Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 50 °C
Yield: 89 %

Procedure:
To (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester (161 mg, 0.50 mmol) and RuBr2(R)-BINAP (4.4 mg, 0.0050 mmol) (BINAP was 2,2′-bisdiphenylphosphino-1,1′-binaphthyl), 2 mL of a methanol-water (10/1) solution was added to completely dissolve the (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester and RuBr2(R)-BINAP in an argon atmosphere. Hydrogen replacement at −78° C. was performed three times. After the temperature of the resulting mixture had increased to 50° C., the mixture was allowed to react for twenty hours under a hydrogen pressure of 5.0 kg/cm2. After extraction of hydrogen, the mixture was condensed and purified by silica gel column chromatography. As a result, 144.4 mg (89%) of (3R, 5S)-6-benzoyloxy-3,5-dihydroxyhexanoic acid tert-butylester was obtained. The diastereomer ratio determined by high performance liquid chromatography (HPLC) analysis was (3R, 5S):(3S, 5S)=93.5/6.5 (Chiralcel-AD, hexane/isopropanol=95/5, 1.0 mL/min, UV=210 nm. Retention time: (3R, 5S) 28.2 min, (3S, 5S) 42.9 min).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[C:18]([O:20][CH:21]=[CH2:22])=[O:19].ClC(Cl)C>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([C:18]([O:20][CH:21]=[CH2:22])=[O:19])[CH2:12][CH2:11]3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C=COC(=O)Cl
Reactant: CN1CCN(c2cccc3nsnc23)CC1
Solvent: CC(Cl)Cl
Product: C=COC(=O)N1CCN(c2cccc3nsnc23)CC1

Procedure:
To a 25 ml round-bottomed flask equipped with condenser and N2 inlet were added 620 mg (2.64 mmol) of 4-(2,1,3-benzothiadiazolyl)-N-methylpiperazine, 0.224 ml (2.64 mmol) vinyl chloroformate, and 15 ml dichloroethane. The reaction was refluxed 16 hours, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions collected to give yellow solid 4-(2,1,3-benzothiadiazolyl)-N-vinyloxycarbonylpiperazine, 530 mg (69%). NMR (d, CDCl3): 3.6 (m, 4H), 3.8 (m, 4H), 4.4-5.0 (m, 2H), 6.6-7.6 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:3]=1[C:4]([NH2:6])=[O:5].O=[CH:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:5])[NH:6][CH:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH:11]2
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: NC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1NC(=O)c2c(Cl)cccc2N1
Yield: 21.4 %

Procedure:
A mixtre of 2-chloro-6-nitrobenzamide (0.3 g), iron powder (0.5 g) and t-butyl (N-2-oxoethyl)carbamate (1.0 g) in glacial acetic acid (5 mL) was heated at 50-55° C. for 2 h. The mixture was concentrated and the residue was partitioned between sat. NaHCO3 and EtOAc. The organic layer was dried (MgSO4), concentrated, and the residue was subjected to flash chromatography (silica gel/heptane-EtOAc 100:0 to 20:80 gradient) to afford the title compound as an off-white solid (0.1 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[N:17]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH3:29].C(O)C>Cl.O>[CH:14]([N:7]1[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=3[O:28][CH3:29])=[N:17][C:6]1=2)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Yield: 67.5 %

