Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[CH2:24][CH2:25]1)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1

Procedure:
To a solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (140 mg, 0.37 mmol) in DCM (4 mL) p-toluenesulfonic acid monohydrate (6 mg) and 3,4-dihydro-2H-pyran (38 μl, 0.42 mmol) were added at room temperature. After stirring for 1 h and 10 min saturated NaHCO3 was added. It was extracted with DCM, washed with brine, dried (MgSO4) and evaporated. The crude material was chromatographed over silica gel (prewashed with Et3N) (hexane:EtOAc—9:1 as eluent) yielding pure 3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (83 mg, 48%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]#[CH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1C2CCCC1CCC2.B(O)O.Br[C:23]1[CH:56]=[CH:55][C:26]([CH2:27][C:28]2[N:29]([C:41]3[CH:42]=[C:43]([N:47]4[S:51](=[O:53])(=[O:52])[NH:50][C:49](=[O:54])[CH2:48]4)[CH:44]=[CH:45][CH:46]=3)[CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[N:32]=2)=[CH:25][CH:24]=1>C1COCC1>[CH:1]1([CH2:7][CH:8]=[CH:9][C:23]2[CH:56]=[CH:55][C:26]([CH2:27][C:28]3[N:29]([C:41]4[CH:42]=[C:43]([N:47]5[S:51](=[O:52])(=[O:53])[NH:50][C:49](=[O:54])[CH2:48]5)[CH:44]=[CH:45][CH:46]=4)[CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[N:32]=3)=[CH:25][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: C#CCC1CCCCC1
Agent: B1C2CCCC1CCC2
Agent: OBO
Solvent: C1CCOC1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(C=CCC4CCCCC4)cc3)c2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-cyclohexyl-1-propyne (145 μL, 1 mmol) in 2 mL dry THF at 0° C. was added 2 mL 0.5 M 9-BBN solution in THF. The resulting solution was stirred at room temperature under nitrogen for 4 hr. Then it was condensed under vacuum and used as boronic acid derivative according to general procedure G, reacting with 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) to give 5-{3-[2-[4-(3-cyclohexyl-propenyl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:38])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[C:48]([N:34]1[CH2:35][CH2:36][CH:31]([CH2:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]3[CH3:38])=[O:37])=[CH:24][CH:25]=2)[CH2:32][CH2:33]1)(=[O:50])[CH3:49]
Reactant: CC(=O)Cl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CCNCC3)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(piperidin-4-ylmethoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide (0.075 g, 0.14 mmol) was dissolved in dichloromethane at room temperature. DIEA (0.1 mL, 0.56 mmol) and acetyl chloride (0.2 mL, 2.8 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (0.049 g, 49%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][N:29]1[C@H:36]([C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:51]=[C:50]([CH3:58])[CH:49]=3)=[CH:42][CH:41]=2)=[O:38])[C@@H:35]([C:59](O)=[O:60])[CH2:34][C:31]2([CH2:33][CH2:32]2)[CH2:30]1.Cl.NO.CN1CCOCC1>CN(C=O)C>[OH:17][NH:8][C:59]([C@H:35]1[CH2:34][C:31]2([CH2:32][CH2:33]2)[CH2:30][N:29]([CH3:28])[C@@H:36]1[C:37]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:51]=[C:50]([CH3:58])[CH:49]=2)=[CH:44][CH:45]=1)=[O:38])=[O:60]
Reactant: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)O)CC4(CC4)CN3C)cc2)c2ccccc2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)NO)CC4(CC4)CN3C)cc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To BOP (120.0 mg, 0.24 mmol) was added to a solution of (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylic acid (140 mg, 0.20 mmol) in DMF (1.0 mL) at 0° C. followed by hydroxylamine hydrochloride (28.0 mg, 0.40 mmol). 4-methylmorpholine (0.07 mL, 0.70 mmol) was then added to the above mixture at 0° C. and stirred at this temperature for 2 h. The product (70 mg) was purified by preparative HPLC. ESI (M+H)+475.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][OH:12].[H-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(SC)n1

