Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:44][C:45]([F:54])([F:53])[C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:48][C:47]4[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=4[C:45]([F:44])([F:53])[F:54])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1ccccc1C(F)(F)F
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4C(F)(F)F)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 37 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-(trifluoromethyl)aniline yielded the title compound (37% yield) as a yellow foam. MS (ISP): m/z=734.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[Cl:19][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: O=C(CC1CCCC1)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(CC1CCCC1)c1ccc(CCl)cc1
Yield: 58.1 %

Procedure:
The product of Example F (450 mg, 0.002 mole) was dissolved in 5 mls of benzene and 250 mg of thionyl chloride was added. The mixture was refluxed for one hour. After cooling, the solution was poured into dilute K2CO3 and extracted with ethyl acetate. The organic phase was dried over Na2SO4, stripped and chromatographed on silica gel using 5% ethyl acetate/hexane as the eluent to give 275 mg of the title compound as an oil (56% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:56]([C:51]1[CH:52]=[C:53]2[C:48](=[C:49]([F:60])[CH:50]=1)[C:47](=[O:61])[N:46]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:14][CH:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[C:31]=1[CH2:30][O:29][C:26](=[O:28])[CH3:27])[N:55]=[CH:54]2)([CH3:57])([CH3:58])[CH3:59]
Reactant: O=C(c1ccc(Nc2cc(Br)cn3ccnc23)cc1)N1CCOCC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cc3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Yield: 12.8 %

Procedure:
[4-(6-Bromo-imidazo[1,2-a]pyridin-8-ylamino)-phenyl]-morpholin-4-yl-methanone (270 mg, 0.68 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (670 mg, 1.35 mmol) and K2CO3 (188 mg, 1.36 mmol) were dissolved in a 10:1 mixture of dioxane in H2O (11 ml). Under N2 atmosphere, Pd2(dba)3 (62 mg, 0.068 mmol) and X-phos (129 mg, 0.27 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature, poured into water (100 mL) and extracted by DCM (100 ml). The organic extracts were washed with saturated aqueous solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate 2:1) to afford the desired product as a yellow solid (60 mg, yield 25%). LC-MS: 689[M+1]+, tR=1.506 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17]#[N:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[NH2:29][OH:30]>CCO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:13]([C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17]([NH:29][OH:30])=[NH:18])=[N:14][C:10]=3[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: NO
Solvent: CCO
Product: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzonitrile (1.1 mg, 2.99 mmol) in EtOH (20 mL) is added hydroxylamine 50% aqueous solution (3.94 mL 59.71 mmol) at room temperature. The solution is stirred at 80° C. for 2 hours. The reaction mixture is cooled to room temperature and the ethanol removed in vacuo. EtOAc (50 mL) is added and the organics washed with H2O then dried (Na2SO4), filtered and concentrated to afford 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (1.1 g, 92%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]=[C:5]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1>CC(C)=O>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]#[C:40][CH2:39][N:24]2[CH:23]=[C:22]([C:9]3[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]([N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[N:6][C:7]=4[N:8]=3)[CH:26]=[N:25]2)=[CH:43][CH:44]=1
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cn[nH]c3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: Fc1ccc(C#CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 17.4 %

