Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:14]#[N:15].CN1C(=O)CCC1>C(OCC)(=O)C>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Yield: 46.2 %

Procedure:
To a mixture of methyl 3-bromo-4-hydroxybenzoate (1.78 g, 7.70 mmol) and copper(I) cyanide (0.897 g, 10.02 mmol) was added NMP (10 mL). The mixture was heated to 200° C. for 2 h under microwave irradiation. The mixture was diluted with ethyl acetate and quenched with 1 N aqueous HCl solution. After the addition of brine, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography. The combined fractions were concentrated under reduced pressure and triturated with cold water to provide the title compound as an off-white solid (0.63 g). LCMS m/z=178.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 3.92 (s, 3H), 6.55 (bs, 1H), 7.04 (d, J=8.72 Hz, 1H), 8.15 (dd, J=8.72, 2.15 Hz, 1H), 8.23 (d, J=1.89 Hz, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[C:20]([NH:22][NH2:23])=[O:21])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([C:20]2[O:21][C:1](=[O:2])[NH:23][N:22]=2)[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:13])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Yield: 51.7 %

Procedure:
1,1'-Carbonyl diimidazole (0.8 g, 0.005 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid hydrazide (1.0 g, 0.004 mole) and triethylamine (0.6 ml, 0.004 mole) in tetrahydrofuran (12 ml). After 18 hours the mixture is concentrated in vacuo and the residue dissolved in ether. The solution Is washed with aqueous 2M HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO 4. Filtered and concentrated in vacuo to obtain a residue which is purified by flash chromatography using 10% ethyl acetate/hexane eluent. Recrystallize from ethyl acetate/hexane to obtain 0.6 g (1.1 g theor., 55%) 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2(3H)-one, mp 246° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24](Br)[CH3:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH:24]([C:21]2[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:12]3[C:11](=[O:27])[CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=[N:13]3)=[CH:19][CH:20]=2)[CH3:25])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(Br)c1ccc(C(=O)Cn2ncc(OCc3ccccc3)cc2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(c1ccc(C(=O)Cn2ncc(OCc3ccccc3)cc2=O)cc1)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(1-{4-[2-(4-Benzyloxy-6-oxo-6H-pyridazin-1-yl)-acetyl]-phenyl}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester is prepared following example 1.1b from 200 mg (0.47 mmol) 5-benzyloxy-2-{2-[4-(1-bromo-ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one (preparation 30c) and 262 mg (1.40 mmol) piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16]Br)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([SH:34])[NH:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([S:34][CH2:16][C:14]2[N:15]=[C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[S:12][CH:13]=2)[NH:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: O=C(Nc1nc(CBr)cs1)N(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(SCc2csc(NC(=O)N(C3CCCCC3)C3CCCCC3)n2)n1
Yield: 20 %

