Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][OH:23])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl.O>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:22][O:23][C:33](=[O:34])[C:32]([CH3:37])([CH3:36])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCO)c2CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCCSc1c(Cl)ccc2c1CCNCC2
Product: Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxyethylthio)-2,3,4,5-tetrahydrobenzo[d]azepine (85 mg, 0.238 mmol) in DCM (3 ml) at 0° C., add triethylamine (331 2.381 mmol) followed by trimethylacetyl chloride (147 μl, 1.190 mmol). Continue stirring for 15 min, dilute with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Deprotection by the General Procedure 1-5, basic workup, and by the General Procedure 2-2 give the title compound. MS (ES+) m/z 342 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[O:21]=[C:2]1[O:1][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1C2CCOC(=O)C21
Reaction time: 15 h
Yield: 60 %

Procedure:
To a stirred solution of ethyl (1SR,5RS,6SR)-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate (34.8 g, 207.2 mmol) in dichloromethane (300 mL), 70% m-chloroperbenzoic acid (51.1 g, 207.2 mmol) was added and refluxed overnight. The following day, additional 70% m-chloroperbenzoic acid (51.1 g, 207.2 mmol) was added and reflux continued for 15 hours. After that time, the mixture was diluted with dichloromethane (200 mL), filtered and washed with 10% Na2SO3 (2×200 mL) and with a saturated aqueous solution of sodium bicarbonate (2×200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to give 22.89 g (60% yield) of ethyl (1SR,6SR,7SR)-2-oxo-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[OH-].[Na+:22]>CO>[CH2:11]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:8][CH2:9][CH3:10])[C:5]([O-:7])=[O:6])[CH2:12][CH3:13].[Na+:22]
Reactant: CCCC(CCC)(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC(CCC)(CCC)C(=O)[O-]
Reaction time: 4 h
Yield: 89.5 %

Procedure:
In a flask equipped with a dropping-funnel and a mechanical strirrer were placed 30 g (0.161 mol) of pure tri-n-propylacetic acid prepared as described above and 75 g of toluene. The mixture was stirred until dissolution after which a hot solution of 6.45 g of sodium hydroxide in 30 g of methanol was added through the dropping-funnel. To the solution thus obtained was added 1 g of CECA WSL black after which the whole was refluxed for 1 hour while being stirred. The black was filtered off and the residual mixture was distilled by adding little-by-little through the dropping-funnel 88 g of toluene to prevent the mixture from forming a mass. Distillation was suspended when the temperature at the head of the column reached 105° C, after which the mixture was cooled to room-temperature. The precipitate which formed was centrifuged out and rinsed twice with 20 g of acetone. It was then dried in a rotatory evaporator at 80° C for 2 hours and then at 105° C under atmospheric pressure in a ventilated drying-oven for 4 hours. In this way, 30 g of sodium tri-n-propylacetate were obtained which represents a yield of 89.5%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]([Cl:13])(=O)C>CO>[ClH:13].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a stirred solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooled to 0° C. was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was triturated with ether several times to get methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride salt as a white powder (14.5 g) in 100% yield. m/z (M+1) 145; 1H NMR (DMSO-d6) 300 MHz δ 5.7-5.5 (s (br), 1H), 4.55-4.35 (m, 2H), 3.76 (s, 3H), 3.35 (d, J=12 Hz 1H), 3.10 (d, J=12 Hz 1H), 2.25-2.0 (m, 2H).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([F:19])[F:18])=[C:13]([F:20])[CH:12]=2)[O:4][C:3]1=[O:26].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([SH:38])[N:37]=[C:30]2[N:29]=1.C(N(CC)CC)C>CN(C=O)C>[CH:21]1([C:5]2([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]([F:19])[F:18])=[C:13]([F:20])[CH:12]=3)[O:4][C:3](=[O:26])[C:2]([S:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)OC(=O)C1Cl
Reactant: Cc1cc(C)n2nc(S)nc2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCc4ccc(C(F)F)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 55 °C
Yield: 67.9 %

