Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[N:10][C:9]([NH2:12])=[N:8][CH:7]=1.CO.[Br:15]Br>O>[Br:15][C:5]1[S:1][C:2]([C:6]2[N:11]=[N:10][C:9]([NH2:12])=[N:8][CH:7]=2)=[N:3][CH:4]=1
Reactant: BrBr
Reactant: Nc1ncc(-c2nccs2)nn1
Solvent: O
Solvent: CO
Product: Nc1ncc(-c2ncc(Br)s2)nn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 36.5 %

Procedure:
To a vial was added 6-(thiazol-2-yl)-1,2,4-triazin-3-amine (600 mg, 3.4 mmol), methanol (1.2 mL), water (0.6 mL). The mixture was cooled to 0° C. and bromine (816 mg, 5.1 mmol) was added. The reaction was stirred for 45 min and then quenched with saturated sodium bicarbonate solution (20 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were dried over Na2SO4, concentrated, and purified using silica gel chromatography to afford 320 mg of 6-(5-bromothiazol-2-yl)-1,2,4-triazin-3-amine as an off-white solid.
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH3:17])=[CH2:16])=[CH:13][CH:12]=1>CCCCCC>[C:1]([S:9][C:15]([C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1)([CH3:17])[CH3:16])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(S)c1ccccc1
Reactant: C=C(C)c1ccc(Cl)cc1
Solvent: CCCCCC
Product: CC(C)(SC(=S)c1ccccc1)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
Dithiobenzoic acid (6.3 g) and 4-chloro-α-methylstyrene (6 g) were combined and the mixture heated at 70° C. overnight. The residue was subjected to column chromatography (Kieselgel-60, 70-230 mesh, n-hexane as eluent) which gave the title compound as a purple solid (34.2% yield) m.p. 77-78° C. 1H-nmr (CDCl3) d (ppm): 1.97 (s, 6H, 2×CH3), 7.20-7.52 (m, 7H, ArH) and 7.86 (d, 2H, ArH). 13C-nmr (CDCl3) d (ppm): 28.4, 55.7, 126.5, 128.1, 131.9, 132.4, 142.8, 146.0. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:37]#[C:36][CH2:35][N:33]([CH3:34])[CH3:32])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CC2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Yield: 70 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.070 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and N,N-dimethylpropargylamine (0.020 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted 3×with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. Recrystallization with CH2Cl2/hexanes affords the desired product (0.046 g, 70%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: C1COCCN1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21 %

Procedure:
Morpholine (7.0 g, 8.8 mmol) was added to the solution of 5-bromomethyl-2-chloro-pyridine in carbon tetrachloride (20 mL) and stirred at room temperature for 6 h. Water was added to the reaction mixture and the separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. Purification by column chromatography using silica gel (60-120 mesh) and ethyl acetate as eluent afforded 4-(6-chloro-pyridin-3-yl-methyl)-morpholine (1.2 g, 21%) as a brown oily liquid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1([CH:20]=[CH:19][CH:18]=[CH:17][CH2:16]1)[CH2:14][OH:15].O>N1C=CC=CC=1>[C:1]([O:15][CH2:14][C:13]1([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH2:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1(c2cccs2)C=CC=CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2cccs2)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (5 ml) was added to a solution of 1-(2-thienyl)benzyl alcohol in pyridine. The resultant solution was stirred at 70° C. for 3h. Water (50 ml) was added and the reaction mixture was stirred at room temperature for 2h. This was extracted with ethyl acetate (2×50 ml) and the combined organic layers dried over anhydrous MgSO4. Removal of the solvent gave crude product, which was purified by passing through silica gel using 3:1 hexane/ethyl acetate mixture to give 1-(2-thienyl)benzyl acetate.
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[SH-:13].[Na+]>CCO>[C:1]1([C:7]2([C:10](=[S:13])[NH2:11])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CC1
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=S)C1(c2ccccc2)CC1
Temperature: -20 °C

