Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.O[CH2:14][C:15]1[C:16]([CH3:60])=[N:17][C:18]([CH3:59])=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:36]=[N:37][N:38]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:39]=2)=[CH:25][CH:24]=1>ClCCl.O>[Cl:12][CH2:14][C:15]1[C:16]([CH3:60])=[N:17][C:18]([CH3:59])=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:36]=[N:37][N:38]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:39]=2)=[CH:25][CH:24]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CO)c(C)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CCl)c(C)n1
Reaction time: 20 h

Procedure:
Triethylamine (2.2 ml) and methanesulphonyl chloride (1.24 ml) were added to a solution of compound B (10.0 g) in dichloromethane (150 ml). The solution was left to stand for 20 hours and then diluted with water (150 ml). The organic phase was separated, washed with saturated sodium chloride solution (150 ml), and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with a mixture of methanol and dichlormethane (1:19 v/v) to give 3-chloromethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (C) (8.5 g), as a white solid, m.p. 110°-112° C.; NMR (d6 -DMSO/d4 -acetic acid): 2.5(s,3H), 2.65(s,3H), 4.75(s,2H), 5.45(s,2H), 6.9-7.9 (complex m,24H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]1OCC[O:23]1.Cl>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (8) (400 mg, 0.95 mmol) in THF (30 mL) was added HCl solution (1 M, 10 mL). The reaction was stirred at room temperature overnight. After the reaction, all THF was evaporated under vacuum. The aqueous solution was extracted with EtOAc (2×50 mL). The organic layer was washed with water (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated under vacuum to afford the desired product 320 mg (89% yield) that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.35 (s, 1H), 7.91 (d, J=2.7 Hz, 1H), 7.67 (t, J=9.2 Hz, 2H), 7.32 (dd, J=8.6, 2.7 Hz, 1H), 6.24 (d, J=8.6 Hz, 1H), 3.70-3.62 (m, 2H), 3.56-3.49 (m, 2H), 3.04 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:12])[NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([CH2:18][CH2:19][C:20](Cl)=[O:21])([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3](=[S:12])[NH:4][N:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:20](=[O:21])[CH2:19][CH2:18][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CNC(=S)NNc1ccccc1
Reactant: CCOC(=O)CCC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(=O)N(NC(=S)NC)c1ccccc1
Temperature: 80 °C

