Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH:10]=[C:9]([Br:11])[CH:8]=[N:7]2)[CH2:3]1.[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[Br:11][C:9]1[CH:8]=[N:7][N:6]([CH:4]2[CH2:5][N:2]([C:12](=[O:14])[CH3:13])[CH2:3]2)[CH:10]=1
Reactant: CC(=O)Cl
Reactant: Brc1cnn(C2CNC2)c1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CC(n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To 1-Azetidin-3-yl-4-bromo-1H-pyrazole hydrochloride (0.3 g, 1.26 mmol) in CH2Cl2 (15 ml) added ET3N (0.47 ml) and acetyl chloride (0.107 ml, 1.5 mmol) stirred at RT for 2 hours then partitioned between EtOAc and H2O. The organic layer was separated, washed with water H2O, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (276 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[NH2:15].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24]([CH3:27])(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:23][C:21]1[CH:22]=[CH:17][C:18]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([NH:15][CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=3[O:13][CH3:14])[CH2:5][CH2:6][CH2:7]2)[CH:20]=1
Reactant: COc1ccc(OC)c2c1CCCC2N
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c2c1CCCC2Nc1cc(F)ccc1S(C)(=O)=O
Yield: 96.8 %

Procedure:
A solution of 1,2,3,4-tetrahydro-5,8-dimethoxynaphthalen-1-amine (1.1 g mL, 5.31 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (1.02 g, 5.31 mmol) and diisopropylethylamine (3.7 mL, 21.26 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried, and concentrated under reduced pressure to yield 1.95 g of a yellow oil. The residue was purified by PTLC (25% ethyl acetate in hexanes) to give 1.26 g (63%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, 1H), 6.73 (d, 1H), 6.66 (m, 2H), 6.44 (dt, 1H), 6.22 (br d, 1H), 4.79 (br s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 2.96-2.88 (m, 4H), 2.46-2.37 (m, 1H), 2.17-2.12 (br d, 1H), 1.92-1.84 (m, 1H), 1.78-1.60 (m, 2H). MS (ESI) m/z: Calculated: 379.13; Observed: 402.2 (M++23).
Reaction SMILES: Cl.CCOC(C)=O.[C:8]([O:12][C:13](=[O:47])[CH2:14][CH:15]([OH:46])[CH2:16][CH:17]([OH:45])[CH:18]=[CH:19][C:20]1[N:21]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[N:22]=[C:23]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]=1[CH:25]([CH3:27])[CH3:26])([CH3:11])([CH3:10])[CH3:9]>CO.[Pd]>[C:8]([O:12][C:13](=[O:47])[CH2:14][C@H:15]([OH:46])[CH2:16][C@H:17]([OH:45])[CH2:18][CH2:19][C:20]1[N:21]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[N:22]=[C:23]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:24]=1[CH:25]([CH3:27])[CH3:26])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=CC(O)CC(O)CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of (6-{2-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.360 g, 0.61 mmol) in MeOH (20 mL) was added 1N HCl (2 mL) and the solution was stirred for 3 hrs at 25° C. Subsequently, the reaction solvent was removed under reduced pressure and ethyl acetate (50 mL) and saturated NaHCO3 (10 mL) were added. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated to afford, after silica gel chromatography (35% EtOAc/Hex), 7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid tert-butyl ester (0.231 g, 69%). Subsequently, to a solution of 7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid tert-butyl ester (0.241 g, 0.437 mmol) in MeOH (20 mL) was added 10% Pd-C (50 mg; commercially available from Sigma Aldrich), and the reaction vessel was evacuated and filled with hydrogen gas (via balloon) for 3 hours. The reaction mixture was then filtered through a pad of celite and to the filtrate was added The crude product was purified by silica gel chromatography (30-50% EtOAc/Hex) to provide (3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (0.143 g, 59%): MS(APCI+): m/z554.3 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][C@H:13]1[NH:18][CH2:17][C@H:16]([CH2:19][N:20]([CH3:22])[CH3:21])[O:15][CH2:14]1.C(N(CC)CC)C.CN1C(=O)CCC1>C(Cl)Cl>[NH2:7][C:6]1[CH:8]=[C:2]([N:18]2[C@H:13]([CH3:12])[CH2:14][O:15][C@H:16]([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C[C@@H]1CO[C@@H](CN(C)C)CN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C[C@@H]1CO[C@H](CN(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 140 °C

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2R,5R)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and NMP was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (2×) and dried (Na2SO4). Purification via chromatography on silicagel (10% MeOH in dichloromethane), afforded the desired product as a dark yellow foam. LC/MS m/z 295.1 (MH+) Rt 1.85 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CO.C1C=CC=CC=1>ClC(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:24])[CH2:19][CH2:20][N:21]([CH2:9][CH2:10][NH:8][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1cccs1)N1CC1
Solvent: c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1cccs1

