Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]2.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]3)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]c(C(=O)OC(C)(C)C)cc3c2)cc1
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
A solution of tert-butyl 5-amino-1H-indole-2-carboxylate (220 mg, 0.94 mmol), 4-acetylbenzoic acid (155 mg, 0.94 mmol) and TBTU (303 mg, 0.94 mmol) in DMF (6 mL) at 4° C. was treated with diisopropylethylamine (329 uL, 1.89 mmol) and stirred 40 min at 0˜5° C. The solvent was removed under vacuo. The crude product was chromatographed on silica gel eluted with 1% MeOH in CH2Cl2 to give 2 (350 mg, 98%). 1HNMR DMSO-d6) δ11.66 (bs, 1H), 10.34 (s, 1H), 8.09 (d, 1H, J=8.8 Hz), 8.07 (s, 4H), 7.55 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.03 (s, 1H), 2.63 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:30]=[C:29]([NH2:31])[N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:30]=[C:29]([NH2:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 44.4 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 6-chloro-9H-purin-2-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 20-30% ACN in water. The fractions containing the desired compound were collected and concentrated in vacuo. The residue was re-crystallized in an EtOAc/MeOH/hexane mixture to give the title compound (295 mg, 44.4%). 1H NMR (500 MHz, CD3OD) δ ppm 1.50 (d, J=6.83 Hz, 3 H), 3.59-3.66 (m, 3 H), 3.89 (br s, 3 H), 5.56 (br s, 1 H), 6.45 (d, J=1.95 Hz, 1 H), 6.68-6.73 (m, 1 H), 7.58-7.65 (m, 2 H), 7.77-7.89 (m, 2 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10, 389; found 389.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.B1([C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cccc(-c2cccnc2)c1
Yield: 63.8 %

Procedure:
A mixture of 1,3-dibromobenzene (8.7 g, 36.8 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (4.0 g, 24.5 mmol) in EtOH (60 ml) and toluene (60 ml) together with 2N Na2CO3 solution (24.5 ml) was degassed with a stream of N2 for 10 min. Tetrakis(triphenylphosphine)-palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 14 h. The mixture was concentrated under reduced pressure to remove the organic solvents. The organics were extracted with EtOAc (2×125 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography on silica, using 80% diethyl ether in hexane as the eluent, to yield 3-(3-bromophenyl)pyridine (3.66 g, 64%): δH (360 MHz, CDCl3) 7.30-7.42 (2H, m), 7.47-7.60 (2H, m), 7.72 (1H, s), 7.84 (1H, dt, J 8 and 2), 8.62 (1H, dd, J 4.8 and 1.5), 8.83 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:45][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:19][CH:18]=2)=[O:31])(=[O:43])=[O:44])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-tert-butyl-benzenesulfonamide: 1H-NMR (CDCl3) δ 7.76 (2H, d, J=8.7 Hz), 7.53-7.24 (11H, m), 6.43 (1H, br.s), 3.54-3.47 (2H, m), 2.87 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.26 (3H, s), 1.32 (9H, s).
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@@H](C(F)(F)F)CC3)C=2)C=1)(C)CO.[CH3:27][C@@:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH:45]4[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:47][CH2:46]4)[CH:40]=3)[CH:35]=2)[CH2:32][O:31]C(=O)[NH:29]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CCOC(/N=N/C(OCC)=O)=O>>[NH2:29][C@@:28]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH:45]3[CH2:46][CH2:47][CH:48]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50]3)[CH:40]=2)[CH:35]=1)([CH3:27])[CH2:32][OH:31]
Reactant: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1
Product: CCCCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 35 %