Procedure:
With 100 ml of toluene was mixed 18.1 g of 4-methyl-1-phenylthiosemicarbazide as prepared in Synthesis Example 1, and 18.1 g of β-carboethoxypropionyl chloride was added thereto. The mixture was heated at 80° C. for 3 hours and then cooled to obtain crystals of 4-methyl-1-phenyl-1-(β-carboethoxypropionyl)thiosemicarbazide. Ten grams of the product was suspended in 70 ml of ethanol, followed by heat refluxing, and a small amount of sodium ethoxide was added to the reaction mixture. The reaction mixture once became uniform, and then crystals precipitated. After cooling, the thus formed crystals were removed by filtration and dried to obtain 16.0 g (55%) of Compound No. 64. Melting point: 162°-163° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][OH:11])[N:8]=1)[CH3:2].N(C(OCC)=O)=NC(OCC)=O.O[C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:32]3[CH:41]=[CH:42][CH:43]=[CH:44][C:31]=3[CH2:30][C:29]=2[CH:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:25]2[CH:26]=[CH:27][C:28]3[CH2:34][CH:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:32]4[CH:41]=[CH:42][CH:43]=[CH:44][C:31]=4[CH2:30][C:29]=3[CH:45]=2)[N:8]=1)[CH3:2]
Reactant: CCNc1nc(CCO)cs1
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2Cc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNc1nc(CCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)OCC)C3)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
A solution of 2-(ethylamino)-4-thiazoleethanol (0.33 g, 1.9 mmole) and diethyl azodicarboxylate (0.30 mL, 1.9 mmole) in anhydrous DMF (5 mL) was added dropwise over 5 min to a solution of ethyl (±)-10,11-dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate (296.4 mg, 1 mmole) and triphenylphosphine (525 mg, 2 mmole) in anhydrous DMF (5 mL) at RT. The reaction was kept cool in a RT water bath during the addition. After 16 hr, the reaction was concentrated and the residue was reconcentrated from xylenes (2×). Silica gel chromatography (20% EtOAc/hexanes) gave the title compound (145.0 mg, 32%) as a yellow oil: TLC (1:1 EtOAc/hexanes) Rf0.60; 1H NMR (250 MHz, CDCl3) δ7.00-7.30 (m, 4 H), 6.98 (d, J=8.2 Hz, 1 H), 6.77 (d, J=2.6 Hz, 1 H), 6.68 (dd, J=8.2, 2.6 Hz, 1 H), 6.21 (s, 1 H), 5.00-5.25 (m, 1 H), 4.04-4.38 (m, 5 H), 3.81 (d, J=15.1 Hz, 1 H), 3.70-3.90 (m, 1 H), 3.13-3.40 (m, 3 H), 2.99 (t, J=6.7 Hz, 2H), 2.92(dd, J=14.9, 9.3 Hz, 1 H), 2.64 (dd, J=15.6, 5.0 Hz, 1 H), 2.51 (dd, J=15.6, 9.3 Hz, 1 H), 1.27 (t, J=7.2 Hz, 3 H); MS (ES) m/e 451 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN([CH:17]=[O:18])C>>[CH2:11]([O:12][C:17](=[O:18])[CH2:6][CH2:7][CH2:8][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([O:13][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:12])[NH2:1])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
Potassium tertbutylate (3.36 g, 30 mmoles) is added to a solution of tyrosine 4-1 (5 g, 21 mmoles) in 100 ml of DMF, followed by agitating for 30 minutes while cooling down in a water+ice bath, then the bromoester (ethyl 4-bromobutanoate) (3.6 ml, 25 mmoles) in solution in 10 ml of DMF is added. The reaction medium is agitated overnight at ambient temperature, followed by evaporating under reduced pressure, taking up the dry extract in a water/ethyl acetate mixture, decanting, drying the organic phase, filtering, evaporating then purifying by chromatography eluting with a Heptane/ethyl acetate gradient (100/0→0/100). 5.2 g of the expected product 4-2 is obtained.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH:9]([OH:11])[CH3:10])=[CH:7][N:8]=1>C(C#N)(C)=O.O=[Mn]=O>[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1
Reactant: CC(O)c1cnc(Br)s1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanol (1.95 g, 9.37 mmol) in AcCN (90.0 mL) was treated at rt with MnO2 (4.53 g, 46.86 mmol) and the reaction mixture was stirred for 16 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=0.80 min.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9]O)[N:6]=[CH:5]1)[CH2:2][CH3:3].O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=1
Reactant: CCCn1cnc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCn1cnc(CCl)c1

Procedure:
(1-propyl-1H-imidazol-4-yl)methanol (535 mg, 3.11 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 4-(chloromethyl)-1-propyl-1H-imidazole. Then following General Procedure A, the title compound (587 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (744 mg, 4.66 mmol), 4-(chloromethyl)-1-propyl-1H-imidazole, K2CO3 (2.1 g, 15.54 mmol) in DMF (10 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Reactant: ClCc1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
To a solution of Example 340A (0.15 g, 0.53 mmol) in 5 mL DMF was added sodium hydride (0.016 g, 0.67 mmol, 95%). After the solution was allowed to stir at ambient temperature for 30 min, 3-(chloromethyl)furan (0.08 g, 0.67 mmol) was added. The reaction was held at ambient temperature overnight and then quenched with water. The crude was extracted with ethyl acetate and the organics washed with water, then dried over MgSO4, filtered, and concentrated. Flash chromatography over silica gel (50% ethyl acetate/hexane) gave 0.035 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (d, J=1.36 Hz, 3H) 3.80 (s, 3H) 5.38 (s, 2H) 6.39-6.55 (m, 2H) 7.12 (d, J=8.82 Hz, 1H) 7.26 (d, J=1.36 Hz, 1H) 7.46 (dd, J=8.82, 2.71 Hz, 1H) 7.64 (s, 1H) 7.75 (d, J=2.71 Hz, 1H). m/z 363.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=O)=[C:4]2[CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10](/[CH:11]=[CH:12]/[CH2:13][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/CN2CCCCC2)cc1
Reaction time: 2.5 h

