Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.C=O.[BH3-][C:21]#N.[Na+].CC(O)=O>CC#N>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:21]
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h

Procedure:
To (S)-2-(2-chloro-5-nitro-phenoxymethyl)-pyrrolidine (4.82 g, 18.77 mmol) in 167 mL CH3CN at RT was added 37% aqueous formaldehyde (7.58 mL) then NaCNBH3 (1.887 g, 30.03 mmol). The reaction was stirred for 1 h, as the reaction pH was adjusted every 10 min to about 7 by adding small amounts of HOAc. The reaction was concentrated to small aqueous volume and dissolved into 2 N NaOH (aq) and Et2O. The layers were separated, and the organic layer was washed twice with 2 N NaOH then extracted twice with 1 N HCl (aq). The combined acidic aqueous layers were basified to pH>12 with solid NaOH and extracted 3× with EtOAc. The EtOAc layers were washed once with 2 N NaOH then once with a mixture of brine and 2 N NaOH, combined, dried over Na2SO4, filtered, and concentrated down to dryness, to yield the title compound.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[N:9]=[C:8]([NH:15][C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[N:7]=1.[CH:21](N)(C)C>>[Cl:14][C:10]1[C:11]([C:12]#[N:13])=[C:6]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:7]=[C:8]([NH:15][C:16]([C:19]#[N:20])([CH3:18])[CH2:17][CH3:21])[N:9]=1
Reactant: NC1CC1
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CC(C)N
Product: CCC(C)(C#N)Nc1nc(Cl)c(C#N)c(NC2CC2)n1

Procedure:
This compound was prepared in the manner of Example X, substituting 4,6-dichloro-2-(1-cyano-1-methylpropylamino)-5-pyrimidinecarbonitrile and cyclopropylamine for 4, 6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile and isopropylamine. The reaction product was recrystallized from carbon tetrachloride to give 4-chloro-2-(1-cyano-1-methylpropylamino)-6-cyclopropylamino-5-pyrimidinecarbonitrile; mp, 155°-159°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25](=[O:38])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:21]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)CCC.CN1CCCC1=O>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:19][C@H:20]3[CH2:24][CH2:23][N:22]([C:25](=[O:38])[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=4)[CH2:21]3)[N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1nc(C2CCCCC2)c2ccccc2n1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)N1CC[C@H](Nc2nc(C3CCCCC3)c3ccccc3n2)C1
Temperature: 130 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
A mixture of 2-chloro-4-cyclohexylquinazoline (0.25 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.49 g), N,N-diisopropylethylamine (0.52 mL), N-methylpyrrolidone (1.0 mL), and n-butanol (1.0 mL) was stirred at 130° C. for 24 h. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate) to obtain the title compound (0.21 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20](=[O:36])[NH:21][C@:22]3([C:27](=[O:35])[NH:28][S:29]([CH:32]4[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:24][C@H:23]3[CH:25]=[CH2:26])[NH:17][CH2:16]1)=[O:13])[CH2:7]2.[C:37]([O:41][C:42]([C@@H:44]([CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)[C:45](O)=[O:46])=[O:43])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.O>[CH:32]1([S:29]([NH:28][C:27]([C@@:22]2([NH:21][C:20]([C@H:18]3[N:17]([C:45](=[O:46])[C@@H:44]([C:42]([O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:43])[CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]4)[CH2:16][C@H:15]([O:14][C:12]([N:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[CH:11][C:3]=5[Cl:2])[CH2:7]4)=[O:13])[CH2:19]3)=[O:36])[CH2:24][C@H:23]2[CH:25]=[CH2:26])=[O:35])(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)[C@@H](C(=O)OC(C)(C)C)C1CCCCC1)C(=O)NS(=O)(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A 25 mL round-bottomed flask was charged with (3R,5S)-5-(((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate hydrochloride (0.500 g, 0.894 mmol), (S)-2-(tert-butoxycarbonyl)-2-cyclohexylacetic acid (276 mg, 1.07 mmol) and HATU (408 mg, 1.07 mmol) in dry DMF (9 mL). The solution was cooled on an ice-water bath and treated with DIEA (0.467 mL, 2.68 mmol) by dropwise addition. The mixture was stirred at 0° C. for 1 h, then allowed to warm up and stirred at room temperature for 16 h. The mixture was diluted with water (50 mL) and the pH adjusted to 3 with 1N HCl, the mixture was extracted with Et2O (3×20 mL). The combined organic extracts were then washed with 1N HCl (3×20 mL), water (3×20 mL) and brine (3×20 mL). The organic extract was then dried over MgSO4, filtered and concentrated. The crude material was the purified by chromatography (Biotage) eluting with 1-3% MeOH—CH2Cl2 to give the product as a white foam, (394 mg, 59%). MS m/e 662 (M+−Boc).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:9])[O:6][CH2:7][I:8])([CH3:3])[CH3:2].[C:10]([O:18][CH2:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH:22]([N:27]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[NH2:36])[C:28]2=[O:37])[C:21]1=[O:38])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>C(Cl)Cl>[I-:8].[NH2:36][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:34]=1[CH2:35][N:27]([CH:22]1[CH2:23][CH2:24][C:25](=[O:26])[N:20]([CH2:19][O:18][C:10]([C:11]3[CH:12]=[N+:13]([CH2:7][O:6][C:5](=[O:9])[NH:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[CH:15][CH:16]=3)=[O:17])[C:21]1=[O:38])[C:28]2=[O:37]
Reactant: CC(C)NC(=O)OCI
Reactant: Nc1cccc2c1CN(C1CCC(=O)N(COC(=O)c3cccnc3)C1=O)C2=O
Solvent: ClCCl
Product: CC(C)NC(=O)OC[n+]1cccc(C(=O)OCN2C(=O)CCC(N3Cc4c(N)cccc4C3=O)C2=O)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Iodomethyl isopropylcarbamate [6318] (0.018 g, 0.028 mmol, 1.0 eq) was added to a solution of (3-(4-amino-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl nicotinate [339] (0.03 g, 0.028 mmol, 1.0 eq) in DCM (5 ml). The reaction mixture was stirred at RT for 16 h. The DCM was evaporated under reduced pressure and washed thoroughly with diethyl ether to yield a yellow powder [340], 3-(((3-(4-amino-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methoxy)carbonyl)-1-(((isopropylcarbamoyl)oxy)methyl)pyridin-1-ium iodide, (0.015 g, 40%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.O[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 24 h

