Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:6]1=[O:16])[CH3:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:3]([N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:14][C:13](=[O:15])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)[C:6]1=[O:16])[CH3:4]
Reactant: ClCc1ccccc1
Reactant: CCN1C(=O)CC2(CNC(=O)C2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A suspension of sodium hydride (2.20 g of 60% oil suspension (0.055 mole) washed with toluene) in 50 ml N,N-dimethylformamide was treated gradually with a solution of 10.0 g (0.051 mole) 2-ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 100 ml N,N-dimethylformamide. After stirring 15 minutes, there was added dropwise 6.4 ml (0.055 mole) benzyl chloride and the mixture was stirred overnight, concentrated in vacuo and shaken with water-methylene chloride. The organic layers were dried, evaporated, and the product crystallized from toluene-hexane to afford 11.1 g of the title compound, mp 125-126.5° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O.CCOC(C)=O>CN(C=O)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Temperature: 47.5 °C
Reaction time: 26 h

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (75 g) in DMF (1.3 L) was added phosphorus oxychloride (29.8 ml) at room temperature, and the mixture was stirred at 45-50° C. under Ar atmosphere for 26 h. The mixture was poured into EtOAc (1.5 L), and washed with saturated NaHCO3 solution (1.5 L). The organic layer was separated, and aqueous layer was extracted with EtOAc (2.0 L) two times. The combined organic layer was washed with brine (1.0 L), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in EtOAc/THF (1/1, 700 ml), and NH silica gel (100 g) was added to the solution. The mixture was filtered through a plug of NH silica gel (500 g) with EtOAc as an eluent to give the title compound (47.0 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[CH3:49][C:50]([CH3:53])([O-:52])[CH3:51].[K+]>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([O:52][C:50]([CH3:53])([CH3:51])[CH3:49])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)(C)[O-]
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (2 g) in THF (20 mL) was added potassium tert-butoxide (0.8 g) and the reaction mixture was stirred at ambient temperature for 20 h. Further potassium tert-butoxide (0.8 g) was added and the reaction mixture was stirred at ambient temperature for 411. The mixture was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed with H2O and dried (MgSO4), filtered and evaporated. The resulting oil was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.68 g
Reaction SMILES: C([Li])CCC.[CH2:6]([S:13][C:14]1[N:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:25]Br>O1CCCC1>[CH2:6]([S:13][C:14]1[N:18]=[C:17]([Br:25])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrBr
Reactant: c1ccc(CSc2ncn(-c3ccccc3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1nc(SCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C

Procedure:
n-Butyllithium (50 ml) was added dropwise to a stirred solution of 3-benzylthio-1-phenyl-1,2,4-triazole (31.8 g) in dry tetrahydrofuran (200 ml) at -70° C. Bromine (19 g) was added and the reaction mixture was allowed to warm to room temperature and then quenched with water. After washing with brine, the organic phase was dried and evaporated to give a yellow oil. Purification by chromatography over silica with dichloromethane and petroleum ether afforded the desired product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62](O)=[O:63])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62]([O:45][C@H:36]1[C@H:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:63])([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: CC(C)(C)OP(=O)(OCCCC(=O)O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a suspension of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (100 mg, 0.158 mmol) and 4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (141 mg, 0.475 mmol) in DCM (5 mL) at 0° C., was added DCC (98 mg, 0.475 mmol) followed by DMAP (1.936 mg, 0.016 mmol) and stirred at room temperature for overnight. After completion of the starting material (by LC-MS), reaction mixture was diluted with DCM (2 mL) and filtered through celite and filtrate was washed with water and brine. Combined organic extracts were dried over anhydrous Na2SO4, concentrated. The resultant residue was purified by flash chromatography on silica gel using an ISCO system (eluted with 7:3 Hexanes and EtOAc) to afford (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4 (ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((meth oxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][CH2:18][NH2:19])[CH3:13].C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14][CH2:12][CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CCOc1ccccc1CCN
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1CCNc1ccc2ncc(Br)n2n1
Temperature: 140 °C
Yield: 90.4 %

