Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:28])[CH2:3][CH2:2]1.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.O>ClCCl>[CH2:35]([S:36]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:28])[CH2:5][CH2:6]1)(=[O:38])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCN(S(=O)(=O)Cc2ccccc2)CC1
Yield: 72 %

Procedure:
1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one (18.5 mg, 0.0460 mmol) in dichloromethane was mixed with phenylmethanesulfonyl chloride (17.5 mg, 0.092 mmol) and triethylamine (12.8 μL, 0.0920 mmol) for 1 hour under cooling with ice. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1 (v/v)) to give the title compound as a pale yellow solid (18.4 mg, yield 72%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:45][CH2:44][C:17]([CH3:46])([O:18][CH2:19][CH:20]=[CH:21][CH2:22][C@H:23]([CH3:43])[O:24][C:25]2[CH:26]=[CH:27][C:28]([F:42])=[CH:29][C:30]=2[CH2:31][O:32][CH2:33]3)[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C>[C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:46])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:43])[O:24][C:25]2[C:30]([CH2:31][O:32][CH2:33]3)=[CH:29][C:28]([F:42])=[CH:27][CH:26]=2)[CH2:44][CH2:45]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)cc1COC3
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1COC3
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of ethyl (2S)-2-(tert-butoxy)-2-[(20S)-15-fluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetate: (46.1 mg, 0.072 mmol) in ethanol (3 mL) were added (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (9.04 mg, 0.014 mmol) then sodium borohydride (13.65 mg, 0.361 mmol) and the mixture was stirred at rt. After 10 min, LCMS indicated completion of reaction. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. The crude was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give ethyl (2S)-2-(tert-butoxy)-2-[(20S)-15-fluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17-heptaen-3-yl]acetate (36.5 mg, 0.057 mmol, 79% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ δ 7.15 (dd, J=9.0, 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.79 (dd, J=8.9, 4.5 Hz, 1H), 6.56 (s, 1H), 5.97 (s, 1H), 4.93 (d, J=12.2 Hz, 1H), 4.75-4.66 (m, 3H), 4.56-4.39 (m, 2H), 4.29-4.15 (m, 2H), 3.97-3.81 (m, 1H), 3.56-3.34 (m, 2H), 3.14 (d, J=11.7 Hz, 1H), 2.83 (d, J=12.2 Hz, 1H), 2.61 (s, 3H), 2.03-1.53 (m, 10H), 1.34-1.13 (m, 18H). LCMS (M+H) calcd for C35H50FN4O6: 641.37. found: 641.6.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[S:8][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[NH:6][C:4]1=[O:5]>C1CCCCC1>[CH2:2]([C@@H:3]1[C:4](=[O:5])[NH:6][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S:8]1)[CH3:1]
Reactant: CC[C@@H]1SC2(CCN(C)CC2)NC1=O
Solvent: C1CCCCC1
Product: CC[C@H]1SC2(CCN(C)CC2)NC1=O

Procedure:
The obtained (R)-2-mercaptobutyric acid was purified by distillation and then reacted with ammonium acetate and 1-methyl-4-piperidone in boiling cyclohexane. The crude reaction mixture was analyzed by GC on a chiral column and found to contain AF267A accompanied by a small (2–3%) amount of AF267B.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])[CH2:18][CH2:17]2)[N:7]=1.[C:31]1([C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]O1)=[O:32].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>ClCCl>[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([N:27]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:31]4=[O:32])[CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: O=C1OCc2ccccc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: CS(=O)(=O)Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6ccccc6C5=O)c4)CC3)cccc2n1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A solution of trimethylaluminum (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of phthalide (1 eq) in dichloromethane was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and the solution was concentrated under reduced pressure. The crude 2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in dichloromethane then N,N-diisopropylethylamine (1 eq.) and methanesulfonyl chloride (1 eq.) were added successively. The reaction mixture was stirred for 2 hours at room temperature then partitioned between saturated aqueous ammonium chloride solution and dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SPE cartridge, Silica) eluting with a gradient from dichloromethane-methanol (100:2) to (98:2) affording the title compound (yield 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.C([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)(OC(C)(C)C)=O.[H-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([O:35][CH:32]2[CH2:33][CH2:34][NH:30][CH2:31]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(OC3CCNC3)ccc21
Yield: 13.7 %

