Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1.S(=O)(=O)(O)[OH:14]>O>[CH3:1][N:2]1[C:6]([C:7]([NH2:8])=[O:14])=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(C)c(C#N)c1[N+](=O)[O-]
Solvent: O
Product: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
27.2 g of 1,3-dimethyl-4-nitropyrazole-5-carbonitrile and 65 ml of concentrated sulfuric acid are stirred at 80° C. for 6 hours. The mixture is poured into 700 g of ice and water, and the precipitate is filtered off and suspended in ice-water; the suspension is neutralized with sodium bicarbonate to yield 27.3 g of 1,3-dimethyl-4-nitropyrazole-5-carboxamide, mp 164° to 165° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH2:45][CH2:46][CH:47]=O)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>C1COCC1>[CH3:2][O:3][CH:4]=[CH:47][CH2:46][CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]2)[CH2:40][CH2:41]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=COC)CC2)CC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Under nitrogen gas stream, a mixture of 405 g (1180 mmol) of methoxymethyltriphenylphosphonium chloride with 4.0 l of THF was cooled down to −30° C., 122 g (1090 mmol) of t-BuOK was added thereto, and they were stirred for 1 hour. To this mixture was added by drops a solution of 240 g (907 mmol) of the crude 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propanal in 2.4 l of THF while being maintained at a temperature lower than −30° C. After finishing of the dropping, the reaction temperature was gradually raised up to room temperature, and the mixture was stirred for further 5 hours. The reaction mixture was filtered with Celite, the solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 152 g of a crude 1-methoxy-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N+:20]([O-])=O)[CH:13]=2)=[O:10])[CH:6]=[C:5]([O:23][CH3:24])[C:4]=1[O:25][CH3:26]>C(O)C.[Pd]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:9]([C:7]2[CH:6]=[C:5]([O:23][CH3:24])[C:4]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:8]=2)=[O:10])=[CH:13][C:14]=1[NH2:20]
Reactant: COc1ccc(CS(=O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CS(=O)c2cc(OC)c(OC)c(OC)c2)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A room temperature solution of Example 90A (75 mg, 0.20 mmol) in ethanol (5 mL) was treated with 10% Pd/C (10 mg), stirred under a hydrogen atmosphere for 3 hours, heated to reflux, stirred for 3 hours, cooled to room temperature, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography with 50% ethyl acetate/dichloromethane to provide the desired product.
Reaction SMILES: C(NC(C)C)(C)C.[C:8](=[O:10])=O.CC(C)=O.C([Li])CCC.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]#[N:26].CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:25]([C:21]1[S:20][C:24]([CH:8]=[O:10])=[CH:23][CH:22]=1)#[N:26]
Reactant: N#Cc1cccs1
Reactant: O=C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)s1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a flame-dried 3 neck 1 L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6 M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50% ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84%) of 2-cyano-5-formyl-thiophene.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH2:28][C:29]4[CH:30]=[N:31][C:32]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:33][CH:34]=4)[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH2:28][C:29]4[CH:30]=[N:31][C:32]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)=[CH:33][CH:34]=4)[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccc(N5CCOCC5)nc4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4ccc(N5CCOCC5)nc4)c4cc(F)ccc34)nc12
Reaction time: 2 h
Yield: 81.9 %

Procedure:
2-[6-Fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (50 mg, 0.074 mmol) was combined with dichloromethane (1 mL) and trifluoroacetic acid (0.17 ml, 2.22 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.15 ml, 2.22 mmol) was added. After 20 min the reaction mixture was concentrated in vacuo and the residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to afford 33 mg (77%) of 2-[6-fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a light yellow solid. MS: (M+H)+=545; 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 8.52-8.60 (m, 1H), 8.45 (s, 1H), 8.31 (br. s., 1H), 8.19 (d, J=8.3 Hz, 1H), 7.89 (d, J=9.5 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.16 (t, J=9.0 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 5.63 (br. s., 2H), 4.37 (br. s., 1H), 3.65 (br. s., 4H), 3.44-3.57 (m, 2H), 3.39 (br. s., 4H), 3.27 (s, 3H), 1.30 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:8]3[C:22]([C:23]#[N:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:22]1[C:8]2[C:7]([O:6][CH:4]3[CH2:3][CH:2]([NH:1][C:33](=[O:36])[CH:34]=[CH2:35])[CH2:5]3)=[N:12][C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[N:10][C:9]=2[N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=1)#[N:24]
Reactant: Cn1cc(Nc2nc(OC3CC(N)C3)c3c(C#N)cn(COCC[Si](C)(C)C)c3n2)cn1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CC(Oc2nc(Nc3cnn(C)c3)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a solution of 4-[(3-aminocyclobutyl)oxy]-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (cis:trans 1:1) (380 mg, 0.84 mmol) in DCM (10 mL) was added acryloyl chloride (68 μL, 0.84 mmol) and DIPEA (146 μL, 0.84 mmol). The reaction solution was stirred at rt for 10 min. The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, dried over Na2SO4 and evaporated. The product was purified via flash chromatography eluting with a gradient of 0%-100% EtOAc in heptanes to give the title compound (317 mg, 75% yield) as a 1:1 cis:trans isomeric mixture. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1H) 8.42-8.63 (m, 1H) 8.11 (s, 1H) 7.96 (br. s., 1H) 7.43-7.62 (m, 1H) 6.00-6.31 (m, 2H) 5.61 (ddd, J=9.69, 7.05, 2.64 Hz, 3H) 4.07-5.26 (m, 2H) 3.81 (d, J=5.79 Hz, 3H) 3.56 (t, J=7.93 Hz, 2H) 2.84-2.99 (m, 1H) 2.51-2.58 (m, 2H) 2.08-2.20 (m, 1H) 0.84 (t, J=8.06 Hz, 2H) −0.12 (br. s., 9H). m/z (APCI+) for C24H32N8O3Si 509.1 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]([CH3:33])[C:11]([C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([OH:31])[C:14]=1[OH:32])=[O:12].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:31][C:15]1[C:14]([OH:32])=[C:13]([C:11](=[O:12])[N:10]([CH3:33])[CH3:9])[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OCc2ccccc2)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
Benzyl bromide (3.94 mL, 33.2 mmol) was added to a stirred suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (10.5 g, 30.1 mmol), potassium iodide (5.50 g, 33.2 mmol) and K2CO3 (4.58 g, 33.2 mmol) in DMF (100 mL). The reaction was allowed to stir at 80° C. for 24 h. The reaction mixture was poured into water (200 mL), washed with Et2O (2×200 mL), and the combined organic layers were washed with 1M HCl (aq.) (400 mL), brine (2×400 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g, 0-50% EtOAc in toluene) to afford ethyl 3-(benzyloxy)-5-(dimethylcarbamoyl)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (41) (4.36 g, 33%) as a pale yellow solid: m/z 439 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.53-7.47 (m, 2H), 7.42-7.29 (m, 3H), 7.08-7.01 (m, 2H), 6.90-6.84 (m, 2H), 5.09 (s, 2H), 3.96 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.82 (br s, 6H), 0.97 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:28]#[N:29])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:28]#[N:29])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (306 mg, 1.74 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (601 mg, 2.61 mmol), HATU (992 mg, 2.61 mmol) in anhydrous DMF (15 mL) is added DIPEA (431 μL, 2.61 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-80% EtOAc in heptane) to give a pure product (106) as white solid (473 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])[C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Reactant: O=C(Cl)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1C(=O)c1ccccn1
Temperature: 85 °C
Yield: 45.5 %

Procedure:
To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (0.15 g, 0.55 mmol) in dry acetonitrile (5 mL) was added potassium carbonate (90 mg, 0.66 mmol) and 2-pyridinecarbonyl chloride (106 mg, 0.60 mmol) and the reaction mixture heated at 85° C. for 24 h. To the mixture was added ethyl acetate (30 mL) and the organic phase washed with 10% aqueous sodium bicarbonate (50 mL) before it was dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by Biotage SP4 (12+M silica column) eluting 0-4% MeOH in DCM to give the title compound as an off-white solid (95 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH:24]([C:25](O)=[O:26])[CH:23]2[CH2:28][CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH:24]([C:25](=[O:26])[NH:1][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])[CH:23]2[CH2:28][CH:20]1[CH2:21][CH2:22]2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To the solution of 2-amino-1-(4-bromo-phenyl)-ethanone (HCl salt, 1.0 g, 4 mmol) and 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (0.98 g, 4 mmol) in DMF (13 ml) was added HATU (1.64 g, 4.3 mmol), followed by slow addition of diisopropylethylamine (2.2 ml, 12.7 mmol). The mixture was stirred for 4 hours and was diluted with EtOAc. The organic phase was washed with 1 N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbarnoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g). m/z: 460.9 (M+Na)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27](B(O)O)=[CH:26][N:25]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:27]4[CH:26]=[N:25][C:24]([Cl:23])=[CH:29][C:28]=4[CH3:30])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: Cc1cc(Cl)ncc1B(O)O
Product: Cc1cc(Cl)ncc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 2-chloro-4-methylpyridine-5-boronic acid following a procedure analogous to that described for Intermediate 15. LC (method 6): tR=1.40 min; Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18][C:17]1=[O:25].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:35][C:12]([F:11])([F:34])[C:13]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[C:17](=[O:25])[CH2:18][CH2:19][CH:20]([CH:23]=[O:24])[CH2:21][CH2:22]1
