Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[C:53]5=[N:54][O:55][N:56]=[C:52]5[C:51]([N+:57]([O-:59])=[O:58])=[CH:50][CH:49]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[C:53]5=[N:54][O:55][N:56]=[C:52]5[C:51]([N+:57]([O-:59])=[O:58])=[CH:50][CH:49]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a slurry of N-[3-({3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}amino)-3-oxopropyl]-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (24, 29 mg, 0.028 mmol) and K2CO3 (76 mg, 0.552 mmol) in N,N-dimethylformamide (6 mL) and tetrahydrofuran (2 mL) was added thiophenol (40 μL, 0.389 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. Purification by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 14 min; retention time =10.6 min) afforded 6 (15 mg, 52%) mp 170-171° C.; 1H NMR (500 MHz, CDCl3) δ 9.54 (br s, 1H), 8.68 (br s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.07 (t, J=5.35, 1H), 7.92 (t, J=5.4 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 6.40 (d, J=8.9 Hz, 1H), 5.36 (m, 1H), 3.43 (m, 1H), 3.24-3.17 (m, 4H), 3.10 (m, 2H), 2.88 (br s, 3H), 2.35 (d, J=7.2 Hz, 2H), 2.23 (t, J=6.9 Hz, 2H), 2.18 (t, J=7.1 Hz, 2H), 2.04 (t, J=7.2 Hz, 2H), 1.94-0.96 (m, 35H), 0.93 (s, 3H), 0.86 (d, J=6.2 Hz, 3H), 0.84 (d, J=2.1 Hz, 3H), 0.82 (d, J=2.1 Hz, 3H), 0.62 (s, 3H); 13C NMR (125.8 MHz, DMSO d6) δ 171.9, 170.8, 170.3, 145.1, 144.4, 144.2, 138.6, 137.9 122.3, 120.5, 99.1, 56.6, 56.1, 55.5, 49.3 (×2), 45.5. 43.3, 41.8 (×2), 41.5, 36.4, 36.2, 35.6 (×2), 35.5 (×2), 35.3 (×2), 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.2, 26.0, 24.9, 24.3, 23.8, 23.2, 22.6, 22.4, 20.5, 18.8, 18.5, 11.6; IR (film) νmax 3173, 3075, 2919, 2848, 1634, 1538, 1331 cm−1; CI m/z 861.5965 (MH+, C48H77N8O6 requires 861.5966).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21][NH:22]C(=O)C(F)(F)F)[N:19]=2)=[CH:11][CH:10]=1)#[N:8]>CO.O>[NH2:22][CH2:21][CH2:20][C:18]1[N:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[O:16][CH:17]=1
Reactant: N#Cc1ccc(-c2nc(CCNC(=O)C(F)(F)F)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2nc(CCN)co2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
K2CO3 (0.20 g, 1.45 mmol) was added portionwise to a solution of N-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (0.15 g, 0.49 mmol) in dry methanol:water (10 mL, 7:3 v/v). The reaction mixture was stirred at room temperature for 3 h and then diluted with water. The crude product was extracted with chloroform. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get 4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile (80 mg), which was used for the next step without further purification. MS (ESI) m/z: Calculated for C12H11N3O: 213.09. found: 214.0 (M+H)+.