Procedure:
In a similar fashion using route 51 general procedure 119, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (0.2 g, 0.6 mmol), 1-boc-3-pyrrolidinol (0.45 g, 2.3 mmol), NaH (60% in mineral oil; 57 mg, 2.3 mmol) and NMP (2 ml) gave the title compound (33 mg, 14%) after purification by preparative HPLC (acidic conditions 2). Boc deprotection occurred in situ during heating.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[CH:6][NH:7]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:21])=[CH:23][CH:24]=1)=[CH:6][NH:7]2
Reactant: C1COCCN1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)O)cc3)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)N4CCOCC4)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.6 %

Procedure:
4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid (260 mg, 0.76 mmol), morpholine (99.5 mg, 1.14 mmol), WSC (189 mg, 0.99 mmol) and HOBT (151 mg, 0.99 mmol) were added to DMF (10 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 80 mg of powdery white 5-fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one (yield: 26%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([OH:11])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25].O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([O:11][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:10]=1)=[O:5])[CH3:2]
Reactant: COCCOCCBr
Reactant: CCOC(=O)c1cc(O)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(OCCOCCOC)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3.4 g 5-Hydroxy-2H-pyrazole-3-carboxylic acid ethyl ester and 3 g K2CO3 in 50 ml acetonitrile, 4 g 1-(2-Bromo-ethoxy)-2-methoxy-ethane were added. After stirring for 1 h at RT the reaction was heated to 50° C. for 4 h. Then 50 ml of water were added and the mixture was extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with a DCM/MeOH gradient. Yield: 1 g.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:28]2[NH:33][C:32](=[O:34])[CH:31]=[C:30]([CH3:35])[N:29]=2)[NH:17]C(OCC2C=CC=CC=2)=O)=[CH:11][C:10]=1[C:36]([CH3:39])([CH3:38])[CH3:37])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:17][CH:16]([C:28]1[NH:33][C:32](=[O:34])[CH:31]=[C:30]([CH3:35])[N:29]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:36]([CH3:37])([CH3:38])[CH3:39])[CH:11]=1
Reactant: Cc1cc(=O)[nH]c(C(Cc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)NC(=O)OCc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(=O)[nH]c(C(N)Cc2ccc(O)c(C(C)(C)C)c2)n1
Yield: 81.6 %

Procedure:
A suspension of 2-[2-(4-benzyloxy-3-tert-butylphenyl)-1-benzyloxycarbonylaminoethyl]-6-methyl-4-pyrimidinone (1.76 g, 3.35 mmol) and 20% palladium hydroxide/carbon (0.15 g) in methanol (30 ml) was stirred in a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=10:1), giving the titled compound (824 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[NH:19][N:18]=[N:17]3)=[C:12]([F:22])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:24][CH2:25][CH2:26][F:27])[N:18]=[N:17]3)=[C:12]([F:22])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: FCCCBr
Reactant: O=c1[nH]nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 75.8 %

Procedure:
A mixture of 7.0 g (0.023 mole) of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-5H-tetrazol-5-one, 4.23 g (0.030 mole) of 1-bromo-3-fluoropropane, and 4.14 g (0.030 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide was heated at 70° C. for approximately seventeen hours. The mixture was allowed to cool to room temperature before being poured over ice. The solid that formed was removed by filtration and dried. This solid was then placed on a silica gel column and eluted with with methylene chloride. The product-containing fractions were combined and the solvents evaporated under reduced pressure, leaving 6.35 g of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, m.p. 86°-88° C.
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[CH2:26][N:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[NH:37][C:36](=[O:38])[O:35][N:34]=3)[C:28]2=[O:39])=[CH:8][C:7]=1[F:40]>C(O)C>[ClH:5].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:18][CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH2:26][N:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[NH:37][C:36](=[O:38])[O:35][N:34]=3)[C:28]2=[O:39])=[CH:8][C:7]=1[F:40]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(-c3noc(=O)[nH]3)c2=O)C1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c(-c2cccn(C[C@@H]3CNCCO[C@H]3c3ccc(Cl)c(F)c3)c2=O)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.7 %

Procedure:
14 N Hydrogen chloride-ethanol solution (0.5 ml, 7.00 mmol) was added to a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-{[2-oxo-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)pyridin-1(2H)-yl]methyl}-1,4-oxazepane-4-carboxylate (180 mg, 0.35 mmol) in ethanol (2 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethanol (4 ml), and the mixture was heated under reflux for 10 min. The precipitated crystals were collected by filtration to give the title compound (149 mg, 0.325 mmol, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH2:27][CH3:28])[C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C)cc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.64 g), iodoethane (0.20 mL) and cesium carbonate (1.26 g) in DMF (5 mL) was stirred at 50° C. for 4 h. After, stirring at room temperature over weekend, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.68 g) as a brown oil.
Reaction SMILES: O[CH2:2][C@H:3]([N:5]([CH2:16][C@H:17]([OH:19])[CH3:18])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:18][C@H:17]1[O:19][CH2:2][C@@H:3]([CH3:4])[N:5]([C:6]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:15])[CH2:16]1
Reactant: C[C@H](CO)N(C[C@@H](C)O)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@H](C)CO1
Temperature: 0 °C

