Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=O)[N:23]=[C:22]1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[C:18]#[C:19][CH3:20].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:23]=[C:22]1[N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C#N
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=CC(=O)OCC)c1C#N
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
0.038 g of sodium hydride was added to a 5 ml tetrahydrofuran solution of 0.243 g of ethyl diethylphosphonoacetate at 5° C. under a nitrogen atmosphere. 0.310 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate dissolved in 5 ml of tetrahydrofuran was added, and the mixture was stirred for 30 minutes. 50 ml of ethyl acetate and 25 ml of 0.1N sodium hydroxide were added to the solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.380 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:7).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][S:18][C:12]=3[NH:11][C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:10]1[N:11]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[C:12]2[S:18][CH:17]=[CH:16][C:13]=2[C:14](=[O:15])[N:9]1[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2sccc2c(=O)n1CCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3ccsc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.9 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (3.2 g), potassium carbonate (2.9 g) and acetonitrile (150 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (4.8 g, 97%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[C:1]([Si:5]([O:8][C:9]1[CH:10]=[C:11]([F:16])[C:12]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[C:13]([F:15])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(F)cc(O[Si](C)(C)C(C)(C)C)cc2F)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl(3,5-difluorophenoxy)dimethylsilane (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 1 hr at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield tert-butyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane in 91% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.21 (s, 6 H) 0.97 (s, 9 H) 1.37 (s, 12 H) 6.33 (d, J=9.39 Hz, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:33]([C@@H:40]1[CH2:44][O:43][C:42](=[O:45])[NH:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Li]CCCC>C1COCC1>[CH2:33]([C@@H:40]1[CH2:44][O:43][C:42](=[O:45])[N:41]1[C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)O)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a stirred solution of (2E)-3-[3-(tert-butoxycarbonyl)phenyl]prop-2-enoic acid from the previous step (0.186 g, 0.749 mmol) in THF (3 mL) was added triethylamine (0.110 mL, 0.787 mmol) and the mixture was cooled to −20° C. Pivaloyl chloride (0.0969 mL, 0.787 mmol) was added and then the reaction mixture was stirred at −20° C. for 15 min, warmed to 0° C. and stirred for 40 min. Meanwhile, to a cooled (−78° C.) solution of (R)-4-benzyl-2-oxazolidinone (0.305 g, 1.72 mmol) in THF (5 mL), was added nBuLi (1.1 mL, 1.6M in hexanes) dropwise and the mixture was stirred for 30 min. The slurry was warmed to 0° C. and added via cannula into the anion solution. After one hour, the reaction was quenched by the addition of 10 mL 20% aqueous NH4Cl solution, warmed to room temperature and extracted with 2×50 mL ether. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure, and chromatographed on a 4″ 25 mm SiO2 column using 18% EtOAc:hexanes. The clean fractions were combined and the solvent was removed under reduced pressure to give tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate as an oil (0.273 g, 89%). TLC Rf=0.3 (1:4 EtOAc:hexanes, UV visualization); HPLC RT=2.9 min, method B; M+H=408.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:22][C:23](=[O:25])[NH2:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:22][C:23]([NH2:24])=[O:25])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CC(N)=O)Cc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[carbamoylmethyl-(4-chloro-benzyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.32 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification ESI-MS m/z: 267 (M+1), UV retention time: 0.82 min.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.N#N>CO>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: N#N
