Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=1)[NH:26][CH:25]=[CH:24]2>ClCCl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[C:24]2[C:23]3[C:27](=[C:28]([CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:29]=[C:21]([F:20])[CH:22]=3)[NH:26][CH:25]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
64 mg (0.35 mmol) of the compound from Example 153A and 0.03 ml (0.42 mmol) of trifluoroacetic acid were added to 80 mg (0.35 mmol) of the compound from Example 87A in 2.5 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 110 mg (80% of theory) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[C:23]1([NH2:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([NH:29][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Solvent: O
Product: c1ccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)cc1
Yield: 51 %

Procedure:
0.300 g (0.90 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V) and 3 mL of phenylamine are combined, then reacted for 0.3 hours at 130° C. in the microwave. Then the reaction mixture is combined with water and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. The residue is triturated with diethyl ether and suction filtered. 0.18 g of product I (51%) is obtained (m.p. 174° C.-175° C.). 1H-NMR (400 MHz, DMSO): 8.59 (1H, s); 7.63 (2H, d); 7.31 (2H, t); 7.22 (2H, t); 7.03 (1H, t); 6.99 (2H, d); 6.80 (1H, t); 3.83-3.73 (4H, m); 3.31 (2H, t); 3.23 (4H, m); 3.12 (2H, t).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19](O)=[O:20])=[N:8][C:9]=2[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[NH2:26]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([NH:26][C:25]([CH3:28])([CH3:27])[C:24]([O:23][CH3:22])=[O:29])=[O:20])=[N:8][C:9]=2[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 4 b, using 5-cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 422.1 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>ClCCl>[CH3:37][O:36][C:35](=[O:38])[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:12]3[C:7]4[O:6][CH2:5][O:4][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 0 °C

Procedure:
The title compound was prepared from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and triethylamine (20.6 mg, 28.4 μl, 204 μmol) in dichloromethane (1 mL). Methyl carbonochloridate (7.06 mg, 5.78 μl, 0.075 μmol) was added to the mixture stirring at 0° C. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temp. The reaction was diluted with dichloromethane and quenched with sat NaHCO3 (4 mL). The aqueous layer was extracted with DCM (1×5 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as a white solid (9 mg, 34%), MS (ISP) m/z=390.3 [(M+H)+].
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]([CH3:28])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([CH3:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]O)=[CH:45][CH:44]=1>O>[CH2:7]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]([CH3:28])[C:25]([O:27][CH2:47][C:46]3[CH:49]=[CH:50][C:43]([Cl:42])=[CH:44][CH:45]=3)=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([CH3:29])[CH3:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCC(C)(C)N2Cc1ccccc1
Reactant: OCc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)OCc1ccc(Cl)cc1)c1ccc2c(c1)CCC(C)(C)N2Cc1ccccc1
Yield: 83.5 %

Procedure:
To 30 ml of benzene were added 3.2 g of 2-(1-benzyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionic acid (Compound 54), 4,4 g of p-toluenesulfonic acid and 14.3 g of 4-chlorobenzyl alcohol. The solution was heated and refluxed with removing water. The reaction mixture was concentrated, followed by washed petroleum ether and addition of ethyl acetate. Then the mixture was washed with sodium hydrogencarbonate, water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (Hexan acetate) to give 3.7 g of 4-chlorobenzyl 2-(1-benzyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 59).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC1CCCN1
Solvent: CO
Product: CC1CCCN1c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.9 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added 2-Methylpyrrolidine (82 μL, 0.848 mmol). The resulting mixture was stirred at RT for 2 days. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give two racemic pairs of diasteriomers 2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. (Hc1, Diastereomer 1, racemic, first to elute) (79.5 mg, 0.240 mmol, 33.9% yield). LC-MS (M+H)+=332.1; 1H NMR (500 MHz, MeOD) δ ppm 7.16 (2H, d, J=5.49 Hz), 7.04 (2H, s), 4.42-4.54 (1H, m), 4.09-4.22 (1H, m), 3.86-4.00 (1H, m), 3.71-3.82 (1H, m), 3.24-3.31 (1H, m), 3.10-3.22 (1H, m), 2.54-2.65 (1H, m), 2.05-2.16 (2H, m), 1.94-2.05 (2H, m), 1.69-1.80 (1H, m), 1.27 (3H, d, J=6.10 Hz). (Hc2, Diastereomer 2, racemic, second to elute) (89.5 mg, 0.270 mmol, 38% yield). LC-MS (M+H)+=332.1; 1H NMR (500 MHz, MeOD) δ ppm 7.14 (2H, d, J=5.49 Hz), 6.99-7.08 (2H, m), 4.42-4.54 (1H, m), 4.13-4.22 (1H, m), 3.86-4.00 (1H, m), 3.71-3.83 (1H, m), 3.25-3.32 (1H, m), 3.14-3.25 (1H, m), 2.52-2.67 (1H, m), 2.05-2.19 (2H, m), 1.94-2.05 (2H, m), 1.68-1.78 (1H, m), 1.19-1.32 (3H, m). The relative stereochemistry for Hc1 and Hc2 was not determined
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1.CCOCC.[Zn]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]([OH:10])[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(C)C(O)c1ccc(OC)cc1

