Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>>[CH:37]1([C:40]([N:33]2[CH2:32][CH2:31][CH:30]([C:23]3[CH:22]=[C:21]4[C:26]([CH2:27][CH:28]([CH3:29])[N:19]([C:17]5[CH:18]=[C:13]([N:10]6[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]6)[N:14]=[C:15]([NH2:36])[N:16]=5)[CH2:20]4)=[CH:25][CH:24]=3)[CH2:35][CH2:34]2)=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(C3CCN(C(=O)C4CC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and cyclopropanecarbonyl chloride. LCMS (M+H)+: m/z=490.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.C(N(CC)CC)C.C(O)(=O)C.Cl.[NH2:38][C@@H:39]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42]C(C)(C)C)=[O:41]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][CH:20]([NH:38][C@H:39]([C:40]([OH:42])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(=O)CC3)cc12
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(N[C@H](C(=O)O)C(C)(C)C)CC3)cc12
Reaction time: 8 h

Procedure:
To a mixture of Example 83B (100 mg, 0.296 mmol), triethylamine (0.091 mL, 0.652 mmol), and acetic acid (0.085 mL, 1.482 mmol) in dichloromethane (3 mL) was added (S)-tert-butyl 2-amino-3,3-dimethylbutanoate hydrochloride (133 mg, 0.593 mmol) and MP-(CN)BH3 resin (Biotage, 2.17 mmol/g, 546 mg, 1.186 mmol). The reaction mixture was shaken on an orbital shaker overnight. The reaction mixture was diluted with 5 mL dichloromethane and the resin filtered off, rinsing with dichloromethane and methanol. The crude material was purified via column chromatography: Analogix Intelliflash™ 280, 12 g silica cartridge, 0-4% methanol/dichloromethane gradient over 30 minutes. The material was dissolved in 5 mL dichloromethane and treated with excess trifluoroacetic acid and stirred at room temperature overnight. The volatiles were removed in vacuo, the residue was dissolved in 5 mL methanol, and the mixture was treated with excess 2 M HCl/diethyl ether. The solution was stirred at room temperature for 20 minutes and then diluted with diethyl ether. The resultant solid was collected by filtration and dried under high vacuum to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H) 8.80-9.10 (m, 3H) 8.36 (s, 1H) 7.46-7.57 (m, 2H) 7.27-7.39 (m, 1H) 6.60-6.78 (m, 2H) 4.02 (d, J=10.07 Hz, 1H) 3.76-3.88 (m, 3H) 3.51-3.61 (m, 1H) 3.15-3.36 (m, 2H) 2.57-2.93 (m, 2H) 2.34 (s, 1H) 1.99-2.16 (m, 1H) 1.78-1.98 (m, 1H) 1.15 (s, 9H). MS (ESI+) m/z 453.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:15]#[N:16])[C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:4]=1[F:21])=[O:29]
Reactant: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1ccc(CNC(=O)c2c(Cl)ncn2COCC[Si](C)(C)C)c(F)c1Oc1cc(Cl)cc(C#N)c1
Yield: 86.6 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-ethyl-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.075 g, 0.246 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.075 g, 0.271 mmol), EDC (0.052 g, 0.271 mmol) and HOBT (0.041 g, 0.271 mmol) in DMF (4 ml) was stirred at RT under an atmosphere of nitrogen for 16 h then ethyl acetate (100 mL) and saturated aqueous NaHCO3 solution (100 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (100 mL), water (100 mL), dried over MgSO4, filtered and concentrated. The material was purified on silica gel (hexanes/ethyl acetate) to give the title compound (0.12 g, 74%) in ca. 85% purity. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (s, 1H), 7.34 (t, 1H), 7.28-7.32 (m, 1H), 7.09-7.20 (m, 3H), 7.02 (d, 1H), 5.75 (s, 2H), 4.69 (d, 2H), 3.61 (t, 2H), 2.57 (q, 2H), 1.18 (t, 3H), 0.95 (t, 2H).