Procedure:
A mixture of 7.7 parts of 1-(2-thienylcarbonyl)aziridine, 10.8 parts of 4-(4- chlorophenyl)-4-piperidinol, 8 parts of methanol and 54 parts of benzene is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and dissolved in trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 4.3 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-2-thiophenecarboxamide; mp. 153° C.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[CH3:3][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:33](=[O:34])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:24][CH:25]=2)[N:9]=1)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
(4-{4-[1-Methyl-1-(methylsulfonyl)ethyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)amine (1.5 g, 3.98 mmol) was dissolved in dioxane (15 mL). Sodium bicarbonate (503 mg, 5.98 mmol) was added, followed by phenyl chloroformate (0.502 mL, 3.98 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 20 mL DCM and 20 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (700 mg).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([CH3:12])[N:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>CO>[NH2:22][C:21]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH3:12])=[N:5][C:4]=2[N:3]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: N#CCc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc2cc(-c3ccc(F)cc3)c(N)nc2n1
Temperature: 20 °C
Yield: 78 %

Procedure:
60 ml of 40% strength by weight aqueous potassium hydroxide solution were added to a suspension of 90 g (0.66 mol) of 4-amino-5-formyl-2-methylpyrimidine and 88.7 g (0.66 mol) of p-fluorophenylacetonitrile in 900 ml of methanol at 40° C., a homogeneous solution being formed. After cooling to about 20° C., the precipitate formed was separated off. 1 l of water was added to the alcoholic phase, with the result that further product crystallized out. Yield: 78%; mp.: 252°-254° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH2:24][CH2:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[NH2:30][C:26]1([CH2:25][NH:24][C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:29][O:28][CH2:27]1
Reactant: NCC1(N)COC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NCC3(N)COC3)cc1OCC2

Procedure:
Following the procedures of Example 551, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 3-(aminomethyl)oxetan-3-amine were reacted to give 524. LC/MS (ESI+): m/z 396.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[N:16]=[C:12]3[NH:11][C:10]([CH3:25])=[C:9]2[C:26]([NH2:28])=O)=[CH:4][C:3]=1[F:29].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[N:16]=[C:12]3[NH:11][C:10]([CH3:25])=[C:9]2[C:26]#[N:28])=[CH:4][C:3]=1[F:29]
Reactant: COc1ccccc1-c1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)c(F)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1-c1cn2c(n1)NC(C)=C(C#N)C2c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.8 %

Procedure:
To a suspension of 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxamide (351 mg, 0.85 mmol) in CH2Cl2 (10 mL) at 0° C. was added Et3N (0.73 mL, 5.27 mmol) followed by trifluoroacetic anhydride (0.38 mL, 2.72 mmol) over a period of 10 min. The reaction mixture was stirred at 0° C. for an additional 40 min and quenched with 10% Na2CO3 (5 mL) and H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was triturated with ether and purified by column chromatography on silica gel eluting from 30% to 50% EtOAc in hexanes to give 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carbonitrile (120 mg, 36%) as a yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(I)C=CC=CC=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH3:15]
Reactant: c1ccccc1
Reactant: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(=O)Oc1ccccc1

Procedure:
The procedure of Example 1 is repeated except that 5 mmols of benzene are employed instead of the phenyl iodide of Example 1. Also, an additional 10 mls. of acetic acid solvent is employed. After the 4 hours of reaction at 75° C., no detectable phenyl acetate is formed. This again underscores the criticality of use of an aryl iodide of this invention as catalyst.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][C:54](O)=[O:55])[CH2:47][CH2:46]1>C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:54](=[O:55])[CH2:53][CH2:52][CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
7.10 g. (18.7 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran, prepared according to the method of Example 6, 4.33 g. (21.0 mmoles) of dicyclohexylcarbodiimide and 4.26 g. (20.3 mmoles) of γ-morpholinobutyric acid hydrochloride are combined with 325 ml. of methylene chloride and stirred at room temperature for a total of 24 hours. The insoluble by-product of dicyclohexylurea is separated by filtration and the methylene chloride is removed using a rotary evaporator. The viscous residue is dissolved in about 100 ml. of benzene and the benzene solution is filtered to remove a small amount of insoluble material. The benzene is removed using a rotary evaporator and the remaining residue is triturated with approximately 250 ml. of ether. The solid which forms is filtered, washed with ether and dried to yield a solid. The material is crystallized from benzene/ether to give the solid product.
Reaction SMILES: N[N:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[N:4][CH2:3]1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19]1[S:20][C:21]2[C:26](S(C)(=O)=O)=[N:25][CH:24]=[N:23][C:22]=2[N:31]=1.C[N:33](C=O)C>>[Cl:8][C:5]1[N:4]=[CH:3][N:2]=[C:7]([NH:33][C:26]2[C:21]3[S:20][C:19]([C:13]4[C:12]([Cl:11])=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:18])=[N:31][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:6]=1
Reactant: CS(=O)(=O)c1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Reactant: CN(C)C=O
Reactant: NN1C=CC(Cl)=NC1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Nc2ncnc3nc(-c4c(Cl)cccc4Cl)sc23)ncn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 3-amino-6-chloropyrimidine (57 mg, 0.44 mmol) in DMF (2 mL) at 0° C. was added NaH (24 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 10 minutes. A solution of 2-(2,6-dichlorophenyl)-7-(methylsulfonyl)thiazolo[4,5-d]pyrimidine (88 mg, 0.24 mmol) in DMF (1 mL) was then added at 0° C. The reaction mixture was warmed up to room temperature and stirred for 0.5 hour. The reaction was quenched with ice-water and extracted with EtOAc (3×25 mL). The combined organic extract was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 5-50% EtOAc/hexanes gradient to give the desired compound as a white solid (71 mg, 71%). 1H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.72-7.63 (m, 1H). LCMS (ESI) m/z: 490 [M+H+].
Reaction SMILES: I[C:2]1[S:3][C:4]2[C:12]([CH:13]=1)=[CH:11][C:10]1[S:9][C:8](I)=[CH:7][C:6]=1[CH:5]=2.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]1[NH:31][C:30]2[CH:32]=[CH:33][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:35][C:29]=2[N:28]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[C:45]([O-:48])([O-])=[O:46].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]1[NH:28][C:29]2[CH:35]=[CH:34][C:33]([C:2]3[S:3][C:4]4[C:12]([CH:13]=3)=[CH:11][C:10]3[S:9][C:8]([C:34]5[CH:33]=[CH:32][C:30]6[NH:31][C:27]([CH:23]7[CH2:24][CH2:25][CH2:26][N:22]7[C:45]([O:48][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:46])=[N:28][C:29]=6[CH:35]=5)=[CH:7][C:6]=3[CH:5]=4)=[CH:32][C:30]=2[N:31]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Ic1cc2cc3sc(I)cc3cc2s1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2cc(-c3cc4cc5sc(-c6ccc7[nH]c(C8CCCN8C(=O)OC(C)(C)C)nc7c6)cc5cc4s3)ccc2[nH]1
Temperature: 140 °C
Yield: 36.3 %