Procedure:
A mixture of 3-chloro-6-cyclopentyl-6-{-[4-(difluoromethyl)-3-fluorophenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (200 mg, 0.514 mmol), from Step 1, below, and 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (93 mg, 0.514 mmol) in DMF (4 mL) was treated with triethylamine (52 mg, 0.514 mmol, 1 equiv). The mixture stirred and heated at 55° C. for 4 h. The reaction was cooled to room temperature, and the DMF removed in vacuo. Water and ethyl acetate were added to the resinous material, resulting in the precipitation of a solid. This was filtered, washed with ether, and allowed to air dry, affording 186 mg (68%) of the title product. 1H NMR (DMF-d7) δ 1.81-2.00 (m, 8H) 2.56-2.62 (m, 2H) 2.71 (s, 3H) 2.76 (s, 3H) 2.80 (m, 1H) 3.07(m, 2H) 3.14 (d, J=6 Hz, 1H) 3.32 (d, J=18 Hz, 1H) 7.40 (t, J=57 Hz, 1H), 7.24 (s, 1H) 7.66 (m, 2H) 7.84 (m, 1H,). MS (APCI) calcd for C26H27F3O3S: 532.58; MS found; (M+H+) 533.1. Anal. Calc'd for C26H27F3O3S: C, 58.64; H, 5.11; N, 10.52; S, 6.02. Found: C, 58.26, 58.33; H, 5.25, 5.14; N, 10.69, 10.61; S, 5.78, 5.79.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:5]([CH3:26])[CH:4]=1)#[N:2].O[Li].O.C1COCC1>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:5]([CH3:26])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1COc1ccnn1-c1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Charged methyl 2-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (112 mg, 0.32 mmol), LiOH.H2O (14 mg, 0.32 mmol), water (2 mL) and THF (2 mL) to a flask, then the mixture was stirred at room temperature for 30 min, added another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The aqueous phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (300 MHz, DMSO-d6): δ 2.37 (3H, s), 5.37 (2H, s), 6.10 (1H, d, J=1.8 Hz), 7.62 (1H, d, J=1.5 Hz), 7.70-7.77 (4H, m), 8.08 (1H, s), 8.68 (1H, d, J=5.4 Hz). [M+H] Calc'd for C18H14N4O3, 335; Found, 335.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]1(O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH3:11][N:12]([CH:21]1[CH2:22][CH2:23][N:24]([C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH2:25][CH2:26]1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=C=O
Reactant: Oc1ccccc1
Reactant: CN(CCc1ccccc1)C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN(CCc1ccccc1)C1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 ml of phenol isocyanate was added to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]piperidine in 15 ml of chloroform. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added diethyl ether for crystallization. The resulting crystals were collected by filtration and recrystallized from ethyl acetate to obtain 0.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-anilinocarbonylpiperidine as colorless prism-like crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: OCc1ccccc1O
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCc1ccccc1Cl
Yield: 79.6 %

Procedure:
A solution of 2.42 g (19.47 mmol) of 2-hydroxybenzyl alcohol in 100 ml of dry acetonitrile is mixed with 4.12 g (19.47 mmol) of 2-chlorobenzyl bromide and 2.96 g (21.42 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 3.856 g (15.5 mmol, 79% yield) of a solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([O:11][CH2:12][CH2:13][O:14][C:15]([F:18])([F:17])[F:16])=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.O=P(Cl)(Cl)Cl.N1C=CC=CC=1>CC#N.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([O:11][CH2:12][CH2:13][O:14][C:15]([F:18])([F:16])[F:17])=[C:6]([CH:10]=1)[C:7]#[N:9]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1OCCOC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: N#Cc1cc(Cl)c(Cl)nc1OCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of 5,6-dichloro-2-(2-(trifluoromethoxy)ethoxy)nicotinamide (240 mg, 0.75 mmol) in MeCN (10 mL) were added POCl3 (350 mg, 2.3 mmol) and pyridine (360 mg, 4.5 mmol) at room temperature. After being stirred for 2 hours at room temperature, the mixture was diluted with 10 mL of sodium hydroxide solution, then extracted with ethyl acetate (2×50 mL), the combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated to give 5,6-dichloro-2-(2-(trifluoromethoxy)ethoxy)nicotinonitrile (0.20 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[C@H:8]([OH:12])[CH2:9][N:10]([C:17]([N:16]([CH3:20])[CH3:15])=[O:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: OC1CNCC1Oc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1

