Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[CH2:3]([C:6]1[S:7][C:8]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]=1)[CH2:4][CH3:5]>C(O)C>[CH2:3]([C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]=1)[CH2:4][CH3:5]
Reactant: CCCc1ncc(C=CC=CC(=O)OCC)s1
Reactant: [H][H]
Solvent: CCO
Product: CCCc1ncc(CCCCC(=O)OCC)s1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Hydrogen was passed through a mixture of 25 g of ethyl 5-(n-propyl-5-thiazolyl)-2,4-pentadienoate, 250 ml of ethanol and 12.5 g of activated carbon containing 10% palladium with stirring for 2 hours and the mixture was filtered and the filter was washed with ethanol. The filtrate was evaporated to dryness under reduced pressure to obtain 23 g of raw ethyl 2-propyl-5-thiazole-pentanoate.
Reaction SMILES: [F:1][C:2]([F:33])([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[NH:17][CH2:18][C:19]([NH:21][CH:22]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)=[O:20])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C(O)(C(F)(F)F)=O>ClCCl>[NH:24]1[CH2:25][CH:22]([NH:21][C:19](=[O:20])[CH2:18][NH:17][C:14]2[C:15]3[C:10](=[CH:9][CH:8]=[C:7]([C:2]([F:1])([F:33])[C:3]([F:6])([F:4])[F:5])[CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nccc3ccc(C(F)(F)C(F)(F)F)cc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1nccc2ccc(C(F)(F)C(F)(F)F)cc12)NC1CNC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Into a 8 mL sealed tube, was placed a solution of tert-butyl 3-(2-[[7-(pentafluoroethyl)isoquinolin-1-yl]amino]acetamido)azetidine-1-carboxylate (as prepared in the previous step, 100 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL), TFA (0.5 g). The resulting solution was stirred for 5 h at 0° C. The resulting mixture was concentrated under vacuum. The residue was washed with 3×5 mL of ether. This resulted in 0.12 g (crude) of N-(azetidin-3-yl)-2-[[7-(pentafluoroethyl)isoquinolin-1-yl]amino]acetamide as a white solid.
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=1>[OH-].[Na+]>[N+:18]([C:14]1[CH:13]=[CH:12][C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[CH3:17])([O-:20])=[O:19]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Combine potassium hydroxide (3 g, 0.054 mol) and phenol (15 g, 0.16 mol), and heat to 110° C. until the potassium hydroxide is dissolved. Cool the mixture to room temperature and add 5-fluoro-2-nitrotoluene (7.75 g, 0.05 mol) in one aliquot. Heat the reaction mixture to 130° C. for 30 min, cool to room temperature, and then pour into 10% NaOH (200 mL). Extract the aqueous solution with ether (2×100 mL), combine the organic layers and wash with 10% NaOH (2×100 mL), water (2×100 mL), dry over Na2SO4 and concentrate in vacuo. Chromatograph on silica gel eluting with hexanes/ethyl acetate to give 2-nitro-5-phenoxytoluene as a solid: 1H NMR (300 MHz, CDCl3) 2.59 (s, 3H), 6.81–6.85 (m, 2H), 7.06–7.09 (m, 2H), 7.22–7.26 (m, 1H), 7.40–7.45 (m, 2H), 8.03–8.06 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[O:23])=[CH:20][CH:19]=1>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:22]([C:21]1[CH:31]=[CH:32][C:18]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:19][CH:20]=1)=[O:23]
Reactant: O=C(c1ccc(Br)cc1)c1cccc(Cl)c1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)c1cccc(Cl)c1
Yield: 21 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and 4-bromo-3′-chlorobenzophenone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 99:1, as the eluent affording 51 mg (21% yield) of the title compound as a yellow solid: mp 194.7-196.7° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1 H), 10.17 (d, J=7.0 Hz, 1 H), 8.69 (s, 1 H), 8.54 (d, J=5.4 Hz, 1 H), 8.01 (d, J=8.7Hz, 2 H), 7.83-7.79 (m, 3 H), 7.76-7.72 (m, 2 H), 7.70-7.66 (m, 1 H), 7.62-7.59 (m, 1 H), 7.56-7.51 (m, 2 H), 7.21 (t, J=6.9 Hz, 1 H); 13C NMR (400 MHz, DMSO-d6) δ 193.2, 159.3, 157.7, 157.4, 148.4, 145.7, 140.4, 139.4, 133.7, 132.0, 131.8, 130.8, 129.8, 129.1, 129.0, 128.3, 127.6, 121.3, 118.3, 117.8, 114.3, 108.8; MS (ESP) m/z 426 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(cnn2-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Reaction time: 15 h