Procedure:
To a mixture of 4-(benzoxazol-2-yl)phenol (0.3 g; 1.4 mmol), N-(2-hydroxyethyl)phthalimide (0.27 g; 1.4 mmol), triphenylphosphine (0.56 g; 2.1 mmol) and THF (5 ml) is added diisopropyl azodicarboxylate (0.42 ml; 2.1 mmol). The reaction is stirred 24 hours, diluted with ethyl acetate, washed with H2O, 2N HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to dryness. The residue is purified by gradient elution column chromatography using CH2Cl2 and 1% MeOH/99% CH2Cl2 to yield N-[2-[4-(benzoxazol-2-yl)phenoxy]ethyl]phthalimide which is used directly in Step D.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([NH:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][C:19]=1[OH:28])=O)[CH:9]=[CH:8]2)(=O)C.C1C=C(Cl)C(Cl)=CC=1.Cl(O)(=O)=O>O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]1[O:28][C:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][CH2:26][CH3:27])=[CH:23][C:18]=3[N:17]=1)[CH:9]=[CH:8]2
Reactant: CCCCc1ccc(O)c(NC(=O)c2ccc3cc(OC(C)=O)ccc3c2)c1
Agent: [O-][Cl+2]([O-])O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCCCc1ccc2oc(-c3ccc4cc(O)ccc4c3)nc2c1
Temperature: 201.5 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
5.40 g (14.3 m mole) of 2-(6-acetoxy-2-naphthoylamino)-4-butylphenol, 0.43 g of p-toluenesulfuric acid monohydrate and 40 ml of O-dichlorobenzene were placed in a 100 ml round-bottom flask, followed by heating and stirring for 30 minutes at 200-203° C. After the reaction, O-dichlorobenzene was distilled off under reduced pressure. To the resultant, 2.00 g (30.3 m mole) of potassium hydroxide and 60 ml of ethanol were added, followed by heating and stirring for 20 minutes at 60° C. After the reaction, the reaction mixture was poured into 600 ml of water. To the reaction mixture, 8 ml of chloric acid was added to precipitate a crystal. The crystal was filtered, washed with water and recrystallized from a mixture solvent of acetoneethanol to obtain 2.18 g of 2-(6-hydroxy-2-naphthyl)-5-butylbenzooxazole (Yield: 42.4%).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=O)[C:14]2([CH3:18])[CH3:17])=[CH:9][CH:8]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29]N)[CH:25]=[CH:26][C:27]=1[Cl:28].C(OCC)C>O>[Cl:28][C:27]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[Cl:21])[NH:29][C:13]1[C:14]([CH3:18])([CH3:17])[C:15]3[CH:16]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=3[CH2:11][C:12]2=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 39.7 %

