Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:3]=12.[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1>N1C=CC=CC=1>[CH2:22]([N:21]1[C:3]2=[C:2]([NH:1][S:32]([CH:29]3[CH2:31][CH2:30]3)(=[O:34])=[O:33])[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Yield: 6.7 %

Procedure:
Following the procedure set forth for the preparation of Example 1A, 8-amino-1-benzyl-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (250 mg, 0.001 mol) in pyridine (4 mL) was reacted with cyclopropanesulfonyl chloride (144 mg, 0.001 mol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 40 mg of the product (13.2% yield).
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]([CH3:14])=[N:5]1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[CH3:14][C:6]1[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([CH2:3][C:2]2[S:15][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:1]=2)[N:5]=1
Reactant: CCOC(=O)c1cc(C)nn1CC(N)=S
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cc(C)nn1Cc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 94.6 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (227 mg, 1.00 mmol) obtained in Example 7b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (283 mg, 1.00 mmol), the title compound (374 mg, 94%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N(CC)CC)C.[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>C(#N)C>[CH3:19][Si:20]([CH3:23])([CH3:22])[N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)N1C(=O)c2ccccc2C1=O

Procedure:
250 g (1.7 moles) of phthalimide were suspended in 2.75 liter of acetonitrile and after 250 ml (1.8 moles) of triethylamine were added, the mixture was heated to gentle reflux 250 ml (1.97 moles) of trimethylchlorosilane were added in 10 minutes and the reaction mixture was then concentrated to a thick paste. 2.5 liter of light petroleum (80°-110° C) were added, the triethylammonium hydrochloride was filtered off and washed with 500 ml of light petroleum. The filtrate and washings were combined and concentrated until crystallization started. After cooling in the refrigerator for several hours, N-trimethylsilylphthalimide was isolated by filtration, washed with a small portion of light petroleum (40°-60° C) and dried in vacuo. The compound was further purified by recrystallization from ligroin (80°-100° C).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])[CH:11]=[CH:10][C:9]=1[OH:19].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[CH:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]([O:19][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)=[C:8]([Cl:7])[CH:13]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(F)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.30 g of potassium carbonate, 0.40 g of 2-chloro-4-sec-butoxyphenol, 0.37 g of p-fluorobenzyl bromide and 15 ml of N,N-dimethylformamide is stirred at room temperature overnight. The reaction mixture is poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chomatography to give 1-sec-butoxy-3-chloro-4-(4-fluorobenzyloxy)benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:29])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:41]=[CH:42][CH:43]=[N:44]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:29])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH:44][CH:43]3[CH2:41][CH2:42]3)=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-[4-(4-carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.51 g, 1.22 mmol), HATU (0.47 g, 1.24 mmol)), and DIEA (0.2 mL, mmol) in DMF (10.0 mL) was stirred at room temperature for 1 h. Cyclopropyl amine (0.2 mL, 1.53 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was purified by reverse phase HPLC to furnish the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.45-12.40 (m, 1H), 8.44-8.43 (d, 1H), 7.95-7.2 (m, 5H), 4.43-4.34 (m, 1H), 2.97-2.82 (m, 2H), 2.26-2.19 (m, 1H), 1.94-1.79 (m, 3H), 1.39-1.24 (m, 9H), 0.73-0.55 (m, 4H); MS: 457.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:23][CH2:22][C@@:19]2([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[O:18][C:17](=[O:32])[N:16]([C@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:12]=3)[CH3:15])[CH2:21][CH2:20]2)[CH2:36][CH2:35][CH2:34]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: C1CNC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using azetidine in Step 2. LC-MS Method 2 tR=1.193 min, m/z=477.2; 1H NMR (CD3OD) 1.57 (d, 3H), 2.16 (m, 2H), 2.26 (m, 2H), 2.48 (m, 1H), 2.50 (m, 2H), 3.01 (m, 1H), 3.11 (m, 1H), 3.25 (m, 1H), 3.40 (m, 2H), 4.20 (m, 2H), 5.59 (m, 1H), 7.08 (d, 2H), 7.14 (m, 4H), 7.33 (m, 2H), 7.37 (m, 2H), 7.54 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]2[C:21]([CH3:24])=[N:22][O:23][C:3]1=2.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=3[C:4]3[C:21]([CH3:24])=[N:22][O:23][C:3]=3[CH:2]([NH:1][C:25](=[O:27])[CH3:26])[N:8]=2)=[CH:16][CH:15]=1)#[N:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(C#N)cc1)=NC2N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NC1N=C(c2ccc(C#N)cc2)c2ccccc2-c2c(C)noc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a round bottomed flask was added 4-(4-amino-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-6-yl)benzonitrile (69 mg, 0.22 mmol) and DMAP (2.7 mg, 0.022 mmol). The flask was purged with nitrogen, MeCN was added (5 mL), and the solution was cooled to 0° C. Acetic anhydride (49.5 μL, 0.53 mmol) and triethylamine (79 μL, 0.57 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and purified on a Biotage (isocratic elution 50% EtOAc:50% Hexanes) to provide the title compound as white solid (64 mg). LC/MS m/z 357 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: c1csc(C2CCCN2)c1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1cccs1