Solvent: CO
Product: Brc1cnc2ccc(N3CCNCC3)nn12
Temperature: 120 °C
Yield: 70.9 %

Procedure:
3-Bromo-6-chloro-imidazo[1,2-b]pyridazine [13526-66-4] (1.1 g, 4.5 mmol) and piperazine [110-85-0] (3.6 g, 41.8 mmol) were ground together in a mortar to an intimate mixture and transferred to a 15 mL round bottomed flask containing a magnetic stir bar. The flask was fitted to a reflux condenser, N2 blanketed, and the reaction pot immersed in an ambient temperature oil bath. While the neat solid mixture stirred, the bath was heated to 120° C. over 0.5 h and held at nominal temperature for a total of 17 h. The bath was removed and the molten reaction allowed to cool and to solidify. The solid mass was dissolved in methanol, transferred to a separatory funnel, and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to afford 0.9 g of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine as a light yellow solid which was used without further purification. LRMS (ESI) m/z 282.1/284.1 [(M+H)]+, calc'd for C10H12BrN5: 282.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH:13]1[CH:17]([O:18][CH3:19])[CH2:16][O:15][CH2:14]1.[NH2:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[H-].[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([O:12][CH:13]2[CH:17]([O:18][CH3:19])[CH2:16][O:15][CH2:14]2)[CH:5]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)O)cc1OC1COCC1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1COCC1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
1.0 g (3.7 mmol) of 4-methoxy-3-(4-methoxytetrahydrofuran-3-yloxy)benzoic acid (starting compound A1) is heated to reflux for 2 h in 4 ml of oxalyl chloride. Excess oxalyl chloride is removed in vacuo and coevaporated using 2×20 ml of toluene. A solution of 600 mg (3.7 mmol) of 4-amino-3,5-dichloropyridine in 10 ml of tetrahydrofuran is added dropwise to a suspension of 220 mg (7.4 mmol) of 80% strength sodium hydride in 10 ml of tetrahydrofuran. The mixture is stirred for 1 h at RT, the acid chloride is then added dropwise in a further 10 ml of tetrahydrofuran and the reaction mixture is stirred at RT overnight. It is concentrated, the residue is treated with 50 ml of water and the mixture is extracted with 3×50 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, concentrated and the residue is crystallized from 50 ml of isopropanol. 1.2 g of the title compound of m.p. 175-177° C. are obtained.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[C:19]=1[NH:27][C:28]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:29])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Nc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1nnn[nH]1

Procedure:
5-Aminotetrazole hydrate (45 g, 0.44 mol) was refluxed in toluene (300 mL) in the presence of a Dean-Stark trap. After removal of the theoretical amount of water (7.9 mL) the mixture was allowed to cool, concentrated in vacuo, and the resulting solid stirred with acetonitrile (500 mL). Triethylamine (61 mL, 0.44 mol) and 2,6-diisopropyl phenylisocyanate (89.3 mL, 0.44 mol) were added sequentially and the mixture refluxed for 4 hours. The mixture was then allowed to cool, concentrated in vacuo to about 200 mL, and acidified with 1M citric acid. The solid was filtered, washed with water (1L), ethyl acetate (1L), and dried in vacuo to give the title compound (b), m.p. >240° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1C.COC(=O)C1C=CC(CBr)=CC=1.[CH2:21]([O:23][C:24]([C:26]1[O:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[O:27][C:28]([CH2:31][N:4]2[C:3]([CH2:2][OH:1])=[CH:7][N:6]=[CH:5]2)=[CH:29][CH:30]=1)=[O:25])[CH3:22]
Reactant: Cc1[nH]cnc1CO
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: COC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc(Cn2cncc2CO)o1

Procedure:
The following compounds were obtained using the same procedure as in Example A1 but replacing 4-hydroxymethylimidazole hydrochloride with 4-hydroxymethyl-5-methylimidazole and 4-bromomethylbenzoic acid methyl ester by 5-chloromethylfuran-2-carboxylic acid ethyl ester.