Procedure:
To a mixture of benzyl (R)-1-hydroxypropan-2-yl((R)-2-hydroxypropyl)carbamate (15.5 g, 58 mmol) in 150 mL THF stirred at 0° C. was added triphenyl phosphine (15 mL, 64 mmol) and stirred for 30 min. The mixture was further treated with diethyl azodicarboxylate (10 mL, 64 mmol) dropwise. The mixture was stirred at 0° C.—RT over 15 h. The mixture was concentrated in vacuo, then was treated with 4:1 hexane/ether 300 mL to precipitate the triphenylphosine oxide. The mixture was filtrated and washed with 4:1 hexane/ether 100 mL. The liquid was concentrated and purified by silica gel chromatography eluting with 20% ethyl acetate/hexane to give (2R,5R)-benzyl 2,5-dimethylmorpholine-4-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([NH:19][CH2:18][CH2:17][Cl:16])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCl
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CC(NCCCl)C(=O)N1Cc1ccccc1

Procedure:
74.8 g (0.4 mol) of N-benzylmaleimide are reacted with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine in accordance with the working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an RF value of 0.24 (on silica gel using ethyl acetate: petroleum ether=1:1) are obtained.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>CCOC(C)=O>[ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:38]5[O:39][C:35]([CH:31]6[O:32][CH2:33][CH2:34][O:30]6)=[CH:36][CH:37]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccc(C7OCCO7)o6)ccc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tri-n-butylstannyl)furan; tlc Rf, 0.25 (100% EtOAc on silica); m/z (M+1+) 490.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in ethyl acetate (3.0 ml) was stirred under refluxing for 3 hours. Water (20 ml) was added to the resulting reaction solution, and the mixture was extracted with ethyl acetate (20 ml×3). After drying the organic layer, the solvent was distilled off under reduced pressure, and the resulting light yellow oily substance was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1) to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophathalimide as a colorless transparent oily substance (0.513 g, 1.41 mmol, 65% yield). The product was recrystallized by adding ethanol (1.0 ml) thereto to obtain the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: FC(F)(F)c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, off-white solid (72 mg, 56%), MS (ISP) m/z=439.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (intermediate M) (0.1 g, 0.29 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.38 mmol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:26])[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.O>ClCCl>[O:30]=[C:28]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3([CH3:26])[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[NH:1]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.1 %

Procedure:
A solution of ethyl 4-[4-[[(1S,2S)-2-aminocyclohexyl]amino]-1-piperidyl]-4-methyl-piperidine-1-carboxylate (87 mg, 0.24 mmol) in dichloromethane (5 mL) was added with triphosgene (0.1 mmol) at 0° C. followed by with diisopropylethyl amine (0.5 mmol) and stirred at room temperature for 12 h. Water (2 mL) was added followed by dichloromethane (20 mL), the phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified with preparative LC/MS (high pH) to give the title compound as white solid 24 mg (25%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.96 (s, 3H), 1.22 (t, J=7.08 Hz, 3H), 1.31-1.49 (m, 6H), 1.55-1.63 (m, 1H), 1.66-1.87 (m, 7H), 1.91-1.99 (m, 2H), 2.08-2.22 (m, 2H), 2.24-2.31 (m, 1H), 2.89-3.10 (m, 4H), 3.33-3.43 (m, 2H), 3.45-3.53 (m, 2H), 3.54-3.63 (m, 1H), 4.08 (q, J=7.08 Hz, 2H). MS (M+1): 393.3.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:7][CH:6]=1.[CH3:19][Mg]Br.C(=O)([O-])O.[Na+]>C1COCC1>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:17])[CH3:19])=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Reactant: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (6.54 g, 24.8 mmol, Step-2) in THF (80 mL) is added dropwise 1.06M methylmagnesium bromide (46.7 mL, 49.5 mmol) at 0° C. The reaction mixture is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with EtOAc (300 mL). The organic layer is washed with water (100 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1) to give 4.51 g (83% yield) of the title compound as colorless oil.