Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[Si:12]([O:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26](OC)=[O:27])[CH2:22][CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[OH-].[Na+]>O>[Si:12]([O:19][CH:20]1[CH2:21][CH2:22][CH:23]([CH2:26][OH:27])[CH2:24][CH2:25]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
Lithium aluminum hydride (696 mg, 18.4 mmol) was added to a tetrahydrofuran solution (25 ml) of methyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (2.50 g, 9.18 mmol) under ice-cooling. The resulting mixture was warmed up to room temperature and then stirred overnight. After completion of the reaction, water and a 15% aqueous sodium hydroxide solution were added thereto and stirred. The solid formed was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (hexane-ethyl acetate=1:1) to obtain (4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methanol (2.08 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=2[C:40]2[CH:45]=[CH:44][N:43]=[N:42][CH:41]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.Cl.N>O1CCOCC1.CO.O>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][C:31]=2[C:40]2[CH:45]=[CH:44][N:43]=[N:42][CH:41]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 900, 30.3 g, 44.4 mmol) in 1,4-dioxane (250 mL) at room temperature was added a 4M solution of HCl in 1,4-dioxane (300 mL) dropwise over 30 minutes. The resulting suspension was left to stir at room temperature for 3 hours before concentration in vacuo. The residue was azeotroped with diethyl ether (3×300 mL) followed by a diethyl ether trituration (200 mL) to provide crude material as a fawn coloured solid. This material was suspended in methanol (200 mL) and filtered through Celite, washed with methanol (400 mL) and the resulting filtrate concentrated in vacuo to give a sand coloured solid. This material was suspended in water (100 mL) and treated with 880 ammonia (60 mL) portionwise until pH 9-10 was achieved. The resulting solution was washed with diethyl ether (3×75 mL) and the aqueous layer acidified to pH=5 with citric acid. The mixture was then extracted with ethyl acetate (3×200 mL) and brine (100 mL) added to aid separation. The combined organic layers were washed with water (200 mL), dried over MgSO4 and concentrated in vacuo to approximately 100 mL whereby a precipitate was observed. This mixture was allowed to cool for 18 hours and the resulting solid filtered and washed with cold ethyl acetate (10 mL) and dried in vacuo at 60° C. to provide the title compound as a sand coloured crystalline solid (17.5 g) containing 8.2% by weight ethyl acetate solvate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:31][N:32]2[CH2:54][CH2:53][C:35]3([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]4[CH:44]=[CH:45][C:46]5[S:50][C:49]([CH3:51])=[N:48][C:47]=5[CH:52]=4)=[O:42])[CH2:36]3)[CH2:34][CH2:33]2)[S:29][CH:30]=1.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:51][C:49]1[S:50][C:46]2[CH:45]=[CH:44][C:43]([C:41]([N:37]3[CH2:36][C:35]4([CH2:53][CH2:54][N:32]([CH2:31][C:28]5[S:29][CH:30]=[C:26]([CH2:25][CH:24]=[O:23])[CH:27]=5)[CH2:33][CH2:34]4)[O:40][CH2:39][CH2:38]3)=[O:42])=[CH:52][C:47]=2[N:48]=1
Reactant: Cc1nc2cc(C(=O)N3CCOC4(CCN(Cc5cc(CCO)cs5)CC4)C3)ccc2s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(C(=O)N3CCOC4(CCN(Cc5cc(CC=O)cs5)CC4)C3)ccc2s1
Reaction time: 0.67 h

Procedure:
Dess-Martin periodinane (0.27 g) was added to stirred solution of (9-((4-(2-hydroxyethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylbenzo[d]thiazol-5-yl)methanone (example 49, step b) (0.20 g) and trifluoroacetic acid (0.033 mL) in DCM (5 mL). After 40 min, the reaction mixture was treated with aqueous saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (30 mL). The mixture was extracted twice with ethyl acetate, the combined organics were washed with saturated sodium bicarbonate solution, acetic acid (0.08 mL) was added, then the solution was dried over sodium sulphate, filtered, and evaporated in vacuo. Yield 0.2 g. Used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:32])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[CH:31][CH:30]=4)=[C:15]([CH3:16])[CH:8]2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCCC2NC(/C=C3\C(=O)Nc4ccc(F)cc43)=C(C)C2C1=O
Temperature: 25 °C
