Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][N:12]1[C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC1CNN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
4-(2,2-Dimethylpropionyloxy)-pyrazolidine-1-carboxylic acid 1-benzyl ester, 30, (1.45 g, 4.23 mmol) is dissolved in dichloromethane (21 mL). The solution is cooled to 0° C. and triethylamine (1.30 mL, 9.31 mmol) added dropwise via syringe. The cold bath is removed and the reaction allowed to warm to room temperature and continue stirring 20 minutes. 4-Fluorophenylacetic acid (848 mg, 5.50 mmol) is added. After stirring for 5 minutes, the reaction mixture is transferred via cannula into a solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrogen chloride in dichloromethane (21 mL) maintained at 0° C. The reaction is allowed to stir and gradually warm to room temperature over 12 hours. The reaction is washed with a 5% aqueous solution of Na2CO3 (2×50 mL). The combined aqueous layers are extracted several times with dichloromethane (50 mL) and the combined organic layers washed with brine, dried, filtered and concentrated in vacuo. The crude product is purified over silica (2:1 to 1:1 hexane/ethyl acetate) to afford 1.71 g (91% yield) of the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([Cl:22])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(C)n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(=O)Cl)c(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
According to Scheme 2, Step 2: To a solution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid (37.8 mmol, 9.30 g) and five drops of DMF in DCM (94 mL) was added oxalyl chloride (76 mmol, 6.66 mL) dropwise, at 0° C. The reaction mixture was allowed to warm up to room temperature and was stirred for 3 hours. After concentration, the residue was treated with toluene and was co-evaporated to dryness to yield 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride. To a solution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride (37.8 mmol) in acetonitrile (94 mL) was added a solution of TMSCHN2 (41.5 mmol, 83.0 mL) dropwise, at 0° C., and then the reaction mixture was allowed to warm up to room temperature and was stirred overnight. After cooling the reaction mixture to −10° C., HBr 48% (14.8 mL) was added dropwise and the reaction mixture was stirred for 2 hours at −10° C. At 0° C., 10% NaOH solution was added to the reaction mixture to reach pH=7. The reaction mixture was diluted with water and EtOAc and the aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone (30.6 mmol, 9.90 g, 81%) which was used without any purification.
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=2[CH:25]=1)([OH:7])=O.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:24][N:14]1[CH2:13][C:12]2[CH:25]=[C:8]([C:5]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:7])[CH:9]=[CH:10][C:11]=2[NH:17][CH:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15]1=[O:23]
Reactant: NCc1cccnc1
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)CC1Nc2ccc(C(=O)NCc3cccnc3)cc2CN(C)C1=O
Reaction time: 23.5 h