Procedure:
Under nitrogen atmosphere, the acetic acid (1 mL) suspension of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 92.3 mg, 0.452 mmol) and (3,4-dichlorophenyl)hydrazine hydrochloric acid salt (Compound Y1, 96.5 mg, 0.452 mmol) was stirred at ambient temperature of 90° C. for 3.5 hr. After cooling to room temperature, the reaction mixture was added with diethyl ether and water, and the resulting mixture was extracted twice with diethyl ether. The organic layer was washed three times with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography {Merck Kieselgel60, solution for elution:hexane/ethyl acetate (4:1)} to obtain the title compound (pale yellow solid, 62.1 mg, 40%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:8][C:9]1[CH:18]=[C:17]([NH2:19])[C:16]([Cl:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH2:7].O>N1C=CC=CC=1>[CH2:5]([O:8][C:9]1[CH:18]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[C:16]([Cl:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH2:7]
Reactant: CC(=O)Cl
Reactant: C=CCOc1cc(N)c(Cl)cc1C(=O)OC
Solvent: O
Solvent: c1ccncc1
Product: C=CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Acetyl chloride (6.5 g) is added dropwise to a stirring solution of the amine of step 4 above (5 g) in pyridine (80 ml) cooled in an ice bath. The reaction mixture is allowed to warm to RT with stirring for 45 minutes. Water is added, the mixture again cooled in ice, and partitioned between H2O and CH2Cl2. The organic layer is separated and washed successively with H2O, 10% HCl, aqueous saturated NaHCO3, dried, filtered and evaporated affording a solid residue which is recrystallized from Hexane-Ethyl acetate, M.P. 110°-112° C. NMR (90 MHz, DMSO-d6) shows the correct compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C@:5]12[CH2:13][C@:12]1([C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].[C:24]([O-:27])([O-])=O.[Cs+].[Cs+].CN([CH:33]=[O:34])C>>[CH3:24][O:27][C:33](=[O:34])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([CH2:5][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C@:5]3([CH2:13][C@:12]3([C:17]3[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=3)[CH:14]([CH3:16])[CH3:15])[C:6]2=[O:11])[CH:3]=1
Reactant: CC(C)[C@@]1(c2ccc(I)cc2)C[C@@]12C(=O)Nc1ccc(F)cc12
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(I)cc3)C(C)C)c3cc(F)ccc32)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92 %

Procedure:
(1S,2S) and (1R,2R)-5′-fluoro-2-(4-iodophenyl)-2-isopropylspiro[cyclopropane-1,3′-indolin]-2′-one (0.88 g, 2.1 mmol), methyl-(3-bromomethyl)-benzoate (725 mg, 3.15 mmol) and Cs2CO3 (1.37 g, 4.2 mmol) were mixed in anhydrous DMF and stirred at room temperature for 14 hours. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether) to give the title product as white solid (1.10 g, 92%). LC/MS m/e calcd. for C28H25FINO: 569, observed (M+H)+: 570.1
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5ccccc5)nc43)cc2)CCC1
Temperature: 100 °C

Procedure:
To a suspension of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (20 g) in toluene (200 mL) and ethanol (200 mL) was added saturated aqueous sodium bicarbonate (150 mL) and phenyl boronic acid (9.9 g). The reaction was degassed for 5 minutes and the Pd (PPh3)4 (1.0 g) was added. The reaction was again degassed for 5 minutes and then heated to 100° C. for 2 days or until reaction is complete by LCMS. The reaction mixture was cooled to room temperature, and dichloromethane (250 ml×3) and water (100 mL) were added to the reaction. The organics were washed with saturated sodium bicarbonate (1×250 mL) and water (1×250 mL), dried over sodium sulfate and concentrated. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product with some impurities. The solid was re-crystallized with ethyl acetate affording an off-white solid (7.2 g). 400 M Hz 1H NMR (DMSO-d6) δ: 8.23 (d, J=8.0 Hz, 1H), 8.04-7.98 (m, 3H), 7.94 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.46-7.35 (m, 6H), 7.18-7.14 (m, 1H), 6.90 (bs, 1H), 6.33 (dd, J=7.6 Hz and 4.4 Hz, 1H), 2.48-2.40 (m, 4H), 2.09-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.30 (m, 9H); LCMS: 533 [M+H].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3-oxo-2,3-dihydro-1H-indene-5-carboxylic acid (3 g, 17 mmol) in DCM (50 mL) and MeOH (10 mL) was added TMSCHN2 (17 mL, 34 mmol) dropwise and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient solvent system of 10:1 to 3:1 petroleum ether/EtOAc to give methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (2.0 g, 61%). MS ESI calcd for C11H10O3 [M+H]+ 191, found 191.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:23][CH:22]([CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:24])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: OCCOCCOCc1ccccc1
Reactant: ClCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(COCCOCCOCc1ccccc1)COCCOCCOCc1ccccc1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A solution of n-butyl lithium in THF (1.6 N, 1.59 mL, 2.55 mmol) was added to 10 mL of a solution of diethylene glycol monobenzyl ether (500 mg, 2.55 mmol) in THF at −78° C., and the mixture was stirred for 15 minutes. Then, DL-epichlorohydrin (0.1 mL, 1.28 mmol) was added thereto. The mixture was stirred at room temperature for one hour and under reflux for one hour. Next, the THF solvent was evaporated under reduced pressure, and the residue was stirred at 100° C. without a solvent to complete the reaction. Aqueous saturated ammonium chloride was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative liquid chromatography (water:acetonitrile=1:1, 0.05% TFA) to obtain 2-[2-(2-benzyloxyethoxy)ethoxy]-1-[2-(2-benzyloxyethoxy)ethoxymethyl]ethanol (129 mg, yield: 23%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=1)[CH3:2].C(Cl)[Cl:25]>FC(F)(F)/C=C/C(O)=O>[ClH:25].[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:5]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCOc1cc(C)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C(O)/C=C/C(F)(F)F
Product: CCOc1cc(C)nc(N2CCNCC2)c1
Product: Cl
Reaction time: 2 h

