Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[C:6]1=[O:33].[C:38](Cl)(Cl)=[O:39]>>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH2:27][CH2:28][C:29]2[O:30][C:38](=[O:39])[NH:32][N:31]=2)[C:6]1=[O:33]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)NN)cc1
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCc2n[nH]c(=O)o2)cc1

Procedure:
Prepared by reacting N-{4-[1-(2-fluorobenzyl)-3-(3-hydrazinocarbonyl-propyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide with phosgene according to the general procedure of Kramer et al. as described in J. Heterocyclic Chem. 1994,31, 1439. MS, m/z(M+H)=533.1821.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9](O)=[O:10])=[C:6]([N:12]([CH3:14])[CH3:13])[N:5]=[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>C1COCC1>[NH2:37][C:9](=[O:10])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[O:24])=[CH:18][CH:17]=2)=[N:5][C:6]=1[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.940 g, 1.98 mmol) in THF (18 mL) was added 1,1′-carbonyldiimidazole (0.353 mg, 2.18 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by the addition of aqueous ammonia solution (28% NH3, 0.94 mL). After stirring for 16 hours at room temperature, the reaction mixture was partitioned between EtOAc and water and the separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo and the remaining residue was passed through a short pad of silica gel. Removal of acidic impurities via PS-carbonate resin then gave N-(4-{[5-(2-amino-2-oxoethyl)-4-chloro-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide as a white solid (0.670 g, 71%).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:17]2[CH2:16][S:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O.CCCCCC.C(OCC)(=O)C>[CH2:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[C:17]=2[CH2:16][S:15]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1CSC2
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccc2c1CSC2
Yield: 58.8 %

Procedure:
A solution of 3.0 g of 1,3-dihydro-N-(1,1-dimethylethyl)benzo[c]thiophene-4-sulfonamide in 50 ml of trifluoroacetic acid was stirred at ambient temperature for 4 hours. The brown solution was concentrated in vacuo. 1-Chlorobutane was added to the resulting brown oil and the mixture concentrated in vacuo. Repeating this procedure gave an oil which on trituration with 1-chlorobutane gave a brown solid. Purification of the crude reaction product by chromatography, using hexane/ethyl acetate (3:2) as eluent gave 1.4 g of 1,3-dihydrobenzo[c]thiophene-4-sulfonamide as a pale yellow solid, m.p. 146°-148°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.CN.[CH:24]([NH:27]C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:27][CH3:24])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CC(C)NC(C)C
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 400 mg; 1.15 mmol) in THF (20 ml) was treated with methylamine (0.7 ml, 2M in THF; 1.4 mmol) and diisopropylamine (0.4 ml; 2.9 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>CN(C)C=O.CO.[Cu]>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylformamide, and 6.15 g of p-bromobenzotrifluoride and 500 mg of a copper powder were added to the suspension, followed by stirring in a nitrogen stream at 125° C. for 18 hours to effect the reaction. The reaction mixture was allowed to cool, diluted with 50 ml of methanol and then filtered. The filtrate was immediately dried to a solid, and 150 ml of chloroform and 100 ml of water were added to the residue. The resulting mixture was adjusted to a pH of 9.5 with 5 N sodium hydroxide and any insoluble matter again separated by filtration. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 5.6 g of oily 5-(p-trifluoromethylphenoxy)-2-methylpyridine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>CS(C)=O.O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[N:20][CH:21]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. The mixture was allowed to cool to ambient temperature, and a solution of 2,5-dibromopyridine (1.12 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, poured in water, then extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as an amber oil. The crude product was purified by chromatography on a silica gel column eluted with 1:8 EtOAc/hexane to give 1.40 g (84%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid after standing. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 1H, J=2.2 Hz), 7.64 (dd, 1H, Ja=8.7 Hz, Jb=2.3 Hz), 6.64 (d, 1H, J=8.8 Hz), 7.04 (d, 2H, J=8.8 Hz), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.85-1.70 (m, 2H), 1.45 (s, 9H), 1.30-1.20 (m, 2H); LRMS (ESI), m/z 371/373 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:40])[C:28]=1[O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:5][CH:6](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:47]([C:51]1[CH:58]=[CH:57][C:54]([CH2:55]Br)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>C(#N)C.C(OCC)(=O)C>[C:47]([C:51]1[CH:52]=[CH:53][C:54]([CH2:55][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2/[CH:18]=[CH:17]/[CH:6]([CH2:5][C:4]2[CH:26]=[C:27]([F:40])[C:28]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:32])[CH3:33])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:57][CH:58]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C

