Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][S:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[C:14]1([S:11]([C:10]2[C:3]3[C:2](=[CH:9][CH:8]=[C:5]([CH:6]=[O:7])[CH:4]=3)[NH:1][N:24]=2)(=[O:13])=[O:12])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C=O)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)-benzaldehyde (2.4 g, 6.85 mmoles) in THF (10 mL) and 4M HCl (20 mL) was stirred in a round bottom flask at 3° C. A solution of sodium nitrite (0.49 g, 7.19 mmoles in H2O (2 mL) was added. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.84 g, 5.5 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].CI.[C:23](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1C
Yield: 64.6 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, 1.11 mmol), methyliodide (0.08 mL, 1.22 mmol) and potassium carbonate (0.15 g, 1.11 mmol) was stirred for 30 minutes under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(2-chloro-4-methyl-5-methoxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.22 g, yield:61.1%).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc(F)nc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-])=O.[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1/C=C/c1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(O)ccc1/C=C/c1ccc(O)cc1
Yield: 81.2 %

Procedure:
To a solution of the product of 3-nitro-4-[(E)-2-(4-hydroxyphenyl)-vinyl]phenol (216 mg, 0.84 mmol) in acetone (6 mL) was added a solution of ammonium chloride (89.9 mg, 1.68 mmol) in 2 mL of water. The mixture was heated to reflux, and the oil bath was removed. Zinc dust (164.8 mg, 2.5 mmol) was added in small portions to the reaction mixture to maintain a moderate reaction. After the reaction subsided an additional portion of zinc (82.4 mg, 1.25 mmol) was added. The reaction mixture was then heated to reflux for an additional 2 h. The precipitate was removed by filtration, washed with acetone (2×20 mL) and with ethyl acetate (2×30 mL). The combined washings were concentrated in vacuo and the crude product was purified by column chromatography using 5% methanol in dichloromethane to afford 3-Amino-4-[(E)-2-(4-hydroxy-phenyl)vinyl]phenol (155 mg, 72%). MS (ES) m/z: 228.11 (M+11), 134.06; 13C-NMR (DMSO-d6): δ 158.3, 156.9, 147.9, 130.4, 130.2, 127.9, 126.9, 124.5, 122.0, 115.9, 115.5, 114.2, 105.4, 102.2. Mp. 229-232° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Br:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][CH2:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(COc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 1d (0.034 g, 0.193 mmol) was reacted with the product from Example 225c (0.078 g, 0.193 mmol) for 15 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 1d (0.019 g, 0.109 mmol) and continued heating at 80° C. (18 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.041 g, 32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.15 (s, 2 H) 6.30 (d, J=7.35 Hz, 1 H) 6.79 (d, J=8.46 Hz, 2 H) 6.95-7.08 (m, 2 H) 7.16 (d, 1 H) 7.20-7.30 (m, 4 H) 7.45-7.55 (m, 2 H) 7.81 (d, J=8.82 Hz, 1 H) 8.47 (d, J=7.35 Hz, 1 H) 9.01 (d, J=8.46 Hz, 1 H) 9.98 (s, 1 H); Ms (ESI+) m/z 546.0 (M+H)+; (ESI−) m/z 542.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:2]3[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1783.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[NH2:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1>CC(O)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:13]1[N:12]=[C:11]([NH2:10])[C:16]([F:17])=[CH:15][N:14]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: OCc1cccc(Br)c1
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1nc(OCc2cccc(Br)c2)ncc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a magnetically stirred mixture of t-BUOK (1.0 M in t-BuOH, 1.36 ml, 1.36 mmol) was added (3-bromophenyl)methanol (0.25 g, 1.36 mmol). To the resulting solution was added 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and the mixture was capped and stirred at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and the resulting precipitate was collected by filtration. The solid was washed with water, washed with cyclohexane, and dried in a vacuum oven. A CH2Cl2 solution of the compound was loaded onto Biotage SCX column and eluted with CH2Cl2 followed by 2.0 M NH3 in MeOH. The solvent was evaporated under reduced pressure to give the title compound (0.100 g, 49%) as an off-white solid: mp 143-145° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=2.5 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.28 (s, 2H), 5.20 (br s, 2H); GCMS (EI) m/z 297, 299 (M)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C1COCCN1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 30% yield; NMR Spectrum: 1.95-2.01 (m, 2H), 2.36 (br s, 4H), 2.44 (t, 2H), 3.55 (br s, 4H), 4.35 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.54-7.58 (m, 2H), 7.87-7.89 (m, 2H), 8.27 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]([NH2:13])[CH3:12].CCN(CC)CC>>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][CH:11]([CH3:12])[CH3:10])[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Product: CC(C)Nc1ncnc(Cl)c1N
Temperature: 25 °C

Procedure:
4,6-Dichloropyrimidin-5-amine (492 mg, 3 mmol), propan-2-amine (284 μl, 3.3 mmol) and Et3N (836 μl, 6 mmol) were combined and heated at reflux. The mixture was refluxed for 5 days and each day additional isopropylamine (0.77 mL, 9 mmol) was added. The reaction mixture was cooled to room temperature, concentrated, slurried in water, filtered, rinsed with additional water and dried under reduced pressure to provide the title compound 52A as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.72 (1H, s), 6.53 (1H, d), 5.02 (2H, s), 4.20 (1H, octet), 1.18 (6H, d).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[CH:58][C:57]=1[S:61](Cl)(=[O:63])=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:57]2[CH:58]=[N:59][O:60][C:56]=2[CH3:55])(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1oncc1S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 12 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-4-sulfonyl chloride as starting materials in 12% yield. LCMS for C28H30ClN8O4S (M+H)+: m/z=609.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>ClCCCl.ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: O=C(Cl)CCCCCl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCCCl)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of 4-chloroquinolin-3-amine (4.00 g, 22.39 mmol) and 5-chlorovaleryl chloride (1.30 mL, 33.6 mmol) dissolved in 150 mL of 1,2-dichloroethane was heated to reflux. After 2.8 days more 5-chlorovaleryl chloride (1.0 mL, 7.7 mmol) was added. After 16 hours more the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 3.78 g of 5-chloro-N-(4-chloroquinolin-3-yl)pentanamide as a tan solid.
Reaction SMILES: [C:1]1([CH:7](Cl)[CH:8]([C:10]([F:13])([F:12])[F:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C>[C:1]1([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(Cl)c1ccccc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=Cc1ccccc1)C(F)(F)F
Yield: 71 %