Yield: 26.1 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 209 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(5-methyl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (19 mg, 26%). MS (M+H)+=349; 1H NMR (DMSO-d6) δ: 9.03 (s, 1H), 8.49 (d, J=8.5 Hz, 1H), 8.43-8.46 (m, 2H), 8.39 (d, J=3.0 Hz, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 2.48 (br. s., 3H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:13]3([CH3:21])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:22]>>[NH2:22][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:13]3([CH3:21])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(Cl)c12
Reactant: N
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(N)c12

Procedure:
To the compound from Step B (0.2 g, 0.64 mmol) was added methanolic ammonia (saturated at 0° C.; 40 mL). The mixture was heated in a stainless steel autoclave at 100° C. for 14 h, then cooled and evaporated in vacuo. The crude mixture was purified on a silica gel column (5×5 cm) with CH2Cl2/MeOH (50/1, 30/1, 20/1) gradient as eluent to give the title compound as a white solid (0.12 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:29]=[C:28]([C:30]2[C:39]3[C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=4[S:42][C:38]=3[C:37]([Br:47])=[C:36]3[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]3)[CH:27]=[C:26]([Br:48])[C:15]=1[O:16][C@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][CH:52]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:21]([O:20][C:18](=[O:19])[CH:17]([O:16][C:15]1[C:26]([Br:48])=[CH:27][C:28]([C:30]2[C:39]3[C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=4[S:42][C:38]=3[C:37]([Br:47])=[C:36]3[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]3)=[CH:29][C:14]=1[Br:13])[CH2:25][C:53]1[CH:52]=[CH:51][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: BrCc1cccc2ccccc12
Reactant: C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccc2ccccc2c1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: -74 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Diisopropylamine (distilled over CaH2, 0.233 mL, 1.78 mmol) was added to anhydrous tetrahydrofuran (0.91 mL) and cooled to -74° C. under a dry argon atmosphere. n-Butyllithium (2.5 M in hexane, 0.71 mL, 1.78 mmole) was added dropwise and the mixture was warmed to 0° C. for ca. 20 minutes then recooled to -75° C. Hexamethylphosphoramide (2 mL) was added followed 10 minutes later by the slow (0.5 hour) dropwise addition of a solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-propionic acid, tert-butyl ester (1.004 g, 1.48 mmole) in anhydrous tetrahydrofuran (3 mL). After stirring one hour at -75° C., 2 bromomethylnaphthalene (0.393 g, 1.78 mmol) was added dropwise. After stirring 0.5 hour at -80° C. the reaction mixture was allowed warm to room temperature overnight. The reaction mixture was quenched with dilute aqueous ammonium chloride and was partritioned between water (100 mL) and a 1:1 methylene chloride: ether solution (200 mL). After one more extraction with methylene chloride the organic layers were combined, washed with water (100 mL) and purification by flash chromatographed (eluent 7:3 pet ether:ethyl acetate) and HPLC (2 times) (First column:Waters Silica Prep Pak; isocratic, 98:2 hexane:ethyl acetate; Flow rate =225 mL/min; Second column: Waters Silica Prep Pak; gradient, 75:25 to 60:40 petroleum ether:methylene chloride) to provide the title compound as a white solid (0.280 g, 23%); NMR (CDCl3); δ8.35 (d, J=8 Hz, 1 H), 7.88-7.80 (m, 5 H), 7.66 (ddd, J=6, 5, 1 Hz, 1 H), 7.61 (d, J=2 Hz, 1 H), 7.60 (d, J=2 Hz 1 H) 7.58-7.56 (m, 2 H), 7.51-7.41 (m, 4 H), 7.18 (ddd, J=7, 1, 1 Hz, 1 H), 6.83 (dd, J=7, 1 Hz, 1 H) 5.44 (t, J =8 Hz, 1 H), 1.34 (s, 9 H); MS (FAB+): [M+], 3 bromine pattern, 814 (30%) 816 (95%) 818 (100%) 820 (42%); Anal. Calc. for C39H29Br3O3S: C, 57.30; H, 3.58, N, 0.00. Found: C, 57.55; H, 3.75, N, 0.02.