Procedure:
1.7 g (3 mmol) of 4-[(4E)-3-{3,5-difluoro-4-[(triisopropylsilyl)oxy]benzyl}-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzonitrile in 35 ml of acetonitrile are mixed with 627 mg (4.5 mmol) of potassium carbonate and 1 g (4.5 mmol) of 4-tert-butylbenzyl bromide and stirred under reflux for 12 hours. The solvent is stripped off in vacuo, and the residue is taken up in ethyl acetate. The organic phase is washed once with sodium bicarbonate solution and once with sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 628 mg (85% purity, 0.76 mmol, 25% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:16]=1[C:15]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:14]=1[Cl:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc[nH]n1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccc(Cl)c2Cl)nc2nc[nH]n12

Procedure:
Compound 27 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,3-dichlorobenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[Cl-].[NH4+:10]>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:10][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CO
Product: c1cc(CCNCCc2ccncc2)ccn1
Yield: 16.7 %

Procedure:
A mixture of 4-vinylpyridine (10.0 g, 95.1 mmole) and ammonium chloride (5.1 g, 95.1 mmole) in MeOH (90 mL) was heated to reflux under argon for 27 h. The resulting mixture was filtered and the filtrate was concentrated on the rotavap. The residue was dissolved in H2O (200 mL), and the solution was basified to pH 10.5 using 2 N NaOH. CH2Cl2 extraction (3×100 mL), drying (MgSO4), and concentration gave a yellow oil (5.73 g, 49% crude). 2.9 g of this oil was chromatographed on silica gel (12% MeOH/CH2Cl2) to afford the title compound as a yellow oil (1.81 g, 16%). MS (ES) m/e 228 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:16]1([NH:15][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:14])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenylaminocarbonylpyrrolidine (1.1 g, 3.8 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. To the reaction mixture was added 100 mL of water and the aqueous layer was washed with EtOAc. The aqueous layer was then made basic with 30 mL of 10% NaOH and extracted therein with 20 mL EtOAc. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a white solid (0.40 g, 56%). ES (+) MS m/e=191 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]([OH:23])=O)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:24]([CH3:26])[CH3:25]>ClCCCl.CN(C)C=O>[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CN(Cc2ccccc2)CCO1
Temperature: 65 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Oxalyl chloride (372 μL, 4.27 mmol) was added to a mixture of 4-benzylmorpholine-2-carboxilic acid hydrochloride (1.00 g, 3.88 mmol) and N,N-dimethylformamide (15.0 μL, 0.194 mmol) in DCE (20 mL). The mixture was heated at 65° C. for 3 hours. After cooling to 0° C., Me2NH (2M solution in THF, 9.70 mL, 19.4 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford desired product (803 mg, 83.4%) as brown oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][NH2:39])[CH3:35]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 90% purity by LC/MS. MS(ESI+): mz=437.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.C(N(C(C)C)C(C)C)C.ClC(Cl)(O[C:21](=[O:27])OC(Cl)(Cl)Cl)Cl.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]([O:60][Si](C(C)(C)C)(C)C)([C:56]([F:59])([F:58])[F:57])[C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=3)[CH2:40][CH2:39]2)=[O:37])=[CH:32][C:31]=1[F:68]>ClCCl>[F:68][C:31]1[CH:32]=[C:33]([C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]([OH:60])([C:52]([F:53])([F:54])[F:55])[C:56]([F:58])([F:59])[F:57])=[CH:47][CH:46]=3)[CH2:42][CH2:43]2)=[O:37])[CH:34]=[CH:35][C:30]=1[NH:29][C:21]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncn1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Pyrimidin-4-amine (0.337 mmol, 0.032 g) and N-ethyl-N-isopropylpropan-2-amine (1.145 mmol, 0.189 mL, 0.148 g) were stirred in dichloromethane (2 mL) at room temperature. Triphosgene (0.125 mmol, 0.037 g) was added and the reaction stirred for 30 minutes. (4-Amino-3-fluorophenyl)(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazin-1-yl)methanone (0.168 mmol, 0.1 g) was added and the reaction heated to 120° C. in the microwave for 10 minutes. The reaction mixture was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (eluant dichloromethane/methanol 0% to 5%) to afford the title compound (63 mg). MS (ESI) m/z 715.7 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Cl>O1CCCC1CO>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylacetate (521 mg) in tetrahydrofuran-methanol (1:1, 12 mL) was dropwise added a 1N aqueous sodium hydroxide solution (3 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was poured into water, and the reaction mixture was neutralized with 1N hydrochloric acid (3 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylacetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (473 mg, 94%). melting point: 136-137° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[O:4]1.CC(C)([O-])C.[K+].Cl[C:39]1[N:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41]([OH:43])=[O:42]>CN(C=O)C>[CH3:12][C:9]1([CH3:11])[O:10][CH:6]2[CH:5]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[O:4][CH:3]([CH2:2][O:1][C:39]3[N:47]=[CH:46][CH:45]=[CH:44][C:40]=3[C:41]([OH:43])=[O:42])[CH:7]2[O:8]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC2C(COc3ncccc3C(=O)O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a stirred solution of 1-[9-(6-hydroxymethyl-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-3-phenyl-urea (43 mg, 0.1 mmol) in dry N,N′-dimethylformamide (1 mL) at 23° C. was added potassium tert-butoxide (45 mg, 0.4 mmol). After 30 min, 2-chloronicotinic acid (60 mg, 0.4 mmol) was added to the solution. The resulting mixture was stirred at 23° C. for 15 h and then quenched with water (1 mL), suspended in ethyl acetate (50 mL), washed with brine (3×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. Preparative reverse-phase HPLC was used to obtain the pure compound (15 mg, 27% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.15 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 8.05 (dd, J=8.5 Hz, 3.5 Hz, 1H), 7.94 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.32 (t, J=12.5 Hz, 2H), 7.05 (t, J=12.5 Hz, 1H), 6.96 (dd, J=12.5 Hz, 8.5 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H), 5.80 (t, J=7.5 Hz, 1H), 5.10 (dd, J=9.0 Hz, 2.5 Hz, 1H), 4.67 (m, 1H), 4.53 (dd, J=20.0 Hz, 4.0 Hz, 1H), 4.36 (dd, J=20.0 Hz, 4.0 Hz, 1H), 1.59 (s, 3H), 1.38 (s, 3H). MW calculated for C26H25N7O7 (MH+) 548, found 548 by LCMS.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([CH2:17][CH3:18])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH3:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[CH2:17]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:14][CH:15]=1)[CH3:18]
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6.00 g (20.3 mmol) of 4-[3-(diethylamino)propoxy)benzenamine dihydrochloride in 50 mL of pyridine under a nitrogen atmosphere and cooled to ca -10° C. add 2.0 mL (25.4 mmol) of methanesulfonyl chloride dropwise. Maintain the temperature below 0° C. during the addition. Stir the reaction mixture at ambient temperature for 5 h then add 10 mL of H2O. Evaporate the solvent in vacuo and dissolve the residue in 50 mL of H2O (pH=ca. 3). Extract the aqueous solution with 2×100 mL of diethyl ether. Adjust the pH of the aqueous solution to pH=13 with 20% aqueous sodium hydroxide solution and extract this solution with 3×50 mL of methylene chloride. Adjust the pH of the aqueous solution to pH=8.5 with concentrated hydrochloric acid and saturate the solution with sodium chloride. Extract the mixture with 3×100 mL of methylene chloride. Wash the organic extracts with 25 mL of saturated aqueous sodium chloride solution, combine the extracts and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:26]([OH:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:9][CH:8]=3.[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([OH:36])(=[O:35])[CH2:33][CH2:32][C:31]([O:27][C@H:26]1[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=32)[C@@H:10]([C@H:11]([CH3:18])[O:12][CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:30])=[O:37]
Reactant: CC(C)=CCO[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCO[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)CCC(=O)O)C(C)(C)[C@@H]1CC3
Temperature: 60 °C
Yield: 56.3 %

Procedure:
A mixture of (3β,5α,20S)-4,4-dimethyl-22-oxacholesta-8,14,24-trien-3-ol (Example 1; 0.50 g), dry pyridine (8 ml), succinic anhydride (3.0 g), and 4-dimethylaminopyridine (20 mg) was heated at 60° C. overnight. After cooling the reaction mixture was poured into a 0.1 M aqueous solution of hydrochloric acid and the product extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20S)-4,4-dimethyl-22-oxacholesta-8,14,24-trien-3-ol hydrogen butanedioate (0.35 g). M.p. 60-67° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8](O)=[O:9])[N:3]=[CH:4][CH:5]=1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[CH3:15][C:12]1[CH:13]=[CH:14][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[C:7]([CH:11]=1)[C:8]([Cl:19])=[O:9]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (15, 3.56 g, 17.52 mmol) in DCM (150 mL) cooled to 0° C. was added oxalyl chloride (1.90 mL, 21.9 mmol) and DMF (68 μL, 0.89 mmol). The solution was slowly warmed to ambient temperature and stirred overnight. The mixture was concentrated in vacuo and the resulting solid was azeotroped with DCM and concentrated in vacuo to provide 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (3) as a yellow solid.