Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC1C=CC(C#C[Si](C)(C)C)=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-:26].[Na+].O.[CH2:29]1[CH2:33]O[CH2:31][CH2:30]1>CO>[CH2:12]([O:26][C:31]#[C:30][C:29]1[CH:33]=[CH:4][CH:3]=[CH:2][CH:1]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCOc1ccc(C#C[Si](C)(C)C)cc1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCOC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Dodecyloxy[(trimethylsilyl)ethynyl]benzene (3.09 g, 8.62×10−3 mol) was dissolved in a mixture of 20 ml of MeOH and 20 ml of THF. 5N NaOH (2.1 ml, 1.05×10−2 mol) was added and the solution was stirred for 3.5 h at room temperature under N2. Water was added to the reaction mixture. The aqueous layer was extracted three times with CH2Cl2. The combined organic layers were dried over MgSO4. The product was chromatographed on silica gel with 4:1 hexane:CH2Cl2 as the eluent. Yield=2.430 g (98% based on 3.09 g of 4-dodecyloxy[(trimethylsilyl)ethynyl]benzene). 1H NMR (250 MHz, CDCl3): δ 7.41 (d, 2H, J=8.8 Hz, Ph), 6.83 (d, 2H, J=8.7 Hz, Ph), 3.95 (t, 2H, J=6.6 Hz, —OCH2—), 2.99 (s, 1H, ethynyl-H), 1.78 (quint, 2H, J=6.9 Hz, —OCH2CH2—), 1.10-1.51 (m, 18H, —CH2—), 0.88 (t, 3H, J=6.6 Hz, —CH3). CI MS m/z: 287.236 ((M+H)+) (calcd 287.237).
Reaction SMILES: FC1C=C(F)C=CC=1CN1C2C=CC=C(N)C=2C=N1.[N:20]1[CH:21]=[C:22]([C:29]([OH:31])=O)[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][N:39]1[C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=2[CH:41]=[N:40]1>>[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][N:39]1[C:47]2[C:42](=[C:43]([NH:48][C:29]([C:22]3[N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[N:20][CH:21]=3)=[O:31])[CH:44]=[CH:45][CH:46]=2)[CH:41]=[N:40]1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Nc1cccc2c1cnn2CC1CCCCO1
Agent: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Product: O=C(Nc1cccc2c1cnn2CC1CCCCO1)c1cnc2ccccn12

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-amine, respectively. MS (APCI) m/z=376 (M+H).
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].[CH3:18]I.N#N>CN(C=O)C>[CH3:12][O:15][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:3]=1)[N:9]([CH3:18])[N:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2cn[nH]c2c1
Reactant: CI
Agent: N#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(cnn2C)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
A solution of 6-methoxy indazole (it) (5 g, 33.75 mmol; see Tet Lett., 43(15): 2695 (2002)) in DMF (200 mL) was treated with potassium carbonate (6.06 g, 43.87 mmol) at room temperature. After stirring at for 15 minutes, methyl iodide (2.33 mL, 37.12 mmol) was added. The resulting mixture was heated at 110° C. for 18 hours. LC showed minor starting material left. Additional methyl iodide was added (2.33 mL) and stirring continued for an additional 18 hours. LC showed a 2:1 mixture of the N1 to N2 alkylated isomers. The solvent was evaporated in vacuo and the residue taken up in DCM and washed with 1N HCl. The organic layer was filtered through 1 PS paper, evaporated in vacuo and purified on the Biotage eluting with 4:3, 3:1 hexane/Et2O. The desired combined fractions (N1 isomer) were evaporated in vacuo to provide the desired product (2t) as a yellow oil (2.57 g; 47%). 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H); MS (ESI+) m/z 163 (M+H) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([NH:21][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(C)(C)C(=O)Cl
Product: C[C@H](NC(=O)C(C)(C)C)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 using (2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60 mg, 0.16 mmol) and pivaloyl chloride (0.078 mL, 0.64 mmol). Yield 53 mg (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.[OH-:21].[Na+].OO.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:20]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[C:9]([OH:21])[C:8](=[O:10])[C:6]=2[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(C=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 8.5 g quantity of 5'-chloro-2'-hydroxyacetophenone and 6.0 g of p-tolualdehyde were dissolved in 105 ml of ethanol. Then 17 ml of an aqueous solution containing 10 g of sodium hydroxide was slowly added thereto dropwise and stirred at room temperature for 4 hours. Then 350 ml of ethanol and 17 ml of an aqueous solution containing 3.5 g of sodium hydroxide were added to the reaction mixture, and 8.3 ml of a 30% aqueous hydrogen peroxide solution was further added dropwise slowly and stirred at room temperature for 12 hours. A 10% aqueous HCl solution was added to adjust the reaction mixture to pH 3. The crystals precipitated were collected by filtration and washed serially with 10 ml of water, 5 ml of ethanol and 10 ml of diethyl ether, thus giving 6.0 g of 6-chloro-3-hydroxy-2-(4-methylphenyl)-4H-1-benzopyran-4-one as crystals.