Reaction SMILES: [O:1]([CH2:8][C:9]#[C:10][C:11]1[S:15][CH:14]=[C:13]([C:16]2[C:20]3[CH2:21][C:22]4[N:23]=[CH:24][C:25]([C:28](O)=[O:29])=[CH:26][C:27]=4[C:19]=3[NH:18][N:17]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.CN(C)C(=O)C>[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:28]([C:25]2[CH:24]=[N:23][C:22]3[CH2:21][C:20]4[C:16]([C:13]5[CH:12]=[C:11]([C:10]#[C:9][CH2:8][O:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[S:15][CH:14]=5)=[N:17][NH:18][C:19]=4[C:27]=3[CH:26]=2)=[O:29])[CH2:45][CH2:44]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cnc2c(c1)-c1[nH]nc(-c3csc(C#CCOc4ccccc4)c3)c1C2
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cnc3c(c2)-c2[nH]nc(-c4csc(C#CCOc5ccccc5)c4)c2C3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Example 1094D (68 mg, 0.16 mmol), N-cyclohexylcarbodiimide-N′-methyl polystyrene (1.0 g, 1.28 mmol) and 1-hydroxybenzotriazole hydrate (44 mg, 0.33 mmol) in (2:1) dichloromethane/N,N-dimethylacetamide (10 mL) was agitated for about 15 min. 1-Methylpiperazine (77 mg, 0.77 mmol) was added, the mixture was agitated at room temperature for about 18 h, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (100:8:0.1) as the mobile phase to provide the title compound. 1H NMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.39 (m, 4H), 3.40 (m, 2H), 3.63 (m, 2H), 3.97 (s, 2H), 5.09 (s, 2H), 7.03 (m, 3H), 7.38 (m, 2H), 7.80 (s, 1H), 8.01 (m, 2H), 8.41 (s, 1H), 13.41 (s, 1H).MS (ESI): m/z 496 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:9]([OH:27])[C:8]=1[C:28](=O)[CH3:29])(=[O:5])=[O:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[F:31][C:2]([F:1])([F:32])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:9]([OH:27])[C:8]=1[CH2:28][CH3:29])(=[O:4])=[O:5]
Reactant: CC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCc1c(OS(=O)(=O)C(F)(F)F)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-acetyl-3-hydroxy-4-(5-methyl-7-nitroindan-4-yloxy)phenyl trifluoromethanesulfonate (477 mg) in dichloromethane (5 mL) were added triethylsilane (0.960 mL) and trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature overnight. Adding water, the reaction mixture was stirred for 1 hour and extracted with dichloromethane. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from dichloromethane and hexane to give the title compound (274 mg).
Reaction SMILES: COC1C=C(CNCCCNCCCCNCCCNCC2C=CC(O)=C(OC)C=2)C=CC=1O.OCC[CH:38]1[N:43]2[C:44]3[C:49]([CH2:50][CH2:51][CH:42]2[CH2:41][CH2:40][CH2:39]1)=[C:48]([OH:52])[CH:47]=[C:46]([O:53][CH:54]([CH2:56][CH2:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:55])[CH:45]=3.C(N(CC)CC)C.[C:72]([O:75][C:76](=[O:78])[CH3:77])(=O)[CH3:73]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:76]([O:75][C:72]1[CH:47]=[C:46]([O:53][CH:54]([CH2:56][CH2:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH3:55])[CH:45]=[C:44]2[C:73]=1[CH:50]([CH2:49][CH2:48][OH:52])[CH2:51][CH:42]1[CH2:41][CH2:40][CH2:39][CH2:38][N:43]12)(=[O:78])[CH3:77]
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1C(CCO)CCCC1CC2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1C(CCO)CC1CCCCN21
Temperature: 25 °C

Procedure:
A solution of 4.09 g. (0.01 mole) dl-6-(2-hydroxyethyl)-7-hydroxy-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline in 60 ml. methylene chloride containing 1.01 g. (0.01 mole) triethylamine is cooled to 0° C. while stirring in a nitrogen atmosphere. To this is added a solution of 1.22 g. (0.01 mole) 4-dimethylaminopyridine in 5 ml. of methylene chloride followed by 1.02 g. (0.01 mole) acetic anhydride. After stirring at 0°-5° C. for one hour, the mixture is allowed to warm to room temperature, extracted with methylene chloride and the extracts washed with sodium bicarbonate. After drying over anhydrous magnesium sulfate and evaporation of solvent, the desired product is obtained. It can be purified by column chromatography on silica gel if desired.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[CH:24]=[N:23]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CCNCC1
Reactant: Cn1cc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(F)c2cccnc2c1N1CCN(C(=O)c2cnn(C)c2)CC1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
1-(5-Fluoro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.038 g, 0.14 mmol) was combined with 1-methyl-1H-pyrazole-4-carbonyl chloride (0.030 g, 0.21 mmol) and triethylamine (0.058 mL, 0.42 mmol) in methylene chloride (1.0 mL, 16 mmol) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (45 mg, 85%). LCMS calculated for C20H21FN5O2 (M+H)+: m/z=382.2; Found: 382.1.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH:28][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1)=[O:14]
Reactant: CCn1cc(C(=O)O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)Nc2ccc(CC(=O)OC)cc2Cl)c2ccccc21
