Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14](OC3C=CC([N+]([O-])=O)=CC=3)=[O:15])[C:12]([O:26][CH3:27])=[N:11][C:10]([CH3:28])=[C:9]2[C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CO.C(Cl)Cl>[C:46]([O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][NH:39][C:14]([N:13]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:29]([O:31][CH3:32])=[O:30])=[C:10]([CH3:28])[N:11]=[C:12]1[O:26][CH3:27])=[O:15])([CH3:49])([CH3:47])[CH3:48]
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)NCCCC(=O)OC(C)(C)C)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99460.8 %

Procedure:
To a solution of 5-methyl 1-(4-nitrophenyl) 6-(4-fluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate (88.7 mg, 0.200 mmol) and K2CO3 (41.5 mg, 0.300 mmol) in CH3OH/CH2Cl2 (0.1/2.0 mL) was added tert-butyl 4-aminobutanoate (31.8 mg, 0.200 mmol). After stirring at rt for 1 h, the mixture was washed with saturated Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% 2 M NH3/MeOH in 50% EtOAc/Hexanes) to afford the product (92.2 g, 99%). mp 135-138° C.; 1H NMR (CD3OD) δ 7.29-7.23 (m, 2H), 6.97-6.88 (m, 2H), 6.65 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 3.38-3.30 (m, 2H), 2.43 (s, 3H), 2.28 (t, 2H, J=7.2 Hz), 1.89-1.78 (m, 2H), 1.43 (s, 9H); ESMS m/e: 464.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:22]=[C:23]=[O:24].N[C:26]1[C:31]2[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=2[CH:29]=[CH:28][CH:27]=1>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([NH:22][C:26]2[C:31]3[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=3[CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(Cl)cc2)N1
Temperature: 80 °C
Yield: 68 %

Procedure:
Commercially available p-chlorobenzylamine (0.98 ml, 8 mmol) was dissolved in 40 ml of AcOEt and at 0° C. triphosgene (2.37 g, 1 equiv.) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 20 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1f (1.42 g, 7.11 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleum ether 1). The solvent was evaporated and to the crude 5% HCl was added. The solid was filtrated, washed with water, MeOH and diethyl ether obtaining 1.6 g of a white product. Yield=68% 1HNMR (DMSO, 200 MHz) δ 4.27 (2H, d, J=5.6 Hz), 4.61 (2H, s), 6.47 (1H, dd, J=7.8 Hz, J′=1.2 Hz), 6.81 (1H, t, J=8.2 Hz), 7.35 (5H, m), 7.73 (1H, dd, J=8.2 Hz, J′=1.2 Hz), 8.10 (1H, bs), 10.65 (1H, bs); [M+1] 332.4 (C16H14ClN3O3 requires 331.75).
Reaction SMILES: [Sn](Cl)Cl.[F:4][C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]([C:11]#N)=[N:9][CH:10]=1.Cl.S(Cl)(Cl)=[O:18].C[CH2:22][OH:23]>>[NH2:13][C:7]1[C:8]([C:11]([O:23][CH3:22])=[O:18])=[N:9][CH:10]=[C:5]([F:4])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ncc(F)cc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Agent: Cl[Sn]Cl
Product: COC(=O)c1ncc(F)cc1N
Temperature: 90 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Tin dichloride (45 g, 230 mmol) was added to a solution of 5-fluoro-3-nitropyridine-2-carbonitrile (Ark Pharm, 7.2 g, 43 mmol) in EtOH (80 mL). The mixture was stirred at 90° C. for 2 h, and then concentrated under reduced pressure. Aq. HCl (10 M; 40 mL, 400 mmol) was then added and the mixture was heated under reflux for 6 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue was dissolved in MeOH (120 mL). Thionyl chloride (7.2 mL, 99 mmol) was added. The solution was then stirred at 90° C. for 24 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (300 mL), washed with a saturated aq. NaHCO3 (300 mL) and brine (200 mL), dried over Na2SO4 and concentrated again under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound (4.6 g, 63%). LCMS calc. for C7H8FN2O2 (M+H)+: m/z=171.0. found 171.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20](Cl)[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[CH3:33][CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:35]4[CH2:36][CH2:37][CH2:38][CH:34]4[CH3:33])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CC1CCCN1
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)CC2)c(Cl)c1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1