Reaction SMILES: [C:1](=[NH:20])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:21]([CH:23]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=1)[C:24](OC)=O)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:24]=[C:23]([CH2:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)[C:21](=[O:22])[N:20]=3)=[CH:11][CH:10]=2)=[CH:14][CH:15]=1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 135 °C
Yield: 18.4 %

Procedure:
A mixture of 4-(4-fluorophenoxy)phenethyl carbamimidate (50 mg, 0.182 mmol), methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (49.0 mg, 0.219 mmol) and K2CO3 (101 mg, 0.729 mmol) in NMP (2 mL) was heated with a microwave reactor at 135° C. for 2 h. Purification via MDAP then afforded the title compound (15 mg, 18.35% yield). LCMS: rt=3.14 min, [M+H+]=449
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[NH:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:6][C:5]=2[C:4](=O)[CH2:3]1.Cl.[NH2:24][NH2:25].C(N(CC)CC)C>C(O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[C:4](=[N:24][NH2:25])[CH2:3]1
Reactant: NN
Reactant: CC1CC(=O)C2=C(C1)NN=C(c1cccc(C(F)(F)F)c1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1CC(=NN)c2cc(-c3cccc(C(F)(F)F)c3)nnc2C1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
To an ethanol solution (3 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-4,6,7,8-terahydro-1H-cinnolin-5-one (230 mg, 0.74 mmol) obtained in Example 65 were added hydrazine hydrochloride (77.3 mg, 0.74 mmol) and triethylamine (0.206 mL, 1.48 mmol) and stirred at room temperature over night. The reaction liquid was concentrated, followed by purification of residue with silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain an objective compound (29.5 mg, 12.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[F:42][C:43]([F:49])([F:48])[S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:44]([C:43]([F:49])([F:48])[F:42])(=[O:46])=[O:45])[CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(C2CCNCC2)sc1COc1ccc(C#N)c(Cl)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C2CCN(S(=O)(=O)C(F)(F)F)CC2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg 2-Chloro-4-(4-methyl-2-piperidin-4-yl-thiazol-5-ylmethoxy)-benzonitrile was dissolved in 20 ml dichloromethane. 0.25 ml N,N-Diisopropylethylamine and 50 mg dimethylaminopyridine were added. Then 0.26 ml trifluoromethanesulfonylchloride were added to the ice cooled reaction mixture. The cooling bath was removed and the reaction mixture stirred at room temperature overnight. The reaction mixture was washed with 10 ml saturated NaHCO3 solution and then dried over MgSO4. The solvent was removed in Vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 350 mg 2-Chloro-4-[4-methyl-2-(1-trifluoromethanesulfonyl-piperidin-4-yl)-thiazol-5-ylmethoxy]-benzonitrile as amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:27])[C:16]1[CH:26]=[C:23]([O:24][CH3:25])[C:21]([OH:22])=[C:18]([O:19][CH3:20])[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:27])[C:16]1[CH:17]=[C:18]([O:19][CH3:20])[C:21]([O:22][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:23]([O:24][CH3:25])[CH:26]=1)[CH3:13]
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: CCOC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.44 g, 0.002 mol), syringic acid ethyl ester (0.54 g, 0.0024 mol), anhydrous potassium carbonate (0.72 g, 0.005 mol), and DMF (20 mL) into a 100 mL three-necked bottle in turn, wherein the solution appears orange and turbid, irradiating with incandescent lamp, heating to 90° C., stifling to react for 12 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.7, Rf of product=0.5), and the reaction solution appears deep yellow, filtering to obtain orange filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(cyclohexane):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain 0.45 g light yellow 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3,5-dimethoxybenzoic acid ethyl ester, a yield is 61.6%, m.p. 121.7-123.2° C.
Reaction SMILES: C(OC(C1[C:13]([C:14]([O:16]C)=O)=[CH:12][C:11]([Cl:18])=[N:10][CH:9]=1)=O)(C)(C)C.[C:19]([O:23][C:24]([C:26]1C(C(O)=O)=CC(Cl)=NC=1)=[O:25])(C)(C)C.[H-].[Na+].CI.[CH3:40][N:41]([CH:43]=[O:44])[CH3:42]>O>[Cl:18][C:11]1[CH:12]=[C:13]2[C:40](=[CH:9][N:10]=1)[N:41]([CH3:42])[C:43](=[O:44])[C:26]([C:24]([O:23][CH3:19])=[O:25])=[C:14]2[OH:16]
Reactant: COC(=O)c1cc(Cl)ncc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)cc1C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(O)c2cc(Cl)ncc2n(C)c1=O

Procedure:
Methyl 5-(tert-butoxycarbonyl)-2-chloroisonicotinate. To a solution of 5-(tert-butoxycarbonyl)-2-chloroisonicotinic acid (1 g, 3.7 mmol) in dry DMF (10 mL) was added NaH (60% suspension in mineral oil, 0.37 g, 9.24 mmol) in small portions with stirring and cooling using an ice-bath. After addition, the reaction mixture was treated with MeI (0.524 mL, 9.24 mmol) dropwise, and then stirred at room temperature for 1 hour. The reaction mixture was poured into water and stirred at room temperature for 3 hours. The precipitate was filtered and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: N#Cc1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1
Yield: 92 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0 mmol), 2-chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 263 (1.60 g, 92%) was obtained as a yellow solid.