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
Methyl iodide (36 ml) was added to a mixture of methyl 3,5-dihydroxybenzoate (104 g), potassium carbonate (79 g) and dimethylformamide (1200 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between water (2.5 liter) and petrol (b.p. 60°-80° C., 600 ml). The aqueous layer was washed with petrol (b.p. 60°-80° C., 600 ml) and then extracted with toluene (2×1 liter). The toluene extracts were combined, washed with water (4×800 ml), dried (MgSO4) and evaporated to give methyl 3-hydroxy-5-methoxybenzoate as an oil (33 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:19])=[O:18]
Reactant: CCCCC(O)CSc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CSc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 42.0 g (0.172 mole) of 1-(p-chlorophenylthio)hexan-2-ol and 21.6 g (0.189 mole) of methane sulfonyl chloride in 100 ml of toluene is slowly added 20.8 g (0.206 mole) of triethylamine over a 1/2 hour period at less than 15° C. When the addition is completed, the mixture is stirred for 1/2 hour, and is allowed to warm to ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([OH:13])=[O:12]>CCO.O=[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: O=[Pt]=O
Solvent: CCO
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.0 g (27.15 mmol) of 3-(2,4-difluorophenyl)acrylic acid in EtOH (50 mL) is hydrogenated over PtO2 catalyst under atmospheric pressure and stirred overnight at RT. After filtration to remove the catalyst, the filtrate is concentrated in vacuo to afford 3-(2,4-difluorophenyl)propanoic acid as a white solid: m.p. 104° C. 1H NMR (CDCl3, 400 MHz) δ 2.67 (t, 2H, J=7.6 Hz), 2.94 (t, 2H, J=7.6 Hz), 6.80 (m, 2H), 7.18 (dd, 1H, J=14.8 Hz and 8.0 Hz). The title A compound, (2,4-difluorophenyl)piperazin-1-yl-propanone hydrochloride is obtained analogously to the title B compound of Example 4 as a white solid: m.p=221° C. LC/MS (M+1=255.1). 1H NMR (DMSO-d6, 400 MHz) δ 2.66 (t, 2H, J=7.6 Hz), 2.81 (t, 2H, J=7.6 Hz), 3.01 (m, 2H), 3.05 (m, 2H), 3.69 (m, 4H), 7.02 (dt, 1H, J=8.4 Hz and 2.4 Hz), 7.18 (dt, 1H, J=10.0 Hz and 2 8 Hz), 7.29 (dd, 1H, J=15.6 Hz and 8.8 Hz), 9.65 (br s, NH). Anal. calculated for (C13H16F2N2O HCl+0.2 H2O): C, 53.05; H, 5.96; Cl, 12.04; F, 12.91; N, 9.52; O, 6.52. Found C, 53.01; H, 5.96; N, 9.74.
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3](O)=O.C([N:18](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCOCC1.Cl.O.ClCCl>[CH3:1][C:2]([NH2:18])([CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CC(C)(C)C(=O)O)cc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(C)(C)N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of 2,2-dimethyl-3-(4-methoxyphenyl)propanoic acid (36.0 g, 0.17 mol) in toluene (160 mL) was added triethylamine (19.2 g, 0.19 mol) and cooled to 0° C. To this cooled mixture was added diphenylphosphoryl azide (52.3 g, 0.19 mol) and the reaction mixture was stirred at room temperature for 15 min and then heated at 75° C. for 2.5 h. The progress of the reaction was monitored by TLC. After the completion of the reaction, as indicated by TLC it was cooled to room temperature and quenched with water (500 mL) and extracted with EtOAc (2×500 mL). The organic extracts were combined and dried over Na2SO4, filtered and concentrated to give an oil. This oil was dissolved in a mixture of 1,4-dioxane (108 mL) and 6 N HCl (180 mL) and heated at reflux for 1 h. After 1 h, the reaction mixture was cooled to room temperature and diluted with water (100 mL) and dichloromethane (400 mL). The organic layer was separated and pH of the aqueous layer was adjusted to ˜14 with 6 M NaOH (200 mL) and extracted with dichloromethane (3×500 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 20.0 g (65%) of 2-methyl-1-(4-methoxyphenyl)-2-propanamine as a yellow oil; 1H NMR (200 MHz, CDCl3) δ 7.10 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 3.79 (s, 3H), 2.59 (s, 2H), 1.10 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:29][CH2:28][CH2:27][NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 120 °C

Procedure:
3.0 g (10.05 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine, 2.41 g (15.07 mmol) of N-Boc-ethylenediamine and 3.89 g (30.15 mmol) of diisopropylethylamine are dissolved in 50 ml of DMSO and heated at 120° C. for 16 h. Ethyl acetate and water are added, and the removed organic phase is washed twice more with water. The organic phase is dried with magnesium sulphate. Removal of the solvent results in 4.49 g (99% of theory) of product.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].Cl.[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>>[Br:13][C:9]1[N:10]=[C:11]2[N:23]([CH2:22][CH2:21][CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:2][C:3](=[O:4])[NH:5][C:6]2=[N:7][CH:8]=1
Reactant: NCCC1CCOCC1
Reactant: O=C(CBr)Nc1ncc(Br)nc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CCC2CCOCC2)c2nc(Br)cnc2N1
Temperature: 85 °C
Yield: 50.7 %

Procedure:
2-Bromo-N-(3,5-dibromopyrazin-2-yl)acetamide (3.30 g, 8.83 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride (1.46, 8.83 mmol) and diisopropyl ethylamine (6.67 mL, 35.3 mmol) were combined and heated at 85° C. Upon complete consumption of starting material (by TLC), the reaction solution was condensed and purified via Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (1.53 g, 4.48 mmol, 50% yield). MS (ESI) m/z 341.4 [M]+, 343.1 [M+2]+.
Reaction SMILES: CO.C(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:29])[C:14]([N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)[N:18]=[CH:17]2)=[O:15])=[CH:9][CH:8]=1.O>ClCCl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH3:29])[C:14]([N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:18]=[CH:17]2)=[O:15])=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2cn(C(=O)N(C)c3ccc(F)cc3)cn2)cc1
Agent: O=C=O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)n1cnc(-c2ccc(O)cc2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an methanol-dry ice cooled solution of N-(4-fluorophenyl)-4-(4-methoxyphenyl)-N-methyl-1H-imidazole-1-carboxamide (0.283 g, 0.870 mmol) in dichloromethane (8 ml) was added borontribromide (0.164 ml, 1.740 mmol). The dark reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. TLC showed the reaction to be completed, then was poured into a mixture of ice and water and stirred for 30 min. There was no precipitation. The mixture was extracted with DCM:IPA (70:30), the organic phase was dried over MgSO4 and filtered. DCM was removed by vacuum and the product precipitated from IPA, filtered and dried under vacuum. (Yield: 210 mg, 78%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH:5]([C:7]1[N:16]=[C:15]([OH:17])[C:14]2[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10][C:9]=2[N:8]=1)[CH3:6].ClC(C)C#N>>[CH3:1][N:2]([CH3:3])[CH:5]([C:7]1[N:16]=[C:15]([OH:17])[C:14]2[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10][C:9]=2[N:8]=1)[CH3:6]
Reactant: CNC
Reactant: CC(Cl)c1nc(O)c2c(n1)CCC(C)(C)C2
Agent: CC(Cl)C#N
Product: CC(c1nc(O)c2c(n1)CCC(C)(C)C2)N(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of dimethylamine (2M solution in tetrahydrofuran, 4.0 mL, 8.0 mmol) was added 2-(1-chloroethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (synthesized according to the method of reagent preparation 18 using 2-chloropropionitrile in step 1) (50 mg, 0.21 mmol) and the reaction mixture was stirred in a sealed tube for 16 hours at 80° C. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between brine (50 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give 2-[1-(dimethylamino)ethyl]-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (50 mg, 96%). MS (EI) for C14H23N3O: 250 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl-].C[NH3+].C[CH2:34][N:35]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[N:11]=[C:10]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:35][CH3:34])=[O:26])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Reactant: CCN=C=NCCCN(C)C
Agent: C[NH3+]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)cnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.2 %

Procedure:
To a solution of 4-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoic acid (78.3 mg) in anhydrous DMF (3 mL) were added methylammonium chloride (25.4 mg), EDCI hydrochloride (72.2 mg), HOBt (57.7 mg) and triethylamine (0.052 mL) at room temperature, and the mixture was stirred at room temperature for 96 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (72.0 mg).