Reaction SMILES: Cl.CN(C(ON1N=N[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:26](N(C(C)C)CC)(C)[CH3:27].[C:35](=[O:38])(O)[O-:36].[Na+]>CN(C=O)C>[CH2:15]1[CH2:14][CH2:13][CH:12]([C@H:11]([NH2:16])[C:35]([OH:36])=[O:38])[CH2:27][CH2:26]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HCl (1.717 g, 6.87 mmol), HATU (2.618 g, 6.89 mmol) and diisopropylethyl amine (4.00 mL, 23.0 mmol) were added to a solution of the compound from Example 1, step 2 (1.704 g, 6.24 mmol) in anhydrous DMF (10 mL) at RT. The reaction was stirred at RT for 2.5 h. The reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ether (150+100 mL). The organic phases were washed with water (100+50 mL), dried (MgSO4) and concentrated in vacuo to give 2.994 g of a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1>CN(C)C=O>[F:36][C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([F:37])[CH:33]=1)[CH2:29][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1cc(F)cc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 75 mg of 1-(bromomethyl)-3,5-difluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 85 mg of (8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:15]
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1)C(F)(F)F

Procedure:
To a solution of N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (Stage 128.3; 1.465 g, 4.19 mmol) in acetonitril (35 ml) under N2-atmosphere, piperidine (1.25 ml, 12.7 mmol) is added. After 30 min at rt the reaction mixture is diluted with water and partially concentrated in vacuo. The aqueous residue Is acidified to pH 5 by addition of 0.1 N HCl and extracted 3× with AcOEt. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/AcOEt 3:2) gives the title compound: MS: [M+1]+=355; 1H-NMR (DMSO-d6): 11.48 (s, HN), 8.02 (s, 1H), 7.91 (dd, 1H), 7.77 (d, 1H), 3.52 (s, 2H), 2.32 (sb, 4H), 1.50 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]I)=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:3]([C:5]([CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:29]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: ICCc1ccc(OCCCCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a suspension of sodium hydride (4.3 g) in dimethylformamide (212 ml) was added diethyl ethylmalonate (20 g) at 0° C. and the mixture was stirred at room temperature for an hour. To the solution, 2-(4-(4-phenylbutyloxy)phenyl)ethyl iodide (40 g) was dropwise added at 0° C., and the mixture was stirred for 20 minutes and allowed to stand at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give the subject compound (46 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(COCc2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccc3c(c2)OCO3)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 240 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) and 4-methoxybenzylbromide. Colorless crystals (240 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([CH3:28])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:40])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(F)ccc1C(c1ccc(F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65 mg (0.17 mmol) of the compound from Example 101 were introduced into 8 ml of dichloromethane at 0° C., 41 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 67 mg (99% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[CH3:22][NH:23][CH3:24].C=O.[C:27](O)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:22][N:23]([CH2:27][C:21]1[N:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH3:24]
Reactant: CC(=O)O
Reactant: CNC
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1CN(C)C

Procedure:
2-(Methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine (0.75 gm.) is added to a solution of 50% aqueous dimethylamine (0.215 gm., 37% formaldehyde (0.19 gm.) and acetic acid (0.35 g.) and heated at 50° C. for 3 hours. After cooling, the reaction mixture is diluted with aqueous sodium bicarbonate and the resultant precipitate is collected by filtration. After drying, the crude product is recrystallized from ethyl acetate to yield 3-(dimethylaminomethyl)-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 172°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of ethyl (2E)-3-(4′-methoxybiphenyl-4-yl)prop-2-enoate (1 g, 3.5 mmol) in ethyl acetate was added acetic acid and degassed well with argon and added palladium carbon (100 mg) and stirred under hydrogen for overnight, TLC shows a new spot, RM filtered through celite and washed with ethyl acetate and concentrated to afford white solid (0.7 g, Yield: 71.4%).