Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl.O1CCOCC1>CCOC(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (137 mg, 0.5 mmol) was added 4-chloro-7-methoxyquinazoline (97 mg, 0.5 mmol) according to the procedure described in Example 1B. The resulting compound was dissolved in EtOAc (5 mL) and 4N HCl in dioxane (0.2 mL, 0.8 mmol) was added. The mixture was sonicated, stirred and concentrated in vacuo to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-yloxy)phenyl)urea as the mono-hydrochloride (103 mg, 0.22 mmol, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.15 (s, 1H), 8.69 (s, 1H), 8.28 (d, 1H), 7.58 (s, 1H), 7.45-7.35 (m, 3H), 7.27 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CN1CCCC1=O>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:3]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[N:5]=3)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Temperature: 150 °C
Reaction time: 7 h
Yield: 84.4 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and N-acetylpiperazine (166 mg, 1.3 mmol) and the resulting mixture was stirred at 150° C. for 7 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (105 mg, 85%) as a white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])/[C:7](/[NH:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])=[CH:20][C:19]=1[Cl:35])=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1>O.O1CCCC1.CO.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9](/[CH:8]=[C:7](\[NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[O:25])=[CH:20][C:19]=2[Cl:35])/[C:6]([OH:37])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)/C(=C/c1ccc(Br)cc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)/C(=C/c1ccc(Br)cc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
A solution of lithium hydroxide monohydrate (10.6 mg, 0.25 mmol) in water (1 mL) was added to a solution of (Z)-3-(4-bromophenyl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (Example 224; 69 mg, 0.13 mmol) in tetrahydrofuran/methanol/water (3:1:1; 1.5 ml). The mixture was stirred for 4 h at room temperature and then acidified. The product was filtered off and purified by HPLC (Waters system) to give (Z)-3-(4-bromophenyl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid (33 mg, 49% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN([C:15]([O:19][N:20]1N=[N:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.N1C=CC=C[C:44]=1[C:49]1[O:53]N=CC=1C(O)=O>CN(C=O)C>[N:27]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:21]1[C:44]([C:49]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]2)=[O:53])=[CH:15][O:19][N:20]=1
Reactant: O=C(O)c1cnoc1-c1ccccn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(O)[C@@H]1CCCNC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)[C@@H]1CCCN(C(=O)c2conc2-c2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-pyridin-2-ylisoxazole-4-carboxylic acid (7 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z calcd for C17H21N3O3: 315.1583, found 315.1586.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1.S(Cl)([Cl:15])=O.[CH3:17]O>>[ClH:15].[CH3:17][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCC1CCNCC1
Product: COC(=O)CCCC1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-piperidin-4-yl-butyric acid (1.1 g; 5.30 mmol) in methanol (5 mL) is added thionylchloride (0.69 g; 5.80 mmol) and the reaction mixture is stirred at room temperature for 2 hours. All volatiles are then removed under high vacuum and the resulting residue triturated with diethyl ether, sucked to dryness and washed (diethyl ether) to afford the desired compound (1.06 g; 4.8 mmol).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[O:27]1[CH2:29][CH:28]1[CH2:30][OH:31]>CCO.C(N(CC)CC)C>[OH:27][CH:28]([CH2:30][OH:31])[CH2:29][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: O=C(NCCCCc1ccc(O)c2ccccc12)OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCCc1ccc(OCC(O)CO)c2ccccc12)OCc1ccccc1
Yield: 84.4 %

Procedure:
A solution of benzyl 4-(4-hydroxynaphthalen-1-yl)butylcarbamate (20, 287 mg, 0.82 mmole), oxiran-2-ylmethanol (21, 0.07 mL, 1.00 mmole) and triethylamine (0.01 mL, 0.05 mmole) in absolute EtOH (9.28 mL) was subjected to microwave irradiation at 130° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford butylcarbamate 22 (293 mg, 83%) as a light yellow thick oil: 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.52-7.45 (m, 2H), 7.37-7.28 (m, 5H), 7.18 (d, J=7.7 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.09 (br s, 2H), 4.71 (br s, 1H), 4.29-4.20 (m, 3H), 3.98-3.81 (m, 2H), 3.23 (q, J=6.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.65 (d, J=4.5 Hz, 1H), 2.06 (t, J=5.8 Hz, 1H), 1.83-1.53 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:8][CH:7]=1)C.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:43])=[O:3])=[CH:7][CH:8]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid ethyl ester (52 mg, 0.083 mmol) in THF (3 mL) was added LiOH monohydrate (15 mg, 0.35 mmol) in water (1.5 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid as a white solid (47 mg, 95%). MS (ES+) m/z [(M+H)+]: 598.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].S1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH2:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:29])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1>O.CO.O1CCCC1>[O:2]=[S:3]1(=[O:5])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH2:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:29])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1
Reactant: O=S([O-])OO
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(N)c2c1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(N)c2c1
Reaction time: 2 h