Procedure:
1-Phenylcyclopropanenitrile (1-1, 10.0 g, 69.8 mmol) and sodium hydrosulfide hydrate (0.98 g, 17.5 mmol) were mixed in a 350 mL glass bomb and dissolved in 50 mL anhydrous EtOH. The resulting solution was cooled to −20° C. and a stream of H2S was bubbled through the mixture for 30 min. The bomb was sealed and heated to 90° C. for 2 days. The dark mixture was cooled to −25° C. and N2 was bubbled through for 1 h. The reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (3×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude thioamide was triturated with hexanes to provide pure 1-phenylcyclopropanecarbothioamide (1-2) as a white solid.
Reaction SMILES: O.[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10].[H][H]>[C].[Pd].C1(C)C=CC=CC=1>[F:2][C:3]([F:15])([F:16])[C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCc1cccc(C(F)(F)F)c1
Yield: 97.8 %

Procedure:
Palladium carbon (10%, 6 gm) was added to water (20 ml) and then added 3-(trifluoromethyl)cinnamic acid (100 gm) and toluene (1000 ml). The resulting contents were hydrogenated with hydrogen gas at a pressure of 4 kg at 45 to 50° C. for 2 hour 30 minutes. The reaction mass was then filtered through celite bed and the layers were separated. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 98.7 gm of 3-[3-(trifluoromethyl)phenyl]propionic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].Br[C:17]1[CH:18]=[N:19][C:20]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:21][CH:22]=1.CCN(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:24]1([O:23][C:20]2[N:19]=[CH:18][C:17]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=3)=[CH:22][N:21]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Brc1cnc(OC2CCCC2)nc1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(OC3CCCC3)nc2)cc1
Temperature: 25 °C

Procedure:
To 33.1 mg (0.17 mmol) N-[2-(4-ethynyl-phenyl)-1-methyl-ethyl]-acetamide (I58.3) and 40.0 mg (0.17 mmol) 5-bromo-2-cyclopentyloxypyrimidine (I14.1) in 2.0 mL THF are added 11.6 mg (0.02 mmol) bis(triphenylphosphin)palladiumdichlorid, 1.57 mg (8.00 μmol) CuI and 56.0 μL (0.33 mmol) DIPEA. The reaction mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:17]1([CH2:20][NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:17]1([CH2:20][NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([O:34][C:13]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:8]=[C:7]([C:5]([N:1]6[CH2:4][CH2:3][CH2:2]6)=[O:6])[S:15][C:14]=45)=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:19][CH2:18]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NCC1CC1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 53.8 %

Procedure:
This material was prepared by reacting 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (88 mg, 0.35 mmole) with 6-hydroxy-2-methyl-1-benzo[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide 130a (110 mg, 0.42 mmole) and Cs2CO3 (228 mg, 0.70 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (90 mg, 54%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.46 Hz), 7.96 (1H, d, J=2.26 Hz), 7.89 (1H, s), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz), 6.75 (1H, d, J=5.46 Hz), 4.62 (2H, t, J=7.72 Hz), 4.10 (2H, t, J=7.82 Hz), 3.20 (2H, t, J=6.31 Hz), 2.62 (3H, s), 2.35 (2H, m), 1.07 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2.[CH2:29]([OH:34])/[CH:30]=[CH:31]\[CH2:32][OH:33].C([O-])(O)=O.[Na+]>CN1CCCC1=O.Cl[Pd]Cl>[OH:33][CH2:32][CH2:31][CH:30]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2)[CH2:29][OH:34]
Reactant: OC/C=C\CO
Reactant: CC(C)C1=NCCc2ccc(C=Cc3cc(Br)c4cc(C#N)ccc4c3)cc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)C1=NCCc2ccc(C=Cc3cc(C(CO)CCO)c4cc(C#N)ccc4c3)cc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A solution of Example 1K (3.09 g, 10 mmol) in N-methylpyrrolidinone (10 mL) was treated with PdCl2 (120 mg, 1 mmol), cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and NaHCO3 (1.01 g, 12 mmol), heated to 130° C., stirred for 1 hour, cooled to room temperature, and purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:24])[C:7](=[O:12])[C:6]([C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccc(Br)cc2c(-c2ccccc2)c1-c1cnc[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c(-c2cnc[nH]2)c(-c2ccccc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A flask containing 6-bromo-3-(3H-imidazol-4-yl)-4-phenyl-1H-quinolin-2-one (23 mg, 0.063 mmol) (Example 134), K2CO3 (30 mg, 0.22 mmol), methyl iodide (4 μL, 0.063 mmol) and 0.1 mL of DMF was stirred at 25° C. for 3 hrs. The compound was purified by RP-HPLC, eluting with 30-70% CH3CN in 0.1% TFA/H2O over 20 mins to give 13 mg (42%) the title compound as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 7.90 (dd, 1H), 7.70 (d, 1H), 7.62 (m, 3H), 7.34 (m, 3H), 6.60 (s, 1H), 3.92 (s, 3H). Diff Noe, irradiation at 3.92 ppm (N—CH3) enhanced 7.70 ppm (d, 1H, H-8). Mass spectrum (ESI, m/z) calcd. for C19H1BrN3O2 379.0, found 380.0 (M+H).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)#[CH:10].[N:16]([C:19]1[S:20][C:21]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[C:22]([CH3:24])[N:23]=1)=[N+:17]=[N-:18]>>[CH2:28]([NH:27][C:25]([C:21]1[S:20][C:19]([N:16]2[CH:10]=[C:9]([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[N:18]=[N:17]2)=[N:23][C:22]=1[CH3:24])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C#Cc1ccsc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3ccsc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 3-ethynylthiophene to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 66% yield: mp 123-126° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.82-7.81 (m, 1H), 7.51-7.32 (m, 7H), 6.11 (br s, 1H), 4.63 (d, J=6.0 Hz, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.4, 153.3, 144.8, 137.4, 130.3, 128.9, 127.9, 127.9, 126.8, 125.7, 124.4, 122.6, 116.4, 44.3, 17.4; MS (ES+) m/z 382.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Reactant: NCCCN1CCOCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCCN4CCOCC4)ccc3Cl)ccn2)n1
Yield: 45.6 %

