% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and were concentrated under reduced pressure to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.054 mmol, 75%) as a clear, colorless film. LCMS: m/e 747.5 (M+H)+, 2.26 min (method 2).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH2:41]([C:43]1[S:44][C:45]([CH:51]=O)=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=1)[CH3:42].O>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:45]1[S:44][C:43]([CH2:41][CH3:42])=[N:47][C:46]=1[CH:48]([CH3:49])[CH3:50]
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: CCc1nc(C(C)C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: ClCCl
Product: CCc1nc(C(C)C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)OC)s1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
1,1,3,3-Tetramethylguanidine (107 mg, 0.93 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 300 mg, 0.62 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then 2-ethyl-4-(1-methylethyl)thiazole-5-carboxaldehyde (Example 61; 224 mg, 1.24 mmol) was added. The solution was stirred over a weekend at room temperature, then water was added and the layers were separated. The aqueous layer was extracted with two portions of dichloromethane then the combined organic layers were washed in turn with brine, 0.5N hydrochloric acid solution, water and brine. The dried (MgSO4) organic extracts were evaporated and the resulting oil was purified by chromatography over silica gel. Evaporation of the appropriate fractions afforded (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]3-[2-ethyl-4-(1-methylethyl)thiazole-5-yl]propenoic acid methyl ester (220 mg, 65% yield).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[N:15][N:16]=[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[NH:19][C:18]2=[O:27])[NH:10][C:9]=1[CH3:28])=[O:7].CO.[Li+].[OH-].Cl>O>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:27])[C:17]2=[N:16][N:15]=[CH:14][C:11]1[NH:10][C:9]([CH3:28])=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:7])[C:12]=1[CH3:13]
Reactant: COC(=O)CNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.2 %

Procedure:
2-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-acetic acid methyl ester (399 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (128 mg, 33% yield) as a red solid. LC-MS (m/z) 386 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[Cl:29][C:30]1[N:35]=[CH:34][C:33]([CH2:36][Zn+])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:33]5[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Clc1ccc(C[Zn+])cn1
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(Cl)nc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 6-chloro-pyridin-3-ylmethylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.17 min; Mass spectrum (ESI+): m/z=475/477 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.[C:50]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)(=[O:53])[NH:51][NH2:52]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][C:28]([NH:52][NH:51][C:50]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:53])=[O:30])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)NNC(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg) was added to a mixture of the product of step (a) (0.5 g), diisopropylethylamine (0.34 ml), 1-hydroxybenztriazole (333 mg) and DMF (10 ml) at ambient temperature. The mixture was stirred for 5 minutes and benzyl carbazate (325 mg) in DMF (2 ml) was added. The mixture was stirred for 18 hours at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ice-water (25 ml) containing 1M sodium hydroxide (2 ml) and ethyl acetate (50 ml). The ethyl acetate extract was washed with water (20 ml), 0.25M citric acid solution (20 ml), water (20 ml) and saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation to give benzyl 3-[3-(1-t-butoxycarbonylpiperidin-4-yl)propanoyl]carbazate as a foam (790 mg); NMR Spectrum (d6 -DMSO) 0.8-1.1 (m, 2H), 1.3-1.5 (m, 12H), 1.6 (br d, 2H), 2.1 (br t, 2H), 2.62 (m, 2H), 3.9 (br d, 2H), 5.07 (s, 2H), 7.32 (s, 5H), 9.08 (s, 1H), 9.6 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[N:4]([CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:13][CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: Cn1cc(Br)c2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 7-bromo-4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (200 mg) obtained in Step 4-4 of Preparation Example 4, t-butyl 4-hydroxypiperidine-1-carboxylate (180 mg), K2CO3 (168 mg) and N,N-dimethylformamide (4 ml) were added, and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][C:9](=[S:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][CH2:22]CCCC.C(I)C>CN(C)P(=O)(N(C)C)N(C)C>[CH2:21]([S:18][C:9]1[S:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:22]
Reactant: S=C1N=C(c2ccccc2)C(c2ccccc2)S1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCSc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
