Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[NH:34][CH2:33][C@@H:32]3[CH3:38])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:12][CH2:11]1)[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH:45]=O>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[N:34]([CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[C:42]([F:41])[CH:43]=4)[CH2:33][C@@H:32]3[CH3:38])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:14][CH2:15]1)[CH3:2]
Reactant: CCOC(=O)CCCCCN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1cccc(F)c1
Product: CCOC(=O)CCCCCN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Yield: 54.1 %

Procedure:
The title compound was made by a procedure identical to that of Example 96 with 1.50 g of 6-(4-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-hexanoic acid ethyl ester (2.72 mmol) and 0.68 g of 3-fluorobenzaldehyde (5.5 mmol) to give 0.97 g of desired compound as a light yellow solid. 1H NMR (300 MHz, d6-DMSO): □ 1.01-1.03 (d, J=5.8 Hz, 6H); 1.12-1.17 (t, 3H), 1.22-1.29 (m, 2H); 1.35-1.56 (m, 4H); 1.90-2.02 (m, 2H); 2.23-2.33 (m, 7H); 2.48-2.66 (m, 6H); 3.25-3.33 (m, 3H); 3.54-3.56 (m, 1H); 3.72-3.76 (dd, 1H); 3.98-4.05 (q, 2H); 4.95 (s, 1H); 6.62-6.71 (m, 3H); 6.97-7.43 (m, 9); 9.34 (s, 1H). MS: 659.0 (M+1, 80%), 437.2(85%), 221.2(100%), 209.1(70%). Calculated for C39H51FN4O4 0.11 CH2Cl2: C, 70.30; H, 7.73; N, 8.38; F, 2.84. Found: C, 70.32; H, 7.78; N, 8.41; F, 3.00.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
A mixture of 4-n-butylbenzaldehyde (5 g, 30.8 mmol), nitromethane (3.31 mL, 61.6 mmol), ammonium acetate (3.56 g, 46.2 mmol) and acetic acid (50 mL) was stirred for 5 hours at 100° C. The mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.7 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[Cl:16][N:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([NH:24][C:25]2[CH:26]=[C:27]([S:52]([OH:55])(=[O:54])=[O:53])[C:28]([CH:31]=[CH:32][C:33]3[C:34]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:35][C:36]([NH:39][C:40]4[NH:45][N:44]([Cl:46])[N:43]=[C:42](Cl)[CH:41]=4)=[CH:37][CH:38]=3)=[CH:29][CH:30]=2)[NH:18]1>>[Cl:16][N:17]1[N:22]=[C:21]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=2)[CH:20]=[C:19]([NH:24][C:25]2[CH:26]=[C:27]([S:52]([OH:55])(=[O:54])=[O:53])[C:28]([CH:31]=[CH:32][C:33]3[C:34]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:35][C:36]([NH:39][C:40]4[NH:45][N:44]([Cl:46])[N:43]=[C:42]([NH:1][C:2]5[C:11]6[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=6)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=5)[CH:41]=4)=[CH:37][CH:38]=3)=[CH:29][CH:30]=2)[NH:18]1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(NC2=CC(Nc3ccc(S(=O)(=O)O)c4ccccc34)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Nc3ccc(S(=O)(=O)O)c4ccccc34)=NN(Cl)N2)cc1S(=O)(=O)O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
An aqueous solution of 1-aminonaphthalene-4-sulfonic acid (0.012 mol) was added to the freshly produced solution according to Example 4 of 4,4′-bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid (0.006 mol). The mixture was stirred at pH 5.5 and 20° C. for 24 hours.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54].CCN(C(C)C)C(C)C>CN(C=O)C.C(O)(=O)C>[CH2:1]([NH:8][C:9]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:12]([C:13]([NH:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]2[OH:54])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(NCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(NCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 16.2 mg (0.047 mmol) 6-benzylamino-5-(4-chloro-phenyl)-nicotinic acid, 19.6 mg (0.06 mmol) TBTU, 6.9 mg (0.06 mmol) (1R,2R)-2-amino-cyclohexanol and 23 mg (0.18 mmol) DIPEA in DMF was shaken at room temperature over night. Acetic acid was added and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 14.1 mg (55%) of the title compound. MS (m/e): 436.4 (MH+).
