Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([C:20]2[N:28]=[C:27]3[C:23]([N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25](=[O:36])[N:26]3[C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]3)=[CH:22][N:21]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.C(N(CC)CC)C>C(Cl)Cl>[N:11]1([C:20]2[N:28]=[C:27]3[C:23]([N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25](=[O:36])[N:26]3[CH:29]3[CH2:30][CH2:31][C:32](=[O:35])[CH2:33][CH2:34]3)=[CH:22][N:21]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: CC(C)(C)OC(=O)n1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccccc43)ncc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(=O)n(C2CCC(=O)CC2)c2nc(-n3cnc4ccccc43)ncc21
Reaction time: 0.03 h
Yield: 57.8 %

Procedure:
A solution of oxalyl chloride (6.4 mg) in DCM (0.5 ml) was cooled to −60° C. and treated with a solution of DMSO (8 mg) in DCM (0.5 ml). The reaction mixture was stirred for 2 minutes, then treated with a solution of tert-butyl 2-(1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-8-oxo-8,9-dihydropurine-7-carboxylate (4 mg) in DCM (0.5 ml). After 15 minutes, triethylamine (0.4 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 10 mL DCM and washed with 15 mL of water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to provide 2.3 mg of tert-butyl 2-(1H-benzo[d]imidazol-1-yl)-8-oxo-9-(4-oxocyclohexyl)-8,9-dihydropurine-7-carboxylate, which was deprotected with TFA/DCM (6 ml, 1:1) for 1 h. The mixture was concentrated and the residue was triturated with ethyl ether to provide 1.8 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.5 (dd, 1H), 8.4 (s, 1H), 7.9 (dd, 1H), 7.4 (m, 2H), 4.9 (m, 1H), 3.0 (m, 2H), 2.6 (m, 4H), 2.3 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][CH2:12][C@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[C@@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:12][NH:11][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.41 g (10.2 mmol) of 4-hydroxybenzoic acid and 3 g (10.2 mmol) of (1.1) were suspended in 25 ml of DMF. 1.38 g (10.2 mmol) of 1-hydroxy-benzotriazole (HOBt) and, at 0° C., dicyclohexylcarbodiimide (DCCI) were added. The mixture was stirred at 0° C. for 1 h and allowed to stand at room temperature overnight. After filtration, the solvent was removed in vacuo and the residue was chromatographed on silica gel by means of MPLC using heptanelethyl acetate (1/1). (1.2) was obtained as a colorless solid; melting point 69° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[C:13]=3[N:14]=2)[CH:5]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:34])C.O>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:34])[C:13]=3[N:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc3c(CBr)cccc3o2)c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: COC(=O)c1cccc(-c2nc3c(C=O)cccc3o2)c1
Yield: 32 %

Procedure:
The crude 3-(4-bromomethyl-benzooxazol-2-yl)-benzoic acid methyl ester is treated with HMTA (1.8 mmol) in acetic acid/H2O (3 mL/1.5 mL) in a microwave oven at 130° C. for 20 minutes. The solvent is removed and the mixture is purified by silica gel chromatography (10-20% EtOAc/hexane) to yield 3-(4-formyl-benzooxazol-2-yl)-benzoic acid methyl ester as a white solid. Yield: 32%. 1H NMR (400 MHz, CDCl3) 10.8 (s, 1H), 8.97 (s, 1H), 8.53 (d, J=7.8 Hz, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.94 (dd, J1=7.7 Hz, J2=1 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.0 (s, 3H). LC/MS (ES+): (M+1) 282.1, (M+Na) 304.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a suspension of 3-nitrobenzoic acid (934 mg, 5.64 mmol) in benzene (15 mL) was added oxalyl chloride (0.6 mL, 6.77 mmol) and DMF (7 mL), respectively. The resulting mixture was stirred at room temperature until a clear solution was formed. The solvent was removed under reduced pressure and crude acid chloride was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:15][C:9]1[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=1[NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1NCc1ccc(Br)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(O)ccc1NCc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((4-bromobenzyl)amino)-3-nitrophenol (20 g, 63 mmol) in ethanol (200 mL) was added SnCl2.2H2O (71 g, 314 mmol) and the resulting mixture stirred at 90° C. for 1 h. The mixture was cooled to RT and concentrated to dryness. The aqueous residue was then treated with sat. aq. NaHCO3 to ˜pH 7 and extracted with DCM (5×1 L). The organics were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) 8.17 (s, 1H), 7.48 (d, J=8.4, 2H), 7.30 (d, J=8.3, 2H), 6.11 (dd, J=17.2, 5.5, 2H), 5.90-5.74 (m, 1H), 4.54 (s, 2H), 4.48 (t, J=5.7, 1H), 4.13 (d, J=5.5, 2H).
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N([O-])=O.[Na+]>O.Cl>[O:9]=[C:8]1[O:10][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC[C@@H](C(=O)O)O1
Yield: 59.3 %