5 g of 4,5-bis-phenylthiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (0.89 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is stirred for 30 minutes at room temperature, then 3.18 g of ethyl iodide are slowly added dropwise and the mixture is then stirred for 30 minutes at room temperature, poured onto 1000 ml of ice-water and extracted by shaking twice with diethyl ether. The ether phases are combined, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The remaining pale yellow oil is dissolved in 200 ml of toluene/hexane (1:1) and filtered through 10 g of silica gel. Concentration of the eluate by evaporation yields 2-ethylthio-4,5-bis-phenylthiazole in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH:8]=[CH:9][NH:10]2)=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2[nH]ccc(=O)c2cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2nccc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A two neck round bottomed flask equipped with CaCl2 guard tube was charged with 7-Methoxy-1H-[1,6]naphthyridin-4-one (28 g, 159 mmol) and POCl3 (280 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water and the pH was carefully adjusted to 8 with solid sodium carbonate (highly exothermic reaction). The product was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1CCCCC1.[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16].I[CH2:24][CH2:25][CH2:26][Si:27]([O:32][CH3:33])([O:30][CH3:31])[O:28][CH3:29]>C1COCC1>[CH3:29][O:28][Si:27]([O:32][CH3:33])([O:30][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(=O)OC(C)(C)C
Reactant: CO[Si](CCCI)(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CO[Si](CCCCC(=O)OC(C)(C)C)(OC)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To an 1.5 M solution of LDA.THF in cyclohexane (53.33 mL, 80.00 mmol) and THF (160 mL), cooled to −78° C. in a dry ice/acetone bath, t-butyl acetate (9.29 g, 80.00 mmol) was added dropwise over 15 min. After 1 h at −78° C., 3-iodopropyltrimethoxysilane (23.21 g, 80.00 mmol) was added dropwise over 15 min. The reaction mixture was allowed to stir at −78° C. for 1 h, sealed with a teflon stopper, and kept in a freezer at −15° C. for 3 days. The cold reaction mixture was vacuum filtered through silica gel (300 mL), eluted with 1:1 hexanes/THF (600 mL), and concentrated to provide 21.48 g of a pale yellow oil. A quick distillation produced the volatile components, and 17.76 g of a colorless oil was recovered: bp 55-85° C. (0.2 mm). This material was purified by fractional distillation to provide 6.26 g (28%) of a colorless oil: bp 62-3° C. (0.03 mm); 1 HNMR (CDCl3) δ 3.56 (s, OMe), 2.21 (t, CH2CO), 1.62 (quintet, CH2), 1.45 (m, CH2), 1.44 (s, tBu), 0.66 (m, CH2Si).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
7-Trifluoromethyl-4-quinolinol (320 mg, 1.5 mmol), Cs2CO3 (500 mg, 1.5 mmol) and anhydrous DMF (3 mL) were stirred at 70° C. in a 50 ml round-bottomed flask equipped with a magnetic stirrer. After 20 min, 5-(5-bromopentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 10 (420 mg, 1.4 mmol) in DMF (2 mL) was added and the reaction mixture was stirred for 15 h at 75° C. DMF was evaporated at 60° C. and the reaction mixture was poured in 20 mL of H2O and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=98:2 to 90:10) to give after evaporation 5-(5-(7-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 12 (300 mg, 47% yield) as a white solid.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCN
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)CCCCCCNC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C

Procedure:
A solution of 72 mg (0.18 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxa-diazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2), 30 mg (0.15 mmol) of methyl 7-amino-heptanoate hydrochloride, 87 mg (0.23 mmol) of HATU and 0.8 ml of pyridine in 3.2 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was poured into ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and, after filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative RP-HPLC. This gave 13 mg (0.02 mmol, 13% of theory) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[CH:5][C:6]2[N:7]([N:10]=[C:11]([CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[N:12]=2)[C:8]=1[CH3:9])#[N:2].O=P(Cl)(Cl)[Cl:23].CO.N>O>[Cl:23][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[N:7]2[N:10]=[C:11]([CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[N:12]=[C:6]2[CH:5]=1
Reactant: CCCCC(CC)c1nc2cc(O)c(C#N)c(C)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Solvent: CO
Product: CCCCC(CC)c1nc2cc(Cl)c(C#N)c(C)n2n1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
272 g of 6-cyano-2-(1-ethylpentyl)-7-hydroxy-5-methyl[1,2,4]triazolo[2,3-a]pyridine were introduced into 250 g of phosphorus oxytrichloride and stirred at 105° C. for 4 hours. Then 250 g of methanol were added dropwise, the mixture was briefly boiled and 250 ml of water were run in. The solution was cooled and, at 10° to 20° C., the pH was adjusted to 7.5 with aqueous ammonia, when the target product precipitated. It was filtered off with suction, washed with water and dried at 50° C. under reduced pressure. 264 g of the compound of the formula ##STR11## were obtained. A sample recrystallized from ethanol/cyclohexane has a melting point of 95° to 96° C. and the following analysis:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)CCl.O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:34]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[CH:43]=[N:42][CH:41]=[CH:40]3)=[O:35])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH2:25][NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[C:34]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[CH:43]=[N:42][CH:41]=[CH:40]3)=[O:35])=[CH:22][CH:23]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To 2,4-dimethylbenzoic acid in pyridine was added EDC, DMAP, and tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139), and the solution was capped and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145).