Procedure:
A mixture of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (648 mg, 3 mmol), 2-ethoxy-phenethylamine (1 g, 6 mmol) and triethylamine (1 ml) in isopropyl alcohol (2 ml) was heated in a microwave at 140° C. for 20 min. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column), to gave the titled compound (980 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (t, J=6.95 Hz, 3H) 3.04 (t, J=6.69 Hz, 2H) 3.64-3.72 (m, 2H) 4.06-4.17 (m, 2H) 4.97 (br. s., 1H) 6.40 (d, J=9.60 Hz, 1H) 6.87-7.02 (m, 2H) 7.17-7.32 (m, 2H) 7.47 (s, 1H) 7.54 (d, J=9.60 Hz, 1H). LRMS (ESI) m/z 361 and 363.1 [(M+H)]+, calc'd for C16H17BrN4O: 361.24.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][Cl:23])[P:5]([N:14]([CH2:18][CH2:19][Cl:20])[CH2:15][CH2:16][Cl:17])(=[O:13])[O:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].[Cl:24][CH2:25][CH2:26][N:27]([CH2:38][CH2:39][Cl:40])[P:28](Cl)([N:30]([CH2:34][CH2:35][Cl:36])[CH2:31][CH2:32][Cl:33])=[O:29].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([P:5]([N:14]([CH2:15][CH2:16][Cl:17])[CH2:18][CH2:19][Cl:20])([O:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][P:28]([N:27]([CH2:26][CH2:25][Cl:24])[CH2:38][CH2:39][Cl:40])([N:30]([CH2:31][CH2:32][Cl:33])[CH2:34][CH2:35][Cl:36])=[O:29])=[O:13])[CH2:21][CH2:22][Cl:23]
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=P(OCCSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
5-Hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate, 174 mg (0.387 mmol), and N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 363 mg (0.996 mmol), were dissolved in 15 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 0.4 mL of 1 M solution in tetrahydrofuran (0.4 mmol), was added over a 10-15 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 43 hours. Additional potassium tert-butoxide and N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidoyl chloride were added over the next 4 days to drive the reaction to completion. After 4.5 days, the reaction mixture was diluted with ethyl acetate; and the ethyl acetate layer separated, washed with water and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude di[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfide, 630 mg, was twice purified by preparative HPLC, and the product fractions combined and lyophilized, giving di[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfide, compound 1CC, as a colorless oil, compound 1CC, 56 mg (18% yield), identified by HPLC and 1H and 31P NMR. Mass spectrum: 779 (C20H40Cl8N4O4P2S+4+H+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([OH:15])=O)[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][N:27]([C:13](=[O:15])[CH2:12][N:11]2[CH2:10][CH2:9][CH2:8][N:7]3[C:2](=[O:1])[N:3]=[C:4]([O:16][CH2:17][C:18]4[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=4)[CH:5]=[C:6]23)[CH2:28][CH2:29]1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Reactant: C1COCCN1
Product: O=C(CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O)N1CCOCC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(6-oxo-8-((3,4,5-trifluorobenzyl)oxy)-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl) acetic acid and morpholine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CC3)c3c(-c4ccncc4)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.19 mmol), N-(4-aminophenyl)-N-methylacetamide (72 mg, 0.44 mmol) and TMSCl (0.100 mL, 0.79 mmol) in nBuOH (3 mL) was stirred at 135° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 414.3 (M+H); UV 202.8, 280.8 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[Cl:42][C:43]1[CH:44]=[C:45]([N:50]=[C:51]=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49].ClCCl>O>[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][C:51]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[N:17]=[C:16]4[C:12]=2[N:13]=[CH:14][N:15]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]3)=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Nc5ccc(Cl)c(Cl)c5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reaction time: 2 h

Procedure:
80 mg of product obtained in stage 4 of example 41 are mixed with 37.3 mg of 3,4-dichlorophenyl isocyanate and 5 ml of dichloromethane. Stirring is carried out for 2 hours at ambient temperature, 0.5 ml of water are added and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 35 mg of expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: Nc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1Oc1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C

Procedure:
A mixture of 2-aminopyridin-3-ol (1.00 g, 9.08 mmol) and DMF (20 mL) was cooled in a 0° C. bath and sodium hydride (0.240 g, 9.49 mmol) was slowly added in portions with vigorous stirring (significant gas evolution). After the addition was completed, the mixture was stirred at ambient temperature for 30 minutes to ensure all the NaH was consumed (reaction becomes very viscous). The 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (1.17 mL, 8.26 mmol) was added and the mixture heated to 110° C. under nitrogen overnight. The reaction was cooled to ambient temperature and the DMF removed under reduced pressure. The resulting black sludge was quenched with 0.5 N NaOH (100 mL) and extracted with Et2O). The organic layer was washed with 1N NaOH and brine, dried over sodium sulfate, filtered and concentrated to afford a brown solid. The solids were purified on silica gel eluting with 40% EtOAc/Hexanes to afford 3-(2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18].CCN(CC)CC.N#N>O1CCOCC1>[Cl:12][C:11]1[C:2]([NH:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)CC(O)CN
Reactant: Clc1nc2ccccc2nc1Cl
Agent: N#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)CC(O)CNc1nc2ccccc2nc1Cl
Temperature: 25 °C
Yield: 47.8 %