Procedure:
To a mixture of (E)-3-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (385 mg, 1.1 mmol) and piperidine (160 μL, 1.6 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (340 mg, 1.6 mmol). The mixture and stirred at r.t for 2.5 h and a saturated solution of ammonium chloride (10 mL) was added. The separated aqueous layer was then extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a residue which was purified by automated flash-chromatography (methanol/dichloromethane; 15/85). The title compound was obtained as a bright yellow solid (354 mg, 77%). LCMS m/z 426.1; 428.1 (weak) (M+H)+341.0; 343.0 (strong), ret time=2.15 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]([F:13])[F:12].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:3]([CH:11]([F:12])[F:13])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(F)F)c1Cl

Procedure:
A solution of 2-chloro-1-(difluoromethyl)-3-nitrobenzene (0.43 mmol) and SnCl2 dihydrate (0.86 mmol) in 1 mL EtOH was heated to 110° C. for 6 min in a closed vial. At RT, the mixture was diluted with water, basified with 1M NaOH solution to pH 13-14 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as brown oil;
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25].CC(C)(C)CC(N1CCN(C2C=CC(C(NC3C=CC(C)=C(I)C=3)=O)=CN=2)CC1)=O>>[CH2:24]([O:26][C:27]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=3)=[CH:12][N:13]=2)[CH2:22][CH2:21]1)=[O:28])[CH3:25]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: CCOC(=O)Cl
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)nc2)cc1I
Product: CCOC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1

Procedure:
4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid ethyl ester was synthesized from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and ethylchloroformate in a manner similar to the one described in the synthesis of 6-[4-(3,3-dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide above. LCMS calcd for C20H23IN4O3 (m/e) 494, obsd 495 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:15])[CH2:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(C)(C)C.[C:23]1([C@@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(=O)(=O)(O)O>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:15])[CH2:10][CH2:11][C:12]([N:30]1[C@H:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:33][O:32][C:31]1=[O:34])=[O:14]
Reactant: C=C(CCC(=O)O)c1ccc(F)cc1F
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(CCC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Temperature: 12.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 (100 g) in dichloromethane (800 ml), added triethylamine (97.4 g) at 25-30° C. and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 10-15° C. and added pivaloyl chloride (63 g) to the reaction mixture over a period of 45 minutes. Temperature of the reaction mixture was raised to 25-30° C. and the reaction mixture was stirred for 2 hours at 25-30° C. After completion of the reaction, added (R)-4-phenyloxazolidin-2-one compound of formula-3 (69 g), 4-dimethylamino pyridine (21 g), dimethyl formamide (37 ml) and followed by dichloromethane (200 ml) to the above reaction mixture. Heated the reaction mixture to 45° C. and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30° C. Sulfuric acid was added to the reaction mixture and stirred for 15 minutes. Both organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and isopropyl alcohol was added to the obtained residue at 25-30° C. and stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 0-10° C. and then stirred for 1½ hour at the same temperature. Filtered the obtained solid, washed with chilled isopropyl alcohol and then dried to get title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]([CH2:20][C:21]([N:23]2[CH2:31][C@H:30]3[C@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[CH2:24]2)=[O:22])[C:8]([O:10]C2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:20][C:21]([N:23]2[CH2:31][C@H:30]3[C@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[CH2:24]2)=[O:22])[C:8]([OH:10])=[O:9])=[CH:32][CH:33]=1
Reactant: Cc1ccc(CC(CC(=O)N2C[C@H]3CC=CC[C@H]3C2)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(CC(CC(=O)N2C[C@H]3CC=CC[C@H]3C2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.2 %

Procedure:
To a suspension of 4-nitrophenyl 2-(4-methylbenzyl)-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionate (1.7 g) in methanol (10 ml) was added 1N sodium hydroxide solution (8.0 ml) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified with 1N hydrochloric acid under ice-cooling and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to give 0.4 g of 2-(4-methylbenzyl)-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionic acid as a colorless crystal.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[F:30][P-:31]([F:36])([F:35])([F:34])([F:33])[F:32].[K+]>O>[F:30][P-:31]([F:36])([F:35])([F:34])([F:33])[F:32].[CH2:15]([O:23][C:24]1[CH:25]=[CH:26][C:27]([S+:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:28][CH:29]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccccc1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O
Product: CCCCCCCCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 42 °C
Yield: 74 %

Procedure:
A mixture of 12.12 grams (0.06 mole) of diphenylsulfoxide, 10.3 gram of octylphenyl ether and 20 ml of PP/MSA resulted in an exothermic reaction. The temperature of the mixture increased to 42° C. After the exotherm had subsided, the temperature was raised to 50° C. and maintained at that temperature for 1 hour with stirring. There was obtained a complex reaction product of diphenylsulfoxide and octylphenyl ether. The mixture was then poured into 200 ml of water. A clear yellow solution was obtained. There was added to the solution, 9.5 grams of potassium hexafluorophosphate. A yellow oil precipitated from the solutionwhich solidified to a white crystalline solid upon standing. The mixture was warmed slightly to 40° C. and stirred. There was obtained a quantitative yield of crude product. The product was recovered by filtering and washed twice with water followed by petroleum ether. The crude product was further purified by recrystallization from absolute ethanol. (4-octyloxyphenyl)diphenylsulfonium hexafluorophosphate was obtained at a 74% yield. It had a melting point of 94°-95° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:22].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:22])=[C:4]([F:21])[C:5]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cccc2ccccc12
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}naphthalene (0.96 g, 2.63 mmol) in dichloromethane (10 mL) was added 7N ammonia in methanol (20 mL, 140 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.769 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.37 (m, 1H), 7.94-8.03 (m, 1H), 7.60-7.71 (m, 4H), 7.56 (t, 1H), 7.36 (t, 1H), 6.56 (d, 1H), 4.13 (s, 2H). ES MS: m/z 302 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:40]2[CH:44]=[CH:43][CH:42]=[C:41]2[C:45](O)=[O:46])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:45]([C:41]1[N:40]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=2)(=[O:38])=[O:39])[CH:44]=[CH:43][CH:42]=1)=[O:46]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.8 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (206 mg, 0.490 mmol), 1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carboxylic acid (Int. 5) (160 mg, 0.539 mmol), EDC (282 mg, 1.471 mmol) and DMAP (59.9 mg, 0.490 mmol) in DCM (10 ml) was stirred at RT for 24 hours. The reaction was diluted with DCM and washed with 1N HCl, sat. NaHCO3 (40 ml), and finally with brine. The organic phase was dried over sodium sulfate and the solvent was removed under vacuum; the crude was purified by preparative HPLC-Method 1 to yield (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carbonyloxy)ethyl)pyridine 1-oxide (Int. 6) (95 mg, 0.136 mmol, MS/ESI+698.05 [MH]+, [αD]=−40.97, c=0.6, DCM).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)C)[CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2>Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C)C(C)=O)C4)cc3)nc2c1
Agent: Cl
Product: CNC1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)C1
Temperature: 100 °C
Yield: 46.8 %

Procedure:
A mixture of N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide (0.500 g, 1.18 mmol) and 2 N HCl (80 mL) was heated at 100° C. for 4 hours, cooled, basified to pH 9, extracted with CH2Cl2 (2×200 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 6:3:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.210 g, 47%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.65 (br s, 1H), 8.08 (d, J=8.7 Hz, 2H), 6.65 (s 1H), 6.55 (d, J=7.8 Hz, 2H), 6.43 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.46-3.49 (m, 1H), 3.38-3.42 (m, 1H), 3.26-3.28 (m, 2H), 3.07-3.10 (m, 1H), 2.31 (s, 3H), 2.08-2.11 (m, 1H), 1.81-1.84 (m, 1H). ESI MS m/z 381 [M+H]+.