Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.O>C(Cl)Cl>[OH:4][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@@H](O)c1cccnc1
Solvent: ClCCl
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@@H](O)c4cccnc4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1S)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example 130) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp:>88° C. decomposed; 1H NMR (400 MHz, DMSO-d6) δ 1.38–1.50 (m, 2 H), 1.90–1.98 (m, 2 H), 2.63–2.71 (t, 2 H), 2.78–2.96 (m, 4 H), 3.23–3.27 (m, 1 H), 3.62–3.65 (m, 2 H), 4.62–4.67 (m, 1 H), 4.76–4.79 (m, 1 H), 6.83–6.86 (d, 2 H), 7.03–7.05 (d, 2 H), 7.36–7.38 (m, 1 H), 7.76–7.79 (m, 1 H), 8.46–8.48 (m, 1 H), 8.57–8.58 (m, 1 H); MS (ES) m/z: 427 (MH+); Anal. Calcd. for C22H36N4O2×0.3 H2O×0.3 CH2Cl2: C, 55.87; H, 5.51; N, 11.69. Found: C, 55.92; H, 5.80; N, 11.45.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.O>[N:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To 11-bromoundecanoic acid (1.73 g) dissolved in N,N-dimethylformamide (DMF) was added sodium azide (1.5 g), and the mixture was heated to a temperature of 80° C. and stirred for 5 hours. The reaction mixture was then diluted with cooling water and extracted with ethyl acetate to give 11-azidoundecanoic acid. To the mixed solution of 11-azidoundecanoic acid (1 g) and para-nitrophenol (612 mg) in DMF was added N,N'-dicyclohexylcarbodiimide (920 mg), and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated to give the active ester of 11-azidoundecanoic acid. To the active ester (284 mg) dissolved in DMF were further added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (300 mg) and triethylamine (1.1 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK410 in the yield of 171 mg.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12](=[N:17][C:18]#[N:19])OCCC)[CH:9]=[N:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>CO>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12](=[N:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[NH:17][C:18]#[N:19])[CH:9]=[N:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1ccccc1Cl
Reactant: CCCCNc1cncc(C(=NC#N)OCCC)c1
Solvent: CO
Product: CCCCNc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of propyl 5-n-butylamino-N-cyano-3-pyridinecarboximidate (99 mg, 0.38 mmol) in methanol (2 ml) was added 2-(2-chlorophenyl)ethylamine (71 mg, 0.46 mmol), and the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=200:1) and further crystallized from diethyl ether to give the title compound (90 mg, 0.25 mmol) as colorless crystals in the yield of 67%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:11]I>CN(C=O)C>[I:11][C:3]1[C:4]2[S:8][CH:7]=[CH:6][C:5]=2[NH:1][N:2]=1
Reactant: II
Reactant: c1cc2[nH]ncc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ccsc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of 1H-thieno[3,2-c]pyrazole (1.0 g, 8.05 mmol) in DMF (65 ml) at room temperature was added potassium hydroxide (1.36 g, 24.2 mmol) and iodine (3.07 g, 12.1 mmol). The maroon reaction mixture was stirred at room temperature for 3 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 2.0 g (99%) of 3-iodo-1H-thieno[3,2-c]pyrazole as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.38 (br. s., 1H), 7.68 (d, J=5.3 Hz, 1H), 7.21 (d, J=5.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[C:18]1(C)C=CC=C[CH:19]=1>CCO>[CH2:18]([O:8][C:7](=[O:9])[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:10])[CH3:19]
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C(O)c1ccc(Cl)cc1

Procedure:
A solution of 4-chloromandelic acid (12.3 g, 65.9 mmol) in toluene (50 mL), EtOH (16 mL), and concentrated H2SO4 (0.1 mL) was refluxed for 12 hours while removing water using a Dean-Stark trap. The mixture was concentrated in vacuo, diluted with DCM, and washed with dilute aqueous NaHCO3. The separated DCM layer was dried (MgSO4), filtered, and concentrated in vacuo to give (4-chlorophenyl)-hydroxy-acetic acid ethyl ester as a colorless oil (10.0 g) that crystallized upon standing.
Reaction SMILES: [CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2([NH:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7]2)=[CH:9][CH:10]=1)#[CH:15]
Reactant: CCCNC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(NCCC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; propyl-[1-(4-trimethylsilanylethynyl-7 phenyl)-cyclopropyl]-amine (Intermediate 119, 80.0 mg, 0.30 mmols) in methanol (8 mL) was treated with potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight at ambient temperature. The crude alkyne (58 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].Cl[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: OCCO
Reactant: Clc1ccccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCCOc1ccccn1
Reaction time: 48 h