Procedure:
Prepared in 20% yield as described in general procedure (L) from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and 2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]([O:30][C:31]([CH2:33][S:34](Cl)(=[O:36])=[O:35])=[O:32])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([S:34]([CH2:33][C:31]([O:30][CH2:28][CH3:29])=[O:32])(=[O:36])=[O:35])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccccc1NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc(Cl)cc1)c1ccccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a stirred solution of 48 g of methyl 2-(4-chlorophenylmethylamino)-phenylacetate in 1.2 l of toluene containing 26 ml of triethylamine is added 31 g of ethoxycarbonylmethylsulfonyl chloride in 50 ml of toluene in a dropwise manner over a period of 15 minutes maintaining the temperature of the reaction below 10°. The reaction mixture is then allowed to stir overnight at room temperature and poured into 2 1 of ice-water and the organic layer separated. The toluene extracts are washed with 3×750 ml brine, separated, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 40 g of methyl 2-[N-(4-chlorophenylmethyl)-ethoxycarbonylmethylsulfonylamino]-phenylacetate which may be crystallized from ether-hexane (4:1); m.p. 86°-88°.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[N:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:41]3[CH:42]=[CH:37][N:38]=[C:39]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:40]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1ccnc(N2CCOCC2)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(N3CCOCC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 4-(4-bromopyrimidin-2-yl)morpholine following a procedure analogous to that described in Example 35. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=517 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.25 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.30 (m, 1H), 2.50 (m, 2H), 3.15 (m, 1H), 3.29 (m, 4H), 3.84 (m, 4H), 5.59 (q, 1H), 7.05 (d, 1H), 7.12 (d, 2H), 7.25-7.40 (5H), 7.94 (d, 2H), 8.17 (d, 1H).
Reaction SMILES: [OH:1][CH:2]([C:30]1[O:31][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:33][N:34]=1)[CH:3]([NH:6][C:7](=[O:29])[C:8]([CH3:28])([S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16]O[CH2:14][CH2:13]1)=[O:11])[CH2:4][CH3:5].[CH3:41]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[O:11]=[C:10]([N:12]1[CH2:17][CH2:16][CH2:41][CH2:14][CH2:13]1)[CH2:9][C:8]([CH3:28])([S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])=[O:20])[C:7]([NH:6][CH:3]([C:2]([C:30]1[O:31][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:33][N:34]=1)=[O:1])[CH2:4][CH3:5])=[O:29]
Reactant: CCC(NC(=O)C(C)(CC(=O)N1CCOCC1)S(=O)(=O)Cc1ccccc1)C(O)c1nnc(-c2ccncc2)o1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CCC(NC(=O)C(C)(CC(=O)N1CCCCC1)S(=O)(=O)Cc1ccccc1)C(=O)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (222.7 mg, 0.45 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2SO3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 78 mg of 4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; H1 NMR(DMSO-d): 9.0–8.85(3H, m), 8.1–8(2H, m), 7.44–7.3(5H, m), 5–4.9(1H, m), 4.5–4.3(2H, m), 3.6–3.2(11H, m), 3.15–3.05(1H, m), 2.7–2.5(1H, m), 2.05–1.9(1H, m), 1.8–1.7(1H, m), 0.96(3H, t); MS: 568.6(M−1), 570.6(M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:51][NH:52][O:53][CH3:54]>ClCCl>[CH3:54][O:53][N:52]([CH3:51])[C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (13.8 g, 44.8 mmol), EDCI (12.8 g, 67.2 mmol) and HOBT (7.2 g, 53.7 mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol), and the mixture was stirred at RT for 1 h, followed by the addition of N,O-dimethylhydroxylamine (5 g, 53.7 mmol). The reaction was stirred for another 3 h. LCMS showed the reaction was completed. The reaction mixture was washed with water (100 mL), and the organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (11.2 g, 67%) as a white solid. MS (ES+) C16H25N5O4 requires: 351. found: 296 [M−56+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[CH2:22][NH2:23])[CH2:2][CH2:3][CH3:4].[CH3:24][N:25]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][N:27]=[C:26]1[CH3:34].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[CH2:22][NH:23][S:30]([C:29]1[N:25]([CH3:24])[C:26]([CH3:34])=[N:27][CH:28]=1)(=[O:32])=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ncc(S(=O)(=O)Cl)n1C
Reactant: CCCCc1c(CN)cnn1-c1ncc(C)c(-c2cccs2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1c(CNS(=O)(=O)c2cnc(C)n2C)cnn1-c1ncc(C)c(-c2cccs2)n1