Temperature: 15 °C
Yield: 88.4 %

Procedure:
To 1-ethylindole-3-carboxylic acid (160.2 mg, 0.847 mmol) were added methylene chloride (3.5 ml) and oxalyl chloride (108.9 μl, 1.270 mmol) under stirring at 15° C. The reaction mixture was stirred for 2.5 hours at room temperature. The solvent was then distilled off under reduced pressure. To the residue was added methylene chloride (3.5 ml). Under stirring at room temperature, a solution of methyl 3-chloro-4-aminophenylacetate (177.5 mg, 0.889 mmol) in methylene chloride (3.5 ml) and triethylamine (0.37 ml, 2.667 mmol) were added and the mixture was heated under reflux for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform. The resulting solution was washed with 1N HCl ad saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate (277.7 mg, 88%) as a brown amorphous substance. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:12]CC)(=O)[C@@H:2]([C@H:4]([C:6]([O:8][CH2:9][CH3:10])=O)[OH:5])O.C(OC/C=C/CO)[C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1.C(OOO)(C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].C(OCC)C>[CH2:9]([O:8][CH2:6][C@@H:4]1[O:5][C@H:2]1[CH2:1][OH:12])[C:10]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: OC/C=C/COCc1ccccc1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)(C)OOO
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: OC[C@@H]1O[C@H]1COCc1ccccc1
Temperature: -23 °C
Reaction time: 8 h

Procedure:
In 190 ml of dry dichloromethane, 3.3 g of a molecular sieves (powder, 3A) was suspended, and 4.2 ml of isopropyl orthotitanate and 2.9 ml of diethyl L(+)-tartarate were added thereto under stirring at -23° C. The mixture was stirred at the same temperature for 15 minutes. then, 3 ml of a dry dichloromethane solution of 4.7 g of (E)-4-benzyloxy-2-buten-1-ol was added thereto, and the mixture was stirred at the same temperature for 5 minutes. 11 ml of tert-butylhydroxyperoxide (5.17M dichloromethane solution) was added thereto, and the mixture was stirred for further seven hours. Then, the reaction solution was left to stand at -23° C. overnight. To the reaction solution, 190 ml of diethyl ether and 4.2 ml of a saturated sodium sulfate aqueous solution were added, and the mixture was stirred at room temperature for 4 hours. The insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in 240 ml of diethyl ether, and 42 ml of a 1N sodium chloride aqueous solution was added thereto under stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes. The diethyl ether layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to obtain 2.9 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol as colorless oily substance.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[N:25]([CH2:40][CH:41]4[CH2:44][NH:43][CH2:42]4)[CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=4)[N:28]=3)[CH2:20][CH2:19]2)[N:12]=[CH:11][N:10]=1.C(O)=O.C=O>C(O)C>[NH2:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[N:25]([CH2:40][CH:41]4[CH2:44][N:43]([CH3:2])[CH2:42]4)[CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:39])[F:38])[CH:30]=4)[N:28]=3)[CH2:20][CH2:19]2)[N:12]=[CH:11][N:10]=1
Reactant: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CNC2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: O=CO
Solvent: CCO
Product: CN1CC(Cn2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C(N)=O)CC2)C1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-6-{4-[1-azetidin-3-ylmethyl-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide trifluoroacetate (2) (25.00 mg; 0.03 mmol; 1.00 eq.) in ethanol 1 ml added formic acid (0.00 1 ml; 0.08 mmol; 2.50 eq.) and formaldehyde (0.001 ml; 0.04 mmol; 1.20 eq.), stirred at 65° C. for 3 hr. lc-ms showed clean desired peak. Removed off solvent, purified by HPLC, collected title compound 14.8 mg. LC-MS (M+1=533, obsd.=533).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@@H:9]1[C:18](OC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83.4 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (11.21 g: 34.4 mmole) in a mixture of tetrahydrofuran (34 ml) and ethanol (51 ml), sodium borohydride (5.21 g: 137.7 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 75 minutes at room temperature to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (8.47 g). Yield: 83%. Colorless crystals. NMR δ(CDCl3) ppm: 1.48(s, 9H), 1.9 to 2.2(m, 1H), 2.3 to 2.5(m, 1H), 3.06 (s, 3H), 3.65(dd, J=11.2 Hz, J=4.0 Hz, 1H), 3.5 to 3.9(m, 2H), 3.84(dd, J=11.2 Hz, J=7.6 Hz, 1H), 4.1(m, 1H), 5.2(m, 1H). IR ν (KBr) cm-1 : 3490, 1688.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O>N1CCCCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
The reaction mixture of 5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60° C. overnight and filtered. The solid washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M−1]+., 100).