Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8](C)[CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23]C(C)(C)C(C)(C)[O:20]1)[C:10]([O:12]CC)=[O:11])=O)(C)(C)C>Cl>[B:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH:9]([NH:8][CH3:6])[C:10]([OH:12])=[O:11])([OH:23])[OH:20]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Product: CNC(CCCCB(O)O)C(=O)O
Yield: 85.9 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonyl(methyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg) in aq 6 M HCl was heated to reflux for 16 h, concentrated to dryness and purified by preparative HPLC. The residue was redissolved in 2 N HCl and evaporated to give 6-borono-2-(methylamino)hexanoic acid as a white solid (24 mg, 72%). 1H NMR (CD3OD, 300 MHz) δ 3.94 (t, J=5.9 Hz), 2.72 (s, 3H), 1.45-1.34 (m, 4H), 0.81 (t, J=7.0 Hz, 2H). ESI MS found for C7H16B1N1O4 m/z [190.0 (M+1)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][C@@H:18]([CH3:20])[O:17][C@@H:16]([CH3:21])[CH2:15]2)[N:11]=[C:10]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=3[N:24]=[C:23]2[CH:33]([F:35])[F:34])[N:9]=1>O>[F:34][CH:33]([F:35])[C:23]1[N:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][C@@H:18]([CH3:20])[O:17][C@@H:16]([CH3:21])[CH2:15]3)[CH:13]=[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:9]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=2[N:24]=1
Reactant: C1COCCN1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2C[C@@H](C)O[C@@H](C)C2)n1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Morpholine (275 ml, 3.15 mol) was added to 4-chloro-2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-6-(cis-2,6-dimethylmorpholino)pyrimidine (14.4 g, 34 mmol) thus obtained, and stirred at room temperature for 30 minutes and further at 80° C. for 30 minutes. Water was added to the reaction solution, and the precipitated crystals were filtered, and washed well successively with hexane, ether and ethyl acetate, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-4-(cis-2,6-dimethylmorpholino)-6-morpholinopyrimidine (13.7 g, yield 86%).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14]=[O:15])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:23]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([OH:23])=[O:15])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCC#CC=O)ccc(C(C)=O)c1O
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC#CC(=O)O)ccc(C(C)=O)c1O
Yield: 40 %

Procedure:
To 0.58 g of chromium trioxide in 8 ml of 10N sulfuric acid cooled at 0° was added a solution of 1.51 g of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hexynal in 15 ml of acetone over 30 minutes with stirring. The reaction mixture was allowed to warm to 25° over 30 minutes and then concentrated in vacuo to remove the acetone. Water (50 ml) was added and the product was extracted with ether. The ether phase was extracted with 1.0N sodium hydroxide, the aqueous layer was separated, acidified and extracted with ether. The dried (over sodium sulfate) extract was concentrated in vacuo to a solid which was crystallized twice from ether-hexane to give 0.63 g, mp 115-116°, (40% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hexynoic acid, the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]2[CH2:27][CH2:28][O:29][C:30](=[O:33])[N:31]([CH3:32])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:34][CH3:35]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]3[CH2:27][CH2:28][O:29][C:30](=[O:33])[N:31]([CH3:32])[C:25]=3[CH:24]=[CH:23][C:22]=2[O:34][CH3:35])=[N:3][CH:4]=1
Reactant: COc1ccc2c(c1N)CCOC(=O)N2C
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2CCOC(=O)N3C)ncc1Cl
Yield: 4 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 1-Amino-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product was isolated as a light yellow solid (4.0 mg, 4%). mp: 160° C. followed by solidification and melt at 250 and discoloration, MS (ESI+): 483 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.21 (s, 1H), 8.35 (br s, 1H), 8.06 (s, 1H), 7.44 (d, J=8 Hz, 1H), 7.20 (br s, 1H), 7.12 (d, J=8 Hz, 1H), 7.01 (t, 1H), 6.98 (d, J=7 Hz, 1H), 6.40 (s, 1H), 6.21 (br s, 1H), 4.39 (t, 2H), 3.83 (s, 3H), 3.42 (s, 3H), 3.04 (d, J=5 Hz, 3H), 2.98 (t, J=6 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1)([O-])=O.Cl[Sn]Cl>Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cs1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.3 %

Procedure:
4-Nitro-2-thiophenecarboxylic acid (1 g, 5.7 mmol) was added with stirring to a solution of SnCl2. 2H2O (3.25 g, 14.4 mmol) in concentrated HCl (10 ml). The mixture was stirred for 6 hours at ambient temperature and purified by subjecting to chromatography on HP20SS resin, using water as eluant, to give the title compound (0.59 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cnc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cnc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.92 min; [M+H]+=378.55.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl[CH:26]1[CH2:31][O:30][C:29](=[O:32])[O:28][CH2:27]1>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:26]3[CH2:31][O:30][C:29](=[O:32])[O:28][CH2:27]3)[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1OCC(Cl)CO1
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(-c2nn(C3COC(=O)OC3)c3ncccc23)cc(C(C)(C)C)c1O