Procedure:
The title compound was prepared by mixing a sample of (5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-yl)methanamine, (from Step 3 of Example 36), 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride and diisopropylethylamine in dichloromethane. 1H NMR (400 MHz, CD3OD) δ 8.68 (s 1H), 7.94 (m, 1H), 7.78 (m, 1H), 7.56 (m, 1H), 7.37 (m, 1H), 7.29 (m, 1H), 4.09 (s 2H), 3.70 (s 3H), 3.18 (br t, 2H), 2.64 (s, 3H), 2.35 (s, 3H), 1.49 (m, 2H), 1.32 (m, 2H), 0.84 (m 3H). LCMS (ES+) m/z 486 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH2:10][NH:11][C:12]#[N:13])(=[O:5])[CH3:4].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C1C=CC=CC=1>[C:3]([O:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH2:10][N:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]#[N:13])(=[O:5])[CH3:4]
Reactant: CCCCCC(CCCNC#N)OC(C)=O
Reactant: CCOC(=O)C(C)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC(CCCN(C#N)CCCCCC(C)C(=O)OCC)OC(C)=O
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (57% in mineral oil) (5.0 g., excess) in a solvent mixture of benzene (75 ml.) and dimethylformide (75 ml.) is treated, over 30 minutes, with 4-acetoxynonylcyanamide (22.6 g., 0.1 mole) (Example O, Step 5) dissolved in benzene (20 ml.). Stirring is continued for one hour. Then, ethyl 7-bromo-2-methylheptanoate (Example L, Step 4) (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath for 3.5 hours. The cooled reaction is poured into water (400 ml.) and extracted with ethyl acetate (2 × 200 ml.). The organic fractions are combined, washed with brine, then dried over sodium sulfate. The solvent is removed in vacuo to give ethyl 7-[N-(4-acetoxynonyl)cyanamido]-2-methylheptanoate as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@@H:7]([CH2:9][CH2:10]O)[CH3:8])[CH3:3].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1COCC1.CCCCCC>[I:36][CH2:10][CH2:9][C@@H:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: CC(C)=CCC[C@H](C)CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CCC[C@H](C)CCI
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 3.12 g (20.0 mmol) of (S)-(-)-β-citronellol (purchased from Aldrich Chem. Co.) and 2.72 g (40.0 mmol) of imidazole in 50 mL of THF at 0° C. was treated with 5.0 g (19.5 mmol) of triphenylphosphine followed by 4.83 g (19.0 mmol) of I2 in 25 mL of THF dropwise over 20 minutes. The reaction mixture was stirred for 1.0 hour and was diluted with hexane. The organic mixture was washed with aqueous Na2SO3, brine, dried (Na2SO4) and evaporated to provide a crude white slurry. The slurry was purified by flash chromatography (300 g of silica gel) eluting with hexane to provide 4.00 g (79%) of title iodide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:17]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:17]
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3ccccc3o2)cc1I
Yield: 65.8 %

Procedure:
2-(4'-Aminophenyl)benzoxazole (0.14 g, 1.9 mmol) was treated with iodine monochloride (0.37 g, 2.23 mmol) in acetic acid according to the above-described general procedure for iodination. Crude product was purified by flash chromatography on silica gel using ethyl acetate-hexane (1:2) as eluent to give a brown powder (0.42 g, 65.7%), m.p. 188.0-191.2° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH3:40])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([C:33](OC)([O:36]C)[O:34][CH3:35])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:35][O:34][C:33]([C:31]1[CH:30]=[N:29][C:28]2[N:27]([N:26]=[CH:25][C:24]=2[C:22]2[CH:23]=[C:19]([C:17](=[O:18])[NH:16][C@@H:9]3[C@H:8]([NH2:7])[CH2:13][CH2:12][CH2:11][C:10]3([F:14])[F:15])[S:20][C:21]=2[CH3:40])[CH:32]=1)=[O:36]
Reactant: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](NC(=O)OC(C)(C)C)CCCC4(F)F)sc3C)cnn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](N)CCCC4(F)F)sc3C)cnn2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl{(1R,2R)-3,3-difluoro-2-[({5-methyl-4-[6-(trimethoxymethyl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophen-2-yl}carbonyl)amino]cyclohexyl}carbamate (45 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (275 μL, 3.55 mmol) added. The reaction mixture was stirred at room temperature for 1 h, neutralized with saturated sodium bicarbonate (aq) and extracted 3× with dichloromethane. The organic layers were combined and dried with sodium sulfate, concentrated and purified by column chromatography (0-10% MeOH/DCM) to afford the title compound (quantitative yield). LRMS (APCI) calc'd for (C20H21F2N5O3S) [M+H]+, 450.1; found 450.1. 1H NMR (CDCl3, 500 MHz) δ 9.33 (s, 1H), 9.03 (s, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 6.98 (d, J=8.1, 1H), 4.45 (d, J=25.3, 1H), 4.01 (s, 3H), 3.34 (s, 1H), 2.60 (s, 3H), 2.18 (s, 1H), 1.70-1.90 (s, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[C:14]([O:21]C(=O)C)[CH:13]=1.Cl>CN(C)C1C=CC=CC=1.CC(C)=O.[OH-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Cl:10])[C:5]=1[OH:9])[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH3:11])=[CH:13][C:14]=1[OH:21]
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)Nc2cc(Cl)c(O)c(Cl)c2)c(O)c1
Yield: 72.5 %