Reactant: O=C1CCC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.3 %

Procedure:
To a solution of DMSO (1.40 g) in dichloromethane (100 mL) was slowly added a solution of oxalyl chloride (2.48 g) in dichloromethane (200 mL) at −78° C. The reaction mixture was stirred for 5 min, a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-5-(hydroxymethyl)azepan-2-one (6.0 g) in dichloromethane (100 mL) was added dropwise, and the mixture was stirred for 15 min. Triethylamine (8.2 g) was added and the mixture was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.76 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 58 with 5-(tert-butyldimethylsilanyloxy)pentan-1-ol gave 2-(3-(3-(5-(tert-butyldimethylsilanyloxy)pentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.725 g, 44%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.68-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=8.4, 2.0 Hz, 1H), 3.92 (t, J=6.6 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 3.64 (t, J=6.2 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H), 1.99-2.07 (m, 2H), 1.75-1.82 (m, 2H), 1.56-1.62 (m, 2H), 1.47-1.53 (m, 2H), 0.89 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [C:1]([N:6]1[CH:11]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH2:10][N:9]([C:21]([O:23][CH3:24])=[O:22])[CH2:8][CH:7]1[CH:25]=CC(OCC)=O)(=[O:5])[CH2:2][CH:3]=C.C(N(CC)CC)C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[O:5]=[C:1]1[N:6]2[C@H:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=3)[CH2:10][N:9]([C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]2[CH:25]=[CH:3][CH2:2]1
Reactant: C=CCC(=O)N1C(C=CC(=O)OCC)CN(C(=O)OC)CC1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1C[C@@H]2C=CCC(=O)N2[C@H](c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
Grubbs catalyst 2nd generation (124 mg) was added to a solution of methyl 4-(3-butenoyl)-3-(2-ethoxycarbonylvinyl)-5-(3,4,5-trifluorophenyl)piperazine-1-carboxylate (643 mg) in methylene chloride (50 mL), and the reaction solution was heated under reflux for one hour. The reaction solution was left to cool to room temperature. Then, triethylamine (0.2 mL) was added to the reaction solution, which was then stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 174 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH2:8][C:6]=2[N:7]=1.[CH:20]1([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)=[O:25])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]1([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]4[CH3:19])[C:5]4[CH2:10][S:9](=[O:12])(=[O:11])[CH2:8][C:6]=4[N:7]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CS(=O)(=O)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CS(=O)(=O)C2
Temperature: 70 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
To a solution of 2-chloro-5,7-dihydro-4-((S)-3-methylmorpholino)thieno[3,4-d]pyrimidine 6,6-dioxide (96 mg, 0.32 mmol) in DME/H2O (4:1, 10 mL) was added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (106 mg, 0.35 mmol), and Na2CO3 (102 mg, 0.96 mmol) followed by PdCl2(dppf) (15 mg, 0.02 mmol). The resulting mixture was heated to 70° C. and stirred overnight under nitrogen. The solvent was removed under vacuum to give a residue which was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and the solvent removed to give crude product which was purified by preparative TLC (DCM/MeOH=20/1) to give the desired product as a yellow solid (15 mg, 11%).
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH2:16]([O:18][C:19]([CH:21]([NH:30][C@H:31]1[CH2:36][S:35][CH:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:33]([CH2:43][C:44]([O:46]CC[Si](C)(C)C)=[O:45])[C:32]1=[O:53])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH3:17]>C(Cl)Cl>[CH2:16]([O:18][C:19]([CH:21]([NH:30][C@H:31]1[CH2:36][S:35][CH:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:33]([CH2:43][C:44]([OH:46])=[O:45])[C:32]1=[O:53])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC(c2ccccc2)N(CC(=O)OCC[Si](C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC(c2ccccc2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of trifluoroacetic acid (8 ml.) and anisole (0.4 ml.) is cooled in an ice-water bath under nitrogen and treated with (5R)-5[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B-slow isomer) (400 mg., 0.72 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed and the reaction is stirred at ambient temperature for 3 hours, then concentrated in vacuo and azeotroped with toluene. The crude product (440 mg.) is chromatographed on 150 ml. of HP-20 eluted with a gradient from 400 ml. of water:acetonitrile (5:4) to 400 ml. of 100% acetonitrile. The product containing fractions are pooled, evaporated, then precipitated from ethanol (10 ml.) by the addition of water (300 ml.). By this method 171 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H1,3-thiazine-3(4H)-acetic acid (B-slow isomer) are obtained; m.p. 130°-135°; [α]D =-36.1° (c=1, methanol). TLC (ethyl acetate:pyridine:acetic acid: water; 100:20:6:11) spot at Rf =0.79.