Procedure:
2,3-Dichloroquinoxaline (18.05 g, 90.7 mmol) is added to a solution of crude 1a (11.7 g, 99.8 mmol) and Et3N (19 ml, 13.8 g, 136 mmol) in dioxane (210 ml). The solution obtained is heated at reflux (under N2) for 6 h, it is then cooled to room temperature. Et3N, HCl is eliminated by filtration and the filtrate is concentrated under reduced pressure. The dark orange residue is purified by chromatography on a silica column, eluent: CH2Cl2/MeOH (100:0→99:1), to obtain a yellow solid (12.14 g, 48%); 1H NMR (100 MHz, CDCl3) δ: 0.72 (d, 3H), 0.78 (d, 3H), 1.60 (m, 3H), 3.68 (m, 4H), 5.82 (t, 1H), 7.58 (m, 4H); 13C NMR (25 MHz, CDCl3) δ: 22.17, 23.35, 24.60, 44.32, 48.62, 69.67, 125.30, 125.62, 127.91, 130.36, 136.52, 137.92, 140.59, 148.62. Analysis calculated for C14H18N3OCl: C, 60.10; H, 6.49; N, 15.02. Experimental: C, 59.87; H, 6.62; N, 15.25.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[CH3:9][S:10]([O:7][CH2:6][C:2]([CH3:8])([CH3:1])[C:3](=[O:5])[CH3:4])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)C(C)(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(C)(C)COS(C)(=O)=O
Reaction time: 12 h
Yield: 85.5 %

Procedure:
232 g (2 mols) of 3,3-dimethyl-4-hydroxy-2-butanone (for the preparation, see Beilstein H 1, E III, 3239, IV 4030 and Bull. Soc. Chim. France 1954, 2849) in 700 ml of absolute pyridine were reacted with 229 g (2 mols) of methanesulphonyl chloride at 0° to 5° C. After leaving the mixture to stand at 20° C. for 12 hours, it was diluted with methylene chloride and extracted by shaking with ice-water. The organic phase was dried and freed from the solvent in vacuo and the residue was fractionated over a column. 332 g (86% of theory) of 2,2-dimethyl-3-oxo-butyl methanesulphonate of boiling point 106°-120° C./0.12 mm Hg were obtained. ##STR79##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([CH2:17][C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:16]>ClCCl>[N:1]1([C:15]([CH2:17][C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@H](CC(=O)Cl)C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a mixture of piperidine (0.281 g) and triethylamine (0.304 g) in dichloromethane (10 ml) was added dropwise a solution of benzyl (2R)-2-(chlorocarbonylmethyl)-4-methylvalerate (0.816 g) in dichloromethane (5 ml). The solution was stirred at room temperature for 30 minutes and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml), and washed with 7% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution successively. The organic layer was dried over magnesium sulfate, and concentrated in vacuo to give benzyl (2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate (0.931 g) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:29][C:30]([CH3:32])=O>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH:30]([CH3:32])[CH3:29])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)C)C3)cc1

Procedure:
Method as example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) and acetone as starting materials. Purification by prep HPLC (high pH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:35])[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:12]([C:15](OCC)=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:37](=[O:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:12]([C:15]([OH:16])=[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:37](=[O:44])[N:20]3[CH2:21][CH2:22][CH2:23][N:24]([CH3:35])[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN(C)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared in two steps from ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]amino}-2-pyridinecarboxylate and ethyl 3-chloro-3-oxopropionate employing methods similar to those described in Example 457, Steps 3-4. The product was obtained as a white solid: 1H NMR (d6-DMSO, 80° C.) δ 8.65 (1H, b), 7.73 (1H, b), 7.23-7.39 (7H, m), 7.10 (2H, t, J=7 Hz), 5.05 (2H, s), 3.90-4.12 (4H, m), 3.40 (2H, q, J=7 Hz), 3.32 (2H, b), 2.85 (3H, s), 1.74 (2H, b), 1.09 (3H, t, J=7 Hz); ES+ MS: 470 (M+Na+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1>ClCCl>[I:25][CH2:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](CI)C1
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Triphenylphosphine (182.2 g, 695 mmol) and imidazole (47.4 g, 696 mmol) were dissolved in dichloromethane (1.6 L), and iodine (70.4 g, 555 mmol) was then added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 10 minutes. After that, a dichloromethane solution (200 mL) of the (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (55.8 g, 278 mmol) synthesized by a method described in the known method (Bioorg. Med. Chem. Lett., 19, 2829-2834 (2009)) was further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 15 hours. Thereafter, the reaction solution was washed with an aqueous solution of sodium sulfite, was then dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=2%→25%) to obtain (S)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate (73.2 g, 85%) in the form of a colorless oily product.