Procedure:
4,6-dichloro-2-(methylthio)pyrimidine (Compound IV-5) (19.5 g, 0.100 mol) was dissolved in tetrahydrofuran (200 ml) just after distilled, then methyl alcohol (3.2 g, 0.100×1.0 mol) was added thereto. While cooling with ice, 60% sodium hydride (4.4 g, 0.100×1.1 mol) was added thereto while stirring. After stirred for 3 hours, the reaction solution was poured into water and extracted with toluene. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off to obtain the compound (IV-29).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Reactant: Nc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C)CCN1c1nccc(N)n1
Temperature: 220 °C
Yield: 18.4 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), Hunig's base (809 μl, 4.63 mmol) and (3R)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (650 mg, 3.47 mmol) in N,N-dimethylformamide (DMF) (3 ml) was heated in a microwave reactor at 220° C. for 60 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 18% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[S:14][CH:15]=[C:16]([CH3:17])[C:12]=2[C:11](=[O:18])O[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1C(=O)N(CC2C=CC=CC=2)C2SC=CC=2C=1O)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1[C:9](=[O:19])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]2[S:14][CH:15]=[C:16]([CH3:17])[C:12]=2[C:11]=1[OH:18])=[O:24])[CH3:21]
Reactant: Cc1csc2c1c(=O)oc(=O)n2Cc1ccccc1
Reactant: CCOC(=O)c1c(O)c2ccsc2n(Cc2ccccc2)c1=O
Product: CCOC(=O)c1c(O)c2c(C)csc2n(Cc2ccccc2)c1=O
Yield: 80 %

Procedure:
This compound was prepared from 1-benzyl-5-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (59) by applying the same method described for the preparation of 7-benzyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (60). Yield 80%; MP 166° C. 1H-NMR (DMSO-d6): δ 1.32 (t, J=6.8 Hz, 3H), 2.40 (d, J=1.2 Hz, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.22 (s, 2H), 6.84 (d, J=1.2 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 14.04 (b, 1H) ppm; EIMS m/z 344 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:13][C@@H:14]1[C@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:17]([CH2:27][O:28][CH3:29])[O:16][C@H:15]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH2:54][OH:55])=[N:34][C:35]=2[NH:39][CH2:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:55][CH2:54][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[C@H:15]2[C@H:14]([O:13][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8])[C@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21])[C@@H:17]([CH2:27][O:28][CH3:29])[O:16]2)=[C:35]([NH:39][CH2:40][CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:34]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CO)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Methanesulfonyl chloride (0.6 ml, 7.7 mmol) was slowly added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methanol (4.22 g, 5.87 mmol) (preparation 15) and triethylamine (1.2 ml, 8.62 mmol) in dichloromethane (50 ml) and the mixture stirred at room temperature for 30 minutes. Triethylamine (1 ml, 7.2 mmol) and methanesulfonyl chloride (0.5 ml, 6.4 mmol) were then added and stirring continued for a further 15 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (1:3) changing to ethyl acetate:pentane (1:1) to afford the title compound as a gum (4.52 g). MS: 820 (MNa+).
Reaction SMILES: CI.[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1C[O:13][CH2:12][CH2:11]1.C(C1C=CC=CC=1)C>C1COCC1>[O:13]1[C:12]2[C:6](=[CH:7][CH:8]=[CH:9][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCCCCCC
Reactant: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CI
Product: c1ccc2c(c1)CCCO2
Reaction time: 0.25 h

Procedure:
To 0.9 g (4 mmole) of sulfone ketone in 40 ml of THF is added 2.5 ml (5 mmole, 1.25 eq.) of 2 M of Lithium diisopropylamine(LDA) in heptane/THF/ethylbenzene at −60° C. The mixture is stirred for about 15 minutes, and then 1.24 ml (20 mmole, 5 eq.) of methyl iodide is added. The reaction mixture is stirred for 1 hour at −60° C., and then the cold bath is removed. After stirring overnight, the reaction mixture is partitioned between EtOAc and water, washed with 0.5N HCl, aqueous sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to afford 0.68 g of the desired product as an oil, which solidified upon standing. TLC (30% EtOAc/Hexane, Rf=0.39). Mass spec. m/e=239.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1COCC1>[C:14]([O:13][C:11](=[O:12])[CH2:10][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCC1=O
Yield: 97 %