Procedure:
A mixture of 0.076 g (0.0003 mole) of 2-chloro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-43), 0.060 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.078 g of 4-(9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-43a) as an off-white solid.
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:34]([C:35](=O)[C:36]#[CH:37])=[C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][N:24]3[N:23]=2)=[CH:18][CH:17]=1>C(O)C.O>[CH:2]1([NH:7][C:8]2[N:10]=[C:35]([C:34]3[C:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)=[N:23][N:24]4[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=34)[CH:36]=[CH:37][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5 mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M in ethanol, 14 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. To this mixture was added 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0° C. for 30 minutes, followed by room temperature for 15 hours. The reaction mixture was diluted with water (400 mL). The solid precipitate was collected on a filter to provide N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (4.48 g 98%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t, 2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15–2.06 (m, 2H), 1.84–1.52 (m, 6H); 19F NMR (CDCl3): δ −62.70, −112.25 MS m/z 442 (M+1); mp 155–156° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[O:22])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[OH:37][C:35]([C:34]([F:39])([F:38])[F:33])=[O:36].[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[O:22])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(C#N)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2cc(C#N)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-[(2-chloro-5-cyanophenylcarbonyl)amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.2 mmol, 0.55 g) in dichloromethane (12 mL) was added trifluoroacetic acid (3 mL) at room temperature. The reaction mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the solvent was removed under vacuum and the residue was azeotroped with toluene (2×10 mL) and dried under high vacuum to afford 0.43 g (100%) of a yellow solid. HR MS (C18H16ClN3O3): Obs mass, 358.0963. Calcd mass, 358.0959 (M+H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:24])[NH:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:24])[NH:15][C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2[nH]c1=O
Yield: 87.2 %

Procedure:
Cyclohexylamine (13.88 mL, 121.33 mmol) was added to a solution of Compound 112 (9.4 g, 40.44 mmol) in toluene (200 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 10.1 g (87%) of white solids. M.P. 223° C. 1H NMR (DMSO-d6): δ 1.3 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 3.8 (m, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 10.44 (b, 1H); EIMS (neg. mode): 285 (M−H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:53][N:54]1[CH2:60][CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[CH2:61]1C[O:64]CC1>>[CH:44]([OH:45])=[O:64].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][CH:50]=[C:51]([CH2:53][N:54]3[CH2:60][CH2:59][CH2:58][N:57]([CH3:61])[CH2:56][CH2:55]3)[CH:52]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: CN1CCCNCC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN5CCCN(C)CC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of Intermediate 167b (0.22 mmol) in THF (2.5 mL) was added 1-methylhomopiperazine (534 μL, 4.3 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (28 mg, 15%). LCMS (Method 5): Rt 3.27 min, m/z 745 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.58-1.66 (2H, m), 1.68-1.84 (5H, m), 1.84-1.92 (1H, m), 1.95-2.05 (1H, m), 2.05-2.12 (1H, m), 2.32 (3H, s), 2.58-2.66 (6H, m), 2.69 (2H, t, J=5.7 Hz), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.11 (1H, dt, J=11.9, 4.1 Hz), 3.23-3.29 (1H, m), 3.62 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.47 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.04 (1H, d, J=8.6 Hz), 7.14 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.26-7.36 (4H, m), 7.38-7.43 (2H, m), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.12 (1H, s), 8.16 (2.4H, s).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[C@@H:21]12[CH2:27][C@@H:24]([CH:25]=[CH:26]1)[CH2:23][C@H:22]2[CH2:28][C:29](O)=[O:30]>>[C@@H:21]12[CH2:27][C@@H:24]([CH:25]=[CH:26]1)[CH2:23][C@H:22]2[CH2:28][C:29]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20])=[O:30]
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)c(C)c1
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Product: Cc1ccc(-c2nn(NC(=O)C[C@@H]3C[C@@H]4C=C[C@H]3C4)c(=O)c3ccccc23)c(C)c1

Procedure:
The product of Example 159A and 2-[(1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl]acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (s, 1H), 8.37-8.40 (m, 1H), 7.85-7.97 (m, 2H), 7.26-7.32 (m, 1H), 7.20-7.25 (m, 2H), 7.16-7.20 (m, 1H), 6.21 (dd, J=5.7, 2.9 Hz, 1H), 6.05 (dd, J=5.7, 2.9 Hz, 1H), 2.86-2.91 (m, 1H), 2.76-2.81 (m, 1H), 2.41-2.49 (m, 1H), 2.38 (s, 3H), 2.01-2.12 (m, 2H), 2.06 (s, 3H), 1.86-1.93 (m, 1H), 1.33 (dd, J=7.9, 2.5 Hz, 1H), 1.26 (d, J=8.1 Hz, 1H), 0.59 (ddd, J=11.5, 4.3, 2.5 Hz, 1H); MS (APCI+) M/Z 400 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[N:19]([NH2:24])[C:20]([NH2:23])=[N:21][N:22]=2)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:24][N:19]3[C:18]([CH2:17][C:16]4[CH:25]=[CH:26][C:13]([F:12])=[CH:14][CH:15]=4)=[N:22][N:21]=[C:20]3[N:23]=2)=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:23][C:20]3[N:19]([C:18]([CH2:17][C:16]4[CH:25]=[CH:26][C:13]([F:12])=[CH:14][CH:15]=4)=[N:22][N:21]=3)[N:24]=2)=[CH:4][CH:3]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: O=CC(=O)c1ccc(Br)cc1
Product: Fc1ccc(Cc2nnc3nc(-c4ccc(Br)cc4)cnn23)cc1
Product: Fc1ccc(Cc2nnc3ncc(-c4ccc(Br)cc4)nn23)cc1

