Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:5]2[OH:29]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:5]2[OH:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Yield: 74.2 %

Procedure:
1,1-Dimethylethyl N-((6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclohexane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (185 mg, 441 μmol) was dissolved in TFA (2 mL) at ambient temperature for 30 minutes. The reaction mixture was then concentrated, and the product was precipitated with hexanes, filtered, washed with ether, and dried in a vacuum oven to give the title compound (119 mg) as a white solid. MS (m/z)=364 (M+H)+. Calculated for C18H18ClNO5 363.09.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:79])[C:63]=1[N:64]1[CH2:70][CH2:69][CH:68]([F:71])[CH:67]([NH:72][C:73](=[O:78])[C:74]([F:77])([F:76])[F:75])[CH2:66][CH2:65]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:12]1[S:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[C:10]([C:22](=[O:23])[NH:58][C:59]2[CH:60]=[N:61][N:62]([CH3:79])[C:63]=2[N:64]2[CH2:65][CH2:66][CH:67]([NH:72][C:73](=[O:78])[C:74]([F:75])([F:76])[F:77])[CH:68]([F:71])[CH2:69][CH2:70]2)[N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (784 mg, 2.2 mmol) in DCM (40 mL) was added PyBOP (1.46 g, 2.8 mmol) and the mixture stirred at room temperature for 30 min. A solution of N-(1-(4-Amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (647 mg, 2.0 mmol) and DIPEA (0.59 mL, 3.4 mmol) in DCM (40 mL) was then added and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (1.32 g).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[N:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1C2CCN(CC2)C1CN1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1C2CCN(CC2)C1CN1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(1-piperidinylmethyl)-1-azabicyclo-[2.2.2]octan-3-one (8.90 g, 40 mmoles) in absolute ethanol (40 ml) was treated dropwise with a solution of sodium borohydride (1.15 g, 30.4 mmoles) in absolute ethanol (40 ml). The solution was stirred at room temperature for 18 hours, concentrated in vacuo, and diluted with water (100 ml). The aqueous solution was treated with potassium carbonate and extracted with ether, and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residual solid was recrystallized from acetonitrile to afford 3.32 g (37%) of the trans isomer as colorless crystals, mp 130°-131° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37].[CH3:38]I>O.CN(C)C=O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([N:29]([CH3:38])[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of Example 39I (104 mg, 0.193 mmol) in 3 mL of water was added 0.997 N NaOH (0.194 mL, 0.193 mmol). After stirring for 2 hours, the reaction mixture was concentrated to dryness. To a solution of the resulting residue in 3 mL of dimethylformamide was added methyl iodide (0.012 mL, 0.193 mmol). After stirring at room temperature overnight, the reaction solution was concentrated and chromatographed on silica gel eluting with hexane followed by 60% and 80% ethyl acetate in hexane. The resulting yellow solid was suspended in 3 mL of water and 0.997 N NaOH was added (0.160 mL, 0.160 mmol). After stirring for 4 hours, the suspension was lyophilized to 84 mg (79%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1H) 0.69 (t, J=7.17 Hz, 6H) 0.82 (m, 1H) 1.28 (m, 1H) 1.39 (s, 3H) 1.73 (m, 1H) 2.15 (m, 1H) 2.97 (s, 3H) 3.27 (s, 3H) 7.33 (m, 2H) 7.46 (m, 2H) 7.57 (dd, J=8.82, 2.21 Hz, 1H) 7.66 (d, J=2.57 Hz, 1H) 8.05 (d, J=7.72 Hz, 1H) 15.64 (s, 1H). MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:25])[C@H:8]([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:24])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([O:22][CH3:23])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Reactant: BrBr
Solvent: O
Solvent: CO
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C[C@@H]1O

Procedure:
A stirred solution of 3α-hydroxy-2β-methoxy-5α-pregnan-20-one (4.0 g.) in dry methanol (300 ml.) was treated at 0° with a solution of bromine (0.65 ml.) in methanol (15 ml.) at such a rate that the yellow colour disappeared before further addition. The mixture was then poured into water and the precipitated solid was collected by filtration, washed with water and dried in vacuo to give title compound (4.0 g) as white crystals.