Procedure:
To 36.2 g. (0.55 mole) of purified zinc dust is added portionwise a solution of 80 g p-anisaldehyde (0.58 mole) in 80 ml of anhydrous benzene, 20 ml anhydrous ether and 98 g (0.54 mole) of ethyl 2-bromopropionate from a separatory funnel. About 15 ml of this solution is added to the zinc and the flask is warmed until the reaction starts and then heating is removed and allowed to continue exothermally. The addition takes about an hour. The reaction mixture is refluxed for 40 minutes and then cooled in an ice bath and hydrolyzed by the addition of 250 ml of cold 10% sulfuric acid with vigorous stirring. The acid layer is drawn off and the benzene solution is extracted twice with 63 ml of 5% sulfuric acid followed by 30 ml of 10% sodium carbonate solution, then with 3 × 30 ml of 5% sulfuric acid, and finally with 2 × 30 ml of water. The combined acid solution is extracted with 2 × 100 ml of ether and the combined ether and benzene solution is washed with 2 × 50 ml of saturated sodium chloride, then it is dried over sodium sulfate for 11/2 hours and filtered. Most of the solvent is removed on an evaporator. The rest is distilled under vacuum to obtain ethyl β-(p-methoxyphenyl)-β-hydroxy-α-methylpropionate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][OH:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[O:44]=[C:45]1[CH:50]([N:51]2[C:59](=[O:60])[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][C:57]=3O)[C:52]2=[O:62])[CH2:49][CH2:48][C:47](=[O:63])[NH:46]1>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:25][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[C:52](=[O:62])[N:51]([CH:50]1[CH2:49][CH2:48][C:47](=[O:63])[NH:46][C:45]1=[O:44])[C:59]2=[O:60]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of polymer-supported triphenylphosphine (1.46 g, 4.4 mmol) and 3,4-dichlorobenzyl alcohol (0.65 g, 3.6 mmol) was stirred in THF (10 mL) at 0° C. Keeping the reaction mixture at 0° C., a solution of diisopropylazodicarboxylate (0.87 mL, 4.4 mmol) in THF (2.1 mL) was added dropwise. 2-(2,6-Dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (1.00 g, 3.60 mmol) was then added as a solid, the reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was evaporated under vacuum and the residue was chromatographed using a methanol-CH2Cl2 gradient, eluting the product at 95:5 CH2Cl2-methanol. This material was dissolved in ethyl acetate (150 mL) and water (100 mL) was added. The organic phase was then washed with 10% dilute aqueous sodium carbonate (2×50 mL) and water (3×50 mL). The solvent was removed under vacuum and the resulting solid was triturated with ether, filtered and dried to provide the title compound as a white solid (0.41 g, 26% yield); mp 245-247° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.50 (99.78%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.45-2.62 (m, 2H), 2.82-2.96 (m, 1H), 5.12 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 5.38 (s, 2H), 7.49-7.51 (m, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.81-7.88 (m, 2H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 48.8, 68.5, 115.9, 116.8, 120.1, 127.3, 129.0, 130.5, 130.8, 131.2, 133.3, 137.1, 137.5, 155.1, 165.3, 166.8, 169.9, 172.8; Anal. Calcd for C20H14N2O5Cl2+0.3H2O: C, 54.76; H, 3.35; N, 6.39. Found: C, 54.48; H, 3.07; N, 6.29.
Reaction SMILES: N#N.[CH:3](O)=[O:4].CC(OC(C)=O)=O.[NH2:13][CH:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[C:20]([CH:14]([NH:13][CH:3]=[O:4])[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=CO
Agent: N#N
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Under a nitrogen atmosphere (N2), HCOOH (2.44 g, 53 mmol) was added to Ac2O (6.48 g, 63.6 mmol) at 0° C. After it was allowed to warm to ambient temperature the reaction was heated at 50° C. for 15 hr. It was allowed to cool to ambient temperature. This mixed acid anhydride was then added dropwise to a solution of ethyl 2-amino-2-cyanoacetate (128 mg, 1 mmol) in dry THF (5 mL) at 0° C. After the cooling bath was removed, the reaction was maintained at ambient temperature for additional 1 hr. The reaction mixture was concentrated and purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-cyano-2-formamidoacetate (110 mg, 70%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Sn](CCCC)(CCCC)CCCC)[CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:23]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:27]=[CH:26][N:25]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccccc2)ccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(-c3ccccc3)ccn2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.3 g, 1.21 mmol), 4-phenyl-2-(tributylstannyl)pyridine (0.591 g, 1.33 mmol), palladium tetrakistriphenylphosphine (0.140 g, 0.12 mmol) in toluene (2 mL) to give 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpyridin-2-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=367.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][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][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:29]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc([N+](=O)[O-])c1
Yield: 79.3 %