Procedure:
General procedure A was followed with the reaction of (4-bromo-phenyl)-oxo-acetaldehyde and 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine to provide 7-(4-bromo-phenyl)-3-(4-fluoro-benzyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazine and 6-(4-bromo-phenyl)-3-(4-fluoro-benzyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazine (example 5).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.CCN=C=NCCCN(C)C.Cl.[Br:25][CH2:26][C:27]([OH:29])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Br:25][CH2:26][C:27]([N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1)=[O:29]
Reactant: O=C(O)CBr
Reactant: CNc1ccc2nc(C)oc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of N,2-dimethylbenzo[d]oxazol-6-amine (9.4 g, 58.0 mmol) in DCM (100 mL) was added EDC.HCl (26.6 g, 139 mmol), DMAP (0.354 g, 2.9 mmol) and bromoacetic acid (18.5 g, 133.0 mmol) at 0° C. under N2. The reaction mixture was stirred at rt overnight, then diluted with water (200 mL). The product was extracted with DCM (3×100 mL) and the organics were washed with brine, dried over Na2SO4 and concentrated to obtain 2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (10.0 g, 61%), (MS: ESI +ve, 283.1 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 2.59 (s, 3H), 3.23 (s, 3H), 4.04 (s, 2H), 6.76-6.74 (d, J=8.8, 1H), 7.38-7.30 (dd, J=8.8, 1H), 7.73-7.71 (d, J=8, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C:20]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:20]([CH3:19])([OH:26])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1(O)CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CC1(O)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added 4-methylpiperidin-4-ol (163 mg, 1.413 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (374 mg, 1.034 mmol, 73.2% yield). LC-MS (M+H)+=362.0. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2 H, m), 7.04 (2 H, t, J=8.85 Hz), 4.11-4.30 (3 H, m), 3.48-3.63 (2 H, m), 3.14-3.23 (1 H, m), 3.00-3.12 (1 H, m), 2.54-2.66 (1 H, m), 1.94-2.09 (1 H, m), 1.68 (4 H, t, J=4.12 Hz), 1.28 (3 H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCOc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C

Procedure:
To a 500 mL N2 filled round bottom flask was added 1-bromo-4-(hexyloxy)benzene (20.5 g, 80.0 mmol, 1 equiv.) and DMF (160 mL, 0.5 M). The mixture was then sparged with bubbling N2. To this mixture was added N2-sparged triethylamine (39.0 mL, 280 mmol, 3.5 equiv.) via syringe. Finally, copper (I) iodide (254.0 mg, 1.33 mmol, 1.7%), triphenylphosphine (603.0 mg, 2.67 mmol, 3.3%) and PdCl2(PPh3)2 (933.0 mg, 1.33 mmol, 1.7%) were added as a single portion and the head space was flushed with N2. Ethynyltrimethylsilane (16.9 mL, 120.0 mmol, 1.5 equiv.) was added via syringe to the mixture. The flask was sealed with a ground glass stopper, Teflon tape, and then electrical tape and heated to 90° C. for 48 hours. After 48 hours the mixture was diluted with hexanes and extracted with 10% H3PO4 then 5% K2CO3. The organic layer was then dried with MgSO4 and filtered through a plug of SiO2 with 100% hexanes. Upon evaporation, ((4-(hexyloxy)phenyl)ethynyl)trimethylsilane was isolated as a clear oil (16.45 g, 60.2 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ7.42 (d, J=9.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 1.85-1.73 (m, 2H), 1.52-1.42 (m, 2H), 1.41-1.26 (m, 4H), 0.94 (t, J=7.6 Hz, 3H), 0.27 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-:17].[Na+].[Na+].O>CN1CCCC1=O>[OH:17][CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)N(C(=O)CO)c1ccc(F)cc1
Reaction time: 2.5 h

