Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[O:5][C:4]1[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([CH3:20])[CH:17]=1)[C:10]#[N:11]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A solution of compound 21 (15.00 g, 55.91 mmol) in THF (250 mL) was added a solution of sodium hydrosulfite (58.41 g, 335.5 mmol) in water (75 mL). The reaction mixture was stirred at 90° C. After 24 hrs, the starting material was consumed as monitored with TLC (10% EtOAc in hexanes) and reaction mixture was removed from heat. The reaction mixture was concentrated in vacuo until product precipitated in remaining water. The precipitate was collected via vacuum filtration and washed with water. The product was dried overnight in vacuum at 40° C. to afford compound 22. (12.681 g, 95.2% yield, 99.9% HPLC purity). 1H NMR (500 MHz, DMSO-d6): δ 7.08 (d, J=2 Hz, 1H), 6.91 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.80 (s, 1H), 6.73 (d, J=8 Hz, 1H), 6.63 (s, 2H), 5.47 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.B(O)(O)[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH2:21])[CH2:20]2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1C1(c2ccc(C)cc2)C=C(N)N=C(N)C1
Yield: 11 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and p-tolylboronic acid provided the title compound (11% yield). 1H NMR (acetone-d6) δ2.26 (s, 3H, CH3), 3.83 (s, 3H, CH3) 5.24 (bs, 2H, NH2), 6.10 (d, 1H, J=1.1 Hz, Ar), 6.26 (t, 1H, J=1.1 Hz, Ar), 7.06 (d, 2H, J=8.5 Hz, Ar), 7.08 (d, 1H, J=8.8 Hz, Ar), 7.29 (d, 1H, J=2.7 Hz, Ar), 7.35 (dd, 1H, J=9.0 Hz, J=3.3 Hz, Ar), 7.53-7.56 (m, 2H, Ar), 7.70 (s, 1H, NH).
Reaction SMILES: [C:1]1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=C[CH:2]=1.N[C@H](C(OCC)=O)CCC(OCC)=O.C([C:34]1[CH:55]=[CH:54][CH:53]=[CH:52][C:35]=1[C:36]([NH:38][C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:37])#C.[K+].[Br-]>C(Cl)Cl.CO>[C:1]([C:54]1[CH:55]=[CH:34][C:35]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:37])=[CH:52][CH:53]=1)#[CH:2]
Reactant: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Reactant: C#Cc1ccccc1C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC
Agent: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.55 g of 4-ethynylbenzoic acid (obtained from tert.-butyl 4-ethynylbenzoate in 84% yield by hydrolysis with trifluoroacetic acid) in 50 ml of anhydrous ether and 25 ml of anhydrous tetrahydrofuran is added 1.58 ml of triethylamine. This is followed by 1.00 g of phenyl N-phenylphosphoramidochloridate. After stirring the reaction mixture at room temperature under nitrogen for 0.5 hour, 0.90 g of diethyl L-glutamate is added in one portion. The mixture is allowed to stir for another 8 hrs. After a workup, the residue is subjected to column chromatography using a 1% methanol:methylene chloride mixture as the eluent. The major fraction isolated from the column contained 0.68 g (54%) of diethyl N-(ethynylbenzoyl)-L-glutamate as an oil which slowly solidified: NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11°-2.60 (m, 4H), 3.23 (s, 1H), 4.09 (q, 2H, J=6.9 Hz), 4.27 (1, 2H, J=6.9 Hz), 4.80 (m, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4 Hz); IR (KBr) 3330, 3280, 2990, 1735, 1640, 1520, 1380, 1200, 1105, 1020, 855, and 770 cm -1.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[C:16]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
N-Carbobenzyloxy-glycine (2.1 g, 10 mmol) and glycine-tert-butyl ester (1.3 g, 10 mmol) were coupled using benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (4.4 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in acetonitrile following the method described in Example 23 to give 2.5 g(79%) of N-carbobenzyloxy-glycylglycine-tert-butyl ester after chromatography on silica gel.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]([CH3:11])=[N:9][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1.[OH-].[Na+]>CN(C=O)C>[CH3:11][C:10]1[C:6]([CH2:5][C:1]#[N:2])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: Cc1nn(-c2ccccc2)nc1CCl
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)nc1CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
1.8 g of sodium cyanide was suspended in 30 ml of DMF, and 5.0 g of 4-chloromethyl-5-methyl-2-phenyl-1,2,3-triazol was added under cooling with ice. After stirring for 3 hours at room temperature, an aqueous solution of sodium hydroxide was added to the reaction solution to make it alkaline, and extracted with toluene. The organic phase was washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the deposited crystals were washed with hexane to obtain 4.3 g of the aimed compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[O:9][CH3:10].[NH2:13][CH2:14][C@@H:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:19][CH2:18][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:16]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:28]([N:17]1[CH2:18][CH2:19][C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C@@H:15]([CH2:14][NH:13][C:8](=[O:11])[O:9][CH3:10])[CH2:16]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CN
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1CN(Cc2ccccc2)CC[C@@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