Procedure:
By using 3.2 g of the compound of Example 1 and 1.6 g of 5-chloro-2-oxo-1,3-dioxane, the reaction is carried out in a similar manner as Example 78 (i) to give 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-oxo-1,3-dioxan-5-yl)-1H-pyrazolo-[3,4-b]pyridine.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]3[N:38]=[CH:37][N:36]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:35]=3)=[CH:31][CH:32]=2)[C:27]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[N:26]1>ClCCl>[CH:1]1([C:4]([NH:64][C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[C:30]([C:34]5[N:38]=[CH:37][N:36]([C:39]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[N:35]=5)[CH:29]=4)[N:25]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][O:19]4)[N:26]=3)[CH:59]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CC1

Procedure:
To a solution of cyclopropanecarboxylic acid (0.024 g, 0.274 mmol) in 2.5 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.057 g, 0.298 mmol). The reaction was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added to the solution. The reaction was stirred at room temperature for 2 days while 2 additions of one equivalent of reagents were necessary. The reaction mixture was then partitioned between water and dichloromethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 672 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]([C:11](=[O:33])[C@@H:12]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6]1=[O:38].C([O-])(O)=O.[Na+].[CH:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][C:52](Cl)=[O:53])=[CH:46][CH:45]=1>O1CCOCC1>[CH2:26]([O:25][C:23]([NH:22][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:11]([N:10]1[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6](=[O:38])[C@@H:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:52]([O:51][CH2:50][C:47]1[CH:48]=[CH:49][CH:44]=[CH:45][CH:46]=1)=[O:53])=[O:33])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 100 ml of a 50% aqueous solution of dioxane was dissolved 3.8 g of (S,S)-3-(3-aminopropyl)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-2-oxopiperazine-1-acetic acid produced in Reference Example 33. To the solution was added 1.52 g of NaHCO3, to which was added dropwise, under ice-cooling, 1.24 ml of Z-chloride. The mixture was stirred for 1.5 hour at room temperature. Dioxane was distilled off. To the residue was added a 3% aqueous solution of KHSO4 to adjust the pH to 2. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of NaHCO3 and dried (Na2SO4), followed by concentration under reduced pressure. To the concentrate was added ether. The mixture was subjected to decantation twice to afford 4 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=3[NH:13][C:12]2=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=3[N:13]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:12]2=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3c([N+](=O)[O-])cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(=O)n(S(=O)(=O)c2ccc(C)cc2)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4-nitro-1,3-dihydro-2H-benzimidazol-2-one from Step B (500 mg, 1.50 mmol) in DMF (50 mL) was added potassium carbonate (207 mg, 1.50 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Methyl bromoacetate (252 mg, 1.65 mmol) was added dropwise and the reaction mixture was stirred for 1 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=406 (M+1).
Reaction SMILES: [N:1]([CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[N+:2]=[N-:3].[OH-].[Na+]>CO.O1CCCC1>[N:1]([CH:4]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)C1(c2ccc(COc3cccc(C(N=[N+]=[N-])c4ccccc4)c3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C3(C(=O)O)CC3)cc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 1-(4-((3-(azido(phenyl)methyl)phenoxy)methyl)-phenyl)cyclopropanecarboxylate (0.569 g, 1.375 mmol) in methanol (12.9 mL) and tetrahydrofuran (5.1 mL), was added 2M aqueous sodium hydroxide (12.9 mL). The reaction was stirred at 50° C. for 3 hours 30 minutes and then at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to pH4 using 2M aqueous hydrochloric acid with stirring. The mixture was extracted with dichloromethane (×3), and the combined organic extracts washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (0.552 g, quantitative yield). The material was used directly in the next step with no further purification
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:23][CH3:24])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7]1=[O:25].[H-].[Na+].I[CH3:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:23][CH3:24])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[N:16]([CH3:33])[S:17]([CH3:20])(=[O:18])=[O:19])[C:7]1=[O:25]
Reactant: CI
Reactant: COc1c2c(c(NS(C)(=O)=O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2c(c(N(C)S(C)(=O)=O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C

Procedure:
A cold (0° C.) solution of N-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]methanesulfonamide (60 mg, 0.14 mmol) in anhydrous DMF (1 mL) was treated with sodium hydride (6.8 mg, 0.17 mmol; 60% dispersion in oil). The resultant mixture was stirred at the same temperature for 30 minutes, and treated with iodomethane (38 mg, 0.27 mmol). The reaction mixture was allowed to slowly warmed up to room temperature. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. ES MS M+1=458
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=O)=[CH:5][CH:4]=1.[NH2:13][C@H:14](CO)[CH:15]([CH3:17])[CH3:16]>ClC1C=CC=CC=1>[CH:15]([C@H:14]1[CH2:10][O:9][C:7]([C:6]2[CH:11]=[CH:12][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:13]1)([CH3:17])[CH3:16]
Reactant: CC(C)[C@H](N)CO
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccc(CO)cc2)=N1
Yield: 66 %