Procedure:
A solution of 3.5 g. of 4-(4-chlorophenoxy)-3-pyrrolidinol, 1.8 g. of dimethylcarbamyl chloride and 1.7 g. of triethylamine in 300 ml of methylene chloride was stirred for 60 hr. The solvent was removed under vacuum, 300 ml of benzene was added and the mixture was refluxed for 2 hr., then filtered. After solvent evaporation, the residue was dissolved in cyclohexane-benzene and charcoaled. The product was then crystallized, collected by filtration and recrystallized from cyclohexane-benzene; m.p. 137°-142° C. Analysis: Calculated for C13H17N2O3Cl: C, 54.84; H, 6.02; N, 9.84. Found: C, 54.64; H, 6.01; N, 9.77.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][CH2:14][CH2:15]Cl)[CH3:12]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH2:11][O:13][CH2:14][CH3:15])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CCOCCCl
Product: CCOCCOc1cc(C)c(Br)c(C)c1

Procedure:
According to a method described in [WO 2005/063729 pamphlet, (Reference Example 31)], from 4-bromo-3,5-dimethylphenol (10.0 g) and 2-chloroethyl ethyl ether (5.94 mL), the subject compound (12.8 g) was obtained as a colorless oil.
Reaction SMILES: CO[C:3](=[O:33])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([OH:28])=[C:22]([O:29][CH3:30])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44].COC(=O)N=C(SC)C(C1C=[C:68]([O:70][CH3:71])[CH:67]=C(O)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:24]([OH:26])(=[O:36])[CH3:25].[CH3:27][O:26][C:24]1[CH:25]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:18])=[NH:15])=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:33])[N:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[N:44]=2)[CH:21]=[C:22]([O:29][CH3:30])[C:23]=1[O:28][CH2:67][CH2:68][O:70][CH3:71]
Reactant: COc1ccccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)cc(OC)c1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(O)c(OC)c1
Agent: Cl
Agent: NNc1ncccn1
Product: CC(=O)O
Product: COCCOc1c(OC)cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3OC)c(=O)[nH]2)cc1OC

Procedure:
The same procedure was carried out as in Example (6a), except that {2-(4-hydroxy-3,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (86a)) and 2-methoxyphenylhydrazine hydrochloride were used instead of respectively the {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and 2-hydrazinopyrimidine, to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4](=[CH:16][N:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:18]=2)[C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C[C:28]([N:30](C)C)=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[N:17]1[CH:16]=[C:4]2[C:5]([NH:8][C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11][N:10]=3)=[N:6][CH:7]=[C:2]([C:28]#[N:30])[C:3]2=[N:18]1
Reactant: Cc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(Nc2ncc(C#N)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 17 %

Procedure:
A suspension of [7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine (100 mg, 0.22 mmol), Zn(CN)2 (52 mg, 0.44 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol), in DMA (1.0 mL) was sealed in a microwave vial, purged with nitrogen, and irradiated in a microwave reactor at 150° C. for 30 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-70% ethyl acetate in cyclohexane), to afford the title compound as an off-white solid (15 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br s, 1H), 9.36 (s, 1H), 8.80 (d, J=1.0 Hz, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 7.86 (d, J=1.0 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J=7.4, 1.8 Hz, 1H), 2.50 (s, 3H). LCMS (Method B): RT=3.84 min, m/z: 396 [M+H+].
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]=O.O>OS(O)(=O)=O.O=S(=O)=O>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:13]2)([OH:8])=[O:7]
Reactant: C=O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A solution of terephthalic acid (30 g) in oleum (20-25% SO3, 70 ml) is heated to 150° C. To this solution is added a solution of paraformaldehyde (8.8 g) in oleum (20-25% SO3, 37 ml) over a period of 1-2h. The reaction mixture is stirred at 150° C. for additional 4 h and cooled to 90° C. Water (190 ml) is added to the mixture at a rate so that the temperature stays below 100° C. The precipitate is filtered of, washed with hot (90-95° C.) water and suspended in water (200 ml) and dicalite (1.1 g) is added. The pH of the suspension is adjusted to about 7 with NaOH (approximately 60 ml) and activated carbon (1.1 g) is added. The mixture is filtered and the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 85° C., and the pH is adjusted to about 2 with sulphuric acid (96%, approximated 8 ml). The 5-carboxyphthalide precipitated is separated by filtration and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[O:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:29][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=4)[CH:5]=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1ccc(Sc2ccnc(Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
To a stirred mixture of methyl 4-(2-chloropyrimidin-4-ylthio)benzoate (3.80 g, 14 mmol) and 4-morpholinoaniline (2.89 g, 16 mmol) in 1,4-dioxane (100 mL), was added p-toluensulfonic acid monohydrate (2.57 g, 14 mmol) in one portion. The whole was heated at 100° C. for 16 hours, cooled to room temperature, and poured into water (200 mL). The precipitate was collected by filtration, washed repeatedly with 2% aqueous citric acid, water, and ethyl acetate. It was then dried under high vacuum to afford the product (2.90 g, 51%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)[N:8]=[CH:7]2.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[OH:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:9]2[N:8]=[CH:7][C:6]3[C:11](=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=4)[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)cc1
Temperature: 85 °C