Procedure:
Following procedure of Example 83, 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (0.100 g, 0.2511 mmol), triethylamine (0.1016 g, 1.004 mmol), (DMF (3 mL), ethyl carbonochloridate (0.02641 mL, 0.2762 mmol) and 4-(3-aminopropyl)morpholine (0.07242 g, 0.5022 mmol) were reacted to afford 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(3-morpholinopropyl)benzamide hydrochloride (0.030 g, 20.50% yield) as off white solid. 1H NMR (DMSO) δ 11.20 (bs, 1H), 10.37 (bs, 1H), 8.83 (t, 1H), 8.23 (d, 1H), 7.87 (dd, 1H), 7.84 (d, 1H), 7.82 (d, 1H), 6.58 (m, 2H), 6.55 (d, 1H), 3.94 (d, 2H), 3.72 (t, 2H), 3.40 (d, 2H), 3.32 (q, 2H), 3.12 (m, 2H), 3.03 (m, 2H), 2.21 (d, 3H), 1.93 (m, 2H); Mass spectrum (esi) m/z=488 (100) (M+H—HCl).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20]O)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Br)([Br:39])=O>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][Br:39])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Br)Br
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CO)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CBr)nc12

Procedure:
0.6 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-hydroxymethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are taken up in 7 ml of dichloromethane and 0.25 ml of triethylamine are added at ambient temperature with stirring. Then 0.15 ml of thionyl bromide are added. After 2 hours' stirring at constant temperature the reaction is complete. For working up, the mixture is diluted with 20 ml of dichloromethane and washed successively with 15 ml of water and 15 ml of aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off in vacuo. The residue remaining is recrystallised from diethyl ether. 0.45 g of the title compound remain, pure enough to be used in the subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:54][C:55]([F:64])([F:63])[C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][CH:62]=1)[NH2:59]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:59][C:58]4[CH:60]=[CH:61][CH:62]=[C:56]([C:55]([F:54])([F:63])[F:64])[CH:57]=4)=[O:18])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc2c(n1)CCN(c1ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
A mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 1.0 mL DMF was stirred at room temperature for 10 minutes. Then 3-(trifluoromethyl)aniline (0.025 mL, 0.20 mmol) was added and the reaction heated at 55° C. for 18 hours and then 90° C. for 2 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with dilute aqueous HCl, aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with CHCl3, then gradient 2% to 5% MeOH/CHCl3 to give the title compound as a brownish-tan solid (3 mg, 8%). 1H NMR (CDCl3) δ: 8.15 (s, 1H), 7.93 (s, 1H), 7.80-7.89 (m, 4H), 7.44-7.51 (m, 1H), 7.35-7.40 (m, 1H), 6.94-7.00 (m, 2H), 5.00 (br. s., 2H), 4.39 (s, 2H), 3.73 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:17].CC(O)C.Cl.[H][H]>[Pd].CO>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:17]
Reactant: COc1ccc2nc(C)c(CCCl)c(=O)n2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC1CCc2nc(C)c(CCCl)c(=O)n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 10 parts of 3-(2-chloroethyl)-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 40 parts of 2-propanol saturated with hydrogen chloride and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The oily residue was taken up in 80 parts of 2-propanol and 2,2′-oxybispropane. After stirring overnight at room temperature, the precipitated product was filtered off, washed with a mixture