Reaction SMILES: [ClH:1].O=[C:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C([BH3-])#N.[Na+]>CO>[ClH:1].[ClH:1].[CH:24]([NH:27][CH:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)=O)=C21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)NC(C)C)=C21

Procedure:
The solution of 0.84 g of 1-(2-oxopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine hydrochloride, 1.28 ml of isopropylamine, 0.66 ml of 4.4 N methanolic hydrochloric acid and 0.17 g of sodium cyanoborohydride in 13 ml of methanol is refluxed overnight. Additional 0.085 g of sodium cyanoborohydride are added and the whole is again refluxed for 5 hours. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid and the methanol evaporated. The aqueous solution is washed with diethyl ether, rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The ether extract is evaporated, the residue dissolved in acetone and 0.4 ml of 8 N ethanolic hydrochloric acid are added, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine dihydrochloride melting at 257°-260° with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCc1c(-c2ccccc2)[nH]c2ccc(Br)cc12
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-3-pentyl-2-phenyl-1H-indole (1.711 g, 5 mmol) was reacted with k-t-butoxide (0.589 g, 5.25 mmol) and benzyl bromide (0.901 g, 5.25 mmol) in DMF (15 ml) to give the product (1.285 g, 2.972 mmol, 59%) as a white solid, mp 98-101° C. 1H DMSO-d6) δ 0.75 (t, J=7.0 Hz, 3H), 1.11-1.19 (m, 4H), 1.46-1.52 (m, 2H), 2.60 (t, J=7.5 Hz, 2H), 5.25 (s, 2H), 6.77-6.78 (m, 2H), 7.13-7.22 (m, 4H), 7.32 (d, J=8.7 Hz, 1H), 7.34-7.36 (m, 2H), 7.42-7.49 (m, 3H), 7.75 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 432/434 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl>CN(C)C=O>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][N:11]1[CH2:12][CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[C:10]1=[O:14]
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 48.5 %

Procedure:
500 mg of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone was dissolved in 5 ml of dimethylformamide and 0.2 g of sodium hydride and 0.2 g of 2-dimethylaminoethyl chloride were successively added thereto under ice-cooling. Then the obtained mixture was allowed to react for one hour at room temperature. The reaction mixture was extracted with ethyl acetate, washed with water followed by a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the ethyl acetate off, the residue was purified by column chromatography with the use of silica gel and benzene/acetone and recrystallized from ethyl acetate/hexane to give 300 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](OC(=O)C)(=[O:30])C>C(O)=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][CH:28]=[O:30])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC=O)c3Cl)cccn2c1Br
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a suspension of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg) in formic acid (1 ml) was added acetic anhydride (65 mg), and the mixture was stirred for 1.5 hours. Acetic anhydride (40 mg) was added thereto, and the mixture was stirred for 3 hours. The mixture was concentrated in vacuo, and a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride:methanol=5:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(formylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (102 mg).
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.[CH2:9]([S:16][C:17]#[CH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>Cl[Cu].CC(C)=O>[CH2:9]([S:16][C:17]#[C:18][C:10]#[C:9][S:16][CH2:17][C:5]1[CH:4]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCN(C)C
Reactant: C#CSCc1ccccc1
Agent: Cl[Cu]
Solvent: CC(C)=O