Procedure:
A mixture of 1-Propyl-8-(1H-pyrazol-4-yl)-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.111 g, 0.25 mmol), potassium carbonate (0.052 g, 0.38 mmol), 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.69 g, 0.33 mmol) was taken in acetone (10 ml). The reaction mixture was heated at 80° C. for 2 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was evaporated and the residue was purified by preparative TLC to obtain pure 8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.025 g, 22%) as colourless oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=2[C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cccnc1
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with pyridine-3-boronic acid as in Example 38 to afford 0.067 g (63%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C28H21NO4F3Cl 528.1190, found 528.1186.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2(O)[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].CCN(S(F)(F)[F:35])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2([F:35])[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(O)CCC4)C3=C2)cn1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(F)CCC4)C3=C2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
Example 113. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (120 mg, 0.32 mmol) in DCM was cooled to 0° C. under N2 and treated with DAST (0.42 mL, 3.19 mmol) dropwise. The mixture was stirred for 20 min at 0° C., and the allowed to warm to RT. The reaction mixture was then slowly poured onto a cooled saturated aq. solution of NaHCO3 and extracted with DCM. The combined org layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: isocratic 6% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (42 mg) as a beige solid. UPLC-MS: MS 379.2 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.19 (m, 3 H); 1.46-1.64 (m, 1 H); 1.88-2.09 (m, 1 H); 2.47 (m, 2 H); 2.51-2.79 (m, 4 H); 2.95 (t, J=5.28 Hz, 2 H); 3.73 (t, J=6.06 Hz, 2 H); 4.22 (br. s., 2 H); 7.07 (s, 1 H); 7.33-7.48 (m, 2 H); 7.58-7.67 (m, 1 H); 7.95 (d, J=8.21 Hz, 1 H); 8.13 (s, 1 H).
Reaction SMILES: S1C=C[C:3](C(O)=O)=[CH:2]1.CN(C)CCN(C)C.C([Li])CCC.Cl.[CH:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[C:30]([OH:32])=[O:31])=[O:24].C(C1SC=C(C(O)=O)C=1)=O.ICC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O>[CH2:2]([O:31][C:30]([C:29]1[CH:28]=[CH:27][S:26][C:25]=1[CH:23]=[O:24])=[O:32])[CH3:3]
Reactant: O=Cc1sccc1C(=O)O
Reactant: O=C(O)c1ccsc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccsc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Thiophenecarboxylic acid (3.48 g) was dissolved in tetrahydrofuran (50 ml), and N,N,N',N'-tetramethylethylenediamine (10 ml) was added. The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (4.6 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of 2-formyl-3-thiophenecarboxylic acid and 5-formyl-3-thiophenecarboxylic acid (2.11 g). This mixture was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.95 ml) and potassium carbonate (1.66 g) were added. The reaction mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-formyl-3-thiophenecarboxylic acid ethyl ester (1.75 g). 2-Formyl-3-thiophenecarboxylic acid ethyl ester (1.66 g) in methylene chloride (20 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.32 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (1.08 g). 2-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (7.8 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-difluoromethyl-3-thiophenecarboxylic acid (0.88 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([CH2:13][NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)[CH2:6]2.CO.[ClH:34]>O1CCCC1>[ClH:34].[ClH:34].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(CNC(=O)CCCCC(=O)NCCc1ccccc1)C2
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(CNCCCCCCNCCc1ccccc1)C2
Temperature: 25 °C

Procedure:
A 1 molar solution of borane-tetrahydrofuran complex (75.5 ml) was added to a solution of the product of step (a) (8.0 g) in tetrahydrofuran (160 ml) under an inert atmosphere. The solution was heated at reflux overnight, cooled to room temperature, and methanol (50 ml) cautiously added. When all effervescence had ceased, methanolic hydrogen chloride (50 ml) was added, and the mixture refluxed for an hour. The suspension was reduced to dryness giving a white solid which was crystallised from aqueous ethanol to give white needles, 6.88 g mp 258°-9°.
Reaction SMILES: CS([N:5]1[C:13]2[C:8]([CH2:9][C:10]3[CH2:15][CH:14]([C:16]#[N:17])[C:11]=3[CH:12]=2)=[CH:7][CH2:6]1)(=O)=O.[OH-].[K+]>CO>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:15][CH:14]([C:16]#[N:17])[C:11]=3[CH:12]=2)[CH:7]=[CH:6]1
Reactant: CS(=O)(=O)N1CC=C2CC3=C(C=C21)C(C#N)C3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#CC1Cc2cc3cc[nH]c3cc21

