Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:8][CH:7]=[N:6][N:5]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1.[N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[CH:46]=O>>[O:13]1[CH2:12][CH2:11][N:10]([C:9]2[C:4]3[N:5]([C:16]([C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]5)=[N:21][CH:22]=4)=[C:2]([NH:1][CH2:46][C:37]4[CH:38]=[CH:39][C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:36]=4)[N:3]=3)[N:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(N)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: O=Cc1ccc2ccccc2n1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(NCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1

Procedure:
Using the procedure described in Example 21, Step C, the title compound was prepared from Compound 23b and 2-quinolinecarbaldehyde. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.66 (d, J=2.2 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.97-8.07 (m, 2H), 7.89 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.70 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.46-7.56 (m, 2H), 6.81 (d, J=9.0 Hz, 1H), 6.03 (d, J=5.6 Hz, 1H), 5.30 (t, J=5.3 Hz, 1H), 4.91 (d, J=5.4 Hz, 2H), 3.81 (s, 8H), 3.49-3.69 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H39N9O3: 622.3 (M+H). Found: 622.3.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=2)[S:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:15]1[CH2:14][C:13]([CH3:12])([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=2)[S:16]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CC(C#C[Si](C)(C)C)Sc2ccc(CO)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
3 ml (21.3 mmol) of trimethylsilylacetylene and 50 ml of THF were introduced into a three-necked flask. A solution of 8.6 ml (21.3 mmol) of n-butyllithium (2.5M in hexane) was added dropwise at -78° C. under a stream of nitrogen and the reaction mixture was permitted to heat to room temperature. This solution was introduced dropwise into a solution of 4 g (19.4 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde in 50 ml of THF at -78° C. The reaction mixture was permitted to heat to room temperature, was poured into an aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 5.9 g (100%) of the expected alcohol were obtained in the form of a yellow oil.
Reaction SMILES: Br.FC1C=CC(C2[S:13][C:12]([NH:14]C(=O)C)=[N:11]C=2C)=CC=1OC.Br[CH:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:35])=[O:34])[CH:27]=1)[C:23](=O)[CH3:24].C(NC(N)=S)(=O)C.NC(N)=S>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[S:13][C:12]([NH2:14])=[N:11][C:23]=2[CH3:24])=[CH:27][C:28]=1[S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]
Reactant: CC(=O)C(Br)c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1
Reactant: COc1cc(-c2sc(NC(C)=O)nc2C)ccc1F
Agent: Br
Agent: CC(=O)NC(N)=S
Agent: NC(N)=S
Product: Cc1nc(N)sc1-c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1

Procedure:
The title compound is prepared as an HBr salt by the same procedure as N-[5-(4-fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (161c) by replacing 1-bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) with 1-bromo-1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one (171c) and N-acetylthiourea with thiourea.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([O:34]CC)=O)[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[N:37]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:44][CH2:43][CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:34])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCN2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
Ethyl 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (Intermediate A) (200 mg, 0.41 mmol) and 2-pyrrolidin-1-ylethanamine (928 mg, 8.12 mmol, 20 eq) were dissolved in MeOH (2.5 mL) and heated to 100° C. in a sealed vial by a microwave oven for 40 min The solvent was evaporated and EtOH (3 mL) was added and heated to 50° C. for two hours and then water (3 mL) was added and the mixture was stirred at room temperature over night. The precipitate was centrifuged (4000 rpm, 3 min) and washed three times with EtOH/H2O 1:1 (5 mL) and dried over night. The residue was dissolved in acetonitrile and purified by HPLC (30-95% MeOH in H2O+0.1% TFA), the pure fractions were freeze-dried, dissolved in acetonitrile and desalted with Na2CO3 (solid phase) and evaporated to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-N-(2-pyrrolidin-1-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide as a white solid (156 mg, 65%); 1H NMR (500 MHz, DMSO): δ 1.67-1.59 (4H, m), 1.72 (3H, s), 2.43-2.37 (4H, m), 2.49-2.47 (2H, m), 3.38-3.33 (2H, m), 6.72 (1H, d), 7.67-7.63 (2H, m), 7.71 (1H, d), 7.88-7.82 (2H, m), 7.96-7.89 (4H, m), 8.07 (1H, s), 9.35 (1H, t);
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[N:22]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[C:23]=S.C(N=C=NC(C)C)(C)C>C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[N:14]=[C:23]([NH:22][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: S=C=Nc1cccnc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: Fc1cnccc1-c1cc2nc(Nc3cccnc3)[nH]c2nc1-c1cccnc1
Temperature: 50 °C
Yield: 33 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.356 mmol) and 3-isothiocyanatopyridine (0.06 mL, 0.534 mmol) in ethanol (2 mL), 1,3-diisopropylcarbodiimide (0.083 mL, 0.534 mmol) was added. The mixture was heated at 50° C. for 2 h. After cooling at room temperature, the solvent was evaporated. The crude mixture was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.045 g, 33% of yield).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21]C(O)=O)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C(C1C=CC(OCC2C3=NC=C(CCC4[NH:57][N:56]=[N:55][N:54]=4)C(=O)N3C=CC=2)=C(CCC)C=1O)(=O)C>>[CH3:29][CH2:28][CH2:27][C:6]1[C:5]([OH:30])=[C:4]([C:1]([CH3:2])=[O:3])[CH:26]=[CH:25][C:7]=1[O:8][CH2:9][C:10]1[C:15]2=[N:16][CH:17]=[C:18]([C:21]3[N:57]=[N:56][NH:55][N:54]=3)[C:19](=[O:20])[N:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: CCCc1c(OCc2cccn3c(=O)c(CC(=O)O)cnc23)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2cccn3c(=O)c(CCc4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccn3c(=O)c(-c4nn[nH]n4)cnc23)ccc(C(C)=O)c1O