Reaction SMILES: [CH:1]1([C:4](=[O:30])/[CH:5]=[C:6](/[NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([CH:25]=3)=[CH:23][N:22]=[C:21]([CH3:26])[CH:20]=4)[CH:15]=2)\SC)[CH2:3][CH2:2]1.Cl.[NH2:32]O>CN(C=O)C>[CH:1]1([C:4]2[O:30][N:32]=[C:6]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([C:16]4[C:17](=[O:28])[N:18]([CH3:27])[C:19]5[C:24]([CH:25]=4)=[CH:23][N:22]=[C:21]([CH3:26])[CH:20]=5)[CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CS/C(=C\C(=O)C1CC1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3cc(C4CC4)on3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To the above crude mixture of (Z)-3-(5-(3-cyclopropyl-1-(methylthio)-3-oxoprop-1-enylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 31 were added hydroxylamine hydrochloride (174 mg, 2.4 mmol) and DMF (2 mL). The resulting mixture was heated at 100° C. for 30 min. The mixture was purified by preparative LC/MS to give 3-(5-(5-cyclopropylisoxazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (D4). 1H NMR (400 MHz, d6-DMSO) δ 9.21 (s, 1H), 9.13 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.29 (dd, J=2.4, 8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.83 (s, 1H), 3.72 (s, 3H), 2.79 (s, 3H), 2.07 (s, 3H), 2.05 (m, 1H), 1.01 (m, 2H), 0.84 (m, 2H). MS m/z 387.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:35])[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]1([CH2:7][C:8](=[O:35])[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(O)Cc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(=O)Cc2ccccc2)CC1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-3-hydroxy-1-oxobut-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (494 mg, 0.98 mmol) from Step F in methylene chloride (10 mL) at room temperature was added Dess-Martin reagent (621 mg, 1.5 mmol). After 3 h, the reaction was diluted with ether and quenched with 1N sodium hydroxide. After stirring for 30 min, the mixture was diluted with water and extracted twice with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate in hexanes) to afford the title product (343 mg).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH:8]([C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:31])[C@H:9]([C:11]([NH:13][C@@H:14]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[OH:18])=[O:12])[CH3:10]>>[NH:8]([C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:31])[C@H:9]([C:11]([NH:13][C@@H:14]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:15][CH2:16][C:17](=[O:18])[O:19][N:13]1[C:3](=[O:5])[CH2:2][CH2:9][C:11]1=[O:12])=[O:12])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (15 ml) was added to Boc-L-Ala-D-Glu-(OH)OBzl (1)(3.26 g) and the mixture was stirred for 20 minutes at room temperature, concentrated in vacuo and washed with diisopropylether. The oil was dissolved in a mixture of water (15 ml) and sodium bicarbonate was added until the pH of the solution became 8-9. The mixture of water (6 ml) and acetone (20 ml) was added to the solution and palmitoyl chloride (2.20 g) was added in one portion. After stirring for 30 minutes at room temperature, the pH of the solution was adjusted to 3 with 1N-hydrochloric acid and the reaction mixture was concentrated. To the residue was added water (30 ml) and the precipitates was collected and dried to give a crude product, which was purified by column chromatography of Silicagel (90 g) with chloroform-methanol (30:1, v/v) as an eluent to give palmitoyl-L-Ala-D-Glu(OH)OBzl (2)(2.00 g). mp. 131°-132° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=O)[N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]2[C:5](=O)[NH:4]1.B.C1COCC1.Cl>CO>[CH2:5]1[NH:4][CH:3]([CH2:2][OH:1])[CH2:8][N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]12
Reactant: O=C1NC(CO)C(=O)N2CCNCC12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OCC1CN2CCNCC2CN1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a flask containing (3S,9aS or 9aR)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D83, 217 mg) was added 1M BH3-THF solution (10.9 mL) and the reaction was brought to reflux (80° C.) overnight. The reaction flask was cooled to 0° C. and treated with 20 mL of MeOH and conc. HCl (2.5 mL). The resulting solution was heated to 60° C. for 4 h. The reaction was checked by direct MS (m/z=172 (M+1), 184 (M+BH3)). The reaction mixture was purified by SCX, obtaining 174 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:39])=[O:38]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(S(C)(=O)=O)C1
