Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])C=C[C:7]=1[Cl:8].[NH:25]1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.ClC1N=C(C(O)=O)C=CC=1>>[Cl:8][C:7]1[N:25]=[C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Agent: O=C(O)c1cccc(Cl)n1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1cccc(Cl)n1
Yield: 49 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 64, indoline-5-sulfonamide (Intermediate 54A, 300 mg, 1.51 mmol) and 6-chloropicolinic acid (262 mg, 1.66 mmol) were converted to the title compound (250 mg, 49%). 1H NMR (DMSO-d6) δ 8.69 (d, J=2.0 Hz, 1H), 8.15-8.13 (m, 2H), 7.72-7.67 (m, 3H), 7.27 (s, 2H), 4.11 (t, J=8.4 Hz, 2H), 3.17 (t, J=8.4 Hz, 2H); MS(ESI+) m/z 338.1 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:11]1[C:15]2[C:16](=[O:33])[N:17](CCS(C3C=CC=CC=3)(=O)=O)[N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[C:12]1[N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35]1)[C:8]#[C:9][CH3:10]>O1CCCC1.O>[CH2:7]([N:11]1[C:15]2[C:16](=[O:33])[NH:17][N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[C:12]1[N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35]1)[C:8]#[C:9][CH3:10]
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)n(CCS(=O)(=O)c3ccccc3)c(=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.11 g potassium-tert-butoxide are added to a solution of 0.52 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione in 5 ml of tetrahydrofuran. The solution is stirred for 10 min at ambient temperature and then diluted with water. It is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is then removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1.NN>[Pd].C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccn2)cc1
Agent: [Pd]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
2-(4-Nitrophenyl)pyridine (1.10 g) and 10% Pd/C (300 mg) were dissolved suspended in 80 mL of an 8:1 solution of 30 mL of THF and 10 mL of ethanol under an atmosphere of dry N2. To this solution was added 1.0 mL of anhydrous hydrazine. The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum. The residue was partitioned between dichloromethane and water and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified via silica gel chromatography to give 653.3 mg of 4-(pyridin-2-yl)benzenamine.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.OO.[OH2:18].C(O)(=[O:21])C>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6](=[O:21])(=[O:18])[C:5]3[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: O
Reactant: Brc1ccc2sc3ccc(Br)cc3c2c1
Reactant: CC(=O)O
Agent: OO
Product: O=S1(=O)c2ccc(Br)cc2-c2cc(Br)ccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 2,8-dibromo-dibenzothiophene (2.50 g, 7.4 mmol; TCl-US) in acetic acid (20 mL; EM Science) was added 30% hydrogen peroxide (10 mL; JT Baker). The solution was heated at reflux overnight (16 h), then cooled to room temperature, 25 mL of water added and the resulting solid was collected by filtration, washed with excess water to afford the title compound (1.65 g, 4.4 mmol, 60% yield). MS(DCl/NH3): m/z 392 (M+18)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)c(F)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(F)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,4-difluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=270.29.