Procedure:
Furthermore, [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid (to be referred to as AS-148) and 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-[2-(1H-tetrazol-5-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (to be referred to as AS-163) could not be formed into an aqueous solution as AS-35 could not. The present inventors confirmed the above finding by their own experiments.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(benzyloxycarbonylamino)propanoic acid (331 mg, 1.48 mmol, Eq: 1.00) was combined with THF (9 mL) to give a colorless solution. Sodium hydride (131 mg, 3.26 mmol, Eq: 2.2) was added. The reaction was stirred at rt for 30 min, then 2-(methylsulfonyl)ethyl methanesulfonate (300 mg, 1.48 mmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% EtOAc in hexanes) to give (S)-2-[benzyloxycarbonyl-(2-methanesulfonyl-ethyl)-amino]-propionic acid (201 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
A solution of 370 mg (1.01 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 5 ml of N,N-dimethylformamide was treated with 0.42 ml (3.03 mmol) of dipropylamine and stirred at room temperature under argon for 2 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The white crystals were filtered off. The product was chromatographed on 20 g of silica gel (ethyl acetate/hexane 1:1, then ethyl acetate). There were obtained 259 mg of 8-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted with ethereal hydrochloric acid into the hydrochloride. By recrystallization from acetonitrile there were obtained 268 mg (54%) of 8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.6) of m.p. 180°-192° (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[I:7][CH2:8][CH2:9][CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13]>>[I-:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:8][CH2:9][CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: CO[Si](CCCI)(OC)OC
Product: CO[Si](CCCn1cc[n+](C)c1)(OC)OC
Product: [I-]
Temperature: 114 °C

Procedure:
N-Methylimidazole (156.8 g; 1.91 mol) and 3-iodopropyltrimethoxysilane (569.8 g; 1.96 mol) were charged to a 1 L, 3-necked flask to form a reaction mixture. The reaction mixture was heated to 114° C. for eight hours during which time the color of the mixture changed from pale yellow to green and then to black. The crude reaction product was washed twice with 80 mL of toluene (2×40 mL). The resulting black oily liquid of N-methyl-N′-(3-trimethoxysilylpropyl) imidazolium iodide was dissolved in 286 g of methylene chloride and maintained as a solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:42][C:43]1[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:42][C:43]2[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(F)ccn1
Reactant: COC(=O)c1cc(N)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cc(NC(=O)c2cc(F)ccn2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A solution of 4-fluoropicolinic acid (1.0 g, 6.4 mmol), HATU (2.9 g, 7.6 mmol), and N-methylmorpholine (0.84 mL, 7.6 mmol) in N,N-dimethylformamide (12 mL) was stirred at 0° C. for 30 minutes. Methyl 4-aminothiophene-2-carboxylate (990 mg, 7.0 mmol) was added, the reaction was stirred for 30 minutes at 0° C., then warmed to room temperature, and stirred for an additional 2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile/H2O (1:1) and the solids were isolated by filtration, washed with water, acetonitrile, then dried to afford methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate as a white powder (1.0 g, 56% yield). M+1=281.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH:15]([CH3:19])[NH:14]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:17]1[CH2:16][CH:15]([CH3:19])[NH:14][CH:13]([CH3:12])[CH2:18]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC1CNCC(C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2ccccc2Br)CC(C)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (100 mg, 0.39 mmol), 2,6-dimethylpiperazine (56 mg, 0.49 mmol), and diisopropylethyl amine (0.202 mL, 1.17 mmol) in CH2Cl2 (2.5 mL) was allowed to stir for 15 min at rt. The reaction mixture was then directly subjected to FCC purification to give the title compound (0.105 g, 81%). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 1H), 7.43-7.37 (m, 1H), 3.70-3.66 (m, 2H), 2.97-2.91 (m, 2H), 2.38-2.33 (m, 2H), 1.06-1.04 (m, 6H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1.[K+].[Br-].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:23]4[CH2:25][CH2:24]4)[CH2:28][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(Cl)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1
Yield: 18 %