Procedure:
To 7 ml of ethanol added was 0.6 mmol (0.126 g) of 1-phenyl-1-chloro-2-trifluoromethylpropane, and then 2 mmol (0.112 g) of potassium hydroxide was added thereto and allowed to react at 50° C. for 18 hours, whereby 1-phenyl-2-trifluoromethylpropene was obtained at a yield of 71%. The results of analyses of the product are shown below.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:19]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:20]([CH3:23])[CH2:21]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:24]([N:19]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:20]([CH3:23])[CH2:21][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred suspension of phtalimide (824 mg, 5.60 mmol), (S)-2-(dibenzylamino)propan-1-ol (1.02 g, 4.00 mmol) and PPh3 (1.47 g, 5.60 mmol) in THF (30 mL) cooled to 0° C. under N2 was added dropwise DEAD (1.2 mL, 7.60 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/methylene chloride 5/5) to afford a white solid (1.08 g, 70%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 4-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (23.6 mg, yield: quantitative).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14]O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)cc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)c(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 276 %

Procedure:
A solution of 7.6 grams (0.028 mole) of phosphorus tribromide in 200 mL of toluene was stirred, and 17.0 grams (0.080 mole) of 2,3,5-trichlorophenylmethanol was washed into the reaction vessel with about 5 mL of toluene. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate and washed with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 21.2 grams of 2,3,5-trichlorophenylmethyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([N:3]([CH2:7][P:8](=[O:11])([OH:10])[OH:9])[CH2:4][CH2:5][OH:6])C.[OH2:12]>Cl>[P:8]([CH2:7][NH:3][CH2:4][C:5]([OH:6])=[O:12])([OH:9])([OH:10])=[O:11]
Reactant: CCN(CCO)CP(=O)(O)O
Reactant: O
Agent: Cl
Product: O=C(O)CNCP(=O)(O)O
Temperature: 315 °C
Yield: 20 %

Procedure:
To a 100 ml Monel autoclave were charged 2.08 g (11.4 mmol) of N-ethyl-N-(2-hydroxyethyl)-aminomethylphosphonic acid and 3.63 g (91 mmol) of dry, powdered NaOH. The two powders were intimately mixed. To this mixture 1 ml of water was added and mixed until the dampness was evenly distributed through the mass. The reaction vessel was then flushed with N2, sealed and heated to 315° C. for two and a half hours. When the vessel had reached 315° C. an internal pressure of 2.2×106N/M2 had been established. By the end of the heating period the pressure had risen to 3.5×106N/M2. The excess pressure generated to this point was released and an additional 9 ml of H2O were introduced. The reaction temperature was adjusted to 300° C. which produced an internal pressure of 4.3×106N/M2. After five hours of heating at 300° C., the internal pressure had reached 4.6× 106N/M2. The reaction was allowed to cool to room temperature at which point the residual pressure was released. The reaction mixture was diluted with water and neutralized with 91 mmol of HCl. The solution was stripped to dryness. The residue was taken up in conc. HCl and the precipitated NaCl was filtered off. The filtrate was concentrated and purified by ion exchange chromatography to yield 0.38 g (20%) of N-phosphonomethylglycine based on the original substrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[C:45]([O:50][CH3:51])[CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[C:45]([O:50][CH3:51])[CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3c(OC)cccc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2c(OC)cccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.33, 7.23, 7.07, 6.81, 5.50, 4.68, 3.89, 2.87-2.80, 2.72-2.61, 2.12-2.01, 1.91, 1.30-1.19; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1627.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CC>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2cc3n(c2c1)CCN(c1nccc(C(F)(F)F)n1)C3C(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (50 mg, 0.19 mmol) in PrOH (2 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (105 mg, 0.58 mmol) and DIEA (185 mg, 0.96 mmol). The mixture was stirred at 100° C. for 4 h. The mixture was concentrated under vacuum and the residue was purified by preparative TLC to afford 1-isopropyl-7-(methylthio)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (45 mg, 57.7% yield) as a yellow oil. LC-MS MS (ESI) m/z 407.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cc(F)ccc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(F)ccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-fluorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-fluorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][CH2:13][C:9]1[S:8][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccs1
Reactant: NCc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1coc(CNCc2cccs2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of furfurylamine (2.0 g, 0.0206 mol) and 2-thiophenecarboxaldehyde (2.31 g, 0.0206 mol) in dichloromethane (60 ml) was stirred at room temperature for 5 minutes before adding portionwise sodium triacetoxyborohydride (5.24 g, 0.0247 mol). After addition was complete (approx. 2 minutes), the reaction mixture was stirred at room temperature for 3 hours and washed with sat'd NaHCO3 (aq.), dried (MgSO4), filtered and concentrated. The product mixture was purified by flash chromatography (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) to obtain the amine as a light yellow oil, 1.65 g (41%). MS (APCI): (M+1)+=194; 1H-NMR is consistent with structure.