Procedure:
EDC (229.4 mg, 1.2 mmol) was added to a solution of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (292.3 mg, 1.0 mmol), 3-(aminomethyl)pyridine (0.122 mL, 1.2 mmol), HOBT.H2O (162.2 mg, 1.2 mmol), and diisopropylethylamine (0.35 mL, 2.0 mmol) in anhydrous DMF (5 mL) at RT. After 23.5 h, the reaction was concentrated on the rotavap (high vacuum), and the residue was partitioned between 10% aqueous Na2CO3 and CHCl3. This caused a solid to precipitate. The layers were separated and the aqueous layer was extracted exhaustively with CHCl3 until all solids had dissolved. The combined CHCl3 layers were diluted with CHCl3, washed with 10% Na2CO3, dried (MgSO4), and concentrated. Crystallization of the residue from EtOAc gave impure title compound. The mother liquors were concentrated, combined with the recrystallized residue and chromatographed (silica gel, 10% MeOH/CHCl3). The title compound was obtained as a colorless solid (341 mg, 89%): TLC Rf 0.37 (10% MeOH/CHCl3); 1H NMR (250 MHz, CDCl3) δ8.58-8.68 (m, 1H), 8.47-8.57 (m, 1H), 7.72-7.81 (m, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.45 (dd, J=8.5, 2.1 Hz, 1H), 7.31 (dd, J=7.7, 4.8 Hz, 1H), 6.44-6.63 (m, 2H), 5.45 (d, J=16.4 Hz, 1H), 5.04-5.15 (m, 1H), 4.64 (d, J=5.9 Hz, 2H), 4.55 (br d, J=4.5 Hz, 1H), 3.76 (d, J=16.4 Hz, 1H), 3.75 (s, 3H), 3.07 (s, 3H), 2.99 (dd, J3=16.0, 6.7 Hz, 1H), 2.67 (dd, J=16.0, 6.4 Hz, 1H); MS (ES) m/e 383.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C=O)=[CH:7][C:6]=1[O:14]C)(=O)C.O.[Li+].[OH-]>C1COCC1>[CH3:1][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:14]
Reactant: COc1cc(OC=O)ccc1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of 4-(formyloxy)-2-methoxyphenyl acetate (16 g, 76 mmol) in THF (50 mL)/H2O (50 mL) was added LiOH (7.7 g, 184.2 mmol). The reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure. The residue was extracted with EA (50 mL×3). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtrated and concentrated in vacuo to give black oil, which was purified by silica gel column (PE:EA=3:1) to afford 4.8 g of product (40%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([C:20]([F:23])([F:22])[F:21])[CH:5]=1)=[O:3].[OH-].[Na+]>CO>[NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:20]([F:21])([F:22])[F:23])[CH:5]=1)=[O:3]
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)Nc1cc(C(=O)O)c(C(F)(F)F)cc1C(N)=O
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Methyl 4-aminocarbonyl-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (0.818 mmol) was dissolved in methanol (2 mL) and was treated with 2M sodium hydroxide (1 mL, 2 mmol) at 45° C. for 1.5 h. The reaction mixture was cooled to ambient temperature and was concentrated to afford an aqueous residue that was washed with ether, then cooled in an ice bath and acidified with 1N hydrochloric acid to pH ˜3. The precipitate was collected by filtration, washed with water, then dried to afford 4-aminocarbonyl-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoic acid (233 mg, 0.733 mmol, 90% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO): δ 13.5 (br s, 1H), 8.74 (d, 1H), 8.21 (br s, 1H), 7.95 (s, 1H), 7.46 (br s, 1H), 6.94 (s, 1H), 3.51-3.43 (m, 1H), 1.63-1.51 (m, 2H), 1.51-1.39 (m, 2H), 0.87 (t, 6H); MS (EI) for C14H17F3N2O3: 319 (MH+).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])=[CH:18][CH:17]=1)[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[N:10]=1>ClCCl>[CH2:1]([NH:3][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:18]=[CH:17][C:16]([N:5]([CH3:4])[C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=3[N:10]=2)=[CH:27][CH:26]=1)[CH3:25])[CH3:2]
Reactant: CC(Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1)C(=O)Cl
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 70% aqueous ethylamine (0.46 g) and dichloromethane (5 ml) was cooled, with stirring, in an ice bath. A solution of the acid chloride (1.05 g; prepared as described in part (a) above) in dichloromethane (5 ml) was added and the mixture was stirred for 7 hours and then allowed to stand overnight. After this time thin layer chromatography indicated that the reaction had not gone to completion and therefore a further portion of 70% aqueous ethylamine was added and the mixture was heated under reflux for a period of 3 hours. The mixture was allowed to cool, made up to 30 ml with dichloromethane and was washed with water (4×20 ml). The organic phase was dried over anhydrous magnesium sulfate and the solvent removed by evaporation. The solid residue was purified by preparative thin layer chromatography on silica gel (eluent dichloromethane/isopropyl alcohol 20:1) to give the title compound (0.74 g), mp 141°-142° C. The pmr spectrum of the compound was consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH:23]([C@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][CH2:33][CH2:34][C:35]1[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[CH:37][CH:36]=1)=O>C1COCC1>[O:31]=[S:27]1(=[O:30])[CH2:28][CH2:29][C@H:25](/[CH:23]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:26]1[CH2:32][CH2:33][CH2:34][C:35]1[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[CH:37][CH:36]=1
Reactant: COP(=O)(CC(=O)Cc1cccc(C(F)(F)F)c1)OC
Reactant: COC(=O)c1ccc(CCCN2[C@@H](C=O)CCS2(=O)=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2[C@@H](/C=C/C(=O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a suspension of sodium hydride (12 mg, 0.5 mmol) in THF (1.0 mL) cooled to 0° C. was added a solution of dimethyl (2-oxo-3-(3-(trifluoromethyl)phenyl)propyl)-phosphonate (160 mg, 0.52 mmol) in THF (2.0 mL). After 15 min a solution of the aldehyde 11 (155 mg, 0.47 mmol) in THF (2.0 mL) was added. The reaction was allowed to warm room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 40% EtOAc/hex) afforded 240 mg (99%) of enone 12.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClCCCl.CC(O)(C)C.[NH2:22][C:23]1[CH:43]=[CH:42][C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CCN(CC)CC>CO.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:33][CH2:34]3)=[O:28])=[CH:42][CH:43]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Zinc(II) chloride (1.0 M in Et2O; 2.00 mL, 2.00 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.399 g, 1.84 mmol) in 1:1 DCE/t-BuOH (15 mL) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (A21) (0.510 g, 1.67 mmol) in 1:1 DCE/tBuOH (15 mL) was added. A solution of Et3N (0.256 mL, 1.84 mmol) in 1:1 DCE/t-BuOH (15 mL) was added dropwise at 0° C. and the resulting mixture was vigorously stirred for a further 30 minutes at 0° C. then at room temperature for 16 hours. The volatiles were removed in vacuo to afford a brown residue which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (15 mL) and water (15 mL) and the resulting suspension filtered to give the title compound A22 as a white solid (0.561 g, 69%); 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 7.45 (d, J=8.6 Hz, 2H), 3.87-3.30 (m, 8H), 1.47 (s, 9H). LCMS-A: rt 6.206 min; m/z 484.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:24][N:25]=[C:26]([C:35]([NH:37][C:38](=[O:42])OCC)=[O:36])[C:27]([NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[O:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:10])[CH3:9].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:23][C:6]1[CH:5]=[C:4]([N:24]2[C:38](=[O:42])[NH:37][C:35](=[O:36])[C:26]([C:27]([NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[O:28])=[N:25]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:9])[CH3:10]
Reactant: CCOC(=O)NC(=O)C(=NNc1cc(Cl)c(C(C)(C)c2noc(-c3ccccc3C)n2)c(Cl)c1)C(=O)NC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NC(=O)c1nn(-c2cc(Cl)c(C(C)(C)c3noc(-c4ccccc4C)n3)c(Cl)c2)c(=O)[nH]c1=O