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([S:32]([Cl:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[ClH:35].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([S:32]([N:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(OC)c2)c1
Product: Cl
Yield: 67.8 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (200 mg), sodium hydride (60% in oil, 140 mg) and 3-methoxybenzenesulfonyl chloride (433 mg), a procedure as in Example 36 was performed to give the title compound as pale-purple crystals (yield 186 mg, 68%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])=[O:6])[CH3:2]>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])=[O:6])[CH3:2]
Reactant: CCOCCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Product: CCOCCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To ethoxyethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)-propanoate (0.25 ml of a solution containing 2 mg/ml in phosphate buffer 0.1M pH 7) was added the enzyme (amount indicated below) diluted in phosphate buffer 0.1M pH 7 (buffer volume such as total reaction mixture volume was 0.5 ml). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixture was analysed by the gradient HPLC method 1, and the chiral CE method 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[I-:10].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.Cl>CN(C=O)C.O>[I:10][C:8]1[CH:7]=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(O)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(O)ccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxyphenol (2.0 ml, 18.2 mmol) was dissolved in dry DMF (50 ml). Sodium iodide (3.3 g, 21.9 mmol) and chloramine-T (5.0 g, 21.9 mmol) was added to the mixture and the reaction was stirred at room temperature for one hour. The reaction mixture was diluted with water (150 ml), acidified with 5% hydrochloric acid solution and extracted with ethyl acetate (2×100 ml). The organic layer was washed with 5% sodium thiosulphate solution (200 ml) and dried over sodium sulphate. The product was purified by flash chromatography on silica gel twice (first with dichloromethane, then with 20% ethyl acetate in petroleum ether). The yield was 0.82 g (18%). 1H NMR (CDCl3, 500 MHz): δ 7.52 (1H, d, J=8.5 Hz), 6.63 (1H, d, J=3.0 Hz), 6.37 (1H, dd, J=8.5 Hz, 3.0 Hz), 5.27 (1H, s), 3.81 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: COc1ccccc1N=C=O
Product: COc1ccccc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3ncccc23)cc1

Procedure:
83.6 mg of solid beige-coloured 3-{4-[3-(2-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-methoxyphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:26])[C:9]=2[C@H:27]([OH:33])[C:28]([O:30]CC)=[O:29])=[CH:4][CH:3]=1.[BH4-].[Na+].BrC1C=[C:45]2[C:40]([CH:41]=C(C)C(C(=O)C(OCC)=O)=C2C2C=CC(Cl)=CC=2)=[CH:39]C=1.[CH3:62][C:63]([OH:67])([C:65]#[CH:66])[CH3:64]>CC#N.O>[C:40]([O:33][C@@H:27]([C:9]1[C:10]([CH3:26])=[CH:11][C:12]2[C:17](=[CH:16][C:15]([C:66]#[C:65][C:63]([OH:67])([CH3:64])[CH3:62])=[CH:14][CH:13]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:28]([OH:30])=[O:29])([CH3:45])([CH3:41])[CH3:39]
Reactant: C#CC(C)(C)O
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC(C)(C)O)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (99) was prepared by the method of Example 67 using the reduction method of Example 51 step 3 for (S)-ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH4 step, from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. The remainder of the sequence follows the method of Example 67 using 2-methylbut-3-yn-2-ol in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 3H), 7.38 (d, J=9 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 7.26 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.51 (s, 6H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.40.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:17][CH2:18][C:19]([C:21]1[CH:26]=[C:25]([S:27](=[O:30])(=[O:29])[NH2:28])[C:24]([Cl:31])=[CH:23][C:22]=1[Cl:32])=[O:20]>C(OCC)(=O)C>[BrH:17].[Cl:32][C:22]1[CH:23]=[C:24]([Cl:31])[C:25]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:26][C:21]=1[C:19]1([OH:20])[CH2:18][S:9][C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:10]1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Reactant: S=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCOC(C)=O
Product: Br
Product: NS(=O)(=O)c1cc(C2(O)CSC(=NC3CCCCC3)N2C2CCCCC2)c(Cl)cc1Cl
Reaction time: 8 h

Procedure:
2.4 g of 1,3-dicyclohexyl-thiourea were added to 3,5 g of 2-bromo-2',4'-dichloro-5'-sulfamoylacetophenone in 40 ml of ethyl acetate. The whole was allowed to stand overnight at 20° C, the crystals were filtered off and washed with ethyl acetate. M.p. 161°-163° C.