Procedure:
A mixture of 2-pyrrolidone (2.66 ml, 34 mmol) and NaH (60% in oil, 1.25 g, 31.3 mmol) in THF (75 ml) was stirred until gas evolution ceased (30 min). tert-Butyl 2-bromoacetate (4.45 ml, 30 mmol) was added and stirred at r.t. overnight then partitioned between water (200 ml) and ethyl acetate (200 ml) to give intermediate 2-(oxo-pyrrolidin-1-yl)-acetic acid tert-butyl ester (5.8 g). It was dissolved in acetic acid (40 ml) and cone. aq. HCl (6 ml) with gas evolution observed. After stirring at r.t. for 2 hours it was evaporated and recrystallized from toluene/ethanol to give 2.58 g of the title compound (60% yield). 1H NMR (500 MHz, DMSO-d6): 1.95 (quintet, J=7.7 Hz, 2H), 2.24 (t, J=8.1 Hz, 2H), 3.38 (m, overalapping with H2O (3.35 ppm), 2H), 3.91 (s, 2H), 12.77 (br., 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH3:10].[CH3:11][O:12][CH:13](Cl)Cl.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:12][C:13]1[C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[CH:7][C:8]=1[CH:3]=[O:2]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C)cc1C=O
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of 1-methoxy-2,4-dimethylbenzene (8.00 g, 58.7 mmol) and 1,1-dichloromethyl methyl ether (7.40 g, 64.7 mmol) in methylene chloride (30 mL) was added titanium tetrachloride (20.0 g, 105 mmol) at 0° C. and the mixture was stirred at that temperature for 20 minutes. This reaction mixture was poured into iced water and the organic layer was taken, washed with saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 9.40 g of the title compound. Yield 98%. Oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:14][CH:15]1[CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:14][CH:15]1[CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: NC1CCCNC(=O)C1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC2CCCNC(=O)C2)cc1OC
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N,N'-Carbonyldiimidazole (9.79 g) was added to a solution of 3,4-dimethoxybenzoic acid (10.0 g) in THF (300 ml) and the whole was stirred for 30 mins. at room o temperature. Then, following by addition of 3-amino-ε-caprolactam (7.04 g), the mixture was stirred for 5 hrs. The resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (8.5 g). This product used in the following reaction without purification. m.p. 190°-191°.
Reaction SMILES: [CH2:1]1[O:4][C@@H:2]1[CH3:3].[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>>[OH:4][C@H:2]([CH3:3])[CH2:1][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: C[C@@H]1CO1
Product: COC(=O)c1ccc(SC[C@@H](C)O)cc1

Procedure:
100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)ccc1Cl
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-chloro-5-fluorophenyl)methanol (24, 25.5 g, 159 mmol) in dry DME (200 mL) at 0° C. was added a solution of PBr3 (25.8 g, 95.2 mmol) in dry DME (150 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at RT for another 3 h. The mixture was diluted with water (300 mL), and extracted with 1:1 petroleum-ether-EtOAc (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give 2-(bromomethyl)-1-chloro-4-fluorobenzene (25).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[NH2:9][CH2:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: [H][H]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCc1cncc(F)c1
Reaction time: 18 h

