Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][Br:19])=[N:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2cc(Br)cnc21
Temperature: 80 °C
Yield: 6.6 %

Procedure:
A mixture of tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x154 (10.8 mmol, 1 eq, 3.37 g), N-bromosuccinimide (1.92 g, 1 eq, 10.8 mmol) and azo-bisiso-butyronitrile (AIBN) (10.8 mmol, 1 eq, 1.77 g) in CCl4 (50 ml) is heated for 2 hours at 80° C. The solvent is removed under reduce pressure, water is added and the resulting mixture is extracted with dichloromethane. The combined organic phases are dried over MgSO4, filtered and volatiles removed under reduced pressure. The product is purified by chromatography on silicagel (hexane/AcOEt 8/2) and recristallized in AcOEt to afford 0.28 g of pure tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C)C=O.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.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 70 °C
Yield: 93.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with trimethylsilyl acetylene (0.71 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trimethylsilanylethynyl-phenyl)-propionic acid methyl ester (615 mg, 93.6%) as an orange solid: mp 72-74° C.; EI-HRMS m/e calcd for C20H28O2Si (M+) 328.1858, found 328.1852.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][S:16]2(=[O:22])=[O:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(O)C>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][S:16]3(=[O:21])=[O:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 83.9 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.00 g, 3.02 mmol) and 4-fluorobenzylamine (1.31 g, 10.5 mmol) in a mixture of anhydrous ethyl alcohol (40 ml) and N,N-dimethylformamide (10 ml) was heated under reflux for 10 h. The solvent was then evaporated in vacuo and the residue was diluted with dichloromethane (500 ml). The organic phase was washed with 5% aqueous acetic acid, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and recrystallization of the white solid obtained from dichloromethane and ethanol gave 1.04 g (84% yield) of the title amide as white crystals; mp 227–228° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 and 2.07 (2×1H, m, CH2), 2.28–2.43 (2H, m, CH2), 3.19–3.31 (2H, m, CH2), 3.64 (3H, s, NCH3), 3.6–3.8 (2H, m, CH2), 4.59 (2H, AB part of ABX system, JAB=14.9 Hz, Δν=36.1 Hz, JAX=6.6 Hz, JBX=5.8 Hz, NCH2), 7.06 (2H, m, aromatics), 7.31 (2H, m, aromatics), 7.52 (1H, broad NH). Anal. Calcd for C17H19FN4O5S: C 49.75, H 4.67, N 13.65. Found: C 49.67, H 4.63, N 13.77.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:15])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-1H-pyrazole (3.42 g, 23.43) and 3-methyl-2-butenoic acid ethyl ester (1 g, 7.81 mmol) in DMF (50 mL) was treated with cesium carbonate (10.1 g, 31.07) and allowed to stir for 3 hours at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried over sodium sulfate and concentrated to afford the desired product, 1.1 g (51%) yield. 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.45 (s, 1H), 3.98-4.05 (m, 2H), 2.82 (s, 2H), 1.62 (s, 6H), 1.18-1.10 (t, 3H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:17]4[CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:16]4[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[H-].[Na+].Cl[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.O>CN(C=O)C>[NH:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:17]4[CH:18]=[C:19]([CH2:21][O:22][C:32]5[CH:41]=[CH:40][C:39]6[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=6)[N:33]=5)[N:20]=[C:16]4[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCc1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2nc(OCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of compound 1h (187 mg, 0.510 mmol) in DMF (2 mL) was added sodium hydride (49.0 mg, 2.04 mmol) in portions at 0° C. The mixture was stirred for 15 min before the addition of 2-chloroquinoline (125 mg, 0.765 mmol). The reaction mixture was stirred at 70° C. overnight. Water was added, and the resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:3 v/v) to obtain the title compound 97 as a yellow solid (27.6 mg, 11% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.23-8.28 (m, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.23-8.15 (m, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.68 (t, J=7.2 Hz, 1H), 7.63-7.55 (m, 1H), 7.44 (t, J=7.2 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 7.03-7.00 (m, 1H), 5.59 (s, 2H), 4.35-4.20 (m, 4H), 3.85-3.69 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H22N10O2: 507.2 (M+H). Found 507.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19](/[C:20](=[CH:28]/[OH:29])/[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: CCOC=O
Reactant: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)C3)n(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)/C3=C\O)n(C)n1
Temperature: 78 °C
Yield: 19 %