Procedure:
2.6 g of the product obtained in Step 3 are introduced into a solution of 7.7 g of potassium hydroxide in 190 ml of methanol. After 12 hours at reflux, the methanol is evaporated off and the residue is taken up in ether. After washing, the organic phase is dried and concentrated to yield the expected product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[N:27]=2)=[CH:14][C:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24][OH:25])[CH2:20]2)=[N:16][CH:17]=1>C(Cl)Cl.CCOC(C)=O>[Cl:11][C:12]1[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[N:27]=2)=[CH:14][C:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][C@H:21]([CH:24]=[O:25])[CH2:20]2)=[N:16][CH:17]=1
Reactant: OC[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame-dried argon purged 20 mL conical flask, oxalyl chloride (0.025 ml, 0.281 mmol) was dissolved in DCM (0.5 ml) and cooled to −78° C. under argon. DMSO (0.030 ml, 0.422 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the previous solution (I don't see issues here). This was stirred for 30 min at −78° C. ((1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl)methanol (60 mg, 0.141 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the reaction mixture. The resulting mixture was stirred for 60 min at −78° C. TEA (0.078 ml, 0.562 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the reaction mixture, after which the reaction mixture was allowed to stir and warm to ambient temp over 2 hr. The reaction mixture was diluted with EtOAc, washed with saturated NH4Cl (30 mL×3), H2O (30 mL), brine (30 mL), dried over Na2SO4 and reduced. The resulting residue was used without further purification. LCMS (m/z): 425.2 (MH+), retention time=0.72.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1.Cl.CN(C)C.C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.O>[C:26]1([S:32]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]2[C:11]([NH2:13])=[O:12])=[O:10])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
Process A: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (0.56 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added drop wise. The mixture was stirred for 1 hour at the same temperature, after which water (5 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (528 mg, 80% yield). Process B: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) was suspended in acetonitrile (10 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.56 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (5 mL) and extraction with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (599 mg, 91% yield). Process C: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (100 mg) and triethylamine (74 mg) were suspended in acetonitrile (1 mL). While the suspension was cooled in an ice bath, benzenesulfonic anhydride (188 mg) was added and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 1 hour, followed by the addition of water (2 mL) and extraction with ethyl acetate (2×4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a brown oil (147 mg, 85% yield).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1c1ccccc1

Procedure:
1.48 g of phthalic anhydride and 0.931 g of aniline were mixed under cooling with ice, and the mixture was reacted at a temperature of 180° C. for 2 hours.
Reaction SMILES: Cl.C(=N)(OCC)C.[F:8][C:9]([F:13])([F:12])[CH2:10][NH2:11].C1(N2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]2[CH3:24])CC1>>[CH3:24][C:18]1[N:11]([CH2:10][C:9]([F:13])([F:12])[F:8])[C:21]([CH:22]=[O:23])=[CH:20][N:19]=1
Reactant: Cc1ncc(C=O)n1C1CC1
Reactant: NCC(F)(F)F
Agent: CCOC(C)=N
Agent: Cl
Product: Cc1ncc(C=O)n1CC(F)(F)F

Procedure:
2-Methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde was prepared from ethyl acetimidate hydrochloride and 2,2,2-trifluoroethylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[CH:9][C:8]=2[O:16][CH3:17])[N:6]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[CH:19]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:28]([C:20]2[CH:19]=[N:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:29])[S:3][CH:4]=1
Reactant: COc1cc(C)cc(OC)c1-c1csc(N)n1
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cnc3ccccc3c2)n1
Reaction time: 48 h
Yield: 97.5 %

Procedure:
1 g of 2-amino-4-(2,6-dimethoxy-4-methylphenyl)-thiazole, 0.76 g of 3-quinolinecarboxylic acid, 0.65 ml of triethylamine and 2.15 g of BOP are dissolved in 10 ml of DMF, and the reaction mixture is left at r.t. for 48 hours. It is then poured into pH 2 buffer solution, a precipitate is separated by filtration, and the yellow solid is successively washed with water, stirred in 5% sodium carbonate solution, filtered off and thereafter dissolved in DCM. The solution is washed with 5% sodium carbonate solution and then, successively, the organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is stirred in ether, filtered off and dried to yield 1.58 g of the expected compound, m.p.=245°246° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[NH2:22])[CH2:15][S:16][CH2:17][CH3:18])([O-])=O.[OH-].[Na+]>O.C(O)C.[OH-].[NH4+]>[NH2:9][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[NH2:22])[CH2:15][S:16][CH2:17][CH3:18]
Reactant: CCSCc1ccc(N)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCSCc1ccc(N)c(N)c1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of sodium dithionite (2.05 g, 11.8 mmol) dissolved in 20 ml water and 5 ml concentrated ammonium hydroxide is added to the ethyl 3-nitro-4-aminobenzyl sulfide (1 g, 3.9 mmol) stirred in 20 ml 95% ethanol. The mixture is heated to reflux and 0.6 g sodium dithionite in 2 ml water and 0.5 ml ammonium hydroxide is added immediately. The mixture becomes colorless, is cooled to room temperature, basified with 5 ml 10% sodium hydroxide, evaporated to 1/2 volume, and washed with chloroform (X 5). The combined chloroform washings are washed with brine, dried (Na2SO4), and evaporated to give 0.65 g (92%) of an oil which is used without further purification.