Procedure:
In a Parr Bottle add 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105 mol), ethanol (336 mL), triethylamine (24 mL), and 5% Pd/C (4 g). Place on a Parr Shaker Apparatus under 60 psi hydrogen for 1 h at ambient temperature. Filter the reaction mixture and bubble ammonia gas into filtrate for 10 min. Add Raney® nickel (5.2 g) and place on a Parr Shaker Apparatus under 500 psi hydrogen for 18 h at 60-70° C. Filter the reaction mixture and concentrate in vacuo. Dissolve in methanol and add 1N hydrogen chloride in ether until form a precipitate. Cool in an ice bath, filter off the precipitate, wash the solid several times with ether, and dry to give the title compound as the hydrochloride salt (12 g, 70%). MS (ES+) m/z: 127 (M+H)+. Dissolve the hydrochloride salt in water, add 0.1 N aqueous NaOH to adjust to pH 10, extract with DCM, dry the organic layer over Na2SO4, filter and concentrate to give the title compound.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18]([O:20][CH3:28])=[O:19])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of Boc-L-Lys(Z)OH (2.00 g, 5.2 mmol) in dry DMF (50 mL) was added Cs2CO3 (1.71 g, 5.2 mmol). The mixture was stirred at rt for 2 h. To the reaction mixture was then added dropwise methyl iodide (392 μL, 6.3 mmol) and the mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (2.00 g, yield 97%). Intermediate 31 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 7.34 (m, 5H), 7.23 (t, 1H), 4.99 (s, 2H), 3.91 (m, 1H), 3.60 (s, 3H), 3.34 (s, 2H), 2.96 (m, 2H), 1.56 (m, 2H), 1.37 (m, 11H), 1.32 (m, 2H).
Reaction SMILES: CC(CC(O)CO)C.[F-:9].[K+].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C1(C)C(C)=CC=CC=1>>[Cl:18][C:17]1[C:12]([F:9])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: [F-]
Agent: CC(C)CC(O)CO
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 150 °C
Reaction time: 6 h

Procedure:
In a 1-liter flange flask fitted with a distillation bridge and stirrer, 29 g (0.06 mol) of polyethylene glycol dimethyl ether 500 and 139 g (2.4 mol) of potassium fluoride were introduced at 120° C. into the melt of 576 g (3.0 mol) of 2,3-dichloronitrobenzene. Subsequently, 20 g (0.19 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 60 mbar and heating to 150° C. After the xylene had been distilled off, the distillation bridge was replaced by a reflux condenser, the reaction suspension was heated to 190° C. and stirred for 6 hours at this temperature. Amount of 3-chloro-2-fluoronitrobenzene formed: 11 GC area-% after 6 hours.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:20]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: OB(O)c1ccccc1
Reactant: O=c1c2cc(F)ccc2cc(-c2ccc(O)cc2)n1Cc1ccc(F)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)ccc2cc(-c2ccc(Oc3ccccc3)cc2)n1Cc1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (54 mg, 0.14 mmol), a compound of formula (Id), in CH2Cl2 (8 mL) was added phenylboronic acid (35 mg, 0.28 mmol), copper (II) acetate (51 mg, 0.28 mmol), and powdered activated 4 Å molecular sieves (500 mg). The mixture was stirred for 10 minutes then treated with triethylamine (99 μL, 0.71 mmol). The resulting suspension was stirred for 72 hours at ambient temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel eluting with 25% EtOAc/hexanes to afford 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (29 mg, 45% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.11 (1H, dd, J=9.4, 2.8 Hz), 7.52 (1H, dd, J=8.6, 5.1 Hz), 7.45-7.36 (3H, m), 7.19-7.14 (1H, m), 7.14-7.09 (2H, m), 7.08-7.03 (2H, m), 7.02-6.93 (3H, m), 6.78-6.72 (1H, m), 6.70-6.64 (1H, m), 6.47 (1H, s), 5.24 (2H, s) ppm.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[CH:8]12[CH2:14][CH:11]([CH:12]=[CH:13]1)[CH2:10][CH:9]2[CH:15]=[O:16].O1CCCC1.Cl>[Zn].CCCCCC>[OH:16][CH:15]([CH:9]1[CH2:10][CH:11]2[CH2:14][CH:8]1[CH:13]=[CH:12]2)[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4]
Reactant: O=CC1CC2C=CC1C2
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OCCC1C(O)C1CC2C=CC1C2
Yield: 71.2 %

Procedure:
Addition reaction was carried out by mixing 98 g of zinc powder, 247 g of α-bromo-γ-butyrolactone, 122 g of 5-norbornene-2-carbaldehyde, and 2 kg of dry tetrahydrofuran and heating the mixture under reflux for 10 hours in a nitrogen atmosphere. The reaction mixture was cooled, to which dilute hydrochloric acid was added for neutralization and hexane was added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 148 g (yield 71%) of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.