111 μL of triethylamine and 37 μL of methyl chlorocarbonate were added to chloroform (2 mL) solution of 93 mg of (3S*,4S*)-3-aminomethyl-1-benzyl-4-o-tolyl-piperidine obtained in Production Example 37, and stirred at room temperature for 50 minutes. Aqueous 1 M sodium hydroxide solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 78 mg of the entitled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:11])[CH3:10].[BH4-].[Na+].O>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:11][CH2:9][CH3:10])=[CH:3][CH:2]=1
Reactant: CCN
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNCc1ccncc1

Procedure:
15.70 g (0.147 mol) of 4-pyridine-formaldehyde was dissolved in 200 mL of ethanol, added under stirring in cold-water-bath with 21 g (0.296 mol) of 65-70% ethylamine aqueous solution, reacted for 0.5 h, monitored with TLC until the reaction was almost completed. Added carefully with 5.6 g (0.148 mol) of sodium borohydride in several batches, small amount in each batch, after the end of addition, added with 30 mL of water, reacted overnight (20 h), the reaction was completed according to TLC monitoring. Evaporated to remove solvent, added with water, extracted with dichloromethane, washed with water and saturated saline in order, dried with anhydrous sodium sulfate, evaporated to remove solvent to obtain yellow thick liquid, 30 g, crude yield 73.4%. 1H NMR(CDCl3, 400 MHz)δ: 1.14(t, 3H, J=7.00 Hz), 2.66(q, 2H, J=7.00 Hz), 3.81(s, 2H), 7.26-7.27(m, 2H), 8.52-8.54(m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.O>CS(C)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and K2CO3 (6.92 g, 50 mmol) in dimethyl sulfoxide (20 mL) was added piperidin-4-ol (2.22 g, 22 mmol) and the reaction was heated to 100° C. for 4 hours. This solution was poured into 200 ml of water and extracted with ethyl acetate (30 mL×3). The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate. The solid was filtered and the filtrate, 10% Pd/C (100 mg) was added and the mixture was stirred under hydrogen atmosphere at ambient temperature overnight. The catalyst was filtered, and the filtrate was concentrated to afford tan solid 3.7 g. MS (m/z): 193 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)=[CH:15][CH:16]=3)[C:11](=[O:27])[C:10]([C:28](OCC)=[O:29])=[CH:9]2)=[CH:4][CH:3]=1.[NH3:33]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]4[CH:25]=[N:24][C:23]([CH3:26])=[N:22][CH:21]=4)=[CH:15][CH:16]=3)[C:11](=[O:27])[C:10]([C:28]([NH2:33])=[O:29])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CCc3cnc(C)nc3)cc2c1=O
Reactant: N
Solvent: CO
Product: Cc1ncc(CCc2ccc3c(c2)c(=O)c(C(N)=O)cn3-c2ccc(F)cc2)cn1
Temperature: 150 °C
Yield: 65 %

Procedure:
Compound T (11 mg, 0.026 mmol, 1.0 eq) was dissolved in 7N ammonia in methanol (1 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 60 minutes. The reaction was concentrated and purified by reverse phase chromatography to afford 6.7 mg (65%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=4.4 Hz, 1H), 8.55 (s, 2H), 8.53 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.76-7.71 (m, 2H), 7.62-7.58 (m, 2H), 7.51 (t, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 1H), 3.06 (t, J=8.3 Hz, 2H), 2.90 (t, J=8.3 Hz, 2H), 2.53 (s, 3H); ES-MS [M+1]+: 403.2.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:8]2=[O:24].[NH2:26][NH2:27]>CO>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:9]2[C:8](=[O:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([CH2:4][C:3]([NH:26][NH2:27])=[O:2])[CH:6]=3)[N:11]=[CH:10]2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1ccc2ncn(Cc3ccc(OC)cc3)c(=O)c2c1
Reactant: NN
Solvent: CO
Product: COc1ccc(Cn2cnc3ccc(CC(=O)NN)cc3c2=O)cc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
[3-(4-Methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid methyl ester (0.050 g, 0.148 mmol) and hydrazine (0.047 g, 0.148 mmol) were stirred at 50° C. in methanol (5 mL) for several hours. The reaction was then cooled to room temperature and filtered to give 0.030 g (60%) of [3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid hydrazide. 1H NMR (400 MHz, CD3OD) δ 10.09 (s, 1H), 9.33 (s, 1H), 8.85 (m, 1H), 8.53 (d, 1H, J=2.0, 8.4 Hz), 8.42 (d, 1H, J=8.4 Hz), 8.14 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=8.4 Hz), 5.93 (s, 2H), 5.04 (bs, 2H), 4.52 (s, 3H), 4.31 (s, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nsc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nsc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a solution of N-tert-butyl-2-(3-methyl-1,2,4-thiadiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (128 mg, 277 μmol) in dichloromethane (4.3 mL) was added trifluoroacetic acid (632 mg, 427 μL, 5.55 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (2 mL) and ammonium hydroxide (0.6 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(3-methyl-1,2,4-thiadiazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 272 μmol, 98%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.80 (s, 1H), 12.57 (s, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 7.34 (s, 1H), 2.53 (s, 3H), 1.62 (s, 9H); MS (EI/CI) m/z: 332.1 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:25])=[C:7]([CH3:24])[N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[CH3:26].Cl[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29]>>[CH2:31]([O:30][C:28]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:25])=[C:7]([CH3:24])[N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[CH3:26])=[O:29])[CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)c1ccc(Cn2c(C)c(C)c3cc(C)c(N)cc32)c(OC)c1