Procedure:
A mixture of 4.0 g (0.029 mol) of 3-nitrophenol, 10.5 g (0.032 mol) of 1-bromooctadecane and 6.0 g (0.043 mol) of anhydrous potassium carbonate in 75 ml of anhydrous DMF was stirred and heated at 75° for 23 hours. The solvent was removed at reduced pressure and water was added to the residue. The product was extracted with ether and the dried extract was concentrated at reduced pressure to a solid which was purified by HPLCusing 15% methylene chloride-hexane to give 9.0 g (80% yield) of 3-(octadecyloxy)nitrobenzene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[C:13](=O)(O)[O-].[Na+]>CO.S(Cl)(Cl)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 94 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (5.0 g, 30.8 mmol) in methanol (50 mL), thionyl chloride (15 mL) was added dropwise at 0° C. After the addition, the mixture was heated to reflux and maintained at the temperature for 1.5 hours. Then the reaction mixture was concentrated to give a residue. To the residue was added saturated sodium bicarbonate (50 mL), and then extracted with ethyl acetate (50 mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 1H-indazole-3-carboxylate as a white solid (5.1 g, 94%). 1H NMR (300 MHz, d6-DMSO): δ 13.91 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.44 (ddd, J=8.3 Hz, J=6.9 Hz, J=1.1 Hz, 1H), 7.30 (ddd, J=7.9 Hz, J=6.9 Hz, J=0.9 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:19]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@@H]1CCC(=O)N1C(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution of 21.9 g (0.1 mol) of benzyl (L)-pyroglutamate (prepared according to Example II(1)) in 150 ml of benzene is added over an hour to a suspension of 4.8 g (0.1 mol) of sodium hydride in 15 ml of dry benzene. The mixture is stirred for one hour at ordinary temperature and 14.1 g (0.1 mol) of benzoyl chloride diluted in benzene are then introduced. The reaction mixture is stirred for 4 hours at 55° C. and then for 18 hours at ordinary temperature. After the mixture has been washed with water, the solvent evaporated off and the residue taken up with ether, white crystals of melting point=101°/2° C. are obtained; yield=70%; Rf=0.68 (A).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[CH:16][CH:17]=[C:7]2[C:6]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]4[CH:15]=[CH:16][CH:17]=[C:7]4[C:6]3=[O:18])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=c1c2cccn2c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c2cccn2c2ccccc2n1CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 140 °C
Yield: 68.4 %

Procedure:
5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg; 0.38 mmol) was added to a 5 mL microwave vessel containing a magnetic stir bar. 4-(4-chlorophenyl)piperidine (82.8 mg; 0.42 mmol), potassium carbonate (78.77 mg; 0.57 mmol), and 2 mL of acetonitrile were added to the vessel. The vessel was sealed and heated to 140° C. for 1 hour, after which the solvent was evaporated and the reaction mixture was purified by flash chromatography to yield 5-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (110 mg; 0.26 mmol; 70%) [M+1]+=420.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:14][CH2:13]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1C1CCN(CCCN)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[1-(3-tert-butoxycarbonylamino-propyl)piperidin-4-yl]benzonitrile (0.73 g, 2.1 mmol) in ethyl acetate (100 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled vigorously for 5 minutes. The reaction mixture was stirred for 10 minutes at 0° C., purged with argon and concentrated. Flushing with ethyl acetate×2 and concentration gave 2-[1-(3-aminopropyl)-piperidin-4-yl]benzonitrile hydrochloride.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2ccccc2)ccn1
Yield: 97.9 %

Procedure:
Using the method of Example 3, Step A, phenol (494 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-phenoxypyridine (1.27 g, 98% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.45 (t, 2H), 7.29 (t, 1H), 7.09 (d, 2H), 6.77-6.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[F:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccnc(-c2ccc(F)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(F)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 18 h
Yield: 67.5 %

Procedure:
To a suspension of 2-fluoro-5-(4-methoxypyridin-2-yl)aniline (174 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (265 mg) and diisopropylethylamine (0.417 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (266 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (248 mg).
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:4][C:5]([O:7]CC)=[O:6])[O:2]1.O[Li].O.C1COCC1.Cl>O>[CH2:20]1[CH2:1][O:2][C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:4][C:5]([OH:7])=[O:6])[O:19]1
Reactant: CCCCCCCCCC1(CC(=O)OCC)OCCO1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC1(CC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a 25 mL flask were added ethyl 3,3-ethylenedioxydodecanoate (1.131 g, 3.95 mmol), LiOH.H2O (840 mg, 20 mmol), THF (5 mL), and water (5 mL). The mixture was stirred at room temperature overnight. The solution was acidified by the addition of 1 M HCl (50 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed once with brine. The organic phase was dried (MgSO4) and concentrated to give 3,3-ethylenedioxydodecanoic acid (0.824 g, 3.19 mmol) in 81% yield. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.20-1.44 (m, 14H), 1.72-1.80 (m, 2H), 2.72 (s, 2H), 3.98-4.10 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 13.9, 22.5, 23.3, 29.13, 29.35, 29.39, 29.50, 31.7, 37.5, 42.2, 64.9 (2 C), 109.2, 174.8.