Procedure:
(R)-2-Amino-2-[6-(4-pentyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol was synthesized as per (R)-2-Amino-2-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol (Example 259) in 35% yield (and 21% recovered starting material) using (R)-4-Methyl-4-[6-(4-pentyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one as starting material. Note that the starting material contained 20% impurity (mixture of reduced DIAD, reduced DEAD).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[N:9]([C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:8][CH2:7][CH2:6]1)([OH:3])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]([C:17](=[O:30])[C:18]3[CH:19]=[CH:20][C:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)[CH2:8][CH2:7][CH2:6][CH:5]([CH2:4][C:1]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)=[O:3])[C:11]=2[CH:12]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CC1CCCN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccc(Cl)cc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)CC2CCCN(C(=O)c3ccc(C4CCCCC4)cc3)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-carboxymethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in dichloromethane (50 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.54 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. To the mixture are added with stirring N-methylpiperazine (0.24 ml) and triethylamine (0.46 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:--methanol=40:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) as colorless amorphous.
Reaction SMILES: OC(C(F)(F)F)=O.Cl[C:9]1[CH:10]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[C:29](=[O:41])[N:30]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:21][CH:20]=2)[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[N:14]=1.[H][H]>C(N(CC)CC)C.[Pd].CCO>[F:40][C:37]1[CH:38]=[CH:39][C:34]([N:30]2[CH2:31][CH2:32][CH2:33][CH:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:11]4[C:12]5[N:13]([CH:15]=[CH:16][N:17]=5)[N:14]=[CH:9][CH:10]=4)=[CH:24][CH:23]=3)=[O:27])[C:29]2=[O:41])=[CH:35][CH:36]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Nc2ccnn3ccnc23)cc1)C1CCCN(c2ccc(F)cc2)C1=O
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a suspension of N-(4-((6-chloroimidazo[1,2-b]pyridazin-8-yl)amino)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide TFA salt (0.013 g, 0.027 mmol) from Example XXI(i) and EtOH (4 mL) in a 500 ml PARR bottle was added 10% Pd/C (20 mg) and 2 drops of triethylamine. The PARR bottle was then charged with Hydrogen gas at 55 psi and allow to shake at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC to furnish 0.008 g of the title compound as a TFA salt. LC/MS, m/e 445 (M+1). HPLC Rt, 1.81 mm. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 mm, hold at 100% B 1 mm, flow rate 4 mL/min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11]([CH2:13][C:14](=O)[CH3:15])=[O:12]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:13]([C:11](=[O:12])[CH3:10])=[C:14]([CH3:15])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CC(=O)CCl
Reactant: Nc1cccnc1N
Solvent: CCO
Product: CC(=O)c1c(C)nc2c(N)cccn12
Yield: 15.7 %

Procedure:
A mixture of 2,3-diaminopyridine (7 g, 64.1 mmol), 3-chloroacetylacetone (8.6 g, 64.1 mmol) in ethyl alcohol (80 ml) was refluxed for 9 hours. The solvent was removed under reduced pressure and the residue dissolved in methylene chloride. A sodium bicarbonate solution was added and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The combined organic layer was dried and evaporated under reduced pressure. Chromatography of the residue on silica gel (methylene chloride:methanol, 100:5) gave a product which after recrystallisation from ethyl acetate gave 1.9 g (15%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:41][C:42]([NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:43])[C:17]([N:19]([C:26]([CH:38]([CH3:40])[CH3:39])([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:27](=[O:29])[NH2:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([NH:41][C:42]([NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:43])[C:17]([N:19]([C:26]([CH:38]([CH3:39])[CH3:40])([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:27](=[O:29])[NH2:28])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:18])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N(C(=O)[C@@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)Nc2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(C(N)=O)(C(C)C)N(C(=O)[C@@H](Cc2ccc(O)cc2)NC(=O)Nc2ccccc2)c2ccccc2)cc1
Yield: 90.5 %