Reactant: CCCCOC(=O)Cl
Product: CCCCOC(=O)Nc1cc2c(cc1C)c(C)c(C)n2Cc1ccc(C(=O)OC)cc1OC
Yield: 99 %

Procedure:
Similarly, starting from methyl 4-(6-amino-2,3,5-trimethylindol-1-ylmethyl)-3-methoxybenzoate and butyl chloroformate, methyl 4-[6-(butoxycarbonyl)amino-2,3,5-trimethylindol-1-ylmethyl]-3-methoxybenzoate (Example 39) was obtained in 99% yield as a white solid; partial NMR: 0.9 (t, 3H, CH2CH3), 1.3 (m,2H,CH2CH3), 1.5 (m,2H, CH2OCH2 0), 4.1 (t,2H,CH2O), 4.1 (t,2H,CH2O).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[CH2:39]([N:46]1[C:55]2[C:50](=[C:51]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)[C:52]([C@H:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:58][OH:59])=[C:53]([CH3:56])[CH:54]=2)[CH:49]=[CH:48][C:47]1=[O:72])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[CH2:39]([N:46]1[C:55]2[C:50](=[C:51]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)[C:52]([C@H:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:58]([OH:6])=[O:59])=[C:53]([CH3:56])[CH:54]=2)[CH:49]=[CH:48][C:47]1=[O:72])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2c(ccc(=O)n2Cc2ccccc2)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2c(ccc(=O)n2Cc2ccccc2)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(1-Benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (65B) (5.4 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-1-benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 7.6-7.5 (m, 3 H), 7.4-7.2 (m, 8 H), 6.59 (d, J=9.6 Hz, 1 H), 5.64 (s, 2 H), 5.02 (s, 1 H), 2.47 (s, 3 H), 0.94 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29ClNO4: 490.2. Found: 490.2; LCMS-ESI+ (m/z): [M+H]+ calcd for C29H27ClNO4: 488.2. Found: 488.0.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:8]=2[N:9]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: CCNc1ccc2nc(Cl)sc2c1
Reactant: [C-]#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNc1ccc2nc(C#N)sc2c1
Temperature: 120 °C

Procedure:
Potassium cyanide (18 mg) and 2-chloro-6-ethylaminobenzothiazole (18 mg) were dissolved in 1 ml DMSO and heated to 120° C. for 4 h. After cooling to room temperature, the reaction was poured into 0.2M potassium phosphate, pH 4.5. The aqueous layer was extracted with ethyl acetate three times, washed with water, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes). 1H-NMR (d6-DMSO): δ 7.85 (d, 1H, J=9.2 Hz), 7.13 (d, 1H, J=2.4 Hz), 6.98 (dd, 1H, J=2.4, 8.8 Hz), 6.44 (br t, 1H), 3.09 (m, 2H), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:40][S:37]([F:38])([F:39])([F:41])([F:42])[C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was filtered, dried and purified by chromatography on silica (ethyl acetate/methanol 8:1) to give 133 mg (47%) amorphous material.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
A mixture of (3,4-dimethylphenyl)boronic acid (802 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (5.00 g) in MeCN (18 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (40.0 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:29][C:30]([NH:32][CH3:33])=[O:31])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:61])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([NH:29][C:30]([NH:32][CH3:33])=[O:31])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:61])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(3-methylureido)propane IIIf2 is allowed to react and worked up by the same procedure as described in (5). m.p. 70°-71° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH:1]#[C:2][CH3:3].Cl[C:5]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>[C:1]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[C:2][CH3:3]
Reactant: C#CC
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
Using a high pressure tube, propyne (5 mL) was condensed in a mixture of 2,4-dichloro-pyrimidine (1.71 g, 11.47 mmol), CuI (228 mg, 1.20 mmol), Pd(PPh3)2Cl2 (0.57 mmol), and Et3N (50 mL) at −78° C. The mixture was slowly warmed up and stirred at room temperature for 12 h. After this period, the mixture was quenched with aqueous NH4Cl. The aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4; and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 5%-15% EtOAc/hexanes to give 19 (1.64 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:26]3[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: CC1CCNCC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 4-methylpiperidine (0.035 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 80° C. and stirring continued for 19.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperidin-1-yl)-pyridin-3-yl)quinoline as a tan solid. Mass Spectrum (ESI) m/e=388.1 (M+1).