Procedure:
To a mixture of L-glutamic acid (1, 25 g, 170 mmol) in water (67 mL) and conc. HCl (35 mL) at 0° C. with stirring was added a solution of NaNO2 (17.5 g, 253.6 mmol) in water (37.5 mL) over a period of 4 h, and then the resulting clear solution was stirred at room temperature overnight. After removal of the solvent by evaporation in vacuo, the residue was treated with EtOAC (80 mL) and filtered. The filtrate was dried over Na2SO4, and concentrated. The residue, after crystallization from EtOAc/benzene/hexane, afforded the title compound 2 as a white crystalline solid (13.12 g, 59%). M. P. 71–73° C.; 1H NMR (400 MHz, CD3OD) δ4.20 (m, 1H, CHO), 1.8–2.3 (m, 4H, CH2CH2).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5]C)=[O:4].[OH-].[K+:11]>CO.O>[CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O-:5])=[O:4].[K+:11]
Reactant: COC(=O)C(C)(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CO)C(=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A solution of methyl 2,2-dimethyl-3-hydroxypropionate (25.0 g, 0.189 mol) in 100 mL of MeOH was treated with a solution of KOH (11.7 g, 0.208 mol) in 50 mL of H2O and the resulting mixture stirred at room temperature for 5 hours. The reaction mixture was heated under reflux for 30 minutes, methanol was distilled and the remaining solution shell frozen and lyophilized to give 26.7 g (90.6%) of potassium 2,2-dimethyl-3-hydroxypropionate as a white solid. The potassium salt (13.0 g, 0.083 mol) was suspended in 100 mL of dry DMF and chloromethylenebenzylether (14.3 g, 0.092 mol) was added. After stirring 48 hours at room temperature the mixture was quenched with 100 mL of H2O and extracted with Et2O (200 mL). The ether layer was separated, washed with H2O (3×100 mL), saturated NaCl (100 mL) and dried over MgSO4. Evaporation and distillation of the residue gave 13.6 g (73%) of benzyloxymethyl 2,2-dimethyl-3-hydroxypropionate as a clear liquid.
Reaction SMILES: [F:1][CH:2]([F:10])[N:3]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[N:4]1.[Br:11][C:12]1[CH:17]=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:15](I)=[CH:14][N:13]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:12]1[N:13]=[CH:14][C:15]2[CH:9]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH:2]([F:10])[F:1])[CH:7]=3)[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:16]=2[CH:17]=1
Reactant: C#Cc1cnn(C(F)F)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1c(-c2cnn(C(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 34.3 %

Procedure:
1-(Difluoromethyl)-4-ethynyl-1H-pyrazole (Preparation 152, 187 mg 1.31 mmole) was dissolved in DMF (4.2 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 444 mg 1.17 mmole) was added. To the solution was added triethylamine (0.80 mL, 576 mg 5.7 mmole) and copper(I) iodide (9 mg 0.047 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37.6 mg 0.046 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 140 minutes. The reaction was added to ethyl acetate (45 mL) and washed with water (3×15 mL) and with brine, then dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% ethyl acetate in chloroform to afford the title compound 157 mg. 1H-NMR (d6-acetone, 500 MHz): δ 3.37 (s, 3H), 7.06 (d, J=0.63 Hz, 1H), 7.70 (t, J=59.6 Hz, 1H), 8.04 (s, 1H), 8.16 (m, 1H), 8.51 (s, 1H), 8.73 (d, J=0.95 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)C(C)C)(C)C.CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Reaction time: 24 h
Yield: 55.5 %