Procedure:
To a solution of oxone (670 mg, 1.117 mmol) in water (2.5 mL), which was cooled below 0° C. in an ice-bath, was added a solution of 2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (300 mg, 0.930 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL) dropwise. The resulting mixture was stirred below 0° C. for 2 hours. The formed precipitate was collected by filtration, washed with water and dried in vacuo to afford the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 355, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.86 (m, 2 H), 7.77 (s, 1 H), 7.64-7.60 (t, J=16.0 Hz, 1 H), 7.51-7.48 (m, 2 H), 7.37-7.35 (d, J=8.0 Hz, 1 H), 5.06 (s, 2 H), 4.37 (s, 2 H), 3.59 (s, 2 H), 2.31 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13]OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:17]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]=[CH:13][N:25]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC=Nc1ccc(C(=O)OCC)cc1
Reactant: CCCCCCCCNc1ccccc1
Solvent: CCO
Product: CCCCCCCCN(C=Nc1ccc(C(=O)OCC)cc1)c1ccccc1

Procedure:
Ethyl N-(4-ethoxycarbonylphenyl)formimidate (Example Ia) (6.6 g, 0.03 mol) and N-octylaniline (6.2 g, 0.03 mol) were heated at 180° until 1.7 ml of ethanol had been collected by distillation. The resulting pale yellow oil was flash distilled to yield the desired product, bp≈235° C. (0.05 mm). ##STR15##
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.C([Cl:23])C=C.[Cl:24][SiH2:25][Cl:26]>>[CH2:2]([SiH:25]([Cl:26])[Cl:24])[CH:1]=[CH2:6].[CH2:2]([Si:25]([Cl:23])([Cl:26])[Cl:24])[CH:1]=[CH2:6]
Reactant: Cl[SiH2]Cl
Reactant: C=CCCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC[SiH](Cl)Cl
Product: C=CC[Si](Cl)(Cl)Cl
Yield: 457.3 %
Yield: 20 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.80 g (3.1 mmol) of triphenylphosphine, 1.25 ml (15.3 mmol) of allyl chloride, and 3.1 g (31 mmol) of dichlorosilane were reacted 150° C. for 1.5 hrs. The resulting mixture was distilled to give 1.00 g of allyldichlorosilane (yield; 13%) and allyltrichlorosilane (yield; 20%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][C:21]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)=[O:22])[C:4](=[O:19])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:32][CH:33]([CH3:37])[CH:34]([NH2:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:35][CH:34]([NH:36][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([C:21](=[O:22])[CH2:20][N:3]2[C:4](=[O:19])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:24][CH:25]=1)[CH:33]([CH3:37])[CH3:32]
Reactant: CC(C)C(C)N
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(C(=O)NC(C)C(C)C)cc1
Reaction time: 12 h
Yield: 48.7 %

Procedure:
4-[2-(2-Methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-benzoic acid (120 mg, 0.29 mmol) and (+/−)-3-methyl-2-butylamine (45 uL, 0.44 mmol) and N,N′-dicyclohexylcarbodiimide (97 mg, 0.47 mmol) and 4-(dimethylamino)-pryridine (58 mg, 0.47 mmol) are dissolved in 5 mL methylene chloride. The reaction mixture is stirred for 12 hours, filtrated and the filtrate evaporated. The residue of the filtrate is purified by preparative HPLC (Method 1) to yield (+/−)-N-(1,2-dimethyl-propyl)-4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-benzamide (68 mg, 48%). LCIMS at 354 nm; [M+H] 482; Rt 3.304 min.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[CH3:17][S:18]([CH2:21][C:22]1[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:24]=[CH:25][N:26]=1)(=[O:20])=[O:19].[H-].[Na+]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:36][CH:35]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2)n1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3)n2)cc1
Yield: 75.5 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(4-chlorophenyl)ethenyl]-1,3-oxazole (227 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (322 mg) as a colorless crystal powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC

Procedure:
(1R,2S) N-Boc-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester (8.5 g, 33.3 mmol) was stirred under a nitrogen atmosphere with 200 mL of 4N HCl/dioxane (Aldrich) at room temperature for 3 hours. The solvent was removed under reduced pressure keeping the temperature below 40° C. This gave 6.57 g (˜100%) of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride as a light tan solid. 1H NMR (300 MHz, CD3OD) δ 1.31 (t, J=7.0 Hz, 3H), 1.69-1.82 (m, 2H), 2.38 (q, J=8.8 Hz, 1H), 4.29 (q, J=7.0 Hz, 2H), 5.22 (d, J=10.3 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.69-5.81 (m, 1H). MS m/z 156 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]([O:21]C)=[O:20])[C:5]2[C:6]([CH3:18])=[C:7]([CH2:14][N:15]([CH3:17])[CH3:16])[N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5]2[C:6]([CH3:18])=[C:7]([CH2:14][N:15]([CH3:16])[CH3:17])[N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(CN(C)C)n2C(C)C
Agent: Cl
Product: Cc1c(CN(C)C)n(C(C)C)c2cc(Cl)cc(C(=O)O)c12
Temperature: 80 °C
Reaction time: 18 h
Yield: 178.4 %