of 2-propanol and 2,2′-oxybispropane and dried in vacuo at 50° C., yielding 7.5 parts (64.0%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-7-methoxy-2-methyl4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride; mp. 170° C. (intermediate 4)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH:9]([CH2:24][CH2:25]O)[CH2:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:74]=[N+:75]=[N-:76])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8][CH:9]2[CH2:24][CH2:25][N:74]=[N+:75]=[N-:76])=[O:14])=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)CC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2-hydroxyethyl)piperazine (0.134 g, 0.33 mmol) and triphenylphosphine (0.100 g) in THF (6 mL) at 0° C. was added diethyl azodicarboxylate (0.060 mL) and diphenylphosphoryl azide (0.081 mL). The mixture was stirred at ambient temperature for 2 days, then concentrated of volatiles in vacuo. Purification by flash column chromatography on silica gel afforded 0.047 g of 1-((4-chlorophenoxy)methyl)carbonyl-2-(2-azidoethyl)-4-(4-fluorobenzyl)piperazine as a clear, colorless oil; NMR (CDCl3) 7.3 (m, 4), 7.0 (t, 2), 6.9 (d, 2), 4.7 (m, 3), 4.4 (br d, 1), 4.3 (m, 1), 4.1 (m, 1), 3.5-3.1 (m, 4), 2.8 (d, 1), 2.7 (d, 1), 2.1 (m, 2), 1.8 (m, 1) ppm.
Reaction SMILES: [In].[NH2:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([CH:10]=[O:11])=[C:5]([Cl:12])[N:4]=1.[I-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]([Cl:12])[C:6]([CH:10]([OH:11])[CH2:17][CH:16]=[CH2:15])=[C:7]([Cl:9])[N:8]=1
Reactant: C=CCBr
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(O)c1c(Cl)nc(N)nc1Cl
Reaction time: 2 h
Yield: 74 %

Procedure:
Indium powder (45.81 g) was added to a mixture composed of 2-amino-4,6-dichloropyrimidine-5-carboaldehyde (63.83 g) and N,N-dimethylformamide (500 mL). Then, sodium iodide (99.66 g) was added at an internal temperature of 10° C. under cooling in an ice bath. Allyl bromide (67.5 mL) was added to the resulting mixture over 20 minutes. After confirming that the internal temperature once increased was decreased, the ice bath was removed and the mixture was stirred for two hours. The reaction mixture was concentrated to about 200 mL under reduced pressure. Then, ethyl acetate (1.5 L) and a saturated sodium bicarbonate solution (1 L) were added to the residue, followed by stirring. The mixture was filtered through Celite and the filtrate was separated. Then, the organic layer was sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated to about 150 mL under reduced pressure. Hexane was added to the resulting residue, followed by stirring. Then, the solid was collected by filtration to obtain the title compound (57.24 g, 74%) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[O-:8][C:9]#[N:10].CN([S+](N(C)C)N(C)C)C.CCOCC>C(#N)C>[CH2:2]([N:10]=[C:9]=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#C[O-]
Reactant: CCCCCCBr
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCCN=C=O
Reaction time: 2 h
Yield: 85 %

Procedure:
1-Bromohexane, 3.3 g (0.02 mole), was added to a stirred solution of 6.2 g (0.03 mole) of tris(dimethylamino)sulfonium cyanate in 12 ml of acetonitrile at 25°. The course of the reaction was followed by glc analysis. One-half of the 1-bromohexane had reacted after 6 min., and the reaction was virtually complete after 2 hours. Ether, 20 ml, was added to the reaction mixture to precipitate dissolved salts, and the reaction mixture was filtered. Distillation of the filtrate gave 2.16 g (85%) of 1-hexyl isocyanate as a colorless liquid, b.p. 50°-51° (10 mm).