Procedure:
2,6-Diiodo-1,5-dithia-s-indacene (117 mg, 0.263 mmol), 2-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (109 mg, 0.263 mmol), Pd(PPh3)4 (9.1 mg), K2CO3 (69 mg, 0.52 mmol), were dissolved in toluene (5 mL)/water (1 mL) under an argon atmosphere. The mixture was heated for 30 minutes at 130° C. (microwave) and 30 minutes at 140° C. Removed all volatiles in vacuo and purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product 2-(5-{6-[2-(1-Boc-pyrrolidin-2-yl)-1H-benzoimidazol-5-yl]-1,5-dithia-s-indacen-2-yl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (36.3 mg).
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)=O>C(N(CC)CC)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
3.60 g (0.025 mol) of Meldrum's acid and 3.8 g (0.025 mol) of p-nitrobenzaldehyde were weighed in to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction mixture was heated to 105° C. during 1 hour and reacted at the same temperature for 1 hour. The product was isolated according to Example 1.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][CH2:14][CH3:15].[Li+].[OH-]>C1COCC1.CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:16])=[O:2])=[C:7]([NH:13][CH2:14][CH3:15])[CH:8]=1
Reactant: CCNc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1cc(F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid methyl ester (128 mg, 0.57 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid (88 mg, 73%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid (40 mg, 0.19 mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethylamine hydrochloride (55 mg, 0.19 mmol) and N-methylmorpholine (31 μL, 0.28 mmol) in THF (4 mL) was added 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 58 mg, 0.21 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.9 mg, 6%) after purification by column chromatography (EtOAc:hexane=1:10 to 2:1).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.Cl[C:46]([O:48][CH2:49][CH2:50][CH3:51])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:46](=[O:47])[O:48][CH2:49][CH2:50][CH3:51])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: CCCOC(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added propyl chloroformate (4.3 μL, 0.039 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C21H29N4O3S (M+H)+: m/z=417.2. Found: 417.0.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:55])[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1>O1CCOCC1.Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:55])[CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Cc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 18 h
Yield: 48 %

Procedure:
Hydrolysis was performed by stirring N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)2-phenylacetamide (0.186 g, 0.207 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (0.039 g, 48% yield): 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.2 (s, 1H), 8.1 (dd, 1H), 7.7-7.6 (m, 3H), 7.5 (t, 1H), 7.4-7.2 (m, 4H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[C:14]([CH2:15][C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>>[O:18]=[C:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8][C:7]2[CH:19]=[CH:20][C:4]([CH2:3][C:1]([NH2:2])=[O:21])=[CH:5][C:6]1=2
Reactant: N#CCc1ccc(Oc2ncccc2CC(=O)O)cc1
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
To 1 g of 2-(4-cyanomethylphenoxy)-3-pyridylacetic acid was added 20 g of polyphosphoric acid, and the mixture was stirred in an oil bath at 151°-152° C. for 2.5 hours. After cooling, to this ice water was added to decompose excess polyphosphoric acid, and the mixture was basified with a 10% sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and then a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a solid, which was chromatographed over 20 g of silica gel and eluted with n-hexane/acetone (2/1-1/1) to obtain crystals. These were recrystallized from acetone to give 300 mg (yield: 30%) of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetamide as white needle crystals having a melting point of 214°-217° C.