Procedure:
4-Amino-2,6-dichlorophenol (16 g.) was put into solution in N,N-dimethylaniline (15 ml.) and acetone (200 ml.), to which the acetone solution of 4-methyl-2-acetoxybenzoyl chloride was added dropwise. After reaction for several hours, by condensing and then acidifying the solution with 4 N hydrochloric acid a precipitate was obtained, which was redissolved in 2 N sodium hydroxide solution. The solution was made acidic with dilute hydrochloric acid, thereby precipitating the product which was recrystallized from aqueous acetone to give white crystals (20.3 g.) of 3',5'-dichloro-2,4'-dihydroxy-4-methylbenzanilide. Yield: 72.5%. The melting point was 246°-247° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9].[C:10]1([C:16]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:9]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccccc3)c(-c3ccccc3)nc2c1

Procedure:
1,2-Diamino-4-methylbenzene (25.0 g, 0.20 mol) and benzil (43 g, 0.20 mol) were refluxed in ethanoic acid (250 ml) overnight. The solvent was evaporated in vacuo and the black residue recrystallised three times from ethanol to give pale brown crystals of 6-methyl-2,3-diphenylquinoxaline, 39.6 g, 65% (m.pt. 114.5-116° C. (lit.iv 115-116° C.)). 1H NMR (CDCl3, 300 MHz) δ 8.08 (d, J 8.4 Hz, 1H, Hs of quinoxaline), 7.97 (bs, 1H, Hs of quinoxaline), 7.60 (d of d, J 8.4 Hz, J 1.8 Hz, 1H, Hs of quinoxaline), 7.50-7.58 (m, 4H, phenyl rings), 7.30-7.38 (m, 6H, phenyl rings), 2.62 (s, 3H, Ch3).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:28])[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=C(C(OO)=[O:45])C=CC=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:28])[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)=[O:45]
Reactant: CSc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To the suspension of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide (0.28 g, 0.52 mmol) (from Example 80 supra) in dichloromethane (5 mL) was added the suspension of 3-chloro-benzenecarboperoxoic acid (133 mg, 0.78 mmol) (Aldrich) in dichloromethane (2 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with 10% of sodium sulfite solution, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methanesulfinyl-phenyl)-amide as a grey solid (Yield 0.16 g, 57%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>ClCCl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH3:27]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCNCC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(N(CC)CC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (229 mg) and diethylamine (420 mg) in dichloromethane (8 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was eluted from a silica column with diethyl ether:chloroform (4:1) and the combined fractions containing product were evaporated under reduced pressure to yield an oil which on trituration with 40-60° petroleum ether yielded the title compound, 85.5 mg, m.p. 116-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH:8]([CH3:28])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 394.6 %

Procedure:
6,7-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one 0.1 g, 0.024 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.6 mL, 0.61 mmol) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.040 mL, 0.61 mmol) was added slowly, warmed to room temperature and stirred for 4 h. Saturated NH4Cl (10 mL) was added to the reaction mixture and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to obtain the title compound (0.04 g, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.49 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 2.98-2.85 (m, 2H), 2.71-2.66 (m, 1H), 2.43 (s, 3H), 2.27-2.23 (m, 1H), 1.96-1.89 (m, 1H), 1.25-1.17 (m, 3H).