Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH:23]([Si:26]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=[O:37])=[CH:28]1)([CH3:25])[CH3:24].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:36]([OH:37])[C:29]3[C:30]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:27]([Si:26]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:23]([CH3:24])[CH3:25])[CH:28]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(C(=O)Nc3ccc(Cl)cc3)nc2)c2cccnc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 14.4 %

Procedure:
To 5-Bromo-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (70, 0.50 g, 1.60 mmol) in tetrahydrofuran (20.0 mL), under an atmosphere of nitrogen at −78° C., tert-butyllithium (3.02 mL, 1.70 M in Hexane) was added. After 20 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.39 g, 1.3 mmol, prepared as described in Example 18) in tetrahydrofuran (10.0 mL) was added to the reaction. The reaction was stirred at −78° C. for 1 hour, then allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (71, 100 mg, 14%). MS (ESI) [M+H+]+=535.3.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])[S:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2csc(CO)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2csc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (100 mg, 0.50 mmol) in dry CH2Cl2 (3.0 mL) was treated at 0° C. with Et3N (0.10 mL, 0.71 mmol) followed by DMAP (6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.64 mmol). After stirring at 0° C. for 30 min and at rt for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl ester which was dissolved in acetone (5.0 mL) and treated with K2CO3 (349 mg, 2.50 mmol) followed by 4-nitro-1H-pyrazole (63 mg, 0.50 mmol) and TBA bromide (32 mg, 0.10 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.49. LC-MS-conditions 02: tR=0.95 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26](=[O:33])[CH:27]=[C:28]([CH2:31][OH:32])[O:29][CH:30]=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:26](=[O:33])[CH:27]=[C:28]([CH2:31][OH:32])[O:29][CH:30]=2)=[N:3][CH:2]=1
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: Oc1ncnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ncnc2ccccc12
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Quinazolin-4-ol (1.0 g, 6.84 mmol) was dissolved in DMF (7 mL). Cs2CO3 (2.23 g, 6.84 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (1.90 g, 6.52 mmol) in DMF (7 mL) was added via syringe. This mixture was stirred at 50° C. for 2 h. Water (150 mL) was added and the mixture extracted with EtOAc (2×100 mL), washed with water (3×100 mL), brine (3×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:5. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 15 was obtained (0.61 g, 26% yield) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>>[CH3:18][N:19]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: CNc1cccc(OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cccc(N(C)c2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (180 mg, 0.693 mmol) and N-methyl-3-methoxyaniline (112 mg, 0.816 mmol) in 3 mL of solvent (ethanol:water=2:1) was refluxed for 20 h. The solvent was removed under reduced pressure and the residue was dissolved in 25 mL of ethyl acetate. The ethyl acetate solution was washed with 25 mL of 1M NaOH, and the aqueous layer was reextracted with ethyl acetate (25 mL). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40-45% ethyl acetate/hexanes) to give the title compound as an oil (250 mg, 0.693 mmol, 100%). 1H NMR (CDCl3): 8.86 (dd, J=0.6, 4.5 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 7.85 (dt, J=1.8, 7.8 Hz, 1H), 7.42 (m, 2H), 6.95 (dd, J=1.8, 8.4 Hz, 1H), 6.86 (m, 1H), 6.82 (m. 1H), 3.85 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:44][CH2:43]2)=[CH:40][CH:41]=1
Reactant: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CC(=O)Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
The 7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.452 mmol) was weighed into a vial and taken up as a suspension in propiononitrile (1 mL). Next was added (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followed by DIEA (0.237 mL, 1.356 mmol). To the stirred white suspension was then added the 1-(4-chlorophenyl)piperazine hydrochloride (116 mg, 0.50 mmol). The reaction was stirred overnight at 90° C. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in DMSO (3 mL) and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (46.6 mg, 26%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.74-4.87 (m, 1H), 3.81 (s, 2H), 3.33 (d, J=2.0 Hz, 2H), 3.01-3.15 (m, 4H), 2.41-2.48 (m, 4H), 1.12 (d, J=6.8 Hz, 6H). [M+H] calc'd for C21H26ClN5O, 400; found, 400.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2].Cl.[NH2:22][OH:23].C([O-])(O)=O.[Na+]>CO>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C#N)cccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
Ethyl 3-(4-cyano-1H-indazol-1-yl)-2,2-dimethylpropanoate (D102) (348 mg, 1.28 mmol), hydroxylamine hydrochloride (1.087 g, 10.26 mmol), NaHCO3 (1.078 g, 12.83 mmol) in MeOH (20 ml) was heated at 65° C. for 24 h then at room temperature over the weekend. The mixture was filtered, concentrated, treated with water and vigorously stirred for 10 mins, filtered and dried to give a colourless solid, dried overnight in vacuo at 45° C. to give the title compound (373 mg, 90%). MS (ES) C15H20N4O3 requires 304, found 305 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[N:12][CH:11]=[N:10]1.[C:16]([Cu])#[N:17].FC1C=CC(C#N)=C(N2C=CC=N2)C=1>CN(C=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13]([CH2:14][OH:15])=[N:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: OCc1ncnn1-c1cc(F)ccc1Br
Reactant: N#C[Cu]
Agent: N#Cc1ccc(F)cc1-n1cccn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1ncnc1CO
Yield: 48 %