Procedure:
A solution of intermediate (20) (0.0302 mole) and sodium acetate (0.0302 mole) in acetic acid (200 ml) was stirred and refluxed for 3 hours. The reaction mixture was poured out into water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding ethyl [[2-[3,5-dichloro-4-[1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazin-6-yl]carbonyl]carbamate (intermediate 21).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.O.[CH3:27][N:28](C)C=O>CN.C(O)C>[CH3:27][NH:28][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:2]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CN(C)C=O
Agent: CN
Solvent: O
Solvent: CCO
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reaction time: 48 h

Procedure:
300 mg (0.87 mmol) (RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is dissolved in a mixture of 1 ml N,N-dimethylformamide and 0.18 ml of a 33% solution of methylamine in ethanol. The reaction vessel is tightly stopped and hold at 120° C. for 48 hours. Water is added and the product extracted with ethyl acetate. Drying and evaporation yields 92 mg (31%) of a slightly yellowish product. MS: m/e=343.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C(CCCCl)N1CCOCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCCC(=O)N5CCOCC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), 4-chloro-1-morpholinobutan-1-one (29 mg, 0.15 mmol) and DIEA (0.1 mL, 0.58 mmol) in NMP (1 mL) was stirred at 80° C. After 10 h, additional 4-chloro-1-morpholinobutan-1-one (51 mg) was added, and the reaction continued overnight. The crude product was purified by RP-HPLC to give 4-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-1-morpholinobutan-1-one as a white powder; ESMS m/z 571.3.3 (M+H+).
Reaction SMILES: [Ca].[Mg:2].[Cl-].[Mg+2].[Cl-].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7]>>[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Mg+2:2].[S:6](=[O:8])(=[O:7])([OH:10])[OH:9]
Reactant: [Mg]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca]
Agent: [Cl-]
Product: O=S(=O)(O)O

Procedure:
Preferably the aqueous solution of calcium ions or magnesium ions of step a) is a solution of magnesium chloride. It is also preferred that the solution contains sulphate ions, preferably obtained from magnesium sulphate and/or sulphuric acid.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:21])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[CH2:12][C:11](=[N:18]O)[C:10]2=[O:20])=[O:6].C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1>O>[C:11]([CH2:12][C:13]1[C:9]([C:10]([OH:20])=[O:29])=[CH:8][C:7]([C:5]([N:4]([CH3:3])[CH3:21])=[O:6])=[C:15]([O:16][CH3:17])[CH:14]=1)#[N:18]
Reactant: COc1cc2c(cc1C(=O)N(C)C)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CC#N)c(C(=O)O)cc1C(=O)N(C)C
Temperature: 50 °C
Yield: 89.3 %

