Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:40][C:39]1[CH:38]=[CH:37][C:36]([C:33]2[N:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][N:34]=2)=[CH:43][CH:42]=1
Reactant: CCCCCc1cnc(-c2ccc(C=O)cc2)nc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1cnc(-c2ccc(C=C(Br)Br)cc2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
A solution of 5.44 g of tetrabromomethane in 80 ml of methylene chloride was placed at 0° C. under argon gasification in a sulphonation flask equipped with a mechanical stirrer and treated within 10 minutes with a solution of 8.6 g of triphenylphosphine in 20 ml of methylene chloride. After completion of the addition, the clear orange solution was stirred at 0° C. for a further 5 minutes and then a solution of 2.08 g of p-(5-pentyl-2-pyrimidinyl)benzaldehyde in 15 ml of methylene chloride was added dropwise within 5 minutes. The mixture was subsequently stirred at 0° C. for a further 30 minutes, then the flask content was poured into 700 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 200 ml of hexane, left to stand at 0° C. for 18 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.7 g) on silica gel with 3% ethyl acetate/petroleum ether gave 2.70 g (80%) of 2-[p-(2,2-dibromovinyl)phenyl]-5-pentylpyrimidine as colourless crystals (purity 94.5%); m.p. 74° C.
Reaction SMILES: O[CH:2]=[C:3]([C:8]1[N:9]([CH3:17])[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:22]>CO>[NH2:22]/[CH:2]=[C:3](/[C:8]1[N:9]([CH3:17])[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])\[C:4]([O:6][CH3:7])=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)/C(=C\N)c1c(C(=O)OC)ccn1C
Yield: 89.9 %

Procedure:
A solution of methyl 2-{2-hydroxy-1-[(methyloxy)carbonyl]ethenyl}-1-methyl-1H-pyrrole-3-carboxylate (65.2 g) and ammonium acetate (105 g) in methanol (800 ml) was heated at reflux for 7 hours. The reaction was cooled and the methanol removed. The residue was partitioned between ethyl acetate and water. Large amounts (>2 L) of ethyl acetate were used to dissolve the residue. The organic solution washed with water, dried (MgSO4) and the solvent removed to yield the title compound as a brown solid (58.4 g).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11].C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:12]1(/[CH:10]=[CH:11]/[C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCc1ccc(I)cc1
Reactant: C=CC1CCCCC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1ccc(/C=C/C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 23 h
Yield: 31.1 %

Procedure:
4-Iodobenzyl alcohol (2.34 g) was dissolved in DMF (40 mL), added with vinylcyclohexane (1.32 g), triethylamine (1.81 mL), and bis(triphenylphosphine)palladium (II) chloride (700 mg), and stirred for 23 hours at 80° C. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residues were purified by silica gel column chromatography (8 to 30% ethyl acetate/hexane) to obtain the title compound (672 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:15][CH:16]([OH:36])[CH2:17][N:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][CH:20]([OH:23])[CH2:21]Cl>C1(C)C(C)=CC=CC=1>[OH:36][CH:16]([CH2:17][N:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][CH:20]([OH:23])[CH2:21][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CC(O)CCl)CC(O)CCl
Reactant: CCCCCCCCCCCCN
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCNCC(O)CN(CCCCCCCCCCCC)CC(O)CNCCCCCCCCCCCC
Temperature: 80 °C
Yield: 49.4 %

Procedure:
A reactor was charged with 286.3 g (1.54 moles) of dodecylamine and 90 g of xylene, and the contents were heated to 80° C. To the contents, a solution with 57 g (0.15 mole) of N,N-bis(3-chloro-2-hydroxypropyl)dodecylamine dissolved in 50 g of xylene was added dropwise over 1.5 hours. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted dodecylamine was then distilled off at 100° C. and 0.5 mmHg. The residue was added with 500 ml of hexane and 2000 ml of acetone to be dissolved therein. The solution was then subjected to extraction and washing with a mixture of 500 ml of xylene and 500 ml of 5% aqueous sodium hydroxide. Thereafter, a xylene layer was taken out and concentrated, thereby obtaining 49.5 g (yield: 48%) of 15,19-dihydroxy-17-dodecyl-13,17,21-triazatritriacontane represented by the following formula. ##STR10##
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[Cl:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>>[Cl:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: Cc1cccc(N)c1Cl
Reactant: ClCC1=NCCN1
Agent: Cl
Product: Cc1cccc(NCC2=NCCN2)c1Cl

Procedure:
2-(2-Chloro-3-methylanilinomethyl)-2-imidazoline was prepared by the method described in Example 1, from 2-chloromethyl-2-imidazoline hydrochloride and 2-chloro-3-methyl aniline (m.p. 248°-249° C.).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.Cl[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>>[N+:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Product: O=[N+]([O-])c1ccsc1-c1ncco1