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH3:28]>[Zn].CCOC(C)=O>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:8][C:9]2[CH:10]=[C:11]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])=[O:38])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(N)c1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1ccc(CC(=O)Nc2cc(CNC(=O)OC(C)(C)C)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirring toluene solution (100 mL) of (3-Amino-4-nitrophenyl)methyl-carbamic acid, 1,1-dimethylethyl ester (1.10 g, 4.12 mmol) were added 4-ethoxyphenylacetyl chloride (980 mg, 1.2 eq) and zinc dust (400 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution was stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 2:1/hex:EtOAc on silica gel to yield the desired product [3-[[(4-Ethoxyphenyl)acetyl]amino]-4-nitrophenyl]methyl-carbamic acid, 1,1-dimethylethyl ester (1.18 g, 67% yield); 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.11 (d, J=9.2 Hz, 1H), 7.22 (m, 3H), 6.93 (d, J=9.2 Hz, 2H), 4.40 (m, 2H), 3.75 (s, 2H), 3.33 (s, 3H), 1.50 (s, 9H), 1.42 (t, J=6.8 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:15])([F:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Br:16][CH2:17][CH2:18]Br.Cl>>[Br:16][CH2:17][CH2:18][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([F:14])([F:15])[F:3]
Reactant: Oc1ccccc1OCC(F)(F)F
Reactant: BrCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)COc1ccccc1OCCBr
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To an aqueous solution (15 ml) of sodium hydroxide (0.63 g) were added 2-(2,2,2-trifluoroethoxy)phenol (2.85 g) and 1,2-dibromoethane (1.68 ml), and the mixture was reacted with stirring at 120° C. for 8 hours. To the reaction mixture was added concentrated hydrochloric acid (1.3 ml), and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and diethyl ether (5/1) as eluent to give 1.78 g of 1-(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene as an oil
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl[CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[O:33][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[O:33][CH:34]=2)[N:3]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
An amount of 150 mg (0.39 mmol) of the compound from example 3A and 98 mg (0.43 mmol) of the compound from example 5A were suspended together with 99 mg (1.18 mmol) of sodium hydrogencarbonate in 2 ml of dry DMF. The reaction mixture was stirred at RT for 20 hours. The batch was thereafter purified directly by means of preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; eluent gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)CC2C=CC(OC)=CC=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.[O:41]1[CH2:44][C:43](=O)[CH2:42]1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([CH:43]3[CH2:44][O:41][CH2:42]3)[CH2:10]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:33]2[CH2:35][CH2:34]2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: O=C1COC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCNC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC2CCN(C3COC3)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (+/−)-2-((2-chloro-5-cyano-3-(pyrrolidin-3-yloxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (36 mg, 0.065 mmol), oxetan-3-one (8.30 μl, 0.129 mmol), acetic acid (7.41 μl, 0.129 mmol) and molecular sieves (30 mg) in dichloromethane (1 mL)/Methanol (1 mL) was stirred at room temperature overnight. Sodium cyanoborohydride (12.21 mg, 0.194 rmnol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product (38 mg) was used without purification.
Reaction SMILES: [C:1]([CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH:11]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Na].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:11][CH2:10][CH:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:28]1
Reactant: O=CCC(C(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C(=O)c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
The 3-benzoyl-3-phenylpropionaldehyde residue obtained from Step B, above, (˜8.85 mmol) was dissolved in 110 mL of methylene chloride. To this solution was added 2-methoxyphenylpiperazine (10.61 mmol) and sodium triacetoxyboranehydride, NaBH(OAc)3, (10.61 mmol). The mixture was stirred at room temperature for 3 hours. Aqueous workup followed by flash chromatography gave pure product 1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine (3.48 g) in 95% yield for last two steps. One equivalent of oxalic acid was added to the free base dissolved in methanol. The solvent was evaporated and the product was dried under vacuum to form the oxalate salt.