Reaction time: 18 h

Procedure:
The solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) and Et3N (58 μL, 0.42 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride (31 μL, 0.39 mmol). After 18 hours, the cloudy mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-95% EtOAc in hexanes to afford the title compound as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](Cl)=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)NC(=O)N1CCn2cc(-c3ccccc3)c(C(N)=O)c2C1
Yield: 39.4 %

Procedure:
A mixture of 0.866 g (2.31 mmol) of N2-tert-butyl-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 6.0 g (95 mmol) of ammonium formate and 0.20 g (0.09 mmol) of 10% palladium-on-charcoal containing 50% water in 50 ml of methanol is refluxed for 6 hours. After cooling, the mixture is filtered through Celite and the Celite is rinsed with dichloromethane. The filtrate is then concentrated under reduced pressure and the residue is taken up in dichloromethane. The solution is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The product is then purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 95 to 50% ethyl acetate in dichloromethane, to give 0.31 g of N2-tert-butyl-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white solid after crystallizing from diethyl ether and drying.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 4-phenyl imidazole (245.1 mg, 1.7 mmol,), Et3N (258.0 mg, 2.6 mmol), and DMAP (20.1 mg, 170.0 μmol) in DCM (5 mL) was slowly added ethyl chloroformate (276.7 mg, 2.6 mmol) at room temperature. The reaction was allowed to stir overnight at room temperature. The solution was poured into water and the organic layer was washed with water, brine and dried (Na2SO4). The crude residue was purified by column chromatography (30% EtOAc/hexanes) to afford a colorless solid (301.0 mg, 80% yield). 1H NMR: 1.47 (t, 3H, J=6.9 Hz), 4.50 (q, 2H, J=7.0 Hz), 7.30 (t, 1H, J=7.0 Hz), 7.41 (t, 2H, J=7.5 Hz), 7.69 (s, 1H), 7.80 (d, 2H, J=7.9 Hz), 8.2 (s, 1H)
Reaction SMILES: [N:1]1([CH2:7]/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[CH:40])[CH:34]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[NH2:41])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.C1COCC1>[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[CH:40])[CH:34]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[NH:41][C:10](=[O:12])/[CH:9]=[CH:8]/[CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:20]
Reactant: O=C(O)/C=C/CN1CCCCC1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCC)c(N)cc23)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#Cc1cccc(Nc2ncnc3cc(OCC)c(NC(=O)/C=C/CN4CCCCC4)cc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
(E)-4-(piperidin-1-yl)but-2-enoic acid (550 mg, 3.4 mmol) and 10 drops of DMF were added in 20 ml DCM, and then oxalyl chloride (0.45 ml, 4.9 mmol) was added dropwise at 0° C. The solution was stirred for 1 hour at room temperature, then concentrated to a yellow solid. This intermediate was added in 50 ml THF, and then was added dropwisely into a solution of 7-ethoxy-N4-(3-ethynylphenyl)quinazoline-4,6-diamine (1 g, 3.28 mmol) and DIPEA (1 g, 7.7 mmol) in 200 ml THF in a ice bath. The reaction was stirred at 40° C. for 4 hours. The resulting reaction solution was concentrated to remove the excess of solvent, the residue was separated between 20 ml DCM and 20 ml saturated aqueous NaHCO3. The organic layer was concentrated and applied on a silica gel column (DCM/MeOH=10/1) to get (E)-N-(7-ethoxy-4-((3-ethynylphenyl)amino)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide as white solid 102 mg (6.8% yield). 1H-NMR (DMSO-d6): δ1.41-1.53 (m, 9H), 2.36 (m, 4H), 3.10-3.12 (m, 2H), 4.17 (s, 1H), 4.26-4.33 (m, 2H), 6.55 (d, J=15.3 Hz, 1H), 6.76-6.83 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.26 (s, 1H), 7.35-7.40 (m, 1H), 7.88 (d, J=8.2 Hz, 1H), 8.00 (s, 1H), 8.52 (s, 1H), 8.92 (s, 1H), 9.49 (s, 1H), 9.71 (s, 1H). MS m/z 456 [M+1].