Procedure:
To methyl 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.44 g, 1.363 mmol) was added 6 N HCl (20 ml, 120 mmol). The reaction was purged with N2, attached a reflux condensor, heated to 80° C., and stirred for 18 hr. LCMS showed that the reaction was complete. The reaction was cooled to RT, diluted with an equal volume of water, washed with EtOAc, and evaporated to dryness under vacuum to give the product 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride salt (0.42 g, 1.216 mmol, 89% yield) as a beige solid. (86% pure by LCMS, contains ˜10% of the des-chloro side product from the previous reaction.) Used as is in the next step. 1H NMR (400 MHz, DMSO-d6) δ=13.19 (br. s., 1H), 10.45 (br. s., 1H), 7.90 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 4.91 (quin, J=6.9 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.79 (d, J=4.8 Hz, 6H), 2.34 (s, 3H), 1.58 (d, J=6.8 Hz, 6H). MS (ES)+m/e 309.2 [M+H]+, 264.1 [M+H]+ −45 (HNMe2).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[C:13]1([B:29]([OH:32])[OH:30])[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
An excess of 1.6 M n-BuLi in hexane (50 mL, 80 mmol) was added to a solution of 1-bromopyrene (20.4 g, 72.6 mmol) in 500 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethyl borate (10.4 g, 100 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (150 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the residue was crystallized (n-hexane) to give the pyren-1-ylboronic acid 12.5 g as a yellow solid (70%)
Reaction SMILES: Cl[C:2]1[C:11]2=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([CH3:15])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([O-])=O.[NH4+].C(O)C>[Pd].C(#N)C>[CH3:15][C:14]1[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[CH:2]2
Reactant: Cc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCO
Product: Cc1c2c(cnc3ccccc32)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 18.1 %

Procedure:
4-Chloro-1-methyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline (250 mg, 0.85 mmol) was combined with ammonium formate (268 mg, 4.25 mmol), ethanol (4 mL), and palladium on carbon (10%, 25 mg). The resulting gray suspension was warmed to 60° C. and stirred at this temperature for 18 hours. The reaction was cooled to ambient temperature and filtered through CELITE filter agent. The methanol was removed under reduced pressure and the resulting material was purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-30% CMA in chloroform) to provide material that was stirred in acetonitrile. A solid was isolated by filtration to provide 40 mg of 1-methyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline as a white powder, mp 128-130° C. MS (APCI) m/z 260 (M+H)+; Anal. calcd for C17H13N3.0.15H2O: C, 77.93; H, 5.12; N, 16.04. Found: C, 78.09; H, 5.51; N, 16.27.
Reaction SMILES: [C:1]([S:5]([NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])[CH:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:33]>C1(C)C=CC=CC=1.CO>[C:1]([S:5]([NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:22][N:21]=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:33])=[O:16])[CH:13]=1)=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C(=O)O)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)(C)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of 0.30 g (0.65 mmol) 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic acid in 2.5 ml toluene and 0.81 ml MeOH at rt was added 1.3 ml (2.6 mmol) 2.0 M TMS-diazomethane in hexanes. After 4 h at room temperature, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-15% MeOH in CH2Cl2) afforded 0.12 g (38%) methyl 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoate. ES-MS [M+1]+=478.2. 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=2.75 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J=8.70 Hz, 1H), 7.24 (m, 1H); 5.87 (d, J=5.31 Hz, 1H,), 5.33 (d, J=5.31 Hz, 1H), 4.38 (q, J=7.70, 2H), 3.71 (d, J=0.82 Hz, 1H); 1.92 (d, J=1.65 Hz, 6H); 1.27 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12](OCC)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+]>CC(O)=O>[C:1]1([C:7]2[S:11][C:10]([CH2:12][OH:13])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OCc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (350 mgs, 1.494 mmol) in anhydrous methanol (5 mL, 124 mmol) was added NaBH4 (226 mgs, 5.98 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. AcOH (2 mL) was added and the reaction was concentrated to dryness. The residue was dissolved in EtOAc, brine and water and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aqueous NaHCO3 and brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation, the residue was triturated with ethyl ether to give the title material as a first crop (150 mgs, 52%). LC (Method B): 2.022 min, LCMS (APCI) calcd for C9H9N2OS [M+H]+ m/z 193.04, found 193.2. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.92-8.03 (m, 2H), 7.44-7.59 (m, 3H), 5.14 (br. d, J=3.90 Hz, 2H), 2.63 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:10]([O:24][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C(OCC1CO1)C1CO1
Reactant: CCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of tetradecanol.