Procedure:
The title compound, white solid, m.p. 97° C. and MS: m/e=312.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-2-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(N2CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C(=O)O
Yield: 87.7 %

Procedure:
The mixture of 6 g of 2-nitro-5-(4-benzylpiperazin-1-yl)benzoic acid, 15 mL of cyclohexene and 3 g of Pd/C (10%) is heated under reflux conditions in 120 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 4.8 g of the title compound. m.p.: 242° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([C:13]([NH:15][CH2:16][C:17]#[CH:18])=O)=[CH:11][C:10]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[O:20])=[CH:9][N:8]=2)[CH2:3]1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([C:13]3[N:40]([CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)[C:17]([CH3:18])=[CH:16][N:15]=3)=[CH:11][C:10]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=3)=[O:20])=[CH:9][N:8]=2)[CH2:3]1
Reactant: COc1ccc(CN)cc1
Reactant: C#CCNC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(C)cnc2-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1

Procedure:
A stirred mixture of (R)-2-(3-hydroxypyrrolidin-1-yl)-N3-(prop-2-yn-1-yl)-N5-(4-(trifluoromethoxy)phenyl)pyridine-3,5-dicarboxamide (Stage 72.2, 0.50 g, 1.115 mmol) and 4-methoxybenzylamine (0.175 mL, 1.338 mmol) in toluene (30 mL) was treated with zinc trifluoromethanesulphonate (61 mg, 0.17 mmol) and heated under reflux for 41 h. The solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, EtOAc 100%) to afford the title compound as a foam. HPLC (Condition 4) tR=4.66 min, UPLC-MS (Condition 8) tR=0.93 min, m/z=568.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.72 (br. s, 1H), 2.19 (s, 3H), 2.74-3.09 (m, 2H), 2.85-3.07 (m, 1H), 3.15-3.31 (m, 2H), 3.64 (s, 3H), 4.15 (br. s, 1H), 4.90 (m, 3H), 6.72-6.86 (m, 5H), 7.35 (d, J=8.59 Hz, 2H), 7.85 (d, J=8.42 Hz, 2H), 7.19-8.03 (m, 1H), 8.78 (br. s, 1H), 10.05-10.20 (m, 1H).
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3Br)[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[N:1]1([C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:24]3[CH:23]=[CH:22][C:21]([C:35]4[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=4)=[C:20]([F:19])[CH:25]=3)[CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccccc1Oc1cc(N2CCC2)ncn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3cc(N4CCC4)ncn3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(azetidin-1-yl)-6-(2-bromophenoxy)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C23H19FN6O, 414.16; m/z found, 415.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=1.5, 2H), 8.11 (d, J=0.9, 1H), 7.60-7.52 (m, 2H), 7.50-7.41 (m, 1H), 7.41-7.31 (m, 3H), 7.17 (dd, J=8.1, 1.2, 1H), 6.89 (s, 2H), 5.73 (d, J=0.9, 1H), 3.98 (t, J=7.5, 4H), 2.41-2.27 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8](I)[N:7]=3.N#N.C[Si](C)(C)N[Si](C)(C)C.C[N:29](C)[CH:30]=[O:31]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:30]([NH2:29])=[O:31])[N:7]=3
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N#N
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Yield: 76 %

Procedure:
Alternatively, a solution of 8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (10.00 g, 0.02558 mol) in N,N-Dimethylformamide (250 mL) was thoroughly degassed with N2. Bis(triphenylphosphine)palladium(II) chloride (0.807 g, 0.00115 mol) was added followed by Hexamethyldisilazane (21.58 mL, 0.1023 mol). The solution was flushed with CO for 2 minutes and then sealed with a CO balloon attached. The reaction was heated to 70° C. for 2.5 hours. Methylene chloride and saturated NH4Cl were added and the mixture was extracted 4 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. A small amount of isopropanol was added and the mixture was triturated overnight. The mixture was filtered to yield 5.97 g (76% yield) of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a fine brown powder. MS (ESI+) 308.0/310.0
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:22]=[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[O:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:7].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][CH:2]([C:18]1[CH:22]=[C:21]([Si:23]([CH3:25])([CH3:24])[CH3:26])[O:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:7])(=[O:29])[CH3:28]
Reactant: CC(CCCC(O)c1coc([Si](C)(C)C)c1)c1ccc2ccccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCC(C)c1ccc2ccccc2c1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[1-hydroxy-5-(2-napthyl)hexyl]-5-trimethylsilylfuran (120 mg, 0.3 mmol) and acetic anhydride (66 mg, 651 mmol) in pyridine (1.3 ml) was stirred at room temperature overnight. After removal of the solvent, the residue was purified by preparative TLC (20×20 cm, 500μ silica gel plate; developed with 30% ethyl ether/hexane) yielding the title compound as a yellow oil.
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]1([N:13]([CH:35]2[CH2:37][CH2:36]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]([NH2:31])=[S:30])=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:12][CH2:11]1>>[CH:35]1([N:13]([CH:10]2[CH2:11][CH2:12]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]4[S:30][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][N:31]=4)=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:36][CH2:37]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CCOC(=O)C(Cl)C=O
Product: CCOC(=O)c1cnc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)s1
Yield: 17 %