Procedure:
In a suitable apparatus (500 ml flask), 23.0 g (0.1 mol) of N-chloroacetyl-N-isopropyl-4-fluoroaniline and 11.7 g (0.11 mol) of sodium carbonate are refluxed (100° C.) in a solution of 140 ml of water and 200 ml of N-methylpyrrolidone. After 2.5 hours, the solvent mixture is stripped off in vacuo and the residue distilled at 2 to 3 torr and 132° to 135° C. This gives 18.1 g (86% of theory) of N-hydroxyacetyl-N-isopropyl-(4-fluoroaniline) with a purity of 99.1% (GC).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15]N(C=O)C.[H-].[Na+].[CH3:22][SiH:23]([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:29])([CH3:15])[CH3:22])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[SiH](C)CCOCCl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0° C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [β-(dimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C. and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole as a crude material. LC/MS (M+H)+: 325, 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 5.45 (s, 2H), 3.55 (t, 2H), 1.35 (s, 12H), 0.95 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[C:6](S(O)(=O)=O)(S(O)(=O)=O)[CH:5]=1)([O-])=O.[NH2:27]C1C=C(S(O)(=O)=O)C2C(C=1)=CC=CC=2.[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1>>[NH2:27][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1
Reactant: Nc1cc(S(=O)(=O)O)c2ccccc2c1
Reactant: Nc1ccc(C=CC2C=CC([N+](=O)[O-])=CC2(S(=O)(=O)O)S(=O)(=O)O)cc1
Agent: c1c[nH]nn1
Product: Nc1ccccc1C=Cc1ccccc1

Procedure:
Diazotized 4-nitro-4′-aminostilbene-2,2-disulfonic acid and 3-aminonaphthalene-1-sulfonic acid were subjected to coupling. The resultant was turned into a triazole, and a nitro group of the triazole was reduced to an amino group by means of a conventionally known method to produce aminostilbene-triazole. Aminostilbene-triazole was dissolved into water, and sodium nitrite and hydrochloric acid were added dropwise to the solution to perform diazotization. The resultant was added dropwise to an aqueous solution of a compound represented by Compound (4) below, and the whole was subjected to coupling, followed by dialysis with sodium chloride. The compound was diazotized with an aqueous solution of sodium nitrite, and was turned into a triazole by adding an aqueous solution of 6-aminonaphthalene-2-sulfonic acid. The triazole was dialyzed with sodium chloride to prepare a coloring material represented by Exemplified Compound 1 below.
Reaction SMILES: [O:1]([C@H:9]([CH3:16])[CH2:10][C:11](OCC)=[O:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CO>ClCCl>[O:1]([C@H:9]([CH3:16])[CH2:10][CH2:11][OH:12])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: C[C@H](CCO)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
The crude product from Example 545A (˜37 mmol) was dissolved in dichloromethane (100 mL). To this stirred solution, chilled to −78° C., was added dropwise a 1M solution of diisobutylaluminum hydride in dichloromethane (185 mL, 185 mmol). The reaction mixture was stirred at −78° C. for two hours, then it was allowed to warm to −30° C. and stirred an additional 0.5 hours. Methanol was then added carefully at −20° C. to quench any remaining hydride. The reaction mixture was then diluted with methyl tert-butylether (200 mL) and washed with aqueous sodium tartrate solution (4×100 mL) and brine (2×100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (6.3 g, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC2CCNCC2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(4-methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid t-butyl ester (6 g, 17.89 mmol) in DCM (50 mL) was added TFA (25 mL) and stirring was continued for 1.5 hrs at room temperature. The volatiles were removed in vacuo and the residues was crystallised from diethyl ether affording after filtration and drying 5.92 g (95%) of 4-(piperidin-4-yloxy)-benzoic acid methyl ester as a solid TFA salt.