Procedure:
2-(3-nitrothiophen-2-yl)oxazole was prepared from 2-(tributylstannyl)oxazole (0.94 g, 2.62 mmol) and 2-chloro-3-nitrothiophene (0.429 g, 2.62 mmol) according to protocol E. Retention time (min)=1.794, method [1], MS (ESI) 197.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:28][CH:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Product: CC(C)(C)c1ccc(CCNC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1523 g, 0.52 mmol) and 2-(4-tert-butylphenyl)ethylamine (0.1210 g, 0.68 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 454 (M+H)+; (ESI−) m/z 452 (M−H)−; 1H NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 3.04 (t, J=7.0 Hz, 2H), 3.92 (q, J=6.6 Hz, 2H), 6.15 (s, 1H), 7.19 (m, 2H), 7.33 (dd,J=8.1, 4.7 Hz, 1H), 7.38 (m, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.86 (dd, J=8.1, 1.0 Hz, 1H), 8.03 (dd, J=8.1, 1.4 Hz, 1H), 8.33 (d, J=1.4 Hz, 1H), 8.62 (dd, J=4.6, 0.8 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[S:14]([N:13]1[CH:12]=[C:11]([CH2:25][NH:26][CH3:27])[CH:10]=[C:9]1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2c(F)cccc2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-1-[(2,6-difluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (213 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 160 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([C:30](O)=[O:31])[CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:22]1[CH:21]=[N:20][C:29]2[C:24]([CH:23]=1)=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cnc2ccccc2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cnc2ccccc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with quinoline-3-carboxylic acid. MS: 415.3 (M+H).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.38 mmol) (from Example 22 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11][CH2:12][CH3:13])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:12][CH3:13])=[O:19])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(Cl)cc(C)c1C#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)c1cc(Cl)cc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a stirred solution of 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (synthesized according to the method described in section a) of example 2) (1.00 g, 4.73 mmol) in dichloromethane (20 ml) is added meta-chloroperoxybenzoic acid (0.58 g, 2.36 mmol, 70% suspension) portion wise at 0° C. The resulting mixture is stirred at 0° C. for 15 min. The white suspension is dissolved in ethyl acetate (25 ml) and the solvent is distilled off. The residue is again diluted with ethyl acetate (15 ml) and washed with 10% sodium sulphite solution (3×15 ml), saturated sodium hydrogen sulfate solution (3×15 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 8% ethyl acetate/hexane) to yield 4-chloro-2-(ethylsulfinyl)-6-methyl-benzonitrile (0.4 g, 1.76 mmol, 37%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[NH:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:11]=1)C.IC.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[N:8]([CH3:36])[C:9]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(Cc1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)[nH]1)c1cccc(C)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C)c1cccc(C)c1
Temperature: 40 °C
Yield: 26.9 %

Procedure:
A solution of 3-(4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid ethyl ester (Example 30, step C; 50 mg, 0.11 mmol), iodomethane (17 mg, 0.12 mmol) and K2CO3 (79 mg, 0.55 mmol) in DMF (2.0 mL) was stirred and heated to 40° C. overnight. The solvent was removed under reduced pressure, and the crude residue was purified on silica gel (EtOAc/CH2Cl2) to give 3-(1-methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid methyl ester (13 mg, 26%). The methyl ester (18 mg, 0.042 mmol) was hydrolyzed using the conditions outlined in Example 30, step D to provide the title compound (12 mg, 69% yield). HPLC: Rt=2.64 (Method A). MS (ESI): mass calculated for C28H28N2O2, 424.22; m/z found, 425.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.23 (m, 4H), 7.21-7.04 (m, 6H), 6.98 (d, J=7.8 Hz, 2H), 4.38 (d, J=9.3 Hz, 1H), 3.54 (dd, J=16.1, 9.3 Hz, 1H), 3.22 (dd, J=16.1, 3.1 Hz, 1H), 3.17 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[N:15]=2)[C:10](=[O:44])[CH2:9]1)=O)(C)(C)C.Cl.O1CCO[CH2:48][CH2:47]1>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:6][CH2:47][CH3:48])[CH2:9][C:10]3=[O:44])[N:19]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)C(=O)C1
Reactant: C1COCCO1
Agent: Cl
Product: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)C(=O)C1