Procedure:
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 18%. White crystals, m.p. 225–226° C.; IR (KBr): ν 1710 (ester C═O), 1661 (amide C═O) cm−1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5](O)=O.CN1CCO[CH2:11][CH2:10]1.C(OC(ON=C([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C#N)=O)(C)(C)C>O.CC(C)=O>[CH:2]1([NH:1][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:11][CH2:10][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCC(=O)O
Reactant: CN1CCOCC1
Solvent: CC(C)=O
Solvent: O
Product: C1CCC(NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
4-Aminobutyric acid (5.16 g) was dissolved in 20 ml of water. To the resulting solution were added 8.4 ml of N-methylmorpholine and 11.08 g of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile in 50 ml of acetone. After stirring the resulting mixture overnight at room temperature, about a half of the solvent was distilled off. Water and ethyl acetate were added thereto and thoroughly mixed to separate the solution. The aqueous phase was washed with ethyl acetate, combined with the organic phase, and extracted with 5% aqueous sodium hydrogencarbonate. After combining the aqueous phases, ethyl acetate was added thereto and the pH was adjusted to about 3 with 6 N hydrochloric acid to separate the solution. The aqueous phase was extracted twice with ethyl acetate. The extracts were combined, washed with water, and dried over anhydrous magnesium sulfate. After removal of the desiccant, N,N-dicyclohexylamine was added thereto for crystallization. Crystals were collected by filtration, washed with ether, and dried to obtain 15.07 g of an N,N-dicyclohexylamine salt (yield 79%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.C[Li].I[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)P(=O)(N(C)C)N(C)C>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:10]#[C:11][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6][CH:7]=1
Reactant: CCCCCI
Reactant: C#CCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC#CCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To 2.2 g (63 mmol) of the silylacetylene of Example 2 dissolved in 50 ml of dry THF and cooled to -78° C. under argon was added dropwise 5.6 ml (7.0 mmol) of a 1.25M solution of methyl lithium in diethyl ether. Upon addition, the reaction was warmed to -10° C. and stirred at -10° C. for 30 min. Iodopentane (1.2 ml, 9.0 mmol) was then added followed by 5.0 ml of hexamethylphosphoric triamide (HMPA) whereupon the reaction mixture was warmed to R.T. and stirred overnight. The reaction was quenched with about 5.0 ml of H2O, then poured into hexane and washed 4× with H2O, and 1× with brine. The organic layer was dried (MgSO4) and the solvent removed to yield a dark red oil which was purified by medium pressure liquid chromotography (MPLC) eluting with hexane to yield 2.14 g of the titled product as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1>[C:19]1([S:25]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1

Procedure:
1-(2,3-Dihydro-1H-indol-5-yl)-ethanone (0.200 g, 1.24 mmol) was dissolved in THF (2 ml) before pyridine (0.303 ml, 3.75 mmol) was added, leaving a yellow solution. The benzenesulfonyl chloride (0.220 g, 1.24 mmol) was then added, as a solid, with stirring. The reaction mixture was stirred at 40 C for 5 h. The mixture was cooled and the THF and pyridine were removed in vacuo. The desired sulfonamide (0.310 g, 1.02 mmol, 82%) was recrystallized from ethyl acetate and hexanes. It had LC-MS (ES+): 302 [MH]+ m/e
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([Cl:17])[N:12]=[C:13](Cl)[C:14]=2[N:15]=1)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([Cl:17])[N:12]=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]=2[N:15]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)OCc1ccc2nc(Cl)nc(Cl)c2n1
Solvent: CCO
Product: CC(=O)OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Yield: 96.6 %

Procedure:
A mixture of (2,4-dichloropyrido[3,2-d]pyrimidin-6-yl)methyl acetate (1.92 g, 7.06 mmol) according to Srinivasan and Broom (1981) J. Org. Chem. 46:1777-1781, and morpholine (1.3 mL, 14.9 mmol) in ethanol (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness. The crude product was purified by flash chromatography (DCM) to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl acetate 5 (2.2 g, 96%). 1H-NMR (CDCl3): δ 8.05 (d, 1H), 7.66 (d, 1H), 5.29 (s, 2H), 4.5 (s, br, 4H), 3.87 (m, 4H), 2.19 (s, 3H)
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[C:18]1([NH:17][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1cccc2ccc(Nc3ccccc3)nc12
Temperature: 50 °C
Yield: 35 %

Procedure:
NaH (60% w/w in mineral oil; 0.549 g, 13.73 mmol) was added to a mixture of 2-chloroquinoline-8-carboxylic acid (181a, 0.95 g, 4.58 mmol) and aniline (0.834 ml, 9.15 mmol) in THF (11 ml) at 0° C.; the reaction was heated to 50° C. for 2 h. The mixture was diluted with 75 ml of Et2O and washed with 1 N NaOH. The organic layer was separated, and the aq. layer was acidified to ˜pH 1 with 5 N HCl and extracted 4 times with 75 ml of EtOAc. All organic extracts were then combined dried over Na2SO4, and concentrated to give 2-(phenylamino)quinoline-8-carboxylic acid (35% yield) as a light-brown solid. MS (ESI, pos. ion) m/z: 265.2 (M+1).