Procedure:
tert-Butyl 4-(4-ethoxy-6-methyl-2-pyridyl)piperazine-1-carboxylate (141 mg, 0.44 mmol) was dissolved in a mixture of DCM (5 ml) and trifluorocrotonic acid (5 ml) and left standing at room temperature for two hours. The mixture was concentrated under reduced pressure, the residue was dissolved in THF, evaporated again, dissolved again in THF. Hydrochloric acid (4N in dioxane) was added to precipitate the product, which was collected by filtration, washed with diethylether and dried under reduced pressure to give 115 mg (quantitative) MS (multi-mode) m/z=222.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19](C4CCNCC4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.[CH:52]1[CH:53]=[CH:54]C2N(O)N=[N:58][C:56]=2[CH:57]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:53]4[CH2:52][CH2:57][CH2:56][N:58]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:54]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol), N,N-dimethylglycine (29 mg, 0.28 mmol), EDCl (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), and N,N-diisopropylethylamine (123 μL, 0.71 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The Prude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 24 mg (20%) of the desired product 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.91 (d, 1 H), 7.80 (d, 1 H), 7.58 (s, 1 H), 7.26-7.41 (m, 5 H), 7.13 (d, 1 H), 6.64 (d, 1 H), 5.65 (s, 2 H), 4.44 (dd, 1 H), 4.13 (dd, 1 H), 2.61-3.68 (m, 5 H), 2.22 (s, 3 H), 2.16 (s, 3 H), 1.68-1.94 (m, 1 H), 1.39-1.65 (m, 1 H); ES-MS m/z 509.36 [M+H]+, HPLC RT (min) 2.54.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[CH:15][C:13]=1[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([Cl:19])=[CH:18][C:12]=2[O:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(Nc2nc(Cl)ncc2F)c(OC)cc1Cl

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,5-dimethoxy-4-chloroaniline gave 2-chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS: purity: 97%; MS (m/e): 316 (M-2H) and 320 (M+2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]3[CH:12]=[C:11](C)[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.P(Cl)(Cl)(Cl)=O.[C:21](=[O:24])([O-])[O-].[Na+].[Na+].[CH3:27]N(C)C=O>>[F:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]3[C:12]([CH:21]=[O:24])([CH3:27])[CH2:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Cc1cn2c(n1)sc1cc(F)ccc12
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C=O)CN=C2Sc3cc(F)ccc3N21
Temperature: 60 °C

Procedure:
The hydrochloride, 20.7 g, was added to 59.5 g of phosphorus oxychloride and 200 ml of dimethylformamide followed by heating at 60° C. for 3 hours. After completion of the reaction, the reaction solution was poured onto ice water containing sodium carbonate. The precipitated crystals were taken out by filtration and recrystallized from ethanol to give 8.77 g of 7-fluoro-3-formyl-3-methylimidazo[2,1-b]benzothiazole. Subsequently, the resulting formyl compound and 1.00 g of sodium borohydride were refluxed in ethanol for one hour. After completion of the reaction, ethanol was removed and the residue was recrystallized from methanol to give 2.74 g of the title compound.