Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:13])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)=[N:31]1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 65 mg, 0.20 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 31 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (71 mg, 77%) as a white foam: [α]32589=−63.3° (c=0.15, methanol); ES-HRMS m/e calcd for C23H31N3O5S (M+H)+ 462.2057, observed 462.2058; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.76-2.30 (m, 8H, 4×CH2), 2.62 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.91 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.46 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.50 (d, J=2.2 Hz, 1 H, Ar), 7.85 (d, Jo=8.5 Hz, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14]([NH:16][C@H:17]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:15])=[O:6].[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62]([N:64]([CH3:71])[C:65]([CH3:70])([C:67](O)=[O:68])[CH3:66])=[O:63])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([N:64]([CH3:71])[C:65]([CH3:66])([C:67]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14]([NH:16][C@H:17]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[S:15])=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:68])[CH3:70])=[O:63])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #82 (670 mg, ≦0.818 mmol, 1 eq.), dichloromethane (5 mL, 0.16 M), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (304 mg, 0.896 mmol, 1.1 eq.), HATU (372 mg, 0.978 mmol, 1.2 eq.) and diisopropylethylamine (440 μL, 2.53 mmol, 3.1 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane) to give #83 (556 mg, 69% over two steps). LC-MS: m/z 994.7 [M+H+], retention time=0.69 minutes; HPLC (Protocol C): retention time=9.333 minutes (purity >98%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.53 (br d, J=8 Hz) and 10.80 (br d, J=8 Hz), total 1H], 7.86-7.91 (m, 2H), [7.80 (d, J=3.3 Hz) and 7.82 (d, J=3.2 Hz), total 1H], [7.64 (d, J=3.2 Hz) and 7.68 (d, J=3.2 Hz), total 1H], 7.62-7.66 (m, 2H), 7.38-7.44 (m, 2H), 7.28-7.36 (m, 5H), 7.19-7.26 (m, 2H), 7.12-7.17 (m, 1H), [6.31 (ddd, J=11, 8, 4.5 Hz) and 6.44 (ddd, J=11, 8.5, 4.5 Hz), total 1H], [4.42 (dd, J=9, 8 Hz) and 4.48 (dd, J=8, 8 Hz), total 1H], 3.22 and 3.24 (2 s, total 3H), 3.13 and 3.17 (2 s, total 3H), 2.89 and 2.97 (2 br s, total 3H), 2.84 and 2.85 (2 s, total 3H), [1.13 (d, J=6.4 Hz) and 1.16 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:23])[CH2:20][CH2:21][Cl:22])=[S:10])=[O:7]>C(O)C>[ClH:22].[CH3:4][O:5][C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:23])[CH2:20][CH2:21][N:2]([CH3:3])[CH3:1])=[S:10])=[O:7]
Reactant: CNC
Reactant: COC(=O)NC(=S)Nc1ccccc1NC(=O)CCCl
Solvent: CCO
Product: COC(=O)NC(=S)Nc1ccccc1NC(=O)CCN(C)C
Product: Cl
Reaction time: 0.5 h

Procedure:
A suspension of dimethylamine in ethanol (20% w/w; 18 ml) was added to a suspension of 1-methoxycarbonyl-3-[2-(3-chloropropionamido)phenyl]thiourea (8.2 g) in ethanol (50 ml). The mixture was heated under reflux, with stirring, for 30 minutes, the ethanol removed by distillation and water (10 ml) added to the residual gum which slowly solidified. The solid was filtered off and dissolved in the minimum of ethanol. Diethyl ether (300 ml) was added, followed by an excess of a saturated solution of hydrogen chloride in diethyl ether. The precipitated solid was filtered off and recrystallised from ethanol to give 1-methoxycarbonyl-3-[2-(3-dimethylaminopropionamido)phenyl]thiourea hydrochloride (3.3 g), m.p. 182°-183° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]Br)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[OH:21])[CH3:12]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:17]2[CH:16]=[C:15]([CH2:19][CH3:20])[C:14]([OH:21])=[C:13]([CH2:11][CH3:12])[CH:18]=2)=[CH:4][N:3]=1
Reactant: CCc1cccc(CC)c1O
Reactant: Nc1ncc(CBr)c(N)n1
Product: CCc1cc(Cc2cnc(N)nc2N)cc(CC)c1O
Yield: 65 %

Procedure:
2,4-diamino-5-bromomethylpyrimidine was reacted with 2,6-diethylphenol using the experimental conditions described in Example 1. 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine was obtained in a yield of approximately 65%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1cc2cc(Br)ccc2s1
Reactant: CCCC[B-](F)(F)F
Agent: [K+]
Product: CCCCc1ccc2sc(C=O)cc2c1
Yield: 84.7 %

Procedure:
The compound was prepared as in Example 3.1 using 5-bromo-2-formylbenzothiophene (241 mg, 1.0 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (246 mg, 1.5 mmol) in place of hexylboronic acid to give 5-butyl-2-formylbenzothiophene (185 mg, 85%). Used without further characterization.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH:19]2[CH2:20][O:21]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: ClCC1CO1
Reactant: CCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(OCC2CO2)cc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
4-Ethoxyphenol (0.25 g, 1.81 mmol), anhydrous potassium carbonate (0.50 g, 3.62 mmol) and epichlorohydrin (0.57 ml, 7.24 mmol) were added to acetone (4.52 ml) and the resulting heterogeneous solution was refluxed for 16 hrs. The mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in toluene (20 mL), washed sequentially with water (15 mL), 5% aqueous NaOH (20 mL) and water again (20 mL). The organic layer was dried with MgSO4 and concentrated under reduced pressure to yield 0.292 g (83%) of 2-((4-ethoxyphenoxy)methyl)oxirane as a white solid (mp=41° C.). 1H NMR (400 MHz, CDCl3) δ 6.91-6.77 (m, 4H), 4.17 (dd, J=11.0, 3.2, 1H), 3.98 (q, J=7.0, 2H), 3.91 (dd, J=11.0, 5.6, 1H), 3.34 (m, 1H), 2.90 (dd, J=4.9, 4.1, 1H), 2.75 (dd, J=5.0, 2.7, 1H), 1.39 (t, J=6.98, 3H). 13C NMR (75 MHz, CDCl3) δ 153.72, 152.78, 115.90, 115.90, 115.59, 115.59, 69.71, 64.18, 50.49, 44.98, 15.15. HRMS (m/z): [MNa]+ calc. for C11H14O3Na+, 217.08. found 217.0826.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:22][C:23]1[N:28]=[C:27]([C:29]2[C:30]([CH3:39])=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH:26]=[C:25]([S:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[CH:45]([NH2:49])[CH2:46][CH2:47][NH2:48])[N:24]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:22][C:23]1[N:24]=[C:25]2[CH:26]=[C:27]([C:29]3[CH:37]=[C:33]([C:34](=[O:36])[NH:48][CH2:47][CH2:46][CH:45]([NH:49][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[C:44](=[O:50])[NH:43][CH2:42][CH2:41][S:40]2)[C:32]([CH3:38])=[CH:31][C:30]=3[CH3:39])[N:28]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)c(-c2cc(SCCNC(=O)C(N)CCN)nc(N)n2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2cc1C(=O)NCCC(NC(=O)C(F)(F)F)C(=O)NCCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
5-{2-Amino-6-[2-(2,4-diaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid tri(trifluoroacetate) (60 mg, 0.079 mmol) obtained in Step 3 of Example 3-8 and 1-hydroxybenzotriazole (43 mg, 0.316 mmol) were dissolved in N,N-dimethylformamide (46 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.316 mmol) and diisopropylethylamine (8.3 μl, 0.473 mmol) were added to the solution, and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and then sequentially washed with a saturated aqueous sodium bicarbonate solution, water (three times), and a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the inorganic salt was filtered and washed with ethyl acetate. The filtrate and washing solution were combined together, and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane:methanol=10:1) to yield N-(4-amino-18,20-dimethyl-11,16-dioxo-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaen-12-yl)-2,2,2-trifluoroacetamide (Compound 75) (12 mg) as a white solid material.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([C:26]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:18])[CH3:19])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:27])[CH:29]=1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 153.7 %

Procedure:
A mixture of [4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (160.0 mg, 54%). MS (ESI) mass calcd. for C22H25FN8O2, 452.49; m/z found 453.3 [M+H]+. 1H NMR (CDCl3): 7.95 (dd, J=9.0, 4.8, 1H), 7.73 (s, 2H), 7.25-7.17 (m, 1H), 7.16-7.10 (m, 1H), 5.00-4.90 (m, 1H), 3.92-3.78 (m, 4H), 3.76-3.25 (m, 6H), 3.18-3.07 (m, 6H), 3.05-2.86 (m, 3H).
Reaction SMILES: [C:1]([O:4][C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(O)C(Cl)=O)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])=[CH:20][C:19]=1[NH2:33].C(N(CC)CC)C.[C:41](OCC)(=[O:43])C>>[C:10]1([CH2:5][O:4][C:1](=[O:3])[CH2:2][C:41](=[O:43])[NH:33][C:19]2[CH:20]=[C:21]([C:22](=[O:23])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[CH:32][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: CC(=O)OC(O)(C(=O)Cl)c1ccccc1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=O)CC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Acetoxymandeloyl chloride (1.10 g, 5 mmol) was added to a mixture of 4-methoxy-3-amino-N-phenyl-benzamide (1.24 g, 5 mmol) and triethylamine (1.25 mL, 9 mmol) in ethyl acetate (50 mL). The flask was agitated briefly then allowed to stand overnight at room temperature. The reaction mixture was diluted with ethyl acetate (150 mL), washed with aqueous sodium bicarbonate solution (150 mL) then brine (100 mL), dried over magnesium sulfate, and filtered. Removal of the solvent followed by trituration in hexanes/ethyl acetate (2:1) gave the product (1.46 g.); m.p. 168-171° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])#[N:16].O>CN(C)C(=O)C>[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:28][CH:27]=1)(=[O:25])=[O:24])#[N:16]
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2C#N)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.82 g, 5.2 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.62 g, 5.2 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-[(2-Cyanophenyl)sulfonyl]benzeneamine (1.00 g, 3.8 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution decanted from an oily solid which was purified by flash column chromatography (5% v/v ethyl acetate/methylene chloride). Recrystallization from methylene chloride/hexane yielded the title propanamide as a white solid (1.08 g, 72%); mp 156°-158° C. 1H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 7.59 (s, 1H, OH) 7.88-8.13 (m, 7H, aromatic) 8.31 (d, 1H, J=6.9 Hz, aromatic) 10.50 (s, 1H, OH). MS (CI, CH4): 399 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:15][CH2:16][N:17](C(C)C)[CH:18](C)[CH3:19].C(NCC)C.O>C1COCC1>[NH2:6][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([N:17]([CH2:18][CH3:19])[CH2:16][CH3:15])[CH:7]=1
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Solvent: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dinitro-5-fluoroaniline (1.6 g, 8.0 mmol) in 20 mL of THF, a mixture of DIPEA (1.1 g, 8.8 mmol) and diethylamine (644 mg, 8.8 mmol) in 5 mL of THF was added slowly. The reaction mixture was stirred at room temperature for 1 h. Water (100 mL) was added to give the desired product as a yellow precipitate. The product was collected by filtration and washed with water (200 mL). The filtrate was concentrated to dryness in vacuo to give the desired product (1.8 g, 90% yield) as a bright yellow solid: 1H-NMR (300 MHz, CDCl3) δ 1.96 (t, 6H, J=7.2 Hz), 3.24 (q, 4H, J=7.2 Hz), 6.08 (s, 1H), 8.75 (s, 1H); 13C NMR (75 MHz, CDCl3) δ12.1, 45.7, 102.7, 123.3, 128.2, 131.6, 147.8, 149.4; ESI MS m/z 255.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH3:11][C:12]([CH3:14])=[O:13].CC[N:17]([CH2:20][CH3:21])CC.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[C:7]([C:6]1[CH:9]=[CH:10][C:3](/[CH:1]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:1]/[C:3]2[CH:10]=[CH:9][C:21]([C:20]#[N:17])=[CH:5][CH:4]=2)=[CH:4][CH:5]=1)#[N:8]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(/C=C/C(=O)/C=C/c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 125.6 %

Procedure:
A mixture of 4-formyl-benzonitrile (1.1 g, 8.4 mmol), acetone (308 μL, 4.2 mmol), LiClO4 (892 mg, 8.4 mmol) and Et3N (117 μL, 0.84 mmol) in toluene (8 mL) was stirred for 2 d at room temperature. A saturated aq. NH4Cl-solution was added to the reaction mixture and the resulting yellow suspension was extracted with CH2Cl2 and the combined organic layers were dried with MgSO4, filtered and evaporated in vacuo to afford NW307.2 as a yellow solid (300 mg, 25%). mp: 137-138° C. 1H NMR (250 MHz, DMSO-d6) δ (ppm): 8.00 (d, 3J=8.3 Hz, 4H, HAr), 7.87 (d, 3J=16.2 Hz, 2H, Hvin), 7.94 (d, 3J=8.4 Hz, 4H, HAr), 7.51 (d, 3J=16.1 Hz, 2H, Hvin). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 188.5 (C), 141.2 (CH), 139.2 (C), 132.8 (CH), 129.2 (CH), 128.4 (CH), 118.6 (C), 112.4 (C). MS (FAB) m/z: 285.19 (M+). Anal. calcd for C19H12N2O: C, 80.27; H, 4.25; N, 9.85. Found: C, 80.04; H, 4.28; N, 9.76%.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:16][NH:15][CH2:14]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:14][N:15]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:16]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: CC(C)(C)N=C=O
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4) (3 mmol) in dichloromethane (10 mL) was added tert-butyl isocyanate (3 mmol) and triethylamine (catalytic amount) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was eluted through a pre-wetted (CH2Cl2) SCX-2 (2 g) cartridge with dichloromethane to yield the desired product as a white foam (424 mg, 33%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][S:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[N:4]1.S(Cl)(Cl)(=O)=O>ClCCCl>[ClH:1].[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][N:9]([CH3:11])[CH3:10])[S:6][CH:7]=1
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Solvent: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: CN(C)Cc1nc(CCl)cs1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Five g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was added to 25 ml. of 1,2-dichloroethane, and 2.1 g. of sulfuryl chloride in 10 ml. of 1,2-dichloroethane was added. An exothermic reaction heated the mixture to 35° as soon as the addition began, so the mixture was cooled while the addition was made. The mixture was then stirred at ambient temperature for 1 hour, and was then heated to 42° for a short time. A 2-phase mixture formed, and the oily portion was removed and dissolved in 10 ml. of methanol. The methanol was removed under vacuum, and the residue was partially dissolved in 10 ml. of methanol, and then precipitated by addition of 25 ml. of ethyl acetate. The mixture was then cooled in the freezer, and the crystals were filtered off, washed with ethyl acetate and dried under vacuum at 30° to obtain 1.4 g. of the desired product, which was identified by nmr analysis as being substantially identical with the product of Example 5.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:14]([CH3:25])=[C:13]([CH3:26])[N:12]=1>O1CCCC1>[CH3:26][C:13]1[C:14]([CH3:25])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCO)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Sodium hydride (7.80 g of a 60% dispersion in mineral oil, 195 mmol) was added in portions to a chilled (0° C.) solution of phenol (18.36 g, 195 mmol) in tetrahydrofuran (200 mL). After the addition was completed the reaction mixture was allowed to stir at ambient temperature for 30 minutes. Solid 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (16.89 g, 65.0 mmol) was added and the reaction mixture was heated at reflux for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography (500 mL silica gel eluting with a gradient of 30–75% ethyl acetate in hexanes) and then heated under high vacuum until it melted. The melt solidified to provide 11.54 g of 3-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]propan-1-ol.