Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[C:10]=1[C:26]#[N:27].[CH3:28][N:29]([C@@H:37]([CH3:58])[C:38](=[O:57])[NH:39][C@H:40]1[C:46]2([CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[O:45][C:44]2[CH:52]=[CH:53][CH:54]=[CH:55][C:43]=2[NH:42][C:41]1=[O:56])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.[NH4+].[Cl-]>[C:26]([C:10]1[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[C:12]2[C:17]([C:9]=1[CH2:8][N:42]1[C:41](=[O:56])[C@@H:40]([NH:39][C:38](=[O:57])[C@@H:37]([N:29]([CH3:28])[C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH3:58])[C:46]3([CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[O:45][C:44]3[CH:52]=[CH:53][CH:54]=[CH:55][C:43]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:27]
Reactant: N#Cc1ccccc1-n1c(C#N)c(CBr)c2ccccc21
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)c2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 96.3 %

Procedure:
Cs2CO3 (9.58 g, 29.4 mmol, Eq: 1.5) was added to a mixture of 3-(bromomethyl)-1-(2-cyanophenyl)-1H-indole-2-carbonitrile (9.89 g, 29.4 mmol, Eq: 1.5) and tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)propan-2-yl)carbamate (8.5 g, 19.6 mmol, Eq: 1.00) in DMF (20 mL) and the mixture heated to 70° C. for 1 h. The mixture was cooled, diluted with sat. NH4Cl and extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated to give a material that was purified by silica gel chromatography to afford tert-butyl (S)-1-((S)-5-((2-cyano-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (13 g, 96.3%) as a light yellow solid.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[N:42]=[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([C:52]([O:54]C)=[O:53])[CH:45]=3)[C:40]([F:56])=[CH:39][N:38]=2)=[CH:32][C:31]=1[C:57]([O:59]C)=[O:58].[OH-].[Na+]>>[C:57]([C:31]1[CH:32]=[C:33]([NH:36][C:37]2[N:42]=[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([C:52]([OH:54])=[O:53])[CH:45]=3)[C:40]([F:56])=[CH:39][N:38]=2)[CH:34]=[CH:35][C:30]=1[O:29][CH3:28])([OH:59])=[O:58]
Reactant: COC(=O)c1cc(Nc2ncc(F)c(Nc3ccc(OC)c(C(=O)OC)c3)n2)ccc1OC
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(C(=O)O)c3)n2)cc1C(=O)O
Yield: 103.8 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (80 mg, 0.18 mmol) and NaOH (200 mg, 5 mmol) gave N2,N4-bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (80 mg). 1H NMR (DMSO-d6): δ 3.75 (s, 3H), 3.80 (s, 3H), 6.94 (d, J=9.6 Hz, 1H), 7.05 (d, J=9.3 Hz, 1H), 7.78–7.80 (m, 3H), 7.94 (dd, J=9.3 Hz, 1H), 8.04 (d, J=3.6 Hz, 1H), 9.10 (s, 1H, NH), 9.30 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −165.56; LCMS: ret. time: 14.65 min.; purity: 100%; MS (m/e): 428.83 (MH+).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([Br:18])=[CH:13][C:14]=1[N+:15]([O-])=O)=[O:9]>CO>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([Br:18])=[CH:13][C:14]=1[NH2:15])=[O:9]
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1sc(Br)cc1N
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Tin(II) chloride dihydrate (74.8 g) was added in portions to a solution of 5-bromo-3-nitrothiophene-2-carboxylic acid methyl ester (21.0 g) in methanol (1 L), and the mixture was stirred at 65° C. for 30 min. The mixture was concentrated and 500 mL of ethyl acetate and 700 mL of Rochelle's salt solution were added to the residue. The mixture was vigorously stirred for 1 h. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 236.09 (C6H6BrNO2S) was obtained in this way; MS (ESI): 236 (M+H+).
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:20][C@H:19]2[NH:29][C:30](=O)[O:31]C(C)(C)C)=[O:16])=[N:11][CH:12]=1.Cl.[CH3:39][N:40]1[CH2:45][CH2:44][C:43]2[N:46]=[C:47](C(O)=O)[S:48][C:42]=2[CH2:41]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.O.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH2:20][C@H:19]2[NH:29][C:30]([C:47]2[S:48][C:42]3[CH2:41][N:40]([CH3:39])[CH2:45][CH2:44][C:43]=3[N:46]=2)=[O:31])=[O:16])=[N:11][CH:12]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)O)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)sc2C1
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (1) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (103.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11])[CH3:23]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(Br)cc1C
Temperature: 25 °C