Procedure:
Ethylene glycol (30.1 g, 484 mmol), 2-chloropyridine (10.0 g, 88 mmol), powdered potassium hydroxide (9.9 g, 176.13 mmol), and 18-crown-6 ether (9.3 g, 35 mmol) were dissolved in anhydrous toluene (500 mL) under a N2 atmosphere. The reaction mixture was stirred vigorously and heated to reflux. After 48 h, the reaction reached 50% conversion. The reaction mixture was concentrated in vacuo to approximately 100 mL volume then diluted with water (100 mL). After stirring for 0.5 h, the organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by Jones column chromatography (100% hexanes to 50% ethyl acetate/hexanes) to give 2-(pyridin-2-yloxy)ethanol as a dark brown oil containing 15% w/w of 18-crown-6 ether. 1H NMR (d6-DMSO, 400 MHz): δ 8.14 (ddd, J=5.0, 2.0, 1.2 Hz, 1H), 7.68 (ddd, J=9.4, 7.2, 2.4 Hz, 1H), 6.95 (ddd, J=8.0, 4.8, 1.2 Hz, 1H), 6.80 (ddd, J=8.4, 1.0, 1.0 Hz, 1H), 4.83 (t, J=5.6 Hz, 1H), 4.26 (t, J=5.2 Hz, 2H), 3.70 (dt, J=10.4, 5.2 Hz, 2H).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:12](Cl)([CH3:15])(=[O:14])=[O:13]>N1C(C)=CC(C)=CC=1C.CCCCCC>[CH3:15][S:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCO
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCCC
Product: CCCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled solution of 158.3 grams of 1-decanol in 1.0 liter of collidine is added dropwise 126 grams of mesyl chloride. The resulting mixture is stirred at room temperature for 1.5 hours and then poured onto ice. The reaction mixture is extracted with ether and the ether extracts are washed with 10% hydrochloric acid. The ether extracts are combined, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to leave an oil which solidifies upon cooling. The oil is dissolved in n-hexane and cooled to yield as crystals, decyl methylsulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:35]([C:38]1[CH:39]=[CH:40][C:41](Br)=[N:42][CH:43]=1)(=[O:37])[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:41]4[CH:40]=[CH:39][C:38]([C:35](=[O:37])[CH3:36])=[CH:43][N:42]=4)[CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccc(Br)nc1
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
After removal of the Boc-protecting group under acidic conditions, in analogy to the procedure described for the synthesis of {(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, g) the title compound was prepared from [(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and 5-acetyl-2-bromopyridine as off-white foam. MS m/e: 627.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Cl[C:14]1[N:15]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:17]2[S:22][C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O.[Cl-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[N:15]=[C:16]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[C:17]3[S:22][C:21]([CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[CH:20][C:18]=3[N:19]=1)[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5cc(F)ccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 51.1 %

Procedure:
A solution of 5-fluoroindole (0.148 g) in DMF (6 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 30 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 3 h the reaction mixture was cooled to room temperature and diluted with water and saturated aqueous sodium chloride solution. The solid separated was filtered, and then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 120 (0.252 g, 51%) as a off white solid. MS m/e 495 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, 2H) 2.08 (t, 3H) 2.18 (s, 6H) 2.95 (d, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.75 (d, 1H) 7.0-7.10 (m, 1H) 7.37 (s, 1H) 7.6-7.7 (m, 1H) 8.33 (d, 1H) 8.5-8.6 (d, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH:10]=[C:9]2[OH:17]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[C:10]([N+:1]([O-:4])=[O:2])=[C:9]2[OH:17]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: ClC(Cl)Cl
Product: O=c1oc2ccc(Cl)cc2c(O)c1[N+](=O)[O-]

Procedure:
Red fuming nitric acid (10 mL) was added to a stirred suspension of 6-Chloro-4-hydroxy-chromen-2-one (2.0 g, 10.17 mmol) in chloroform (200 mL) at 0° C. The resultant solution was stirred at 0° C. for 1.5 h, quenched with water (80 mL), the organics separated and treated with saturated NaHCO3 when a thick yellow solid fell out of solution. The solid was filtered and the filtrate acidified with 3N HCl (pH 2) and extracted with chloroform. The organic extracts were dried to a yellow powder and all solids were combined and identified as 6-chloro-4-hydroxy-3-nitro-chromen-2-one. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.78 (d, 1H), 7.55 (dd, 1H), 7.23 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20].S([O-])([O-])=[O:24].[Na+].[Na+]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:17])([F:18])[F:19])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20])=[O:24]
Reactant: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S(=O)CC(F)(F)F
Yield: 37.1 %