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[CH2:7][CH2:6]2)[O:4]CC1.O.Cl>CCO.O1CCOCC1>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][O:17][CH2:16][N:14]1[CH:15]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:12]=[N:13]1
Reactant: C[Si](C)(C)CCOCn1cc(C2CCC3(CC2)OCCO3)cn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C2CCC(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 98.6 %

Procedure:
4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (487 μmol, 165 mg) was dissolved in EtOH (10 mL) in a 20 mL scintillation vial. To this solution was added H2O (3 mL) followed by 4N HCl in 1,4-dioxane. The resulting reaction mixture was stirred at room temperature for 60 hours. At this point, the reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (×3). The combined organics were dried over Na2SO4 to yield 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclohexanone (141 mg, 480 μmol, 98% yield) as white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[CH3:46][N:47]([CH3:63])[CH:48]1[CH2:52][CH2:51][N:50]([C:53]2[CH:62]=[CH:61][C:56]([C:57]([NH:59][NH2:60])=[O:58])=[CH:55][CH:54]=2)[CH2:49]1>O.CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:60][NH:59][C:57](=[O:58])[C:56]2[CH:55]=[CH:54][C:53]([N:50]3[CH2:51][CH2:52][CH:48]([N:47]([CH3:46])[CH3:63])[CH2:49]3)=[CH:62][CH:61]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(C(=O)NNC(=O)c2ccc(N3CCC(N(C)C)C3)cc2)cc1
Reaction time: 0.17 h

Procedure:
A mixture of 4-butoxybenzoic acid (156 mg) and DMF (10 ml) was mixed with TOTU (264 mg) and N,N-diisopropylethylamine (104 mg). After 10 minutes, 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (200 mg) was added. After one hour, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 424.55 (C24H32N4O3) was obtained in this way; MS (ESI): 425 (M+H+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:12]2[C:16]([CH2:17][O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:21][C:20]=3[F:33])=[C:15]([C:34]([F:37])([F:36])[F:35])[S:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([C:12]2[C:16]([CH2:17][O:18][C:19]3[C:20]([F:33])=[CH:21][C:22]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:23][C:24]=3[F:25])=[C:15]([C:34]([F:36])([F:35])[F:37])[S:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(C3CCCC3)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2c(C3CCCC3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-cyclopentyl-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.39 (d, J=9.6 Hz, 2H), 5.20 (s, 2H), 3.64-3.54 (m, 3H), 2.66 (t, J=7.8 Hz, 2H), 2.05-2.09 (m, 2H), 1.70-1.95 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C19H20F5NO2S, 422.1 (M+H). found 422.1.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[F:8][C:9]1[C:17]2[NH:16][C:15]([CH3:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[F:19][C:20]([F:41])([F:40])[S:21]([O:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][C:30]2[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=2)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>O>[F:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[CH:26][C:25]([O:24][S:21]([C:20]([F:41])([F:19])[F:40])(=[O:23])=[O:22])=[CH:39][CH:38]=4)=[CH:37][CH:36]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc2cccc(F)c2[nH]1
Reactant: O=S(=O)(Oc1ccc(Oc2ccc(CBr)cc2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(F)cccc2n1Cc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (10 ml) and sodium hydride (60% oil suspension; 29 mg), 4-fluoro-2-methylbenzimidazole (110 mg) was added while stirring, and stirring was continued at room temperature for 1 hour. To the reaction mixture, a solution of 4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl bromide (300 mg) in anhydrous N,N-dimethylformaide (3 ml) was dropwise added, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene extract was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to eliminate toluene The residue was purified by silica gel column chromatography to give 4-fluoro-2-methyl-1-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl]benzimidazole (164 mg) as a colorless liquid nD26 1.5615.