Procedure:
Under an argon atmosphere, a mixture of methyl 4-hydroxymethylbenzoate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (2.5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography to give (S)-4-isopropyl-2-(4-hydroxymethylphenyl)-1,3-oxazoline in 66% yield. The compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1Br.[CH2:20]([N:27]1[CH2:32][CH2:31]C(=O)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCCC>[CH2:20]([N:27]1[CH2:32][CH2:31][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:10][CH3:11])[CH:8]=3)[CH:3]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:2]2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(C(OC)c2ccc(F)cc2)c(Br)c1
Solvent: CCCCCCC
Product: COc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2c1ccc(F)cc1

Procedure:
By following the manipulative procedure described above in Example 45, 2-bromo-4'-fluoro-4-methoxybenzhydryl methyl ether and 1-benzyl-4-piperidone are reacted to produce a white solid, m.p. 86°-88°, form heptane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][CH2:33][CH2:34][OH:35])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[S:36](Cl)([C:39]1[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][CH2:33][CH2:34][O:35][S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (0.5 g, 0.96 mmol) in DCM (10 mL) was added TsCl (182 mg, 1 mmol), TEA (97 mg, 1 mmol), and catalytic amount of DMAP. The mixture was stirred at rt for 4 hours. The mixture was diluted with EtOAc and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide the desired product methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(tosyloxy)propyl)thiazole-4-carboxylate (8F) which was used without further purification. LC/MS (APCI): m/z 663.0 (M+H)
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:11])[CH3:8]>C1C=CC=CC=1.CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([C:15]([Cl:4])=[O:17])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C1(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)Cl)CC1

Procedure:
Oxalyl chloride (6.0 g. 47 mmol) was added to a stirred mixture of 1-ethoxycarbonylcyclopropane carboxylic acid (1a) (6 g, 38 mmol) in benzene (25 ml) plus two drops of dimethylformamide. After the gas evolution ceased, the stirring was continued at room temperature for another hour. The reaction mixture was concentrated. The residue was purified by distillation. A fraction collected at 91°-2° C./15 mm was redistilled to give the desired product.
Reaction SMILES: [CH2:1]=[O:2].[N+:3]([C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[N:8][C:7]=1[CH3:13])([O-:5])=[O:4].[OH-].[NH4+]>CS(C)=O.O>[CH3:11][N:10]1[C:6]([N+:3]([O-:5])=[O:4])=[C:7]([CH3:13])[N:8]=[C:9]1[CH2:12][CH2:1][OH:2]
Reactant: Cc1nc(C)n(C)c1[N+](=O)[O-]
Reactant: C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(CCO)n(C)c1[N+](=O)[O-]
Temperature: 140 °C
Yield: 74.8 %

Procedure:
Paraformaldehyde (4.05 g, 0.135 mole) and 5-nitro-1,2,4-trimethylimidazole (4.2 g, 0.027 mole) were combined in 25 ml of DMSO and heated at 140° C. for 48 hours (24 hours are found to be optimum), in a 300 ml glass-lined bomb. The reaction mixture was then evaporated in vacuo at 80° C. to give a dark brown oil. This was dissolved in about 60 ml of water, 5 ml of concentrated ammonium hydroxide are added, and the mixture was extracted six times with 70 ml of ethyl acetate. The ethyl acetate layers were dried over sodium sulfate and evaporated to give 3.74 g of residue. The crude product was dissolved in 3% methanol/chloroform to give a final volume of 8 ml. This is chromatographed preparatively on a partisil M20/50 column, eluting with 3% methanol/chloroform at 10 ml/min., with 4×2 ml injections. The product eluting at 46-55 minutes was collected. Combining the cuts from the four injections and evaporation of solvent gave 600 mg. This major product was a yellow oil which crystallized only with difficulty. The material was rechromatographed preparatively on a Whatman ODS-3 column eluting with 25% Methanol/water at 10 ml/min. The major peak was collected, and the solvent was evaporated to give 390 mg of pale yellow oil which readily crystallized on cooling. This product was 1,4-dimethyl-2-(2-hydroxyethyl)-5-nitroimidazole.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[CH2:11][C@@H:12]([NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])(=O)=O.O>CN(C=O)C>[C:1](=[O:4])([S:3][CH2:11][C@@H:12]([NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 78 °C
Reaction time: 1 h

Procedure:
Potassium thioacetate (1.30 g, 11.51 mmol) was added to a stirring solution of (S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.50 g, 7.67 mmol) in dry DMF (50 mL). The resulting brown solution was heated with stirring at 78° C. for 1 hour. The brown suspension was poured into water and extracted with EtOAc (3×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 2.1 g of compound 76a as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 306.02 (M+H) RT=3.32 min.