Procedure:
To a solution of NaOH (1.6 g, 40.54 mmol) in H2O (30 ml) was added of 2-Hydroxyimino-6-methoxy-3-oxo-indan-5-carboxylic acid dimethylamide (2.8 g, 10.67 mmol). The mixture was heated at 50° C. Then p-Toluenesulfonyl chloride (5.7 g, 30 mmol) was added in portions to the mixture. The mixture was heated at 80° C. for 15 min. After cooling carefully to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and the precipitate was collected and dried to give product (2.5 g, 89.28%). LC-MS: m/e 261 (M−1).
Reaction SMILES: [CH3:1][C:2]([S:7][CH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)([CH3:6])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[C:21]([Si:25]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:26][CH2:27][C:28]([C:31]1[S:35][C:34]([NH2:36])=[N:33][N:32]=1)([CH3:30])[CH3:29])([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.C1(C)C=CC=CC=1>[Si:25]([O:26][CH2:27][C:28]([C:31]1[S:35][C:34]([NH:36][C:3](=[O:5])[C:2]([CH3:1])([S:7][CH2:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH3:6])=[N:33][N:32]=1)([CH3:29])[CH3:30])([C:21]([CH3:22])([CH3:23])[CH3:24])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(SC[C@H]1CCCCO1)C(=O)O
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nnc(N)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(SC[C@H]1CCCCO1)C(=O)Nc1nnc(C(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)s1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
Activation of 300 mg (1.27 mmol) of 2-methyl-2-{[(2R)-oxan-2-ylmethyl]sulfanyl}propanoic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (305 mg, 2.54 mmol) and DMF (1 drop) in DCM (10 mL) at room temperature for 18 h. The solvent is removed by distillation, and then azeotroped with toluene (3×5 mL). This acid chloride is dissolved in toluene (5 mL) and added dropwise to a stirred suspension of 565 mg (1.37 mmol) of 5-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-[1,3,4]thiadiazol-2-ylamine and 0.48 mL (2.75 mmol) of N,N-diisopropylethylamine in toluene (10 mL) at room temperature. After complete addition the reaction is heated to 60° C. for 18 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica, eluent: heptanes, 0-20% ethyl acetate) to yield 658 mg of N-(5-{1-[(tert-butyldiphenylsilyl)oxy]-2-methylpropan-2-yl}-1,3,4-thiadiazol-2-yl)-2-methyl-2-{[(2R)-oxan-2-ylmethyl]sulfanyl}propanamide. Yield: 73%; m/z 612 [M+H], 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.01-1.09 (9H, m), 1.21-1.70 (17H, m), 1.75-1.84 (1H, m), 2.57-2.72 (2H, m), 3.33 (1H, td, J=11.71, 2.06 Hz), 3.38-3.47 (1H, m), 3.70-3.75 (2H, m), 4.10-4.17 (1H, m), 7.34-7.47 (6H, m), 7.56-7.64 (4H, m), 10.94 (1H, br. s.)
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:34]=[C:33]([CH3:35])[C:17]([O:18][CH2:19][C:20]([CH3:32])([CH3:31])[C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[C:16]([CH3:36])[CH:15]=3)=[N:13][C:8]2=[CH:7][CH:6]=1>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:15]=[C:16]([CH3:36])[C:17]([O:18][CH2:19][C:20]([CH3:32])([CH3:31])[C:21]([OH:23])=[O:22])=[C:33]([CH3:35])[CH:34]=3)=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(C)(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(C)(C)C(=O)O
Reaction time: 16 h

Procedure:
50 mg of palladium on carbon (5%) were added to a solution of 150 mg (41%) of benzyl 3-{4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}-2,2-dimethylpropionate in 7.5 ml of ethyl acetate, and the mixture was hydrogenated at 5 bar for 16 h. The catalyst was filtered off and the filtrate was concentrated. This gave 100 mg (80%) of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([OH:7])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:9])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC(=O)O
Reaction time: 1 h

Procedure:
An 11.76 g portion of 97% glutaric anhydride was dissolved in a mixture of 40 ml of 5N sodium hydroxide and 200 ml of water. A solution of 33.8 g of silver nitrate in 100 ml of water was added, the suspension was stirred for 1 hour in the dark, then the solid was collected, washed with water and dried, giving 33.5 g of glutaric acid, disilver salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[N:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Cc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyl-6-bromo-pyridine.