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH2:9][S:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH:39]=O.Cl>C1COCC1>[CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:39][C:38]([O:42][CH2:43][CH3:44])=[O:41])[S:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN1C(=O)CSC1c1ccccc1
Reactant: CCOC(=O)C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C=C1SC(c2ccccc2)N(CCC(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-isopentyl-2-phenylthiazolidin-4-one (0.25 g, 1 mmol) in THF was added LDA (1.1 ml of ˜1 M in THF; freshly prepared from nBuLi and Diisopropylamine) at −78° C. and the reaction mixture was allowed to warm to room temperature. Ethyl glyoxalate (0.24 ml of ˜50% w/v in toluene, 1.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1 N HCl and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. Purification by column chromatography (5 to 15% EtOAc in Hx) gave the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].S([O-])(OC)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Product: COc1cc([N+](=O)[O-])ccc1F

Procedure:
An intimate mixture of 2.0 grams of 2-fluoro-5-nitrophenol, 2.0 grams of potassium carbonate, and 1.0 ml. of methyl sulphate, is heated on the steam bath for 5 minutes and then steam distilled, the volume of liquid in the flask being kept as small as possible. The 2-fluoro-5nitroanisole passes over, and a further quantity is obtained by adding more potassium carbonate (1 gram) and methyl sulphate (0.5 ml.) to the residual liquor, which is then warmed and steam distilled. The 2-fluoro-5-nitroanisole is then recrystallized from hexane.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]([CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:22]([F:31])[CH:21]=2)[CH2:15]1)[C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O>C(O)(=O)C.O.[Zn]>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:13][C@@H:14]2[O:18][C:17](=[O:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[C:22]([F:31])[CH:21]=3)[CH2:15]2)=[N:9]1
Reactant: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Reaction time: 0.33 h
Yield: 41.8 %

Procedure:
5(R)—(N-(2,2,2-Trichloroethyloxycarbonyl)-isoxazol-3-ylaminomethyl)-3-(4-imidazol-1-yl-3-fluorophenyl)oxazolidin-2-one (crude, 1.7 g, ˜2.5 mM), was stirred in a mixture of acetic acid (40 ml) and water (18 ml) under nitrogen at ambient temperature. Zinc dust (824 mg, 12.5 mM) was added, the mixture stirred 20 minutes, a further portion (200 mg) of zinc added, and stirring continued for 1 hour. The mixture was filtered through celite, and the filter pad washed well with a mixture of acetic acid and water (5:1). The filtrates were evaporated, and the residue partitioned between hydrochloric acid (0.5M, 200 ml) and dichloromethane (150 ml). The aqueous phase was washed with dichloromethane (100 ml), then made basic with the minimum quantity of concentrated ammonia solution, re-extracted with dichloromethane (2×150 ml), dried (magnesium sulfate), and evaporated. Recrystallisation from isopropanol (40 ml) gave the desired product (470 mg).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1.I[CH3:15]>CO>[CH3:15][S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1
Reactant: CI
Reactant: CCCc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(O)nc(SC)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 1N solution of potassium hydroxide in methanol (110 mL) was added dropwise at 0° C. to a suspension of 2-mercapto-6-propyl-pyrimidin-4-ol (17.0 g) in methanol (220 mL). The mixture was stirred at room temperature for 15 minutes. After cooling at 0° C., iodomethane (6.8 mL) was added dropwise over 15 minutes. The mixture was stirred at room temperature for 6 hours, then filtered. The first precipitate was successively washed with methanol, water, isopropanol, then dried under reduced pressure. The filtrate was concentrated under reduced pressure, triturated with water, filtered. The second precipitate was successively washed with methanol, water, isopropanol, then dried under reduced pressure. Both precipitates were combined to afford 