Procedure:
To 1.68 g (4.9 mmol) of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-292 of the present invention) in 5 ml of chloroform, 1.02 g (5.1 mmol) of m-chlotoperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.65 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfoxide (yield 37.1%) as a pale yellow solid (m.p. 109-110° C.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3Cl)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:29])[CH:5]=1)(=[O:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3[N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:29])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3Cl)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-chloro-benzenesulfonamide and morpholine (39%, yellow solid), MS (m/e): 489.4 (M−H, 100%)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:31]=[C:30]([OH:32])[C:24]3[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([O:32][C:30]2[C:24]3[CH2:25][C:26]([CH3:28])([CH3:29])[O:27][C:23]=3[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=3)[CH:31]=2)=[CH:7][N:6]=1)=[O:9]
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Temperature: 160 °C
Yield: 48.2 %

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (60.1 mg, 0.348 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (100 mg, 0.348 mmol) and Cs2CO3 (227 mg, 0.696 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluting with 45% to 70% EtOAc in hexanes to give a colorless thick oil (71 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1 H) 8.85 (d, J=1.01 Hz, 1 H) 8.52 (d, J=1.26 Hz, 1 H) 7.27 (d, J=2.27 Hz, 1 H) 7.21 (s, 1 H) 7.15 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 4.03 (s, 3 H) 3.74 (s, 3 H) 2.86 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H21N5O5 m/z 424.20 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 91.4 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (165 mg) as well as ethyl 3-(methylamino)propanoate (55 mg) to give the title compound (178 mg, 91%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[CH:12][CH:13]=1)=[O:6].C([O-])([O-])O[CH2:31][CH3:32].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH:18]=[C:19]3[O:24][CH2:31][CH3:32])=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC([O-])[O-]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC1=CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21

Procedure:
3.5 g of 3,4-dichloro-N1-{6-(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 1 was suspended in 140 ml of ethanol. To the suspension, 14 ml of ethyl orthoformate, 820 mg of (±)-10-camphorsulfonic acid and 3.5 g of 4A molecular sieves were added and the mixture was heated at reflux for 30 minutes. After air cooling, the reaction mixture was filtered. To the filtrate, 8.5 ml of an aqueous 1N sodium hydroxide solution was added and the solvent was distilled off under reduced pressure. To the resulting residue, 100 ml of ethyl acetate was added and the solution was washed in turn with water and a saturated sodium hydrogencarbonate solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (4:1)) to obtain the titled compound (white powder, 530 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC(Cl)=CC=2)[O:28][N:27]=1)([CH3:25])[CH3:24]>CN(C=O)C>[F:22][C:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[O:28][N:27]=1)([CH3:24])[CH3:25]
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)ncnc2cc1O
Temperature: 60 °C
Yield: 12.7 %

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol (200 mg, 0.71 mmol) (prepared as described in example 95A, steps 1 through 3) in anhydrous DMF (6 mL), was added 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (212 mg, 0.71 mmol) and the mixture was heated to 60° C. for 2.5 h. Concentration in vacuo followed by purification via preparative reverse phase HPLC (eluted with a gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O), afforded 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea (41 mg, 13%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.64 (brs, 1H), 9.13 (brs, 1H), 8.48 (s, 1H), 7.55-7.56 (m, 2H), 7.41 (dd, J=8.1, 8.1 Hz, 1H), 7.32 (m, 1H), 7.23 (s, 1H), 6.98 (m, 1H), 6.15 (s, 1H), 3.99 (s, 3H), 1.66 (d, J=22 Hz, 6H); LC-MS (ESI) m/z 454 (M+H)+.
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:15])[C@H:5]2[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]>C(O)(=O)C.O>[OH:9][CH2:8][CH2:7][C@H:6]1[NH:3][C:4](=[O:15])[C@H:5]1[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: COC(C)(C)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: O
Solvent: CC(=O)O
Product: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CCO
Temperature: 65 °C
Yield: 96.8 %

Procedure:
A solution of (6R, 7R)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicylco[4.2.0]octan-8-one (345 mg) in a mixture of acetic acid (5.52 ml) and water (1.38 ml) was heated at 65° C. for 30 minutes. The mixture was cooled to ambient temperature and evaporated in vacuo. Xylene was added to the residue and the resultant suspension was evaporated in vacuo. The crystalline residue was dissolved in a mixture of methanol and xylene and the resultant solution was evaporated in vacuo. This operation was repeated once, and the crystalline residue was washed with hexane to give (3R, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (275 mg).