Yield: 80.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (0.271 g, 0.93 mmol) and 5-fluoro-1,3-dihydro-indol-2-one (0.127 g, 0.84 mmol) were dissolved in 1.4 ml of anhydrous ethanol under stirring at room temperature, the resulting mixture was stirred for 10 minutes in dark, and added with piperidine (0.15 ml, 1.49 mmol). The mixture was refluxed at 70° C. for about 1.5 hours in an oil bath under an argon atmosphere and lots of orange precipitates were formed. After thin lay chromatography showed the disappearance of starting materials, the ice-salt bath was removed, and the reaction mixture was naturally cooled to room temperature, filtered and dried to obtain the title compound (Z)-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-3 a,5,6,7,8,8a-hexahydro-1H-pyrrolo[3,2-c]azepin-4-one 1 (0.288 g, yield 80.76%) as an orange solid.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].C1CCN2C(=NCCC2)CC1>CN(C)C=O.C1CCN2C(=NCCC2)CC1>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:30]4([CH2:32][C:33]#[N:34])[CH2:31][N:28]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH2:29]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 10.0 g, 33.4 mmol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 6.22 g, 33.4 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 20 mL) was added DBU (254 mg, 1.67 mmol, 0.05 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous within 90 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (120 mL) and acetonitrile (80 mL). The resulting mixture was stirred at room temperature for an additional 30 min. The solids were collected by filtration, washed with a mixture of acetonitrile and water (⅔ by volume, 2×20 mL), and dried in vacuum oven at 40-45° C. for 24 h to afford crude (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 14.5 g, 16.2 g theoretical, 89.5% yield) as white solids, which was found to be sufficiently pure (>98.0% by HPLC) for the subsequent reaction without further purification. For 20:
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=1)[C:32]([O:34]C)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=1)[C:32]([OH:34])=[O:33])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinate (160 mg, 0.27 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (160 mg, 3.81 mmol, 14.02 equiv) in water (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 3 with hydrochloric acid (2 mol/L). The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 140 mg (90%) of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid as a yellow semi-solid.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:40])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][C:34](=[O:39])[CH2:35][N:36]=[N+:37]=[N-:38])[O:27]1>C(OCC)(=O)C>[CH3:25][C:26]1([CH3:40])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH:34]([OH:39])[CH2:35][N:36]=[N+:37]=[N-:38])[O:27]1
Reactant: CC1(C)OC(=O)C=C(CC(=O)CN=[N+]=[N-])O1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C=C(CC(O)CN=[N+]=[N-])O1
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(3-azido-2-oxopropyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the resultant residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 67 mg (yield 22%) of (+)-2,2-dimethyl-6-(3-azido-2-hydroxypropyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 1, X is N3, Y is a hydrogen atom, and a substituent is present at the 6-position].
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH:30][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:29])=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C(C)(C)C)cc1
Yield: 55 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-tert-butyl-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 55% of theory; LC (method 5): tR=1.22 min; Mass spectrum (ESI+): m/z=404 [M+H]+.
Reaction SMILES: [NH3:1].[C:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)(=[O:4])[CH3:3]>CO.[OH-].[Pd+2].[OH-]>[NH3:5].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:1])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCCCC1=O
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCC(N)CC1
Reaction time: 18 h

Procedure:
0.88 Ammonia (85 ml) was added to a solution of N-acetylpiperidone (15 g, 106 mmol) in methanol (120 ml), followed by palladium hydroxide (2 g) and the mixture hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through Arbocel®, the filtrate concentrated under reduced pressure and the residue azeotroped with toluene to give a yellow oil. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (96:3.5:0.5 to 84:14:2) to afford the title compound as a clear oil, 9.6 g.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CC#N>[CH2:23]([N:1]([C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:9])[CH2:4][CH2:3]1)[CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an 80° C. heated mixture of trans-4-Aminocyclohexanecarboxylic acid (8 g, 55.97 mmol) and K2CO3 (23.4 g) in 112 mL of CH3CN, was added dropwise a solution of BnBr (23.3 mL, 195.5 mmol) in 70 mL of CH3CN by addition funnel. Reaction stirred overnight at 80° C. The reaction was cooled to room temperature and filtered. Precipitate did not form in filtrate like it did with the cis-somer so the filtrate was concentrated to an oil and carried on to next step (23.01 g, 99% yield).