Procedure:
25.3 g of 4-bromo-2-methyl benzoic acid and 5 mL of concentrated sulfuric acid were added to 425 mL of ethanol. The mixture was heated at reflux temperature for 3 days. The solution was cooled to room temperature, adjusted to neutral pH with the addition of sodium bicarbonate, and concentrated to ca. 100 mL volume under reduced pressure. The reduced mixture was partitioned between ethyl acetate and water, and the organic phase was successively washed with saturated bicarbonate and brine solutions. The organic fraction was dried over anhydrous sodium sulfate, and concentrated to 28.2 g of a clear liquid product; 1H NMR (200 MHz, CDCl3) δ 7.78-7.73 (d, J=8.2 Hz, 1H), 7.38-7.32 (m, 2H), 4.40-4.28 (q, J=7 Hz, 2H), 2.57 (s, 3H), 1.42-1.35 (t, J=7 Hz, 3H).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:50][NH:51][O:52][CH3:53]>C(Cl)Cl>[CH3:53][O:52][N:51]([CH3:50])[C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3×120 mL), H2O (3×120 mL), saturated NaHCO3 aqueous solution (3×120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 27 as a white solid (20 g, 80%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23]Br>>[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(F)ccc2F)c(=O)[nH]c1=O
Yield: 42.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (170 mg, yield: 42.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][C:28]1([C:31]#[N:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:23](=[O:25])[NH:27][C:28]2([C:31]#[N:32])[CH2:30][CH2:29]2)[CH2:10]1)(=[O:14])=[O:15]
Reactant: N#CC1(N)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
The carboxylic acid 5A (195 mg, 0.5 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (65.2 mg, 550 μmol), HATU (380 mg, 1.00 mmol) and ethyldiisopropyl amine (262 μL, 1.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature over night. The reaction was concentrated under reduced pressure. The residue was diluted with 5% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with 1M aqueous hydrogen chloride solution and with saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (2S,4R)-tert-butyl 4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)-pyrrolidine-1-carboxylate 6H as a yellow oil (66%). MS ISP (m/e): 354.2 (100) [(M−BOC+H)]+, 398.1 (25) [(M-Isobutylene+H)]+, 454.1 (12) [(M+H)]+.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])[N:3]=[CH:4][CH:5]=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.N1NN=CC=1.[Cl:42]C1C=CC(I)=C(C=1)C(O)=O>>[Cl:42][C:12]1[CH:13]=[CH:14][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: c1cn[nH]n1
Product: O=C(O)c1cc(Cl)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 1.0 g, 10.86 mmol) and 5-chloro-2-iodobenzoic acid (CAS number 13421-00-6; 2.00 g, 7.24 mmol). The crude solid was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; also commercially available CAS number 1293284-54-4). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) to afford 5-chloro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 38b).
Reaction SMILES: Cl[Si](Cl)(C)C.[I:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=1.CN(C)[C:19](=[O:21])[CH3:20].C(Cl)(=O)C>ClCCCl.ClC(Cl)C.[Zn].O>[I:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:19](=[O:21])[CH3:20])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(=O)N(C)C
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)Cl
Product: CC(=O)Sc1ccc(I)cc1
Temperature: 50 °C
Yield: 85.6 %