Procedure:
Heat a mixture of 5-chloro-6-{4-[2-chloro-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (1.19 g, 0.0025 mol) and 2-methylpyrrolidine (2.5 mL, 0.025 mol) in DMA at 120° C. for 14 h. Partition the reaction mixture between EtOAc and water. Wash the organic layer with water (1×) and brine (1×), then dry (Na2SO4) and concentrate under reduced pressure. Filter the crude product through a silica gel pad (2 inches deep×3 inches in diameter) eluting with 700 mL of 30% EtOAc/bexanes. Concentrate under reduced pressure to give the title compound as an off-white foam.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c(Br)cccc12
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
To a stirred suspension of 1-naphthoic acid (90 g, 0.52 mol) in glacial acetic acid at 100° C. was added bromine (84 g, 0.52 mol). The reaction was stirred at this temperature for 1.5 hours and then allowed to cool overnight. The resulting slurry was diluted with glacial acetic acid, the solid collected by filtration, resuspended in water, filtered and dried in vacuo to give 5-bromo-1-napthoic acid (100 g). The acid was converted to the title compound using a similar procedure to Description 3 (68%).
Reaction SMILES: C(S[C:9]1[N:14]=[N:13][C:12]2[CH2:15][CH2:16][N:17]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][C:11]=2[CH:10]=1)C1C=CC=CC=1.O.[NH2:28][NH2:29]>C(O)C>[C:19]([N:17]1[CH2:16][CH2:15][C:12]2[N:13]=[N:14][C:9]([NH:28][NH2:29])=[CH:10][C:11]=2[CH2:18]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(SCc3ccccc3)cc2C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 4.0 g of 3-benzylmercapto-6-benzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 1.5 g of hydrazine hydrate in 10 cc of 95% ethanol is heated in an autoclave at a bath temperature of 150° for 16 hours. The oil obtained after concentrating the reaction mixture in a vacuum, is divided between chloroform and a small amount of water, and the organic phase is concentrated to a red oil. The title compound is obtained by crystallization from dimethyl formamide. M.P. 220°-223° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[CH:3]=1.C([O-])(=O)/C=C\C([O-])=O.[Cl:32]C1C=CC2OC3C=CC=CC=3C(=O)CC=2C=1.CN1CCNCC1>>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(Cl)ccc2Oc2ccccc21
Reactant: CN1CCN(C2=Cc3cc(Cl)ccc3Oc3ccccc32)CC1
Agent: CN1CCNCC1
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: CN1CCN(C2Cc3cc(Cl)ccc3Oc3ccccc32)CC1
Product: Cl

Procedure:
The 1-[2-chloro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine having a melting point of 119°-120° C. [maleate: melting point 200°-202° C (with decomposition)] used as the starting material can be prepared in analogous manner to that described in Example 14 from 2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-one and 1-methyl-piperazine.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:52][NH2:53]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:53][N:52]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccccc1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccccc3)n2)ccc1-n1cnc(Cl)c1

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (0.500 g, 1.18 mmol), from preparation A) and 6-chloro-2-phenylhexanoic acid (0.294 g, 1.30 mmol, from preparation AAO) were coupled [N-methylmorpholine (0.647 mL, 5.89 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.148 mL, 4.71 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-phenylpentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 471.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[Br:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Yield: 39 %

Procedure:
The reaction mixture of 5-(2-benzyloxy-5-nitro-phenyl)-4-bromo-1-methyl-1H-pyrazole was reduced in the presence of SnCl2.2H2O, in a similar manner as described in Example 1.1, providing 4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.079 g, 0.22 mmol, 39% for three steps). LCMS m/z (%)=358 (M+H79Br, 98), 360 (M+H51Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.45 (s, 1H), 7.15-7.26 (m, 3H), 7.10 (d, J=6.6 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.66 (dd, J=2.8, 8.6 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 4.83 (AB quartet, J=12.0, 17.2 Hz, 2H), 3.62 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@:3]1([CH3:10])[C:7]([OH:9])=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:7]([C@:3]2([CH3:10])[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:9])=[N:16][CH:17]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN1CCC[C@@]1(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC[C@@]1(C)C(=O)NNc1ccc(F)cn1
Yield: 69 %