Procedure:
Treat 4-{4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-3-oxo-piperazine-1-carboxylic acid tert-butyl ester with HCl/dioxane (4M) using the procedure described in Example 1-J step 3 to afford the title piperazine-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([OH:16])=O.[N:17]1([C:23]([S:25][CH3:26])=[S:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([S:25][CH3:26])=[S:24])[CH2:18][CH2:19]1)=[O:16]
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(CC(=O)O)c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCN(C(=S)SC)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In 6.2 ml of methylene chloride were dissolved 310 mg (1.37 mmol.) of 2,3,4-trimethoxyphenylacetic acid and 289 mg (1.64 mmol.) of methyl 1-piperazinecarbodithioate. To the solution was added 395 mg (1.92 mmol.) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 1 hour. A precipitated solid was removed by filtration, and to the filtrate were added methylene chloride and 1-N hydrochloric acid. The organic solvent portion was taken out, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over a silica gel column. The obtained oil was crystallized from a mixture of ethanol and hexane, yielding 257 mg of the desired compound as a white crystalline product, m.p. 119°-120° C., yield 48.8%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].CC1C=CC([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=1)=[O:11]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccnc(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnc(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(2-methylpyridin-4-yl)benzoic acid. ESI-MS (m/z): 338 [M+1]+.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][C:5](O)=[O:6].N1C=CC=CC=1.S(Cl)([Cl:23])=O>CCOCC>[O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][C:5]([Cl:23])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC(=O)CCC(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC(=O)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 50 g 4-oxo-undecanoic acid (Synthesis, 1987, 408) in 350 ml of ether, 22.15 g pyridine was added in at 0° C. Then a solution of 32.72 g thionyl chloride in 50 ml of ether was added in at 0-5° C. and then the reaction mixture was stirred for 20 hours at room temperature. Then the reaction mixture was filtered and evaporated to dryness. The residue (53.83 g yellow oil) was not further purified.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:34])[NH:31]2)=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:34])[NH:31]2)=[CH:27][CH:26]=1
Reactant: Cc1cc2ccc(O)cc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)ncnc2cc1OCCCN1CCOCC1
Yield: 0.1 %

Procedure:
Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.47 mol), (prepared as described for the starting material in Example 1), was reacted with 6-hydroxy-2-methylindole (84 mg, 0.57 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-morpholinopropoxy)quinazoline (157 mg, 73%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Cl-:20].[Li+]>CN1CCCC1=O.O>[Cl:20][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reaction time: 10 h

Procedure:
4-Nitro-2,6-dimethylphenyl trifluoromethanesulfonate (4.06 kg, 13.6 mol) is dissolved in anhydrous N-methylpyrrolidinone (42 L) and to this solution is added anhydrous lithium chloride (900 g) all at once. The internal temperature is raised to 120° at which time the color changes to a dark golden brown. After 10 hours at this temperature the color of the solution is dark brown. The reaction is then cooled to 5° and diluted with cold water (5°, 21 L) at such a rate as to keep the temperature below 15°. Afte the addition is complete the mixture is stirred for 1 hour at 5°. The product is collected by filtration and washed with water (4×1 L). This dark brown solid is dissolved in t-butyl methyl ether (42 L) and stirred first with charcoal and then anhydrous magnesium sulfate (10 pounds). After filtration the solvents are removed in vacuo (40°, 3 Torr) to obtain tan solid which is dried in vacuo (25°, 3 Torr) for 2 days to obtain 4-chloro-3,5-dimethylnitrobenzene, m.p. 101°-105°.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]2[O:15][CH:3]12)=[N:10][O:11][N:12]=3.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]1[OH:15])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C2OC21
Reactant: C1CCNC1
Solvent: CCO
Product: CC1(C)Oc2cc3nonc3cc2C(N2CCCC2)C1O
Reaction time: 31 h
Yield: 60 %

Procedure:
A mixture of 150 mg (0.687 m mol) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 63 μl (0.756 m mol) of pyrrolidine and 2 ml of ethanol was refluxed with stirring for 31 hours. After the solvent was distilled off, the residue was subjected to a preparative silica gel thin layer chromatography using a developing solvent of ethyl acetate-methanol (1:1 (v/v)) to obtain 120 mg (yield: 60%) of the intended compound. A part of the obtained compound was dissolved in dry ether and added with HCl--EtOH to obtain hydrochloride of the intended compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][C:8]1[O:9][C:10]([C:14](=[O:17])[CH2:15][CH3:16])=[C:11]([CH3:13])[N:12]=1>>[CH3:7][C:8]1[O:9][C:10]([C:14]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:17])[CH2:15][CH3:16])=[C:11]([CH3:13])[N:12]=1
Reactant: Brc1ccsc1
Reactant: CCC(=O)c1oc(C)nc1C
Product: CCC(O)(c1ccsc1)c1oc(C)nc1C

Procedure:
Starting with 3-bromothiophene and 2,4-dimethyl-5-propionyloxazole and following the general method of Example 4 the title compound was prepared. Purification by preparative HPLC gave a white solid. M.p. 81°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3-chloro-4-fluoro phenyl isocyanate (0.045 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 52 as a colorless solid (0.067 g, 54%). LCMS m/z (%)=485 M+H+ (81Br 37Cl, 30), 483 M+H+ (81Br35Cl, 100), 481 M+H+ (79Br35Cl, 72), 1H NMR (400 MHz, CDCl3) δ: 7.7 (s, 1H), 7.4 (d, J=1.8 Hz, 1H), 7.3 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 7.1-6.8 (m, 3H), 4.2 (m, 1H), 3.8 (s, 3H), 1.5 (d, J=6.61 Hz, 3H), 1.3 (d, J=6.61 Hz, 31-1).