Reaction SMILES: [OH:1][CH:2](/[CH:16]=[CH:17]/[CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.CN(C)C=O>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:4]([CH2:3][CH:2]([OH:1])[CH:16]=[CH:17][CH3:18])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C/C=C/C(O)CNS(=O)(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC=CC(O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+)-(E)-N-(2-hydroxy-pent-3-enyl)-4-methoxybenzenesulfonamide (1.2 grams, 4.42 mmol) in tetrahydrofuran-dimethylformamide (10 mL, ca. 3:1) at 0° C. is added sodium bis(trimethylsilyl)amide (4.9 mL, 1.0M solution in tetrahydrofuran). After 10 minutes, t-butylbromoacetate (786 mL, 4.83 mmol) is added. The mixture is warmed to room temperature, stirred for 1 hour and quenched with saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 1:1 ethyl acetate-hexanes) to provide [(2-hydroxy-pent-3-enyl)-(4-methoxybenzenesulfonyl)-amino]-acetic acid t-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:16]([OH:18])=O)[CH2:11][C@H:10]1[CH2:12][CH:13]([F:15])[F:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH:31]1([S:34]([NH:37][C:16]([C@@:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C@H:10]2[CH2:12][CH:13]([F:14])[F:15])=[O:18])(=[O:36])=[O:35])[CH2:33][CH2:32]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1CC(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1CC(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (665 mg, 2.507 mmol) in THF (20 mL) was added CDI (528 mg, 3.26 mmol) and the formed solution was stirred at rt for 3 h. Cyclopropanesulfonamide (395 mg, 3.26 mmol) and DBU (0.756 mL, 5.01 mmol) were added and the mixture was stirred at rt overnight. The reaction was diluted with EtOAc and washed with 1.0M HCl solution. The aqueous layer was extracted with EtOAc and the combined organics were washed with 5% citric acid, brine, dried over MgSO4, filtered and evaporated to give crude material. The crude product was purified on the Biotage (acetone/hexanes 5-30%) to give the pure product tert-butyl (1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamate (783 mg, 1.913 mmol, 76% yield) as a white solid. 1H NMR (500 MHz, MeOD) δ 1.01-1.15 (m, 2H), 1.16-1.35 (m, 2H), 1.49 (s, 10H), 1.58-1.77 (m, 2H), 1.92-2.19 (m, 2H), 2.90-2.99 (m, 1H), 5.80-6.10 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16].C(#N)C1C=CC=CC=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:3])[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: CC(Oc1cccc(F)c1C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Sodium hydride (60%; 316 mg; 7.9 mmol) was suspended in DMF and cooled to 0° C. sec-Phenethyl alcohol (966 mg; 7.9 mmol) was dissolved in DMF and added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 1 hour. The solution was then cooled to 0° C. 2,6-Difluorobenzonitrile (1 g; 7.2 mmol) in DMF was cooled to 0° C. and the alcohol mixture was added dropwise to the benzonitrile solution and stirred for 2 hours. The solution was poured over 100 mL of cooled water. The solution was stored in the refrigerator for 3 hours and the solid was collected by filtration and dried under vacuum to yield 1.50 grams of 2-fluoro-6-(1-phenylethoxy)benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][C:24]([CH3:33])([CH3:32])[CH2:23][N:22]3[CH:21]=1)=O>>[CH3:32][C:24]1([CH3:33])[CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]3[CH2:23]1)[CH:29]=[CH:28][CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)(C)C2
Product: CC1(C)Cc2cccc3c(C4=C(c5c[nH]c6cc(F)ccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: COC1C=C(C=CC=1)C=O.C(CC(OCC)=O)#N.N1CCCCC1.[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2.[H-].[Na+].C([O:39][C:40](=O)[C:41]([C:51]#[N:52])=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=1)C>C(O)C.C1(C)C=CC=CC=1>[C:51]([CH:41]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=2)=[C:34]2[C:26](=[C:27]3[CH:28]=[CH:29][N:30]=[C:31]3[CH:32]=[CH:33]2)[O:25][C:40]1=[O:39])#[N:52]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCOC(=O)C(C#N)=Cc1cccc(OC)c1
Agent: COc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC#N
Solvent: C1CCNCC1
Product: COc1cccc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
To a solution of 3-methoxybenzaldehyde (2.0 g, 15.0 mmol) and ethyl cyanoacetate (1.56 mL, 15.0 mmol) in ethanol (10 mL) was added piperidine (0.73 ml, 7.5 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the crude oil was used for the next step. To a solution of 4-hydroxyindole (266.3 mg, 2 mmol) in toluene (5 mL) was added sodium hydride (100 mg, 2.5 mmol, 60%) and the mixture was stirred at room temperature for 0.5 h. To the mixture was added the 3-(3-methoxy-phenyl)-2-cyano-acrylic acid ethyl ester (462.5 mg, 2 mmol) dissolved in toluene (1 mL), then the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 6 mg (0.9%) the title compound. 1H NMR (CDCl3): 8.67 (brs, 1H), 7.54-7.48 (m, 1H), 7.35-7.31 (m, 2H), 7.15-7.01 (m, 5H), 3.88 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[O:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([O:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCCOC)c(OC)cc34)c2)n(-c2ccccc2)n1
Yield: 57 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 168B (0.115 g, 0.33 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.112 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 5 hours, to afford 1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.116 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.55 (s, 2H), 7.56 (m, 6H), 7.41 (m, 3H), 7.18 (d, 1H), 6.94 (d, 1H), 6.41 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H), 3.24 (q, 2H), 1.46 (s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 567 (M−OEt)+.