Procedure:
To a suspension of (S)-1,2-dimethyl-pyrrolidine-2-carboxylic acid (660 mg, 4.61 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (488 mg, 3.84 mmol) and Et3N (1.1 mL, 7.7 mmol) in DCM (20 mL) were added HOBt.H2O (51 mg, 0.38 mmol) and EDCI.HCl (884 mg, 4.61 mmol) and the mixture stirred at RT overnight. The mixture was partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. FCC, using 0-10% MeOH in DCM, gave the title compound as a brown solid (668 mg, 69%). LCMS (Method 4): Rt 0.40, m/z 253 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: BrCCc1ccc(Br)cc1
Reactant: CCc1ccncc1
Product: CC(CCc1ccc(Br)cc1)c1ccncc1
Yield: 40.5 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.47 g (9.35 mmol) of 4-bromophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.10 g of the desired compound (yield: 40.7%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH2:15](Br)[C:16]#[CH:17].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:17][C:16]#[CH:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CONC(=O)c1ccc(Cl)cc1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(OC)C(=O)c1ccc(Cl)cc1
Yield: 36.5 %

Procedure:
0.22 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 1.0 g of N-methoxy-p-chlorobenzamide and 0.68 g of propargyl bromide were added thereto in this order while being cooled with ice. The mixture was heat-refluxed for 8 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.44 g of N-methoxy-N-propargyl-p-chlorobenzamide.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])=[CH2:24]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (1.5 g, 3.64 mmol) and O-(2-vinyloxyethyl)hydroxylamine (749 mg, 7.28 mmol) in THF (30 mL) at 0° C. was added lithium bis(trimethylsilyl)amide as a solution in THF (18 mL, 1 M, 18 mmol) over 5 minutes. The reaction mixture was stirred at ˜0° C. for 1 hour before being quenched with saturated aqueous ammonium chloride. Volatile solvents were removed in vacuo and then diethyl ether (10 mL) and ethyl acetate (20 mL) added. The resultant mixture was sonicated causing a precipitate to form which was filtered off to give the title compound as a yellow solid (1.07 g, 61%). LCMS (Method B): RT=2.79 min, M+H+=483.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9]O)C.[C:15](=O)(O)[O-].[Na+]>O>[C:1]([O:5][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:8]([CH3:6])[CH3:9])(=[O:4])[CH2:2][SH:3]
Reactant: O=C(O)CS
Reactant: O=C([O-])O
Reactant: CCCCC(CC)CO
Agent: [Na+]
Solvent: O
Product: CC(C)CCCCCOC(=O)CS
Yield: 82 %

Procedure:
A mixture of 2.5 g of Amberlyst A-15, 71.0 g (0.763 mol) of thioglycolic acid and 109.8 g (0.843 mol) of 2-ethylhexanol is heated as described in Example 1, using a water separator, until no further water passes over. The residue is neutralized with 15 ml of a 10% sodium bicarbonate solution at 25° C. and washed with 15 ml of a 3% sodium chloride solution. After the aqueous phase (31.9 g of wash water polluted with thioglycolic acid) has been removed, the residue is distilled under reduced pressure (8.5 mbar) at an overhead temperature of 105° C. 129.5 g (82%) of the product are obtained with first runnings of 16.1 g and a residue of 4.9 g.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCOCC1>[O:1]([CH2:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: c1ccc(OCCCN2CCNCC2)cc1
Yield: 97 %

Procedure:
15.1 g of phenoxypropyl bromide and 60 g of piperazine were dissolved in 150 ml of dioxane, and the solution was heated at 80°-90° C. for 1 hour. The precipitated crystals were removed by filtration, and the filtrate was then concentrated. Afterward, the resultant residue was dissolved in chloroform and then washed with water. Chloroform was distilled off to obtain 15 g of 1-(3-phenoxypropyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])=O)[CH3:11].[CH2:23]([O:25][C:26](=[O:31])/[CH:27]=[C:28](\[NH2:30])/[CH3:29])[CH3:24]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:31])=[C:28]([CH3:29])[NH:30][C:15]=1[CH2:17][O:18][C:19](=[O:21])[CH3:20])=[O:22])[CH3:11]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1cccc(Cl)c1