Procedure:
A mixture of Example 14 (475 mg, 0.723 mmol) and 10% Pd/C (50 mg) in ethanol (30 mL) was stirred under an atmosphere of hydrogen for 2 h after which time a further batch of catalyst (50 mg) was added. After 6 h the solids were removed by filtration through celite to afford the crude titled product as a white foam (380 mg). TLC (3% methanol in methylene chloride) Rf =0.23. 1H NMR (300 MHz, CDCl3) d 0.97 (2×d, J=7.0 Hz, 6H), 2.62 (dd, J=13.0, 6.2 Hz, 1H), 2.97 (dd, J=13.0, 4.1 Hz, 1H), 3.64 (s, 3H), 3.70 (d, J=16.6.0 Hz, 1H), 4.19 (d, J=16.6.0 Hz, 1H) 4.90 (m, 2H), 6.38 (d, J=9.0 Hz, 1H), 6.6-7.6 (m, 20H). C34H36N4O5 requires m/z 580.6838; found 580.6852.
Reaction SMILES: [C:1]([N:8]1[C@@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[C@@H:20]([C:21](=[O:23])[NH:24][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
1.58 g (3R)-2-BOC-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid, 0.915 g aminodiphenylmethane, 1.01 g EDC, and 0.709 g HBT are dissolved together in 6 ml DMF and 0.53 g triethylamine is added. The mixture is stirred at room temperature overnight and worked as in Example 5A to give 2.20 g (3R)-2-tert-butoxycarbonyl-3-diphenylmethylcarbamoyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1.[OH:34][C:35]1[C:39]([CH:40]=[O:41])=[CH:38][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:40]([C:39]1[C:35]([O:34][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=4)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=3[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=2)=[N:36][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=1)=[O:41]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
A mixture of methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-(methanesulfonyloxy)benzoate (1.50 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.56 g), potassium carbonate (0.41 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 2 hrs. The reaction mixture was acidified by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3 to 1:1, v/v) to give methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-(methanesulfonyloxy)benzoate as pale-yellow crystals (0.80 g, yield 41%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 136-137° C.
Reaction SMILES: [CH2:1]([O:21][CH2:22][C@H:23]([CH2:25][OH:26])[OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O1CCCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:21][CH2:22][C@H:23]([CH2:25][O:26][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
20 grams of 1-eicosanyl-sn-glycerol and 18 grams of triphenylchloromethane were added to a mixture of 400 ml dry tetrahydrofuran (THF) and 100 ml dry acetonitrile. 15 ml of dry triethylamine was added, and the reaction mixture was refluxed for 17 hours. The reaction mixture was then cooled to room temperature, poured on ice (500 grams), transferred to a separatory funnel, and extracted thrice with 200 ml diethyl ether. The organic phase was washed consecutively with 150 ml water, twice with 150 ml dilute (1.5%) H2SO4, 150 ml water, 150 ml concentrated aqueous sodium bicarbonate, and again with 150 ml water. The solution was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue, a brown oil, was dissolved in 300 ml ethyl acetate, and cooled at −20° C. overnight. The mixture was centrifuged (3,500 rotations per minute) at −10° C., and the mother liquid was poured of. The obtained solid was dissolved in hexane and refrigerated (5±3° C.) overnight. Filtration of the precipitate yielded 26.0 grams of pure (R)-1-eicosanyl-3-trityl-sn-glycerol as an off-white solid. The yield was 79%.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.C([O:15][C:16]([C:18]1[O:19][C:20]2[C:27]([Br:28])=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]=1[CH3:23])=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.CC(C)=O>[OH:15][CH2:16][C:18]1[O:19][C:20]2[C:27]([Br:28])=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]=1[CH3:23]
Reactant: CCOC(=O)c1oc2c(Br)cccc2c1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=C=O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(CO)oc2c(Br)cccc12
Yield: 74 %

Procedure:
51.82 ml of a 1.5 molar solution of DIBAL-H in toluene are added dropwise to a solution, cooled to -78° C. with a bath of solid carbon dioxide and acetone, of 10 g (35.3 mmol) of 2-ethyloxycarbonyl-3-methyl-7-bromobenzofuran in 100 ml of toluene. The solution is allowed to return to room temperature and 50 ml of water and 100 ml of a saturated solution of Rochelle salt are successively added. Extraction is carried out with ethyl acetate (3×80 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent: 2% methanol in dichloromethane). 6.3 g (Yield: 74%) of 2-hydroxymethyl-3-methyl-7-bromobenzofuran are obtained--M.p.: 103° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Product: O=C1Nc2ccc(F)cc2C1=CNc1ccc(OCCCN2CCCCC2)cc1
Yield: 47.9 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (0.57 g, 1.3 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.363 g, 2 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (379 mg, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[C:14]1([CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:21](=[O:22])[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:24][CH3:25])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(NC(=O)C(CC)c3ccccc3)sc2c1
Reaction time: 16 h

Procedure:
6-Ethoxy-benzothiazol-2-ylamine (39 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25%). ESI-MS m/z calc. 340.1, found 340.9 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[H-].[Na+].CS([C:17]1[N:22]=[C:21]([OH:23])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[N:18]=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][O:6][C:17]1[N:22]=[C:21]([OH:23])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[N:18]=1
Reactant: CS(=O)(=O)c1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a round bottom flask fitted with a magnetic stir bar and rubber septum was added 2 mL DMF, 3,4-difluorobenzyl alcohol (14 μl, 0.11 mmol) and sodium hydride (60% in oil, 4.5 mg, 0.12 mmol). The flask was flushed with nitrogen and 2-methylsulfonyl-4-hydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Step A) (43 mg, 0.1 mmol) in 500 μL DMF was added by syringe. After 1 h, the reaction was quenched with aqueous NH4Cl. A precipitate fell out of solution and it was filtered, washed with water and dried under reduced pressure. HPLC/MS: m/e=494 (M+); Rt=4.28 min; 1H-NMR 500 MHz (CDCl3): δ 5.39 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.15-7.22 (m, 4H), 7.22-7.28 (m, 1H), 7.41 (d, J=2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10](C(C)(C)C)=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[C:4](C(C)(C)C)[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)cc(Br)c1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Brc1cccc2c1-c1ccccc1C2

Procedure:
The 4-bromo-2,7-di-t-butyl-fluorene is then reacted with benzene and AlCl3 to produce 4-bromo-fluorene as follows: