Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([O-])[CH:4]=[C:3]([CH2:8][C:9]#[N:10])[CH:2]=1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O>C(Cl)Cl>[C:9]([CH2:8][C:3]1[C:4]([C:15]#[N:16])=[N:5][CH:6]=[CH:1][CH:2]=1)#[N:10]
Reactant: N#CCc1ccc[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#CCc1cccnc1C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
To a suspension of (1-oxy-pyridin-3-yl)-acetonitrile (10 g, 75 mmol) in anhydrous CH2Cl2 under a nitrogen atmosphere was added trimethylsilylcyanide (10.95 mL, 82 mmol) and dimethylcarbamoylchloride (7.55 mL, 82 mmol). The reaction mixture was stirred at room temperature for 72 hours and then concentrated. EtOAc (100 mL) was added to the residue and the organic phase was washed with 1 M NaOH (150 mL), dried over Na2SO4, filtered and concentrated. The resulting solid was purified by column chromatography (50% EtOAc/hexanes) affording 7.08 g (66%) of a yellow solid: mp 48-51° C.; MS (+) APCI m/z 144 [M+H]+.
Reaction SMILES: C([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])C.[O:21]1CCC[CH2:22]1>[Pd].C(O)C>[NH2:18][C:12]1[CH:11]=[C:10]([CH2:9][CH:3]([O:21][CH3:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(=Cc1ccc(OC)c([N+](=O)[O-])c1)CC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC
Yield: 95 %

Procedure:
Next, ethyl 2-ethyl-3-(4-methoxy-3-nitrophenyl)acrylate (4.50 g, 16.0 mmol), 10% palladium on carbon (1.50 g) and a 1:1 mixed solvent (150 mL) of tetrahydrofuran with ethanol were mixed and hydrogenation was carried out at an initial pressure of 294.3 kPa at room temperature. After completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated to afford 3.84 g (95%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1[CH2:48][OH:49]>CN(C=O)C>[OH:49][CH2:48][C@@H:40]1[CH2:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]1[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:8][CH:9]=2)[N:15]=1
Reactant: OC[C@@H]1Cc2ccccc2N1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@H]4CO)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Yield: 26.2 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (S)-indolin-2-ylmethanol (67.3 mg, 0.45 mmol) was added and the reaction mixture was heated at 85° C. overnight. The reaction was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent and gave (S)-tert-butyl 4-(2-(hydroxymethyl)indolin-1-yl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (65.3 mg, 26.2%). MS (ES+) m/z 554.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]([O:10][CH2:11][CH2:12]CC(=O)C)(=[O:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:10][CH2:11][CH2:12][CH2:1][C:2]([CH3:5])=[CH2:3])(=[O:9])[CH3:8]
Reactant: CC(=O)CCCOC(C)=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.3 %

Procedure:
Potassium tert-butoxide (9.4 g, 84 mmol) was added to a mixture of methyltriphenylphosphonium bromide (30 g, 84 mmol) in THF (300 ml), and the mixture was stirred at room temperature for 40 minutes. To the mixture a solution of 4-oxopentyl acetate (9.9 g, 68.8 mmol) in THF (30 ml) was gradually added dropwise while cooling in an ice-bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with diethyl ether twice. The extracts were combined, washed with brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford 4-methyl-4-pentenyl acetate (5.9 g, yield 60.4%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C(C)(C)C)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and pivaloyl chloride as starting materials.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=4)=[CH:20][C:19]=3[N+:34]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:27]=[CH:28][C:29]([Br:32])=[CH:30][CH:31]=4)=[CH:20][C:19]=3[NH2:34])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cc4)cc3N)ccc21
Yield: 66.5 %

Procedure:
The product of Example 93C (517 mg, 0.936 mmol), iron powder (322 mg, 5.76 mmol), and ammonium chloride (328 mg, 6.13 mmol) in water (3 mL) and ethanol (6 mL) were heated at 90° for 30 minutes. The hot reaction mixture was vacuum filtered and the residue washed with methanol and ethyl acetate. The filtrate was concentrated by rotary evaporation under vacuum, the residue partitioned with water (50 mL) and ethyl acetate (100 mL), and the organic phase washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide the title compound as an off-white foam (325 mg, 66%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[I:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[NH2:20].N1C=CC=CC=1>ClCCl>[I:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([F:18])([F:19])[F:17])=[CH:11][C:10]=1[NH:20][C:2](=[O:3])[O:4][CH:5]([CH3:7])[CH3:6]
Reactant: Cc1cc(I)c(N)cc1C(F)(F)F
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(I)c(NC(=O)OC(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
Add a solution of isopropyl chloroformate (99.6 mL, 99.6 mmol, 1M in toluene) dropwise to a solution of 2-iodo-4-methyl-5-trifluoromethylphenylamine (27.26 g, 90.55 mmol) and pyridine (14.6 mL, 181.1 mmol) in dichloromethane (350 mL) at 5° C. under an atmosphere of nitrogen and warm the mixture to room temperature. Stir for 3 h and wash the mixture with 2 N HCl (100 mL) and brine (100 mL). Dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a tan solid (33.59 g, 96%), which is used in the next step without purification. APCI MS m/z 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([F:19])=[CH:6][C:3]=1[C:4]#[N:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:8]3[C:7]([F:19])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:9]=3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Temperature: 140 °C
Yield: 51.6 %

Procedure:
A mixture of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 43; 0.8 g, 2.8 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.8 g, 5.6 mmol), and DIEA (0.5 g, 3.7 mmol) in n-BuOH (4 ml) was heated in a sealed tube at 140° C. for 48 hrs. The reaction mixture was concentrated and purified by column chromatography (DCM:MeOH=50:1) to give the title compound (0.55 g, 50%). MS: Calcd.: 380. Found: [M+H]+ 381.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:30])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1.Cl[CH2:32][C:33](Cl)=[O:34].[OH-].[Na+].Cl>C(O)C.O>[CH3:30][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][CH2:5][N:4]3[CH2:3][CH2:2][O:1][CH2:32][C:33]3=[O:34])[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23]
Reactant: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(CCN4CCOCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of N-[2-(5-{2-[(2-hydroxyethyl)amino]ethyl}-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (220 mg) in ethanol (2 mL) and water (1 mL) were added chloroacetyl chloride (95 μL) and 8M aqueous sodium hydroxide solution (310 μL), and the mixture was stirred at the inside temperature of 20° C. or less for 3 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (100 mg, yield 41%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][C:34]([OH:36])=O.C(N(C(C)C)C(C)C)C.[C:46]([C:50]1[O:54][C:53]([C:55]2[C:56]([NH2:73])=[N:57][CH:58]=[C:59]([C:61]3[N:65]([CH3:66])[N:64]=[C:63]([CH:67]4[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]4)[N:62]=3)[N:60]=2)=[N:52][N:51]=1)([CH3:49])([CH3:48])[CH3:47]>C(#N)C>[NH2:73][C:56]1[N:57]=[CH:58][C:59]([C:61]2[N:65]([CH3:66])[N:64]=[C:63]([CH:67]3[CH2:72][CH2:71][N:70]([C:34](=[O:36])[CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH2:69][CH2:68]3)[N:62]=2)=[N:60][C:55]=1[C:53]1[O:54][C:50]([C:46]([CH3:49])([CH3:47])[CH3:48])=[N:51][N:52]=1
Reactant: O=C(O)CCOC1CCCCO1
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1nc(C2CCN(C(=O)CCOC3CCCCO3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30.4 g, 80.04 mmol), was added portionwise to a stirred solution of 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (12.67 g, 72.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (25.3 mL, 145.52 mmol) dissolved in acetonitrile (200 mL) at 25° C. The resulting solution was stirred at 25° C. for 20 minutes then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (30 g, 72.76 mmol) was added portionwise, washing the last portion into the mixture as a slurry in acetonitrile (100 mL). After stirring for 1 hour the precipitate was collected by filtration, washed with acetonitrile and drying in vacuo to afford 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (35.0 g, 89%) as a beige solid. The filtrate was diluted with DCM (600 mL), washed with water, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 2 to 2.5% 7N ammonia in methanol with dichloromethane. A second crop of product (3.31 g, 6.13 mmol, 8.43%) was also obtained as a cream solid. Both samples were combined to give a beige solid: 1H NMR Spectrum: (DMSO-d6) 1.44 (9H, s), 1.52-1.79 (4H, m), 1.88-2.04 (2H, m), 2.53-2.73 (2H, m), 2.73-2.87 (1H, m), 2.91-3.05 (1H, m), 3.13-3.24 (1H, m), 3.37-3.47 (1H, m), 3.53-3.65 (1H, m), 3.7-3.8 (1H, m), 3.81-3.89 (1H, m), 3.89-3.99 (1H, m), 4.20 (3H, s), 4.29-4.4 (1H, m), 4.54-4.61 (1H, m), 7.60-8.20 (2H, br), 8.85 (1H, s); Mass Spectrum [M+H]+=540.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:14][CH2:13][CH2:12][C:11]1([CH2:15][N:16]([C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([O:29][CH3:30])=[CH:21][CH:20]=1)C=O)[CH2:10][CH2:9][CH2:8]2.O>C1COCC1>[N:7]12[CH2:14][CH2:13][CH2:12][C:11]1([CH2:15][NH:16][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([O:29][CH3:30])=[CH:21][CH:20]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(N(C=O)CC23CCCN2CCC3)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NCC23CCCN2CCC3)c2ccccc12
Yield: 65.6 %

Procedure:
To lithium aluminum hydride (1.76 g, 46.3 mmol) in THF (43 ml), 1-[N-(1-Azabicyclo[3.3.0 ]octan-5-yl )methyl-N-formylamino]-4-methoxynaphthalene (3.00 g, 9.26 mmol) in THF (15 ml) was added dropwise at room temperature. After refluxed for 1 hour, the reaction mixture was cooled and chilled water was added dropwise. Formed solids were removed by filtration and the filtrate was concentrated in vacuo and purified by chromatography to afford the desired compound (1.80 g, 62.7%), as a pale yellow liquid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([S:15][CH2:16][C:17](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:17]=1[CH2:16][S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CSc1ccccc1
Agent: Cl
Product: c1ccc(SCc2nc3ccccc3[nH]2)cc1
Yield: 68.8 %

Procedure:
A 100 mL flask fitted with a stir-bar and condenser was charged with 1,2-phenylenediamine (2.88 g, 26.6 mmol), (phenylthio)acetic acid (4.00 g, 26.6 mmol), and 4M HCl (40 mL). The resultant suspension was heated in a 130° C. bath 48 hr. The mixture was cooled and concentrated in vacuo to a brown syrup. The syrup was taken up in EtOAc (100 mL) and washed with saturated NaHCO3 (2×75 mL) and brine (50 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a tan solid. The crude solid was triturated with hexanes:EtOAc 6:1 (50 mL), filtered, pressed with rubber dam, and rinsed with hexanes:EtOAc 4:1 (2×10 mL). The material was dried to give 4.4 g of 68 as a tan solid (77%). 1H NMR (300 MHz, CDCl3): δ 11.7 (bs, 1H), 7.7-7.4 (m, 2H), 7.4-6.9 (m, 7H), 4.4 (s, 2H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with retention time of 4.0 min.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)(=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[C:39]1[CH2:40][CH2:41][NH:42][CH2:43][CH:44]=1>CS(C)=O.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[C:39]1[CH2:40][CH2:41][N:42]([CH2:12][CH:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)[CH2:43][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2nc1C)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of [(2R)-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-yl]methyl 4-methylbenzenesulfonate (0.400 g, 1.000 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.540 g, 2.497 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.239 g (54%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.35 (silica, methanol:ethyl acetate 1:9); mp 138–141° C.
Reaction SMILES: [CH2:1]1[N:9]2[C:5](=[N:6][C:7]([NH:10]C(C(F)(F)F)=O)=[CH:8]2)O[CH:3]=[C:2]1[Br:17].[CH2:18]1COCC1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[Br:17][C:2]1[CH:3]=[CH:18][C:5]2[N:9]([CH:8]=[C:7]([NH2:10])[N:6]=2)[CH:1]=1
Reactant: O=C(Nc1cn2c(n1)OC=C(Br)C2)C(F)(F)F
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1cn2cc(Br)ccc2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a 250 mL round-bottomed flask was added N-(6-bromoH-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (3.50 g, 11 mmol), THF (15 mL), methanol (15 mL), water (15 mL) and potassium carbonate (16 g, 114 mmol). The mixture was stirred at 60° C. for 16 h. After cooling to rt, the mixture was poured into water (100 mL) and extracted with CH2Cl2 (4×75 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH/CH2Cl2) afforded the title compound (1.01 g, 42%). MS (ESI, positive ion) m/z: 212 (M(79Br)+1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].OC[C:11]1[C:16]([OH:17])=[C:15]([CH2:18][OH:19])[CH:14]=[C:13](C)[CH:12]=1.SCCC(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:1]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:16]([OH:17])[C:15]=2[CH:18]=[O:19])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: Cc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CCS
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(O)c1-c1cccc(O)c1C=O
Reaction time: 8 h

Procedure:
A mixture of 146.0 g m-cresol, 25.2 g 2,6-bis(hydroxymethyl)-p-cresol, 5.0 g 3-mercaptopropionic acid and 1.5 g p-toluenesulfonic acid monohydrate in 200 ml glacial acetic acid were charged into a 1-L reaction vessel equipped with a paddle stirrer, reflux condenser and a nitrogen inlet tube. The mixture was heated to reflux and maintained at reflux to allow formation of the alternating copolymer. After 8 hours, 146.5 g salicyaldehyde were added over time to the reaction mixture to form substantially m-cresol-salicylaldehyde block segments. Reflux was continued for 8 hours. The reaction mixture was slowly poured into 7-L deionized water to precipitate the resin. Once the solvent had exchanged with water, the product was collected on a filter, slurried once in warm deionized water for about 30 minutes, again collected, rinsed with water and dried in a vacuum oven under about 125 mm Hg and at about 100° to 105° C. About 281 g of a block copolymer resin having a number average molecular weight, M n, of 1472 Daltons and a Tg of 233° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccc(Cl)cc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(2,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.03 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which precipitates is filtered and air-dried, yield 5.5 g., m.p. 215°-226°C. Recrystallizations from ethanol gives material with m.p. 224.5°-227°C.
Reaction SMILES: [C:1]([C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][O:45][NH2:46]>>[CH3:44][O:45][N:46]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Cc1ccccc1
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)Cc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.