Procedure:
To a solution of 4-chloro-2-phenylamino-benzoic acid (10.1 g, 41.0 mmol) in DMF (200 mL) was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU, 31.2 g, 82.0 mmol), N,O-dimethyl-hydroxylamine hydrochloride (7.94 g, 82.0 mmol), and N,N-diisopropylethylamine (45.0 g, 350.0 mmol) at room temperature. The resulting mixture was stirred for 24 hr. at room temperature. Completion of the reaction was confirmed by silica TLC (mobile phase; hexane:ethyl acetate=7:3; Rf=0.5). The reaction mixture was diluted with ethyl acetate (600 mL) and the organic layer was washed with water (4×200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were removed under reduced pressure. The crude material was purified over silica gel (100-200 mesh) column chromatography, using gradient polarity mobile phase (ethyl acetate:hexane=1:9-1:4), to give 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (6.62 g, 56.4% yield) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 7.93 (s, 1H) 7.20-7.39 (m, 3H) 7.02-7.17 (m, 3H) 6.88-6.99 (m, 2H) 3.50 (s, 3H) 3.20 (s, 3H). MS calcd. for C15H15ClN2O2 [(M+H)+] 291.0, obsd. 291.0, [(M-C2H6NO)+] 230.0, obsd. 230.0.
Reaction SMILES: C(OC([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][F:24])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][F:24])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)c1cccc(OCCF)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(N)c1cccc(OCCF)c1
Reaction time: 20 h
Yield: 101.6 %

Procedure:
To methyl 3-[(tert-butoxycarbonyl)amino]-3-[3-(2-fluoroethoxy)phenyl)propanoate (5.0 g, 20 mmol) in dichloromethane was added trifluoro acetic acid (5.64 mL, 73 mmol). After stirring for 24 hours at room temperature additional trifluoro acetic acid (1.13 mL) was added and stirring was continued for 20 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (methanol in dichloromethane 0% to 40%)) to yield 4.9 g methyl 3-amino-3-[3-(2-fluoroethoxy)phenyl]propanoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:3]=1.[NH2:27][NH2:28]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][C:4]2[N:3]=[C:2]([NH:27][NH2:28])[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: NN
Reactant: COc1ccc(CCCc2nc(Cl)cc(N3CCOCC3)n2)cc1OC
Product: COc1ccc(CCCc2nc(NN)cc(N3CCOCC3)n2)cc1OC
Yield: 88.9 %

Procedure:
Further, 4-chloro-2-[3-(3,4-dimethoxyphenyl)propyl]-6-morpholinopyrimidine (0.34 g, 0.90 mmol) was reacted with hydrazine (0.29 g, 9 mmol) to obtain 2-[3-(3,4-dimethoxyphenyl)propyl]-4-hydrazino-6-morpholinopyrimidine as a white solid (0.30 g, 0.80 mmol, 89%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][C:21](Cl)=[O:22])[CH2:16][CH2:15]3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([O:33][CH2:34][CH3:35])[N:28]=[C:27]([NH2:36])[CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([O:33][CH2:34][CH3:35])[N:28]=[C:27]([NH:36][C:21](=[O:22])[CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:11]3[O:10][N:9]=[C:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]=3)[CH2:15][CH2:16]2)[CH:26]=1
Reactant: O=C(Cl)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOc1nc(N)cc(N)c1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1nc(NC(=O)CC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of the compound prepared in Example 59 (100 mg) and 4,6-diamino-2-ethoxynicotinonitrile (50 mg, prepared according to the preparation reported in Szczepankiewicz, B. G.; et al. J. Med. Chem. 2006, 49, 3563 and references therein) in pyridine (1.5 mL) was heated to 50° C. overnight and then 80° C. for six days. The mixture was cooled to room temperature, diluted with ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=4:1) to obtain the title compound (18 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Br:13]Br>CC(O)=O.O>[Br:13][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: COc1cc(C(=O)O)ccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)c(Br)cc1Cl
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A solution of 4-chloro-3-methoxybenzoic acid (5.0 g, 26.7 mmol) in HOAc (25 mL) and water (25 mL) was treated slowly with Br2 (1.6 mL 32 mmol). After heating to 60° C. for 2 h, the reaction was stirred cooled to rt overnight. It was quenched with water (300 mL), and the precipitate was filtered and dried to yield 2-bromo-4-chloro-5-methoxybenzoic acid (5.0 g, 70%). (264.87 [M−H]) 1H NMR: (400 MHz, DMSO) δ: 3.90 (s, 3H), 7.46 (s, 1H), 7.82 (s, 1H), 13.63 (s, 1H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]CCl)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NCc2ccccc21
Reactant: ClCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1c2ccccc2CN1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 166 %