Product: C(C#CSCc1ccccc1)#CSCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of trimethylsilylacetylene (10 mL, 71 mmol) in ether (100 mL) under argon at -78° C. was slowly added n-BuLi (2.5 M in hexanes, 28.3 mL, 71 mmol). The solution was warmed to -20° C. and then cooled to -70° C. Sulfur powder (2.3 g, 72 mmol), in a flask connected to the reaction vessel by Gooch tubing, was poured into the reaction mixture. The mixture was warmed to 10° C., becoming a pale yellow solution. Benzyl bromide (8.5 mL, 72 mmol) was added to quench the reaction. The resulting solution was stirred overnight. The solution was quenched by addition of saturated NH4Cl solution (30 mL), and the mixture was extracted with ether (3×50 mL), the combined ether layers washed with brine (1×30 mL) and water (1×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo affording a yellow oil (16.5 g; 100%): GC EI-MS: 220 (M+). Without further purification a solution of this yellow oil (16.5 g, 72 mmol) in THF (150 mL) was treated with water (10 mL) followed by THF solution (100 mL) of tetra-n-butylammonium fluoride (TBAF; 1.1 eq). The resulting reddish brown solution was stirred for 2.5 h, and then washed with brine (3×50 mL), dried (MgSO4, concentrated in vacuo, and distilled (39°-42° C./0.015 mmHg) affording benzylthioacetylene (2) as a yellow oil (10 g, 96%): 1H NMR (acetone-d6) δ 7.5-7.25 (m, 5 H) 4.05 (s, 2 H) 3.38 (s, 1 H); 13C NMR (acetone-d6 δ 137.89, 129.93, 129.38, 128.56, 85.43, 74.82, 40.07; IR 2041, 3286 cm-1. A mixture of CuCl (0.27 g), TMEDA (0.41 mL) and acetone (40 mL) were placed in a three-necked flask, and with stirring O2 was bubbled through the dark green solution for a few minutes. Compound 2 (8 g, 60 mmol) was added dropwise to the stirred green solution which was maintained at room temperature with a water bath. After 3 h, acetone was removed in vacuo and ice cold HCl solution (0.3 mL conc HCl diluted to 50 mL) was added to the concentrate. The suspension was extracted with ether (1×100, 2×50 mL). The combined ether layers were washed with brine (2×50 mL) and water (1×35 mL), dried (MgSO4), and concentrated in vacuo affording 3 as a yellow solid (7.7 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@@H:29]1([CH2:37]O)[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:35][OH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]3[CH2:35][OH:36])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@@H]1CCCC[C@@H]1CO
Product: O=C1c2ccccc2C(OCC2CCCCC2CO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 64 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-1,2-cyclohexane-dimethanol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (337 mg, 64%). 1H NMR (300 MHz, CDCl3): mixture of diastereoisomers: 8.08-7.93 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.58-7.54 (m, 2H, Ar—H), 7.43-7.36 (m, 2H, Ar—H), 7.23-7.11 (m, 5H, Ar—H), 4.61 and 4.25 (d: AB, J=15.0 Hz, 2H, N—CH2); and 4.59 and 4.36 (d: AB, J=15.0 Hz, 2H, N—CH2), 3.53-3.24 (m, 2H, HO—CH2), 2.87-2.61 (m, 2H, OCH2), 1.87-1.09 (m, 10H, CH). 13C NMR (75 MHz, CDCl3): mixture of diastereoisomers: 168.25, 147.42, 145.37, 145.20, 144.84, 144.76, 137.28, 137.12, 134.97, 134.88, 133.03, 131.55, 131.41, 130.15, 130.10, 129.98, 129.94, 128.81, 128.69, 127.98, 127.92, 123.91, 123.81, 123.33, 123.30, 123.10, 123.06, 95.07, 94.97, 63.91, 63.57, 63.44, 63.31, 42.50, 42.43, 40.77, 39.99, 37.18, 27.40, 27.09, 26.21, 26.16, 23.77, 23.44, 23.29. Anal.: calc. for C29H29ClN2O5+0.3 CH2Cl2+0.1 H2O: C, 64.18; H, 5.49; N, 5.11. Found: C, 64.34; H, 5.49; N, 4.95.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=O)=[CH:25][CH:24]=1>>[N:8]1([C:6]2[C:5]3[N:21]=[C:32]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[S:22][C:4]=3[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(-c2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Yield: 80 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using p-toluoyl chloride, yielding the title compound in 80% yield.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:20]>>[C:1]1([CH:7]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)COC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)COCC2c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate 43)) (2.58 g, 10.52 mmol) in ammonium hydroxide (28.7 mL, 736 mmol) was heated to 80° C. in a sealed tube and stirred overnight. The reaction mixture was then concentrated to dryness giving 8-phenyl-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione. The crude material was carried on as-is. LC-MS (M+H)+=245.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:5]=[CH:6][CH:7]=1.[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20](=[O:19])[CH:21]=[CH:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(Br)c1
Reactant: Oc1ccnc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(Br)c1
Temperature: 85 °C

Procedure:
A mixture of 2-[2-(3-bromophenyl)-2-methylpropyl]-2-trifluoromethyloxirane, 4-hydroxyquinoline (2 equiv.), and sodium ethoxide (21 wt. % solution in ethanol, 1 equiv.) in ethanol was heated at 85° C. for 14 hours, quenched with water, and concentrated in vacuo to remove most of the ethanol. The residue was diluted with half saturated aqueous sodium bicarbonate solution and methylene chloride. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate-hexanes gradient and concentration of the product-rich fractions afforded 1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[Br:15][CH2:16][C:17](Br)=[O:18]>C1COCC1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: Nc1ccccn1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)Nc1ccccn1
Reaction time: 8 h

Procedure:
To a solution of 2-aminopyridine (48.8 mmol) in anhydrous THF (98 mL) at room temperature was added Et3N (58.6 mmol) and bromoacetyl bromide (58.6 mmol) dropwise The mixture was stirred overnight and quenched with sat. NaHCO3 (aq). EtOAc was added to the mixture and the layers separated. The aqueous phase was extracted with EtOAc and the combined organics dried (MgSO4) and concentrated in vacuo to a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O=S(Cl)Cl.[CH3:16]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:16])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2-hydroxyphenyl)acetic acid (11 g, 72.3 mmol) in 100 mL of MeOH was added SOCl2 (17.2 g, 144.7 mmol) at 0° C. The mixture was stirred at 50° C. overnight. The reaction was concentrated. The residue was purified column chromatography to give methyl (2-hydroxyphenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NN)cc1C
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Yield: 156.7 %

Procedure:
A solution of 3,4-dimethylphenylhydrazine (7.3 g; 0.053 mol.) and ethyl acetoacetate (6.9 g; 0.053 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100° for 24 h. The solvent was evaporated and the product purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford the title compound (16.8 g; 64%). MS(ES) m/z 203 [M+H].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>>[OH:27][C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CNC[C@H](O)c1ccccc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C[C@H](O)c1ccccc1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-2-(methylamino)-1-phenylethanol (1.2 equiv) to give 156 (19.1 mg, M+1 447.1)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[C:29]([F:30])[CH:28]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)c(F)c4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3,4-difluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2,3′,4′-trifluorobiphenyl-5-yl)-imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (6 mg, 3%): m/z (ES+) 401 [MH+].
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[CH2:11][NH2:12])[CH2:2]1)[CH2:8]2.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[CH2:11][NH:12][C:23]([C:18]3[NH:19][C:20]4[C:16]([CH:17]=3)=[CH:15][C:14]([F:13])=[CH:22][CH:21]=4)=[O:24])[CH2:2]1)[CH2:8]2
Reactant: NCC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC1CN(C3)C2)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 2B (50 mg, 0.30 mmol) was dissolved in pyridine (5 mL). 5-Fluoroindole-2-carboxylic acid (65 mg, 0.36 mmol), 1-hydroxybenzotriazole (51 mg, 0.38 mmol), 4-di(methylamino)pyridine (9.2 mg, 0.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) were added to the reaction mixture. The reaction was stirred at 25° C. for 18 hours. The reaction mixture was filtered through a glass frit. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 Å Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the free base of the title compound. The solid was dissolved in 10:1 ether/methanol (5 mL) and treated with fumaric acid (10 mg/mL solution in 10:1 ether/methanol). The precipitate was filtered and dried under vacuum to afford the title compound as a fumarate: 1H NMR (methanol-d4, 500 MHz) δ 1.95-2.02 (m, 2 H), 2.11-2.20 (m, 4 H), 2.20-2.28 (m, 2 H), 3.37-3.43 (m, 2 H), 3.51 (br s, 2 H), 3.62 (d, J=7.93 Hz, 2 H), 3.76-3.83 (m, 2 H), 6.69 (s, 2.6 H; C4H4O4), 7.00 (dt, J=9.15, 2.44 Hz, 1 H), 7.03 (s, 1 H), 7.26 (dd, J=9.46, 2.44 Hz, 1 H), 7.41 ppm (dd, J=8.85, 4.58 Hz, 1 H); MS (ESI) m/z 328 (M+H)+; Anal. Calcd. for C19H22FN3O.1.3C4H4O4.0.1NH4OAc: C, 60.3; H, 5.79; N, 8.93. Found: C, 59.98; H, 5.76; N, 9.19.