Procedure:
To a flask charged with trans-4-[(8-bromoquinazolin-2-yl)amino]cyclohexanol (1.3 g, 4.035 mmol) was added Pd(PPh3)4 (233 mg, 0.202 mmol), K3PO4.3H2O (2.686 mg, 10.09 mmol), 4-hydroxybenzeneboronic acid (1.113 g, 8.07 mmol) and DMF (16 mL) under argon. The mixture was heated at 80-90° C. under argon overnight, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography (eluted with EA:PE=2:1) to give the title compound as a yellow solid (1 g, 74%). 1 HNMR (DMSO-d6, 400 MHz): δ 9.50 (s, 1H), 9.01 (s, 1H), 7.72-7.61 (m, 3H), 7.31-7.20 (m, 2H), 6.83 (t, 2H, J=7.6 Hz), 4.53 (d, 1H, J=4 Hz), 3.70-3.55 (m, 1H), 3.45-3.36 (m, 1H), 1.99-1.84 (m, 4H), 1.35-1.14 (m, 4H).
Reaction SMILES: [C:1]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][N:16]=2)[NH:11][C:10]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O>C(#N)C>[C:1]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][N:16]=2)[N:11]([C:20]([NH2:21])=[O:26])[C:10]1=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(Cl)cnc2C1C(=O)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccccc2)c2ncc(Cl)cc21

Procedure:
The title compound was prepared from 3-benzoyl-6-chloro-4-azaoxindole (Example 14) according to the procedure of Example 2C, using 3-benzoyl-6-chloro-4-azaoxindole (500 mg, 1.83 mmol), N-chlorosulfonyl isocyanate (0.24 mL), 2.76 mmol) and acetonitrile (20 mL). The crude product was recrystallized from acetonitrile/chloroform. Yield: 121 mg (21%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]1
Reactant: CCCCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(CCc2c(C)cc(OCC)c(F)c2F)CC1
Yield: 27.4 %

Procedure:
0.27 g of Pd/C was added to 6.53 g of the compound 1-1-3-18 having been dissolved in 50 mL of toluene and 50 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 1.8 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-pentylcyclohexyl)ethane (Compound 1-1-3-5) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C1CCN2C(=NCCC2)CC1.[Li+].[Cl-].[O:25]([C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH2:48][CH:49]=O)([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[O:25]([C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH2:48]/[CH:49]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C/CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Trimethyl phosphonoacetate (47 mg, 0.26 mmol) and DBU (39 mg, 0.26 mmol) were successively added to a 0° C. solution of LiCl (11 mg; 0.26 mmol) in MeCN (0.6 mL) under argon. The reaction mixture was stirred at 0° C. for 30 min, after which a solution of 120A compound [4-(1-(3-phenoxy-phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanal] (60 mg, 0.171 mmol) in MeCN (0.5 mL) was added. The reaction mixture was stirred at rt for 2 h, then was concentrated in vacuo. The residue was diluted with ether and successively washed with 1N aq. HCl, sat′d aq. NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient of EtOAc/hexanes from 0 to 40%) to give the title compound as a white solid (65 mg, 89%). [MS+H]+=407, 1H NMR (400 MHz, CDCl3) δ 7.29-7.19 (m, 3H), 7.10-6.97 (m, 3H), 6.95-6.88 (m, 2H), 6.87-6.83 (m, 1H), 6.77 (ddd, J=8.0, 2.5, 0.9 Hz, 1H), 5.75 (dt, J=15.6, 1.5 Hz, 1H), 3.72 (s, 2H), 3.66 (s, 3H), 2.11 (qd, J=7.2, 1.5 Hz, 2H), 1.93 (dd, J=9.5, 5.3 Hz, 4H), 1.67-1.51 (m, 4H), 1.40-1.25 (m, 2H), 1.14-1.02 (m, 2H).