Procedure:
This compound was prepared according to example 2 using ethyl 2-chloro-2-formylacetate and N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) to provide ethyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylate (18.5 mg, 17% yield) as a pale yellow solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].O>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[CH2:14][CH2:13][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
27.6 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide, 27.6 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, a mixture of 17.7 g of 1-bromo-3,3,3-trifluoropropane and 20 ml of N,N-dimethylformamide was added thereto and the mixture was further stirred for 1 hour. Thereafter, the reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 11.3 g of 2-(3,3,3-trifluoropropyl)malononitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([OH:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C([O-])(=O)C.[Na+]>>[C:32]([O:14][CH:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH2:10][N:11]([C:15]2[N:20]=[CH:19][N:18]([CH2:21][C:22]3[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[C:17](=[O:31])[N:16]=2)[CH2:12]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(C(F)(F)F)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)OC1CN(c2ncn(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CC=C1c1ccc(F)cc1
Yield: 94 %

Procedure:
To 4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (20.0 mg, 0.0442 mmol) synthesized in Synthesis Example 190, at room temperature, acetic anhydride (2.0 mL) and sodium acetate (9.00 mg, 0.110 mmol) were added at room temperature and the resultant mixture was stirred at 100° C. for 40 minutes. After the completion of the reaction, the reaction solution was concentrated and to the resultant residue, water was added, followed by filtering a deposited colorless solid and by drying the solid to obtain the title compound (20.6 mg, yield: 94%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 6.0 mmol) in CH2Cl2 (15.0 mL) was added 2-hydroxyisoindoline-1,3-dione (978 mg, 6.0 mmol) and triphenylphosphine (2.36 g, 9.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (1.78 ml, 9.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-((1,3-dioxoisoindolin-2-yloxy)methyl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:7][CH3:8])[N:6]=1.[H-].[Na+].[CH2:18]([O:20][C:21](Cl)=O)[CH3:19]>CN(C)C=O>[CH2:18]([O:20][CH2:21][N:3]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:7][CH3:8])[N:6]=[C:2]1[CH3:1])[CH3:19]
Reactant: CCc1nc(C)[nH]c1Sc1ccccc1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1c(C)nc(CC)c1Sc1ccccc1
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
To a solution of 500 mg of 4-ethyl-2-methyl-5-phenylthioimidazole 2 (2.3 mmol) obtained in Example 1 (2) in 5 ml of dry dimethylformamide is added 140 mg of 60% oil suspension of sodium hydride (3.5 mmol) under ice cooling. Five minutes later, 330 mg of ethoxycarbonyl chloride (3.5 mmol) is added to the mixture, which is stirred for 15 minutes. The reaction mixture is poured onto ice water and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and the filtrate is concentrated. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (2:1) to give 410 mg of the desired product I-2 as an oil. Yield, 65%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1
Yield: 70 %

Procedure:
To a solution of 4-hydroxybenzoic acid (138 g, 1.00 mol) in methanol (1000 mL) was added concentrated sulfuric acid (20 mL), then the reaction heated at reflux for 20 h. The reaction mixture was concentrated to one half the original volume under reduced pressure then partitioned with ethyl acetate (1000 mL) and water (1000 mL). The organic layer was washed with 1 N aqueous sodium hydroxide (2×300 mL), water (300 mL), brine (300 mL) then dried (MgSO4). The solvent was removed under reduced pressure to give the ester as a white solid (106.62 g, 70%) after drying under vacuum at ambient temperature.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH3:12][NH2:13]>C(#N)C>[CH3:7][C:5]1[N:6]=[C:2]([NH:13][CH3:12])[S:3][C:4]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Cc1nc(Cl)sc1S(N)(=O)=O
Reactant: CN
Solvent: CC#N
Product: CNc1nc(C)c(S(N)(=O)=O)s1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
144 g (0.576 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonamide are introduced at room temperature into 600 ml of acetonitrile, and 147 g (1.9 mol) of 40% strength aqueous methylamine solution are metered in at room temperature. The reaction mixture is stirred at 50° C. for 6 h and then concentrated in a rotary evaporator. The residue is mixed with water, filtered with suction and dried.