Procedure:
Following a general procedure (Uchiro and Kobayashi (1999) Tetrahedron Lett., 40: 3179-3182), to a stirred suspension of zinc powder (3.80 g, 58.0 mmol) and dichlorodimethylsilane (7.00 mL, 58.0 mmol) in 1,2-dichloroethane (126 mL) was added a solution of 4-iodobenzenesulfonyl chloride (5.00 g, 16.5 mmol) and N,N-dimethylacetamide (4.60 mL, 50.0 mmol) in dichloroethane (126 mL). The mixture was stirred at 75° C. for 2 h until the zinc powder was no longer visible. The reaction mixture was cooled to 50° C. and acetyl chloride (1.53 mL, 21.5 mmol) was added. After 15 min the mixture was poured into water. The water layer was extracted with CH2Cl2 and the combined organic layers were dried (Na2SO4), filtered and evaporated. The colorless oil thus obtained was chromatographed (silica, CH2Cl2/hexanes, 1:4) affording a colorless oil (3.93 g, 85.0%) which solidified at −20° C. mp 56-57° C. (lit. 54-55° C.)43; 1H NMR δ 2.42 (s, 3H), 7.12, 7.73 (AA′BB′, 2×2H); 13C NMR δ 31.0, 96.7, 128.4, 136.7, 139.0, 193.9; Anal. Calcd. for C8H7IOS: C, 34.55; H, 2.54; I, 45.63; S, 11.53. Found: C, 34.69; H, 2.59; I, 45.52; S, 11.59.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO.[Li+].[OH-].Cl>C1COCC1>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)=[CH:14][CH:15]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)c1coc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(C(=O)O)co2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of methyl 2-[4-(N-Boc-aminomethyl)-phenyl]-oxazol-4-ylcarboxylate (1.66 g, 5 mmol) in THF (25 ml)/methanol (25 ml) was added 1M aqueous LiOH (25 ml, 25 mmol). After stirring at room temperature for 3 h, the solution was acidified with 2M aqueous HCl to pH 5-6, and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layer was washed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo giving the title compound as a white solid (1.58 g, 4.96 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([O:36][CH3:37])[CH:29]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151.) as a brown solid. MS 498 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:34][C:10]2([CH2:15][N:14]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)[C:18]([C:19]#[N:20])=[C:13]3[NH:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:39]>>[CH2:1]([N:8]1[CH2:9][C:10]2([CH2:15][N:14]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:23][CH:22]=4)[C:18]([C:19]([NH2:20])=[O:39])=[C:13]3[NH:12][CH2:11]2)[CH2:34]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2

Procedure:
The desired product was prepared from 1-benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrile using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 465.9.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[CH3:26])[CH:6]=[C:5]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:4]=1>O1CCOCC1.CO>[ClH:1].[CH3:26][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[C:7]1[CH:6]=[C:5]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[N:4]=[C:3]([NH2:2])[N:8]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.[ClH:1]
Reactant: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.0 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.19 g, 0.43 mmol) in methanol (1 mL). The reaction mixture was stirred at r.t. for 30 min The volatiles were removed under reduced pressure to afford the desired product as an HCl salt. Analytic LCMS (M+H)+: m/z=339.2.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[Cl:31]C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1.NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([Cl:31])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, 12-chloro-6-chrysenecarbaldehyde (4A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate.1/3H2O mp 233°-233.5° (dec), (EtOH/Et2O), (C, H, Cl, N, S).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.Cl.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Agent: Cl
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 85.6 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(5-trifluoromethylpyridin-2-yl)piperazine dihydrochloride (319 mg) and by the reaction and treatment in the same manner as in Example 94, the title compound (408 mg) was obtained.
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Cl-:14]>C(Cl)(Cl)Cl>[Cl:14][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1[nH]c2ccccc2cc1CO
Reactant: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccccc2cc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 Grams of 3-hydroxymethylcarbostyril was suspended in 100 ml of chloroform, then a solution containing 2 g of thinyl chloride in 20 ml of chloroform was added dropwise thereto at a room temperature with stirring condition. The reaction mixture was further sitrred at a room temperature for 1 hour. The reaction mixture was concentrated under a reduced pressure, and the residue obtained was recrystallized from methanol to obtain 2.9 g of 3-chloromethylcarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.Cl[C:32]1N=C(N2C3C(=CC=CC=3)CCC2)C=CN=1>>[N:16]1([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:28]([CH3:29])[CH3:30])=[CH:26][CH:25]=3)[N:15]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:32][CH2:18][CH2:17]1
Reactant: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Reactant: Clc1nccc(N2CCCc3ccccc32)n1
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCCc4ccccc43)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1) and 2-chloro-4-(1,2,3,4-tetrahydroquinolin-1-yl)pyrimidine (Method 8), the product was obtained. NMR: 1.8-2.0 (m, 2H), 2.19 (s, 6H), 2.2-2.3 (m, 1H), 2.3-2.45 (m, 1H), 2.7-2.8 (m, 2H), 3.7-3.9 (m, 5H), 5.7 (m, 1H), 6.35 (m, 2H), 6.8 (m, 2H), 7.0-7.05 (m, 1H), 7.1-7.2 (m, 2H), 7.35-7.4 (m, 1H), 7.5-7.6 (m, 2H), 7.9-8.0 (m, 2H), 8.95 (s, 1H); MS (MH+): 420.5.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[N:8]=2)[S:5][CH:6]=1
Reactant: Cc1csc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1csc(-c2nc(=O)c3ccccc3s2)n1
Yield: 48.9 %

Procedure:
4-Methyl-1,3-thiazole-2-carbonitrile (0.27 g, 2.2 mmol) and methyl thiosalicylate (0.75 g, 4.4 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.28 g, 49%) as yellow crystals.