Reaction SMILES: Cl.C[NH:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](N(CC)CC)C.[C:15]1([C:25](Cl)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][NH:3][C:25]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:26]
Reactant: CNCC(=O)O
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1cccc2ccccc12
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a suspension of methylglycinate hydrochloride (3.3 g, 26 mmol) in THF (100 mL) was added at 0° C. triethylamine (11 mL, 78 mmol). After stirring for 5 min, 1-naphthaloylchloride (4.5 mL, 31.5 mmol) was added dropwise and the resulting mixture was stirred overnight at room temperature. 10% HCl was added and the aqueous phase extracted with EtOAc. The combined organic phases were washed with 10% NaOH, brine and concentrated under vacuum. The crude compound was purified by flash chromatography using DCM/EtOAc (98:2) as eluent to give the compound 2a (5 g, 79%). 1H NMR (acetone-d6) δ 3.76 (s, 3H, OMe), 4.24 (d, J=6.0 Hz, 2H, CH2), 7.52-7.58 (m, 3H, Ar), 7.72 (dd, J=1.1 and 7.0 Hz, 1H, Ar), 7.90 (m, 1H, Ar), 8.01 (d, J=8.3 Hz, 2H, Ar), 8.46 (m, 1H, NH); 13C NMR (acetone-d6) δ 41.91 (CH2), 52.22 (OMe), 125.67, 126.07, 126.66, 127.09, 127.49, 128.99, 131.09, 131.22, 134.57, 135.36, 170.12 (CO), 171.13 (CO).
Reaction SMILES: C1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([O:13][Si](C)(C)C)[C@@H]2CCCN2)C=CC=CC=1.[CH:24](=[O:27])CC.[C:28]([O:32][C:33](=[O:35])[NH2:34])([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[C:28]([O:32][C:33](=[O:35])[NH:34][C@H:21]([C:22]1[O:13][CH:7]=[CH:18][CH:23]=1)[C@@H:20]([CH3:19])[CH:24]=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCC=O
Reactant: C[Si](C)(C)OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: CC#N
Product: C[C@@H](C=O)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To a solution of (S)-2-(diphenyl-trimethylsilanyloxymethyl)-pyrrolidine (417.0 mg, 1.3 mmol, 10 mol %) in acetonitrile (26 mL) at room temperature was added 1-propanal (2.6 mL, 38.4 mmol, 3.0 equiv) and 1-furan-2-yl-meth-(E)-ylidene]-carbamic acid tert-butyl ester (2.5 g, 12.8 mmol). After stirring at room temperature for 12 hours, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (EtOAc/heptane) to give ((1S,2R)-1-furan-2-yl-2-methyl-3-oxo-propyl)-carbamic acid tert-butyl ester as a light yellow oil (2.4 g, 74% yield, dr=62:38) [dr=62:38 was determined by integration of one set of 1H NMR signal (major s, 9.68 ppm, minor s, 9.76 ppm)]. 1HNMR (400 MHz, CDCl3) 9.76 (s, 1H), 9.68 (s, 1H), 7.34 (d, J=1.57 Hz, 1H), 6.38-6.17 (m, 2H), 5.08 (m, 2H), 2.94 (m, 1H), 1.44 (s, 9H), 1.09 (t, 3H).