2-methylsulfanyl-6-propyl-pyrimidin-4-ol (15.5 g) as white crystals (mp=158° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1nc2cccc(Cl)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of (S)-1-(7-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 19 (482 mg, 1.77 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (466 mg, 1.95 mmol) and DIPEA (0.91 mL, 5.32 mmol) in IMS (3.5 mL) was stirred in a sealed vial for 48 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The product containing fractions (basic and methanolic) were combined and concentrated in vacuo. Purification by Isolute® SCX-2 was repeated a second time and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM). The basic fractions were combined and concentrated in vacuo and the residue was refluxed in MeOH. After cooling to RT the solid was filtered off and washed with EtOAc affording 138 as a white solid (379 mg, 55%). LCMS: RT 3.65 min [M+H]+ 390.0. 1H NMR (DMSO, 400 MHz): δ 8.20-8.06 (2H, m), 7.94 (1H, s), 7.69-7.36 (6H, m), 7.24-7.19 (2H, m), 5.26 (1H, bs), 1.10 (3H, d, J=7.00 Hz)
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:21][CH2:22][CH3:23])[CH3:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:12](=[O:14])[CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:21][CH2:22][CH3:23])[CH3:16]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(N)ccc21
Reactant: O=C(O)Cc1ccc2c(n1)NCCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CC(=O)OCC)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Yield: 68.6 %

Procedure:
A solution of (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-acetic acid (0.2 g, 0.65 mmol), 3-(5-amino-indol-1-yl)-hexanoic acid ethyl ester (0.19 g, 0.71 mmol), BOP (0.35 g, 0.78 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in DMF (2.5 mL) was stirred for 16 h. Solvents were evaporated. The resulting residue was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted once more with EtOAc. The extracts were combined, washed with H2O, brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (15, 30, 50, and 80%) to give the title compound (0.20 g, 67% yield) as a brown oil. Mass spectrum (LCMS, ESI) calculated for C26H33N4O3 449.3 (M+H); found 449.3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([C:22]#[N:23])=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:24]S(O)(=O)=O>>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([C:22]([NH2:23])=[O:24])=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To concentrated H2SO4 (90 mL) cooled with an ice bath was added 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g, 130 mmol) in portions such that the internal temperature did not exceed 50° C. but did not go below 25° C. After complete addition, the mixture was stirred in the ice bath until the reaction started to cool, at which point the reaction was removed from the ice bath and the mixture was heated to 50° C. The reaction was cooled to ambient temperature and added to ice water slowly over 3 minutes (about 1400 mL of 30% ice in water). The mixture was further cooled in an ice bath to 5° C. and neutralized to about pH 10 with 4M NaOH (about 800 mL) at a rate such that the internal temperature did not exceed 20° C., at which point a solid formed. The mixture was stirred for 20 minutes, then filtered and washed with MTBE (5×150 mL), hexanes (5×100 mL), and dried at under vacuum to afford 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1>C(O)C.[Pd]>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:12][CH:11]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1nccn1-c1ccc(N)cc1
Reaction time: 3 h
Yield: 85.2 %

Procedure:
13.5 g of 2-methyl-1-(4-nitrophenyl)imidazole was hydrogenated in the presence of 10% Pd/c in 160 ml of ethanol at 30° to 40° C. at an initial pressure of 40 kg/cm2. After 3 hours, the reduction mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was recrystallized from a mixed solvent of benzene and n-hexane to obtain 9.8 g of the intended compound having a melting point of 112° to 113° C. Elementary analysis values as C10H11N3 were as follows.