Procedure:
This compound was prepared from (2-(2-bromo-5-fluorophenyl)-2H-1,2,4-triazol-3-yl)methanol and CuCN in DMF at 125–130° C. for 5 h by the method used for the preparation of 4-fluoro-2-pyrazol-1-yl-benzonitrile. Yield: 48% (beige solid) HPLC rt=1.11 min. LC/MS m/z 219 (M+H). 1H NMR (CDCl3, 500 MHz) δ ppm 2.39 (1H, br.s, OH), 4.79 (2H, s, 9-OCH2), 7.32–7.40 (1H, m, 5-CH), 7.50 (1H, d, J=8.2, 2.1 Hz, 3-CH), 7.87 (1H, dd, J=8.5, 5.5 Hz, 6-CH), 8.14 (1H, s, 9-CH). HRMS (ESI) calcd for C10H8FN4O (M+H) 219.0682. found 219.0689 (δ +3.1 ppm).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]([S:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:35])=[CH:26][N:27]=[C:28]2[NH:31][C:32]([NH2:34])=[NH:33])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(C)(C)C>C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>[Cl:35][C:25]1[C:24]2[C:29](=[CH:30][C:21]([S:18]([N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH2:7][C:6]([OH:36])=[O:5])(=[O:19])=[O:20])=[CH:22][CH:23]=2)[C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[N:27][CH:26]=1
Reactant: COc1ccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 18.9 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine t-butyl ester (65 mg, 0.122 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 40 min. The mixture was diluted with PhMe, concentrated in vacuo, and the residue purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (83:15:3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine (11 mg, 0.023 mmol) as a white solid.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]([CH3:54])([CH2:52][OH:53])[CH2:50][OH:51]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]([CH2:52][OH:53])([CH3:54])[CH2:50][OH:51])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(N)(CO)CO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(CO)CO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-amino-2-methyl-propane-1,3-diol (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O5 [(M+H)+] 753.3293, observed 753.3292.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][CH2:10][CH3:11])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.[H][H]>C(O)(=O)C.[Pt]>[Cl:1][C:2]1[C:7]([CH2:8][O:9][CH2:10][CH3:11])=[CH:6][C:5]([NH2:12])=[C:4]([F:15])[CH:3]=1
Reactant: CCOCc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CCOCc1cc(N)c(F)cc1Cl

Procedure:
A solution of 4-chloro-5-ethoxymethyl-2-fluoronitrobenzene (0.9 g, 0.0039 mole) in glacial acetic acid (50 ml) was added to a 250 ml Parr bottle containing platinum IV oxide (0.3 g) under a nitrogen atmosphere. The Parr bottle was placed on a Parr hydrogenation apparatus and charged with hydrogen. The reaction mixture was allowed to shake until hydrogen absorption ceased. The catalyst was removed by vacuum filtration. The 4-chloro-5-ethoxymethyl-2-fluoroaniline produced was used in the next step in acetic acid solution without being isolated.
Reaction SMILES: [CH2:1]([N:8]=C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12]>[N+](C)([O-])=O>[CH2:1]([NH:8][S:11](=[O:13])(=[O:12])[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(O)NCc1ccccc1
Temperature: 25 °C

Procedure:
Benzylisocyanate (13.3 g) is added dropwise to a stirred mixture of nitromethane (160 ml) and 15% fuming sulfuric acid (5.4 ml) at about 10° C. The reaction mixture is refluxed for about one hour, cooled to RT and the solid filtered and washed with nitromethene. The solid is suspended in ether, filtered, dried and used as a crude solid in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].[CH:23](N(CC)C(C)C)([CH3:25])[CH3:24].C(Br)C=C>C(Cl)Cl>[CH2:25]([N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[C:3]2=[O:22])=[CH:8][CH:9]=1)(=[O:14])=[O:15])[CH:23]=[CH2:24]
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.6 %