Procedure:
2,3-dihydro-isoindol-1-one (100 mg, 0.751 mmol) was dissolved in anhydrous acetonitrile and cesium carbonate (730 mg, 0.225 mmol) and 1-benzyloxy-4-chloroethylbenzene (349 mg, 0.150 mmol) were added to the solution and stirred at room temperature for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic was washed with brine, dried over anhydrous sodium sulphate and concentrated. The compound was purified by column chromatography (20% ethyl acetate/hexanes) to yield a yellow solid (82 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 7.91 (d, 1H), 7.37-7.53 (m, 9H), 7.25-7.28 (m, 1H), 6.95 (d, 2H), 5.06 (d, 2H), 4.77 (d, 2H), 4.27 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C@H:32]([CH3:35])[CH2:33][OH:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][C@H:32]([CH3:35])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: C[C@@H](N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H](C)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and (R)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-20% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 116-122°, LC MS m/z=423 (MH+) Retention time=2.04 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 2 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
10 kg tetrahydropyran-4-ol are dissolved in a mixture of 50 L toluene and 10.4 kg triethylamine. 11.55 kg methanesulfonyl chloride in 100 ml toluene are added while maintaining the internal temperature below 20° C. by cooling, and the addition funnel is rinsed with 50 ml toluene. The stifling is continued for one hour. The precipitate is filtered and the filter cake is washed twice with 20 L toluene each. The filtrate is concentrated by vacuum evaporation (60 L were distilled of), seeding crystals and 50 L methylcyclohexane are added. The suspension is cooled to 2° C. After 1 h the product is isolated by filtration, washed with 30 L methylcyclohexane and dried at 30° C. 16.6 kg of the product are obtained as a white solid. Yield: 94%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (2H, m), 1.92-2.00 (2H, m), 3.19 (3H, s), 3.42-3.49 (2H, m), 3.77-3.83 (2H, m), 4.80-4.88 (1H, m).
Reaction SMILES: [CH3:1][N:2]([C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=1)[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1>CO.[Ni]>[CH3:1][N:2]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1)[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1
Reactant: CN(c1ccc([N+](=O)[O-])cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: [Ni]
Solvent: CO
Product: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-methyl-(5-nitro-pyridin-2-yl)-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-amine (10 mmol) in methanol (100 mL) was added Raney Ni. The mixture was stirred at room temperature for 18 hours under 1 atm of H2. After filtration, it was concentrated to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]=[C:6]([C:14]([Cl:17])([Cl:16])[Cl:15])[N:5]=2)[CH2:3][CH2:2]1.[CH3:18][O-:19].[Na+]>CO>[CH:1]1([C:4]2[N:9]=[C:8]([O:19][CH3:18])[N:7]=[C:6]([C:14]([Cl:17])([Cl:16])[Cl:15])[N:5]=2)[CH2:3][CH2:2]1
Reactant: ClC(Cl)(Cl)c1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1

Procedure:
To a solution of 48 g of 2-cyclopropyl-4,6-bis-(trichloromethyl)-1,3,5-triazine in 200 ml of MeOH are added, with stirring, 4.9 g of sodium methylate, and the mixture is stirred for 1 hour at room temperature; it is then filtered and the filtrate is evaporated to dryness. The yield is 28.5 g of the title compound as a light-red oil, which solidifies after some time, m.p. 49°-51° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:37][N:38]1[CH2:43][CH2:42][C:41]2[N:44]=[C:45]([NH2:47])[S:46][C:40]=2[CH2:39]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:22])[NH:47][C:45]2[S:46][C:40]3[CH2:39][N:38]([CH3:37])[CH2:43][CH2:42][C:41]=3[N:44]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCc2nc(N)sc2C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCc2nc(NC(=O)c3ccccc3N3CCN(C(=O)OC(C)(C)C)CC3)sc2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Dissolved 4-(2-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.98 mmol), EDC (0.23 g, 1.20 mmol) and HOBT (0.18 g, 1.20 mmol) into 1 mL of DMF. The mixture stirred for 1 h. To this is added 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (0.16 g, 0.98 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.00 mmol). The mixture is placed under a stream of Ar and heated at 50° C. for 16 h. The mixture is then diluted with 50 mL CH2Cl2, quenched with 20 mL of saturated NH4Cl; washed with 2×20 mL of H2O, and washed with 1×20 mL of brine. The resultant organic phase was dried with MgSO4, filtered and concentrated to provide 0.38 g, 85% yield of 4-[2-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.