Procedure:
N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-(2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-benzamide (as prepared above in Step 4; 0.300 g, 0.793 mmol) was dissolved in anhydrous ethanol (8 mL) and the resulting solution was treated with ethyl formate (0.058 mL, 0.717 mmol) The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.48 mL, 3.97 mmol). This reaction mixture was heated at 78° C. for 0.5 h, which caused the reaction mixture to turn black in color. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH=1 with dropwise addition of 1M HCl(aq). The reaction mixture was diluted with EtOAc (25 mL) and extracted with brine (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash silica gel chromatography (5% MeOH in CHCl3) affording the title compound in 19% yield (0.061 g, 0.150 mmol).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]2[CH2:9][CH2:10][CH2:11][CH:2]12.[OH-].[Na+].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>CN(C=O)C>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]3[CH2:9][CH2:10][CH2:11][CH:2]23)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1CC2CCCC2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(S(=O)(=O)N2C(C(=O)O)CC3CCCC32)cc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
1 g of octahydrocyclopenta[b]pyrrole-2-carboxylic acid (6.45 mmol) was dissolved in 20 ml of DMF, after which 3 equivalents of a 3N solution of NaOH (6.45 ml) were added at 0° C. After 10 min, a solution of 1.55 g of 4-acetylbenzenesulfonyl chloride (1.1 equivalents, 7.1 mmol) in 8 ml of DMF was slowly added dropwise; after it had reached RT, the mixture was stirred at 40° C. for a further 6 h and, after that, the solvent was removed under reduced pressure. The crude product was purified chromatographically.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[N:14]1[CH:19]=[C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)[CH:17]=[N:16][CH:15]=1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OB(O)c1cncnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cn(-c2cncnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a vial containing methyl 1H-indole-3-carboxylate (471 mg, 2.69 mmol), pyrimidin-5-ylboronic acid (1.0 g, 8.07 mmol), copper (II) acetate (635 mg, 3.5 mmol), 4 {acute over (Å)} molecular sieves (4 g) and 1,10-phenanthroline (970 mg, 5.38 mmol) were added DCM (10.7 ml) and triethylamine (0.375 ml, 2.69 mmol). The mixture was stirred at RT for 7 days then filtered through a pad of Celite (washed with MeOH). Evaporation and purification by HPLC (after dilution with DMF and filtration) afforded the title compound as a tan solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:15]([CH2:16]C)=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH2:19][C@@H:20]([C:24]([OH:26])=[O:25])[C@@H:21]([CH3:23])[OH:22].O>CS(C)=O>[Cl:7][C:8]1[C:15]([CH3:16])=[C:14]([NH:19][C@H:20]([C@H:21]([OH:22])[CH3:23])[C:24]([OH:26])=[O:25])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: CCc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
K2CO3 (3.15 g, 22.8 mmol) was added to a solution of 2-chloro-3-ethyl-4-fluorobenzonitrile (2.1 g, 11.4 mmol) and D-allo-threonine (2.04 g, 17.1 mmol) in DMSO (25 mL) at room temperature The reaction mixture was heated to 80° C. and stirred for 72 h then allowed to cool to room temperature. H2O (200 mL) was added and the brown solution was extracted with MTBE (200 mL). The aqueous layer was cooled to 0° C. and solid citric acid monohydrate was added in 200 mg portions until the evolution of gas ceased. The aqueous layer was then extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×300 mL), dried with Na2SO4, filtered and concentrated to provide the title compound (1.44 g, 32%): 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.47 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 5.46 (d, J=8.7 Hz, 1H), 4.55-4.43 (m, 1H), 4.27 (dd, J=5.9 Hz, 8.7 Hz, 1H), 2.90-2.81 (m, 2H), 1.33 (d, J=6.3 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]5[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].[H-].[Na+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][N:12]1[C:11]2[C:10]([CH3:16])([CH3:15])[C:9]3[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]4[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]4)[CH:19]=[CH:20][C:8]=3[C:7](=[O:39])[C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H]3OC(C)(C)O[C@@H]3CO[Si](C)(C)C(C)(C)C)cc1C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Under nitrogen atmosphere, 3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T22-1, 40.0 mg, 65.2 μmol) was dissolved in DMF (0.20 mL), added at 0° C. with methyl bromoacetate (30.5 μL, 134.5 μmol) and sodium hydride (4.5 mg, 132 μmol), and then stirred at room temperature for 2 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (44.5 mg, 85%).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CNCCO
Product: CN(CC=Cc1ccccc1)CCO