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:21]=[CH:20][C:18](N)=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 18.5 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-nitro-2-trifluoromethylaniline (618 mg, 3.0 mmol) was added during 20 minutes while maintaining the temperature of the reaction mixture at 18-19° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 49:1) gave 587 mg (85%) of allyl-4-nitro-2-trifluoromethylbenzene as a light yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.53, (d, 1H, J=2.4 Hz), 8.35, (dd, 1H, J=8.5, 2.4 Hz), 7.59, (d, 1H, J=8.5 Hz), 6.00-5.88, (m, 1H), 5.24-5.12, (m, 2H), 3.68, (d, 2H, J=6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 146.8, 146.6, 134.9, 133.0, 130.3, (q, J=32.2 Hz), 127.7, 126.9, 124.9, 122.2, 122.1, (q, J=6.0 Hz), 118.7, 37.0, (m); Anal HRMS Calcd. for C10H8F3NO2 (M): 231.0507. Found: 208.0515.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[N+:22]([O-])=O)[CH:9]=1)([CH3:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:19])([F:21])[F:20])=[CH:12][C:11]=2[NH2:22])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
5′-Isopropyl-5,2′-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35 g) is dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (30 ml), and thereto is added 10% palladium-carbon (500 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-ylamine (1.88 g). MS (m/z): 340 [M+H]+
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38]2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:49][C:46]3[CH:47]=[CH:48][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH2:38][CH2:39]4)=[CH:44][CH:45]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)nn12
Yield: 76.2 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.239 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 164.97 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a lyophilized powder. (M+H)=498.9. 1H NMR (400 MHz, DMSO, d6) δ 9.42 (s, 1H), 8.94 (s, 1H), 7.80 (dd, 1H, J=1.60, 6.00 Hz), 7.69 (d, 2H, J=8.93 Hz), 7.46 (m, 1H), 7.20 (d, 1H, J=8.28 Hz), 7.13 (m, 3H), 6.94 (m, 2H), 3.70 (s, 3H), 3.67 (m, 7H), 3.01 (m, 6H), 2.83 (s, 3H), 2.07 (m, 2H), 1.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:17])([C:14]([OH:16])=O)[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.CN(C)C=O>[C:24]([NH:28][C:14]([C:12]1([CH3:17])[O:11][N:10]=[C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13]1)=[O:16])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC1(C(=O)O)CC(c2cc(Cl)cc(Cl)c2)=NO1
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C1(C)CC(c2cc(Cl)cc(Cl)c2)=NO1
Reaction time: 0.5 h

Procedure:
100 ml of CH2Cl2 and 70 mg of dimethylformamide were added to 5.00 g (18.2 mmol) of 3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid. At RT, 3.47 g (27.4 mmol) of oxalyl chloride were added slowly with stirring. After 30 min, the solution was concentrated and used without further purification (crude yield 5.50 g). 200 mg (0.68 mmol) of this crude product were taken up in 3 ml CH2Cl2 and added dropwise to a solution of 50 mg (0.68 mmol) of tert butylamine, 69 mg (0.68 mmol) of triethylamine and 10 mg of dimethylaminopyridine in 50 ml of CH2Cl2 at C. For work-up, the mixture was extracted with water, with saturated NaHCO3 solution and once more with water. Drying of the organic phases, filtration and removal of the solvent under reduced pressure gave the product.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][C:15]1[C:19](B(O)O)=[C:18]([CH3:23])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[C:18]([CH3:23])[O:17][N:16]=1
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: Cc1noc(C)c1B(O)O
Product: COc1cc(OC)c(-c2c(C)noc2C)cc1C=O
Yield: 75 %

Procedure:
Ex-33A: 5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 3,5-dimethyl-isoxazole-4-boronic acid in a similar manner as described in Ex-3A, 75% yield. 1H-NMR (CDCl3) δ 10.34 (s, 1H), 7.63 (s, 1H), 6.52 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 2.12 (s, 6H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][OH:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl.[Cl-].[Na+].O>[C:24]([O:15][CH2:14][C@@H:13]([NH:16][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC#CCOc1ccc(C[C@@H](CO)NC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@@H](COC(C)=O)NC(=O)OC(C)(C)C)cc1
Reaction time: 7 h
Yield: 102.8 %

Procedure:
tert-Butyl [(S)-2-(4-but-2-ynyloxy-phenyl)-1-hydroxymethyl-ethyl]-carbamate (402 mg, 1.26 mmol) was dissolved in dichloromethane (6.3 mL), and acetic anhydride (0.179 mL, 1.89 mmol) and pyridine (204 μL, 2.52 mmol) were added at room temperature. The reaction mixture was stirred for 7 hours, then poured into a saturated brine, and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (468 mg).