Reaction SMILES: [NH2:1][C@H:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:23][O:24][B:25](OC)OC>O1CCCC1>[CH:17]1([C@@H:2]2[C:3]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:4][B:25]([O:24][CH3:23])[NH:1]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COB(OC)OC
Reactant: N[C@H](C1CCCCC1)C(O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Reaction time: 1.5 h

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (59 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylborate (27.2 μL, 0.24 mmol) were added to a dry flask and stirred under an atmosphere of nitrogen for 1.5 hours to form a solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine. To this solution was added borane dimethylsulfide complex (100 μL, 1.0 mmol) and the mixture was stirred at room temperature for a further 30 minutes. A solution of 1-tetralone (133 μL, 1.0 mmol) in tetrahydrofuran (5 mL) was added by means of a syringe pump at a rate of 16 mL/min and the reaction was then stirred for a further 1 hour. Thin layer chromatography (silica gel/hexane/ethyl acetate 4:1) showed no starting material. The reaction was quenched by addition of methanol. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate and washed 3 times with IN HCl. The ethyl acetate solution was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated to give (S)-1-hydroxy-1,2,3,4-tetrahydronaphthalene with an ee of 96.5%. The enantiomer ratio was determined by HPLC using a Chiralcel OB 25 cm×4.6 mm column with hexane/2-propanol (9:1) mobile phase at 0.5 mL/min at 25° C. Detection with UV was at 254 nm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[S:10][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH:14]=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([Mg]Br)[CH3:29]>C(OCC)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:9]1[S:10][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH:14]([OH:15])[CH2:28][CH3:29])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C=O
Reactant: CC[Mg]Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOCC
Product: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C(O)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Ethyl 2-[bis(tert-butoxycarbonyl)amino]-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (62d) (915.5 mg, 2.29 mmol) was dissolved in diethyl ether (30 mL), followed by cooling to −78° C. Then, tetrabutylammonium bromide (890 mg, 2.76 mmol) and ethylmagnesium bromide (1 M solution in THF, 2.8 mL) were added, and the mixture was stirred for one hour. Diethyl ether was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=91/9, 85/15) to obtain 327.2 mg of the title compound (33%).
Reaction SMILES: [CH3:1][Si:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[CH:9]=1.C1C(=O)N([Br:63])C(=O)C1>CC#N>[CH3:55][Si:2]([CH3:1])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1[Br:63]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Solvent: CC#N
Product: COCCOC(=O)C1(OCCOC)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (2.28 g, 2.87 mmol) in CH3CN (50 mL) was added NBS (511 mg, 2.87 mmol) and stirred at room temperature for 30 min. Both TLC and LCMS showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-30%, EtOAc/Hexanes, Rf=0.65 in 50% EtOAc) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a yellow oil (2.50 g, 99%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:6]CS([O-])(=O)=O.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=[O:31])[C:24]=2[CH:23]=[CH:22]1>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:6][N:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=[O:31])[C:24]=2[CH:23]=[CH:22]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=S(=O)([O-])CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=Cc1cccc2c1ccn2Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 82.9 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.80 g of [3,5-bis(trifluoromethyl)benzyl]methanesulfonate and 2.00 g of indole-4-carbaldehyde as a starting material to give 4.24 g of 1-[3,5-bis(trifluoromethyl)benzyl]indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 83%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH3:16])[CH:9]=3.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16][Br:17])[CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(ccc3ccc(Br)cc32)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2c(ccc3ccc(Br)cc32)c1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of 3-bromo-7-methylphenanthrene (2.640 g, 9.736 mmol) and N-bromosuccinimide (1.733 g, 9.736 mmol) in 200 ml of carbon tetrachloride was heated to reflux and benzoyl peroxide (25 mg) was added. After 2.5 hour a starch-iodide test showed that no NBS remained and the mixture was cooled to room temperature, washed with water, dried (MgSO4) and evaporated to give 3.14 g of crude product as a solid. Flash chromatography through 330 g of silica gel (10% CH2Cl2 /hexane) gave 2.719 g of a white solid which was recrystallized from 70 ml of cyclohexane (reflux to RT) to yield 2.061 g (60%) of the title compound as a white solid, mp 147°-148° C.