Procedure:
Synthesized according to General Procedure 23. To a stirring suspension of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 0.59 mmol) in CH2Cl2 (0.50 mL), under N2, at 0° C., was added N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) followed by allylbromide (51 uL, 0.59 mmol). The mixture was stirred at ambient temperature for 19 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (220 mg, 0.57 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H), 2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42]>C(Cl)Cl>[Si:16]([O:15][CH2:14][C@@H:2]([NH:1][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
tert-Butyl (4S)-4-amino-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (3.76 g, 11.3 mmol) was dissolved in 100 mL of dry CH2Cl2 and the solution was cooled to 0° C. under N2. Triethylamine (3.10 mL, 22.3 mmol) and 4-chloro-3-nitroquinoline (2.36 g, 11.3 mmol) were then added and the reaction was allowed to warm to ambient temperature and stirred for 2 days. The reaction mixture was then concentrated under reduced pressure to give a yellow solid. The solid was dissolved in 200 mL of CH2Cl2 and was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give yellow solid. Chromatography (SiO2, 20-35% ethyl acetate/hexanes) gave tert-butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[(3-nitroquinolin-4-yl)amino]pentylcarbamate (5.65 g) as a yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH3:14]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: CI
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 1.00 g (7.40 mmol) of 5-fluoroindole in 10 mL of dry dimethylformamide is reacted with 0.335 g (8.88 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.553 mL (8.88 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature overnight, 15 h. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 1.00 g of the title compound, 91% yield. MS, ES+218.2 (M+1); 1H NMR (DMSO-d6) δ 7.428-7.366 (m, 1H); 7.293-7.262 (m, 1H); 6.988-6.937 (m, 1H); 6.384-6.376 (m, 1H); 3.766 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1.[CH:39](=O)[CH:40]([CH3:42])[CH3:41].[BH4-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:39]([N:1]([CH2:3][CH:4]([CH3:13])[CH3:5])[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1)[CH:40]([CH3:42])[CH3:41]
Reactant: NCCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CN(CCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[7-(2-aminoethyl)-chroman-4-yl]-3-phenyl-3-(3-trifluoromethylbenzenesulfonylamino)-propionamide (Example 208, 50 mg, 0.09 mmol) in dry CH2Cl2 (8 mL) was added isobutyraldehyde (83 L, 0.9 mmol) and HOAc (1 drop). The resulting mixture was stirred at RT under N2 After 3 h, MS showed the formation of imine; NaBH4 (17 mg, 0.45 mmol) was then added. The resulting mixture was stirred for 18 h. Quenched with minimum amount of sat. NaHCO3. The organic layer was isolated, dried over MgSO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (97:3) gave final compound. MS m/z: 660.31 (M+H). Calc'd. for Calc'd. for C35H44F3N3O4S-659.82.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=[C:4]([CH2:13][O:14][CH2:15][CH3:16])[N:3]=1.C(O)(=[O:19])C>[OH-].[Na+]>[CH2:15]([O:14][CH2:13][C:4]1[NH:3][C:2](=[O:19])[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=1)[CH3:16]
Reactant: CCOCc1nc(N)c2nc(C)cnc2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2ncc(C)nc2c(=O)[nH]1
Reaction time: 1 h

Procedure:
A suspension of 7.4 g (0.0338 mole) of 4-amino-2-ethoxymethyl-6-methylpteridine in 148 ml of 5% aqueous sodium hydroxide is brought slowly to 85° C. and maintained at this temperature for 2 hours. A further 592 ml of 5% aqueous sodium hydroxide are then added and heating is contained at 85° C. for 1 hour. After cooling, the solution obtained is acidified with acetic acid to pH 5.5, and is then extracted with dichloromethane. The organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from acetone in the presence of Norit. Yld: 4.9 g (66%), m.p. 181°-183° C.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:13]2[C:14]([C:30]([F:32])([F:33])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:17]=[CH:16]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1

Procedure:
The mixture of cis-4-tert-butylcyclohexanol (30.4 mg, 0.000195 mol), (R)-4-(6-hydroxy-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (50.5 mg, 0.000162 mol) and triphenylphosphine (51.1 mg, 0.000195 mol) in tetrahydrofuran (2 mL, 0.02 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0383 mL, 0.000195 mol) was is added dropwise and was stirred and refluxed for 3 hours. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (22.2 mg, 30%). LCMS: Rf=2.41 min (450.46, M+1, 70%; 491.47, M+ACN, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.25 (dd, J=8.7, 1.4 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.52 (dd, J=9.3, 2.3 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 5.98 (br. s., 1H), 4.45 (d, J=8.6 Hz, 1H), 4.41 (d, J=8.6 Hz, 1H), 4.38-4.26 (m, 1H), 2.19 (d, J=13.1 Hz, 2H), 1.89 (d, J=10.0 Hz, 2H), 1.87 (s, 3H), 1.59-1.48 (m, 2H), 1.21-1.05 (m, 3H), 0.89 (s, 9H).