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](O)=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[NH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O.O[N:32]1C2C=CC=CC=2N=N1.CN(C)CCCCN=C=NCC.CN1CCOCC1>ClCCl>[C:25]1([C:23]2[N:32]=[C:18]([CH:17]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][NH:8]3)[NH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC(=O)c1ccccc1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)O
Agent: CCN=C=NCCCCN(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tertbutyl ester (2.77 g, 10 mmol) and 2-amino-1phenyl-ethanone (1.71 g, 10 mmol), and HOBT (1-hydroxybenzo-triazole) (2.70 g, 20 mmol) were dissolved in dichloromethane (100 ml). The solution was cooled to 0° C. and then (4-dimethylamino-butyl)-ethyl-carbodiimide (2.29 g, 12 mmol) was added followed by NMM (N-methyl-morpholine) (1.31 g, 13 mmol). The reaction mixture was then warmed to room temperature. After 72 hours the reaction mixture was extracted with water, and the organic phase extracted consecutively with saturated NaHCO3, 2N citric acid and NaHCO3, dried over MgSO4, filtered and concentrated to yield the title product as a yellow foam. Liquid chromatography (LC) indicated the compound was 86% pure (214 nm), and was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N([CH2:15][CH3:16])CC)C.[CH2:17]([OH:19])[CH3:18]>[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH:17]([C:18]2[CH:16]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=2)[OH:19])=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc(Br)cc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Product: O=C(c1ccc(Br)cc1)C(O)c1ccc(Br)cc1
Yield: 100 %

Procedure:
A solution of 4-bromobenzaldehyde (25.0 g, 0.135 mol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (1.70 g, 0.0068 mol) and triethylamine (4.10 g, 0.0405 mol) in ethanol (125 mL) is stirred at room temperature for 60 hours. The reaction mixture is concentrated to dryness, then taken up in CH2Cl2 (150 mL), washed with 1 M HCl and saturated aqueous NaHCO3 and dried (Na2SO4), then concentrated, giving 25.2 g (100 percent) of a viscous yellow oil which solidifies upon standing at room temperature. 1H NMR (CDCl3) δ 7.73 (d, J=8.5 Hz, 2H), δ 7.52 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H) 13C NMR (CDCl3) δ 197.33, 137.56, 132.33, 132.13, 131.90, 130.43, 129.46, 129.31, 122.93, 75.68.
Reaction SMILES: ClC1C=C(NC2N=C(N[C@@H]3C[C@H]4N(CCC4)C(C)(C)C3)C(F)=CN=2)C=CC=1OCCO.F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[N:42]1[C:46](=[O:47])[N:45]([CH3:48])[N:44]=[N:43]1.CC(C)([O-])C.[K+].[Si:55]([O:62][CH2:63][C@@H:64]([OH:66])[CH3:65])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]>C1COCC1>[Si:55]([O:62][CH2:63][C@@H:64]([O:66][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[N:42]1[C:46](=[O:47])[N:45]([CH3:48])[N:44]=[N:43]1)[CH3:65])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Agent: CC(C)(C)[O-]
Agent: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1ccc([N+](=O)[O-])cc1-n1nnn(C)c1=O

Procedure:
A similar procedure as detailed above for Compound 133 was used. 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (prepared according to US patent application 20110130415) (239 mg, 1.0 mmol), potassium tert-butoxide (146 mg, 1.2 mmol) and (S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (Milestone PharmaTech) (209 mg, 1.1 mmol) in THF (10 mL) was stirred for 2 hr at room temperature to give the product after workup (yield assumed quantitative=410 mg). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:30])[N:6]([CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12])#[N:2].[H][H].O.[ClH:34]>CO.C(O)C.[Pd]>[ClH:34].[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:30])[N:6]([CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12]
Reactant: [H][H]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(C#N)c3C2=O)ccc1OC
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Yield: 80 %

Procedure:
A mixture of 4-cyano-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione (0.5 g, 1.17 mmol) and 10% Pd/C (0.15 g) in 4 N hydrochloric acid (1 mL) and methanol (40 mL) was hydrogenated in Parr Shaker apparatus under 50 psi of hydrogen overnight. To the resulting slurry was added water (2 mL) to dissolve the product. The reaction mixture was then filtered through Celite and the filtrate was concentrated in vacuo. The residue was slurried in ethyl acetate (10 mL) to afford 0.52 g of the crude product. The product was reslurried in hot ethanol (15 mL) to afford 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione hydrochloride (0.44 g, 80% yield): mp 237-239° C.; 1H NMR (DMSO-d6) δ 8.79 (s, 3H, Ar), 8.04-7.89 (m, 3H, Ar), 7.11-6.91 (m, 3H, Ar), 5.83-5.77 (dd, J=4.2, 10.1 Hz, 1H, NCH), 4.49-4.47 (m, 2H, CH2), 4.41-4.31 (m, 1H, CHH), 4.21-4.13 (m, 1H, CHH), 4.04 (q, J=6.8 Hz, 2H, CH2), 3.73 (s, 3H, CH3), 3.64 (s, 3H, CH3), 1.32 (t, J=6.8 Hz, 3H, CH3); 13C NMR (DMSO-d6) δ 167.48, 166.93, 148.95, 147.87, 135.39, 134.71, 132.82, 131.32, 129.50, 128.30, 123.34, 119.89, 112.55, 111.79, 63.87, 55.52, 53.07, 47.46, 41.08, 36.84, 14.66; Anal. Calcd for C21H25N2O6SCl: C, 53.79; H, 5.37; N, 5.97; S, 6.84; Cl, 7.56. Found: C, 53.49, H, 5.47; N, 5.75; S, 6.61; Cl, 7.51.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:31])=O)(C)(C)C.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:17][CH:18]=2)=[CH:27][C:26]=1[O:28][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: C[C@@H]1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1cc(-c2ccc(C(=O)N3CC(C)NC(C)C3)cc2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a mixture of (2R,6S)-4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF (2 mL) was added 2 M Cs2CO3 (0.35 mL, 0.7 mmol) followed by water (0.5 mL). The mixture was stirred at room temperature overnight. LCMS showed the reaction was completed, DMF was removed, followed by addition of 4 N HCl in dioxane (2 mL) and the reaction was stirred at room temperature for 3 hr. The volatiles were removed followed by addition of methanol. This solution was purified by prep-HPLC to afford {4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone (47 mg, yield 46.6%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12].C([O-])(=O)C.[Na+]>O>[Cl:3][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:12][CH:8]=[O:9]
Reactant: CC(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=CC=C(Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
80 g Phosphoryl chloride were added dropwise to 80 ml cooled dimethyl formamide. 48 g acetophenone were added over 45 minutes and the mixture stirred at 0° C. for a further 60 minutes. After standing at room temperature overnight the mixture was poured into a solution of 600 g sodium acetate in 1500 ml water. β-Chlorocinnamaldehyde separated as a red oil. The mixture was ether extracted and the ethereal solution dried over anhydrous sodium sulphate. Evaporation of the ether yielded 44 g of β-chlorocinnamaldehyde. β-Chlorocinnamaldehyde and malonic acid were condensed to give δ-chlorocinnamylidene malonic acid and this was converted to the corresponding chlorosulphonyl derivative using the method described in Example 1(a).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:38][C@H:37]3[N:33]([CH2:34][CH2:35][CH2:36]3)[C:32]([CH3:40])([CH3:39])[CH2:31]2)[C:26]([C:41]#[N:42])=[CH:25][N:24]=1.C1(S(O)(=O)=O)C=CC=CC=1>CC(O)C>[CH3:39][C:32]1([CH3:40])[CH2:31][C@H:30]([NH:29][C:27]2[C:26]([C:41]#[N:42])=[CH:25][N:24]=[C:23]([NH:1][C:2]3[CH:7]=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[C:5]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[CH:4][C:3]=3[F:21])[N:28]=2)[CH2:38][C@H:37]2[N:33]1[CH2:34][CH2:35][CH2:36]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2OCC(C)(C)O)c1=O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2OCC(C)(C)O)c1=O
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A mixture of 1-(5-amino-2-(2-hydroxy-2-methylpropoxy)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (305 mg), (7R,8aS)-N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (262 mg), and benzenesulfonic acid (160 mg) in IPA (2 mL) were heated to 80° C. overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-30%) to give desired product (386 mg, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([CH:17]=[O:18])=[C:15]([OH:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([CH:17]=[O:18])=[C:15]([O:22][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 4-(3-benzyloxy-phenoxy)-2-hydroxy-6-methyl-benzaldehyde (2.5 g, 6.5 mmol) and Et3N (2.72 mL, 19.5 mmol) in DCM (60 mL) at −78° C. was added Tf2O (1.64 mL, 9.76 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Water was added and the solution extracted with DCM (2×25 mL). The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane:EtOAc 80:20) to give trifluoro-methanesulfonic acid 5-(3-benzyloxy-phenoxy)-2-formyl-3-methyl-phenyl ester (2.8 g, 93%). 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 7.43-7.32 (m, 6H), 6.90 (dd, J=2.0, 8.4 Hz, 1H), 6.79-6.67 (m, 4H), 5.06 (s, 2H), 2.61 (s, 3H). MS (ESI) m/z=467 [M+H]+.