Procedure:
7 g of 3-chlorobenzaldehyde, 9.4 g of γ-acetoxyacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol are heated under reflux for 20 hours, the mixture is cooled and the precipitate is filtered off.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][CH:12]([CH3:23])[CH2:13][C:14]1([C:20]([CH3:22])=[CH2:21])[CH2:18][CH2:17][NH:16][C:15]1=[O:19].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH3:11][CH:12]([CH3:23])[CH2:13][C:14]1([C:20]([CH3:22])=[CH2:21])[CH2:18][CH2:17][N:16]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]1=[O:19]
Reactant: C=C(C)C1(CC(C)C)CCNC1=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C1(CC(C)C)CCN(CC(=O)OCC)C1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 91 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide (0.5M in toluene, 16.4 mL, 8.19 mmol) is cooled to 0° C., and a solution of 3-(2-methylpropyl)-3-(propen-2-yl)-2-pyrrolidinone (1.24 g, 6.82 mmol) in THF (10 mL) is added dropwise over 2 minutes After stirring at 0° C. for 40 minutes, ethyl bromoacetate (0.91 mL, 8.2 mmol) is added. The reaction is stirred at 0° C. for 3 hours and for 1 hour at room temperature. After quenching with saturated aqueous ammonium chloride (10 mL), aqueous workup (EtOAc, MgSO4) and purification by column chromatography (1:9:10 v/v CH2Cl2 :EtOAc:hexane) provided 1.66 g (91%) of the title compound as an oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=CC=CC=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.Cl>CCOCC.C1C=CC=CC=1>[C:5]1([C:9]2[CH:18]=[C:17]([CH:16]=[CH:11][CH:10]=2)[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([OH:24])=[O:29])=[O:23])[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Brc1cccc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Under an argon atmosphere, 132 g of magnesium were dispersed in 500 mL of ether. A solution of 142 g of 2-(3-bromophenyl) naphthalene in 500 mL of ether was added to the dispersion, and then the mixture was stirred at room temperature for 1 hour. A solution of 74 g of phthalic anhydride in 150 mL of benzene was added to the mixture, and then the resultant reaction solution was stirred for 3 hours under reflux. After having been cooled to room temperature, the reaction solution was poured into ice water, and then 1 L of 10% hydrochloric acid was added to the mixture. The organic layer was separated and extracted with an aqueous solution of potassium carbonate. The alkaline extract was acidified, and then the resultant solid was washed with boiling water. The resultant crude product was recrystallized with acetic acid. Thus, 121 g of 2-(3-phenylbenzoyl)benzoic acid were obtained (in 69% yield).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C(N(CC)C(C)C)(C)C.Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18]>O1CCCC1>[Cl:22][CH:20]([O:19][C:17]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:18])[CH3:21]
Reactant: COC(=O)CO
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)COC(=O)OC(C)Cl
Reaction time: 3 h

Procedure:
To an ice-water bath cooled solution of methyl glycolate (13.5 mL) and N,N-diisopropylethylamine (30.46 mL) in tetrahydrofuran (180 mL) was added dropwise with stirring 25.0 g of 1-chloroethyl chloroformate. The 0° C. bath was removed, and the mixture stirred for an additional 3 hr. After filtration to remove insoluble amine hydrochloride, the THF solution was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, dried over anh. sodium sulfate, and evaporated under reduced pressure to give 31.1 g of reddish oil. NMR.
Reaction SMILES: OCC1(CN[C:10]([C:12]2[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=3)=[O:11])CCCC1.C(C1C=C2C(=CC=1)N(CC1C=CC=C(OC(F)(F)F)C=1)C(C(O)=O)=C2)#N.Cl.[CH2:62]([O:64][C:65](=[O:70])[CH:66]([CH3:69])[CH2:67][NH2:68])[CH3:63]>>[CH2:62]([O:64][C:65](=[O:70])[CH:66]([CH3:69])[CH2:67][NH:68][C:10]([C:12]1[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:32])[F:33])[CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2)=[O:11])[CH3:63]
Reactant: CCOC(=O)C(C)CN
Reactant: N#Cc1ccc2c(c1)cc(C(=O)NCC1(CO)CCCC1)n2Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CCOC(=O)C(C)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1
Yield: 51 %

Procedure:
3-{[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methyl-propionic acid ethyl ester was prepared in the same manner as 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1-hydroxymethyl-cyclopentylmethyl)amide from 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (300 mg, 83.3 mmol) and 3-aminoisobutyric acid ethyl ester, hydrochloride (168 mg, 0.10 mmol) giving 3-{[5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methylpropionic acid ethyl ester (204 mg, 51%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:13]([OH:19])(=[O:18])[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:15]([C:14]([C:13]([OH:19])=[O:18])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:17])=[O:16]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C(=Cc1ccc(-c2cccs2)s1)C(=O)O
Yield: 100.4 %

Procedure:
3.9 g of 5-formyl-2,2'-bithiophene, 4.2 g of malonic acid, 10 ml of pyridine and 2.5 ml of piperidine were heated at 60° C. for 2 hours. After cooling, 50 ml of water was added into the mixture and acidified by diluted HCl. The crude product collected was recrystallized from ethanol to give a crystal product (5.65 g). The melting point of the product was 220°-221° C. The yield was 86%.