Procedure:
The title compound was prepared from 3-bromo-1-phenylprop-1-ene (0.77 g) and 2-(methylamino)ethanol (3.1 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-methoxyphenol (488 mg) in acetone (15 ml) were added cesium carbonate (1.20 g) and ethyl bromoacetate (375 μl), and the mixture was stirred for 1 hour at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=6/1) gave ethyl 2-(5-chloro-2-methoxyphenoxy)acetate (572 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH3:36][NH2:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CCC1

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268g) and methylamine using a similar method to that described for example 167f.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Yield: 89 %

Procedure:
A solution of tert-butyl 4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate (180 mg, 0.33 mmol) was stirred in dichloromethane (9 mL) and trifluoroacetic acid (4 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 129 mg (88%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (qd, J=11.66, 3.81 Hz, 2 H) 2.10 (d, J=11.87 Hz, 2 H) 2.64-2.88 (m, 2 H) 3.10 (d, J=12.62 Hz, 2 H) 4.27 (br. s., 1 H) 5.80 (d, J=6.31 Hz, 1 H) 7.01-7.55 (m, 8 H) 8.37 (s, 1 H), [M+H]+ 439.6.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][C:25]([F:31])=[C:26]([F:30])[CH:27]=4)[C:22]3=[O:32])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][C:25]([F:31])=[C:26]([F:30])[CH:27]=4)[C:22]3=[O:32])=[CH:18][CH:19]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3cc(F)c(F)cc3C2=O)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2Cc3cc(F)c(F)cc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.0 mg (0.06 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(5,6-difluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate were initially charged in 200 μl of dichloromethane, and 94 μl of trifluoroacetic acid were added. The mixture was stirred at RT for 2 h. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 23.5 mg (99.7% of theory) of the target compound.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([Cl:30])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([S:4][C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].[I:16]N1C(=O)CCC1=O>C(#N)C>[I:16][C:8]1[C:9](=[O:11])[NH:10][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=1[C:12]([F:14])([F:15])[F:13]
Reactant: CC(C)Sc1nc(C(F)(F)F)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CC(C)Sc1nc(C(F)(F)F)c(I)c(=O)[nH]1
Yield: 97.7 %

Procedure:
2-Isopropylthio-6-trifluoromethyl-3H-pyrimidin-4-one (23.3 g) was dissolved in acetonitrile (230 ml) and N-iodosuccinimide (24.2 g) was added at room temperature with stirring. The mixture was refluxed for 2.5 hr and the solvent was removed under reduced pressure. The precipitates were dissolved in ethyl acetate, and then washed with aqueous sodium thiosulfate, water and brine, respectively. The ethyl acetate layer was dried over magnesium sulfite and the solvent was removed under reduced pressure to give 5-iodo-2-isopropylthio-6-trifluoromethyl-3H-pyrimidin-4-one (34.8 g) as pale yellow needles, mp 212-215° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH2:13])([CH3:4])[CH3:3].C(O)(=O)C.[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO>[C:2]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCCC1NC1CCCC1
Temperature: 50 °C
Yield: 58.2 %

Procedure:
To a solution of [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) (500 mg, 2.497 mmol) in 10 ml methanol was added acetic acid (0.714 ml, 12.49 mmol) and cyclopentanone (0.665 ml, 7.491 mmol). The mixture was heated in a 50° C. oil bath for 1.5 hour. The solution was cooled to room temperature and sodium cyanoborohydride (370 mg, 5.0 mmol) was added portionwise. The mixture was heated in a 50° C. oil bath for 2.5 hours. The solution was cooled in an ice bath and quenched by dropwise addition of 6 ml 2N NaOH. The methanol was removed in vacuo. The aqueous layer was diluted with water and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0 to 100%) to provide 0.39 g (58%) of the title compound as a light brown solid. MS (m/e): 269.3 (M+H).