Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1([C:27]2[C:28](F)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25]1>CS(C)=O.CCOC(C)=O>[CH:24]1([C:27]2[C:28]([O:17][C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][CH:13]=3)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: Fc1ncccc1C1CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CC2)c1
Temperature: 125 °C

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (1.17 g, 4.81 mmol) in DMSO (40 mL) was added cesium carbonate (1.88 g, 5.78 mmol) and 3-cyclopropyl-2-fluoropyridine (660 mg, 4.81 mmol). The resulting mixture was heated to 125° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(4-(3-cyclopropylpyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as tan solid. MS (ESI, pos. ion) m/z: 360.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>>[CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:19][CH:20]([OH:23])[CH2:21][O:22][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCCC2
Yield: 60 %

Procedure:
Treatment of (±)-3-[1-(benzyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl]propane-1,2-diol (9.6 g, 0.031 mol) with tert-butyldimethylsilyl chloride (4.86 g, 0.032 mol) and imidazole (2.51 g, 0.037 mol) generally according to the procedure described for Intermediate 3 afforded 7.93 g (61%) of (±)-1-[1-(benzyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. Rf=0.63 (silica, ethyl acetate:hexanes 1:3); 1H NMR (DMSO-d6) δH 7.48 (d, 2H); 7.35 (m, 3H); 7.03 (d, 1H); 6.78 (d, 1H); 4.77 (q, 2H); 4.55 (d, 1H); 3.75 (m, 1H); 3.45 (m, 2H); 2.85 (dd, 1H); 2.69 (m, 4H), 2.51 (dd, 1H); 1.68 (m, 4H); 0.8 (s, 9H); 0.0 (d, 6H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:11][CH:10]=1.[CH3:20][N:21]1[C:26]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][C:24](=[O:33])[N:23]([CH3:34])[C:22]1=[O:35]>C(O)C>[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:30]2[CH2:31][CH2:32][N:27]([C:26]3[N:21]([CH3:20])[C:22](=[O:35])[N:23]([CH3:34])[C:24](=[O:33])[CH:25]=3)[CH2:28][CH2:29]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(OCCCBr)cc1
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCCOc3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Yield: 86.1 %

Procedure:
3 ml of triethylamine was added to 10 ml of an ethanol solution containing 2.5 g of 3-(4-chlorophenoxy)propyl bromide and 1.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione, and the solution was then heated under reflux for 3 hours. Afterward, the reaction solution was concentrated to dryness, and the resultant residue was dissolved in chloroform and then washed with water. The thus obtained chloroform solution was dried and then concentrated, and the residue was recrystallized from ethanol/hexane, thereby preparing 1.96 g (yield: 86%) of 6-[4-(3-[4-chlorophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:17]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:15][C:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][C:5]=1[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
70.6 g (258 mmol) of the above 4-bromo-2-fluoro-N-pivaloylaniline was dissolved in 500 mL of toluene under argon atmosphere, 108 mL (310 mmol) of 1-ethoxyvinyltributyltin and 1.80 g (2.57 mmol) of bis(triphenylphosphine)palladium (II) chloride were added, and the mixture was stirred at 100° C. for 5 hours. The reaction solution was cooled on ice, 500 mL of 2N HCL was added, and the mixture was stirred at room temperature for 2 hours. The insoluble matters were filtered off and the filtrate was extracted once with ethyl acetate. 500 mL of a 10% aqueous solutiuon of ammonium fluoride was added to the organic layer and the mixture was stirred at room temperature for 3 hours. The insoluble matters were filtered off and the organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1-4:1), to give 60.8 g of 3'-fluoro-4'-pivaloylaminoacetophenone (yield: 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=3[O:28][CH3:29])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CCCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-butyl-cinnoline-3-carboxamide (100 mg, 0.31 mmol) and 2,5-dimethoxyphenyl boronic acid (112.6 mg, 0.62 mmol) according to Method A to afford a white solid (96.3 mg, 82%). 1H NMR (300.132 MHz, CDCl3) δ 8.54 (t, J=4.7 Hz, 1H), 7.86 (dd, J=7.6, 2.2 Hz, 1H), 6.96 (t, J=3.0 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J=1.9 Hz, 1H), 7.76-7.68 (m, 2H), 3.79 (s, 3H), 3.64 (s, 3H), 3.48 (q, J=6.6 Hz, 2H), 1.61 (quintet, J=7.2 Hz, 2H), 1.43 (sextet, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H). MS APCI, m/z=381.2 (M+H). HPLC 2.83 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[N:10]=2)[CH2:3]1)(=[O:23])=[O:22]
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-hydroxy-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (571 mg, 1.93 mmol) (obtained as described in Reference Example 66(2)) in methylene chloride (28 ml) were added methanesulfonyl chloride (0.18 ml, 2.32 mmol) and triethylamine (0.33 ml, 2.32 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (1:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (490 mg, yield 91%) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>C(O)C>[ClH:2].[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: Cc1cccc(N)c1C
Reactant: ClCC1=NCCN1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(NCC2=NCCN2)c1C
Yield: 75.1 %

Procedure:
31 g of 2-chloromethyl-2-imidazoline hydrochloride and 48.4 g of 2,3-dimethylaniline are refluxed for 5 hours in 65 ml of absolute ethanol. After cooling, the crystallised substance is collected by suction and recrystallised from water, affording 36 g (77% yield) of the final product with a melting point of 242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:23]([C:22]1[CH:26]=[CH:27][C:19]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[C:20]([N+:28]([O-:30])=[O:29])[CH:21]=1)(=[O:24])[NH2:25]
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3[N+](=O)[O-])c(Cl)cc21
Temperature: 90 °C

Procedure:
To a stirred solution of ethyl 6-chloro-7-hydroxychroman-4-carboxylate (6.40 g, 24.9 mmol) and 4-chloro-3-nitrobenzamide in N,N′-dimethylformamide (75 mL) at ambient temperature was added potassium carbonate (8.61 g, 62.3 mmol). An argon balloon with purge valve was attached, and the stirred mixture was evacuated and purged 5 times with argon. The mixture was stirred in an oil bath at 90° C. under argon. After 15 hours the reaction mixture was cooled to ambient temperature, then poured into a reparatory funnel containing water (1000 mL) and the extracted with ether (2×1000 mL). The organic layers were combined and dried over sodium sulfate, then evaporated to give 10.5 g of brown semi-solid. The crude material was purified by silica gel column chromatography, eluting with 99/1 chloroform/methanol followed by 98/2 chloroform/methanol to provide the desired product (7.74 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 72 h
Yield: 96.7 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (25 g; 0.159 mol) in DMF (600 ml) under argon was treated at room temperature with Na2CO3 (33.7 g; 0.318 mol). The mixture was stirred and treated dropwise with benzyl bromide (32.6 g; 0.19 mol). Stirring was continued for 3 days when the mixture was poured into water and extracted with Et2O. The organic phase was washed with water, brine and dried over MgSO4. Evaporation gave 4-benzyloxy-2-fluoronitrobenzene as a yellow solid (38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]([NH2:34])([CH3:33])[CH3:32]>>[C:31]([NH:34][C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][N:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=2)[CH:24]=[CH:23][CH:22]=1)=[O:21])([CH3:33])([CH3:32])[CH3:30]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)N
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12

Procedure:
5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.10 g, 0.20 mmol) and 2-methylpropan-2-amine (0.020 g, 0.30 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.88 (d, J=7.02 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J=1.22 Hz, 1H), 7.95-8.02 (m, 3H), 7.87-7.93 (m, 3H), 7.58-7.64 (m, 1H), 7.47 (dd, J=7.32, 1.83 Hz, 1H), 7.33 (t, J=9.00 Hz, 2H), 2.82 (d, J=4.58 Hz, 3H), 1.43 (s, 9H). LCMS: retention time: 2.940 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 445 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[CH2:10][O:9][B:8]([OH:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:11]2[CH2:10][O:9][B:8]([OH:12])[C:7]=2[CH:6]=1)([O-:17])=[O:16]
Reactant: OB1OCc2c1cccc2C(F)(F)F
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc2c(c(C(F)(F)F)c1)COB2O
Temperature: -40 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To 4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXX) (1.17 g, 5.79 mmol) cooled to −40° C. was slowly added HNO3 (10 mL, 99%). The reaction mixture was stirred for 3 h at −40° C. and then slowly quenched with crushed ice. The yellow precipitate was filtered and washed with hexane to produce 6-nitro-4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXXI) as a yellow crystalline solid (950 mg, 3.83 mmol, 66% yield). ESIMS found for C8H5BF3NO4 m/z 246.4 (M−H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1>CN(C=O)C>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:4]1[CH:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:3]1=[O:2]
Reactant: COc1ccc(COc2ccccc2)cn1
Reactant: Fc1ccc(CBr)cc1F
Solvent: CN(C)C=O
Product: O=c1ccc(COc2ccccc2)cn1Cc1ccc(F)c(F)c1
Yield: 30.4 %

Procedure:
According to Scheme 16 Method A: The title compound was prepared from 2-methoxy-5-(phenoxymethyl)pyridine (1 eq, 0.46 mmol, 0.10 g) and 4-(bromomethyl)-1,2-difluorobenzene (3 eq, 1.39 mmol, 0.18 mL) according to the procedure described for Example 1 Step 2. Reaction conditions: under reflux for 3 days in DMF (5 mL). The crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 90/10 followed by recrystallization in diisopropyl ether to afford 1-(3,4-difluorobenzyl)-5-(phenoxymethyl)pyridin-2(1H)-one (0.14 mmol, 0.04 g, 29%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].C1COCC1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[O:47]1[CH2:48][CH2:49][N:44]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]([C:12]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]5)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:45][CH2:46]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.0 g, 1.89 mmol) in DMF:THF (3 mL:4 mL) was added morpholine (1.8 mL, 20.6 mmol). The reaction mixture was stirred at RT for 2.5 h. The reaction mixture was concentrated in vacuo to remove volatiles. The residue was poured into ice-water and the resulting white solid was filtered and dried for several hours under high vacuum. The crude product re-crystallized using absolute EtOH to afford tert-butyl 5-(2-(3-(2-morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (830 mg, 75%)
Reaction SMILES: C[O-].[Na+].CO.[C:6]([O:12][CH3:13])(=[O:11])[C:7]([O:9]C)=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[O:9]=[C:7]([CH2:14][C:15](=[O:16])[CH3:17])[C:6]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(=O)OC
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=O)CC(C)=O
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 500 mL flask, 25% sodium methoxide of methanol solution (43.20 g, 0.200 mol), methanol (200 mL) were added, the mixture of dimethyl oxalate (23.60 g, 0.200 mol) and acetone (11.60 g, 0.200 mol) were added dropwise at ice-salt bath. The reaction mixture was stirred for 8 hours at 0˜5° C. The reaction mixture was poured into 200 mL water and extracted with ethyl acetate (150 mL) to remove organic impurity. The aqueous solution was acidified with concentrated hydrochloric acid to pH of 2˜3 and extracted with ethyl acetate (3×200 mL). The organic layer was washed with water (150 mL), and saturated brine (150 mL), dried over anhydrous magnesium sulfate and concentrated to give the product (25.9 g) as yellow oil in 90% yield. 1H NMR (300 MHz, CDCl3): 6.396 (s, 1H, enol isomer), 3.906 (s, 3H), 2.279 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([C:23](=[O:26])[CH2:24]Cl)[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:28]>CC#N>[CH2:1]([N:8]([C:23](=[O:26])[CH2:24][I:28])[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2)C(=O)CCl)[C@H](O)C1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2)C(=O)CI)[C@H](O)C1

Procedure:
To a solution of trans-tert-butyl 4-[benzyl(chloroacetyl)amino]-3-hydroxypiperidine-1-carboxylate (144 g, 376 mmol) in CH3CN (2 L) was added NaI (56.4 g, 376 mmol) in one portion. The mixture was stirred at reflux for 1 h and then concentrated. The residue was dissolved in DCM (1 L) and filtered. The filtrate was concentrated under reduced pressure to afford trans-tert-butyl 4-[benzyl(iodoacetyl)amino]-3-hydroxypiperidine-1-carboxylate, which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:6][O:5][C:4]([NH2:7])=[N:3]1>CCO.CCCCCCC>[CH3:1][C@:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)[CH2:6][O:5][C:4]([NH2:7])=[N:3]1
Reactant: CC1(c2ccc(OC(F)(F)F)cc2)COC(N)=N1
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@]1(c2ccc(OC(F)(F)F)cc2)COC(N)=N1

Procedure:
((RS)-4-Methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine was sepa-rated by chiral HPLC (Chiralpak AD, EtOH/heptane 10:90) to give (S)-4-methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Viscous colorless oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>O1CCOCC1>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:8][C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[NH:1]1
Reactant: NC1(CO)CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCCC2)CS1
Yield: 20 %

Procedure:
1-Amino-1-(hydroxymethyl)cyclohexane (Method B1a) was dissolved in p-dioxane (80 mL) then treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) Rf0.69.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[N:11]=[C:10]([C:27]#[N:28])[N:9]=2)[N:3]=1.Cl.C([O-])(O)=[O:31].[Na+]>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[N:11]=[C:10]([C:27]([NH2:28])=[O:31])[N:9]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C#N)n2)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C(N)=O)n2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidine-2-carbonitrile (21) (50.0 mg, 0.135 mmol, 1.0 eq.) in 1,4-dioxane (0.30 mL) was added concentrated HCl (0.30 mL, 3.6 mmol, 27 eq) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was neutralized with saturated aqueous NaHCO3 and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative TLC (5% methanol in dichloromethane) to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl) pyrimidine-2-carboxamide (22) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.69 (m, 1H), 7.59 (br d, 1H, J=3.2 Hz), 7.33-7.21 (m, 3H), 6.44 (br d, 1H, J=3.2 Hz), 3.82 (s, 3H), 3.01 (m, 1H), 3.00 (s, 3H), 2.90 (m, 1H), 2.42 (s, 3H), 2.16-2.07 (m, 2H). LRMS m/z (M+H) 389 found, 389 required. m.p. 119-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])=[O:5])[CH3:2]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCNC(C)=O
Solvent: C1CCOC1
Product: CCNCCNCCc1[nH]cc(C)c1C(=O)OCC
Yield: 88.3 %

Procedure:
A stirred solution of 2-[(2-acetylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (500 mg, 1.695 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (6.75 ml, 6.75 mmol) under an argon atmosphere. Upon completion of the addition, the mixture Was heated to reflux for 7 hours The mixture was concentrated under reduced pressure. The residue was added with water (10 ml) and adjusted to pH 3 with 2N hydrochloric acid. The resulting mixture was adjusted to pH 14 with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×3). The combined organic extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to, give 2-[2-(2-ethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (400 mg, 88%) as a brown solid.