Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:17]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 2-(methylamino)ethanol (2.14 mL, 26.6 mmol) in DCM (60 mL) was added triethylamine (4.1 mL, 29.3 mmol), N,N-dimethylpyridin-4-amine (1.63 g, 13.3 mmol) and tert-butylchlorodiphenylsilane (7.6 mL, 29.3 mmol). The reaction was stirred overnight at 40° C. After cooling to RT, the reaction was quenched with water (20 mL) and ether (100 mL). The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (4.4 g, 53%) as a colorless oil. NMR Spectrum (DMSOd6): 0.99 (s, 9H), 2.27 (s, 3H), 2.63 (t, 2H), 3.68 (t, 2H), 7.40-7.49 (m, 6H), 7.60-7.65 (m, 4H).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:28]([CH:25]2[CH2:26][CH2:27][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)C1

Procedure:
6.23 g (26.8 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (100 ml) and, while stirring, 5.00 g (26.8 mmol) of N-Boc-3-aminopyrrolidine and 9.02 g (107 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 6.15 g (66%) of yellow solid
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH:33]([OH:35])[CH3:34]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH:33]([OH:35])[CH3:34])=[O:16])[CH2:6][CH2:5]2
Reactant: CC(O)CN
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)O)O2
Yield: 84.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 4.98 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (19.9 mmol), 3.99 g CDI (24.6 mmol) and 3.01 g 3-amino-2-propanol (39.9 mmol), yielded 5.15 g of 6-hydroxy-N-(2-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[F:27])=[O:19].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:23]=[CH:22][C:21]=1[F:27])=[O:19]
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1cc(OCCN2CCOCC2)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Temperature: 130 °C
Reaction time: 1.75 h

Procedure:
Compound 517 (30 mg, 0.08 mmol) was dissolved in acetonitrile (2 mL) in a reaction vial. 4-(2-Chloro-ethyl)-morpholine hydrochloride (44 mg, 0.24 mmol) and K2CO3 (33 mg, 0.24 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for a total of 105 min. in a microwave oven. The reaction mixture was poured into a mixture of EtOAc:H2O (1:1, 10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:9 to 3:2) as the eluent, affording the title compound as a light yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[C@@H:15]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[C:31]([F:34])([F:33])[F:32])[C:23]2=[O:35])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:9]1)(C)(C)C.O.[OH-].[Li+]>O1CCCC1.O>[CH:17]1([CH2:16][C@H:15]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[C:31]([F:33])([F:34])[F:32])[C:23]2=[O:35])[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C:6]([OH:37])=[O:5])[N:9]=2)=[O:36])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (133 mg, 0.26 mmol, prepared as in Example 3) and lithium hydroxide monohydrate (22 mg, 0.52 mmol) in tetrahydrofuran:water (1:1, 10 mL) at room temperature was stirred for 2 h. The reaction mixture was then concentrated in vacuo and partitioned between a 1 N aqueous hydrochloric acid solution and ethyl acetate. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo to afford {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid (118 mg, 98%) as a white foam: HR-ES(+) m/e calcd for C22H23N4O4F3 [M+H]+ 465.1744, observed 465.1744; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.01 (dd, J=7.67, 13.00 Hz, 2H), 7.69-7.80 (m, 1H), 7.59 (d, J=2.13 Hz, 1H), 6.45 (d, J=2.13 Hz, 1H), 4.95-5.12 (m, 2H), 4.81 (s, 2H), 4.72 (d, J=17.90 Hz, 1H), 1.09-2.11 (m, 11H).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.[NH2:46][C@H:47]([C:55]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH2:60][S:61][CH3:62])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl>CN(C=O)C.CO>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([NH:46][C@H:47]([C:55]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH2:60][S:61][CH3:62])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:6])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Yield: 87 %

Procedure:
In an analogous fashion as described in Step A, 7.56 g of Boc-DAla-OH, 5.06 g of HOSu, 8.25 g of DCC, 13.8 ml of DIEA and the HCl salt above were allowed to react in 100 ml of DMF to give 16.67 g (87% of Boc-DAla-Phe-Met-OCH3, m.p. 109°-110° C., [α]D24.5 =-19.73° (c, 1.00 in methanol).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[CH3:13][NH:14][CH3:15]>C1(C)C=CC=CC=1>[BrH:1].[Cl:9][C:7]1[CH:6]=[CH:5][C:4]2[N:10]=[C:11]([N:14]([CH3:15])[CH3:13])[O:12][CH2:2][C:3]=2[CH:8]=1
Reactant: CNC
Reactant: O=C=Nc1ccc(Cl)cc1CBr
Solvent: Cc1ccccc1
Product: Br
Product: CN(C)C1=Nc2ccc(Cl)cc2CO1

Procedure:
2 g (0.008 M) of 2-bromomethyl-4-chlorophenylisocyanate is dissolved in 50 ml. of toluene. To the solution in a reaction vessel, is slowly added 0.36 g (0.008 M) of dimethylamine in 20 ml of toluene with stirring; maintaining the temperature of from 35° to 40° (over a period of about 6 hours) resulting in the separation of the crude title product as the hydrobromide acid addition salt, which may be recovered and refined by washing with diethyl ether m.p. 183°-186°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[C:18]1([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:32]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11](=[O:12])[C:10]4=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]4[C:8]3=[O:17])[CH2:28][CH2:27]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dibromopentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: [OH:1]S(O)(=O)=O.[NH2:6][C:7]1[N:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:20]#N.[OH2:22]>>[NH2:6][C:7]1[N:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:20]([OH:1])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: N#Cc1cnn(CCc2ccccc2)c1N
Product: Nc1c(C(=O)O)cnn1CCc1ccccc1
Temperature: 60 °C
Yield: 47 %

Procedure:
A mixture of conc. H2SO4 (15 mL) and water (15 mL) was treated with 5-amino-1-(2-phenylethyl)-1H-pyrazole-4-carbonitrile (5.0 g, 23.6 mmol), heated at 60° C. for 1 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo, and recrystallised (EtOAc/MeOH) to give the title compound (2.53 g, 47%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL) and N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and then 3-fluoro-benzyl bromide (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-(3-fluorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]([C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH2:35])=[CH:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:23]>>[NH2:35][CH2:34][CH2:33][C:28]1[C:27]2[C:31](=[CH:32][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=2)[NH:30][C:29]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4](=[O:13])[O:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: O=C1C=C(O)C(c2ccccc2)O1
Reactant: CCc1ccc2c(CCN)c[nH]c2c1
Reactant: O=Cc1ccccc1
Product: CCc1ccc2c(CCN)c(C(C3=C(O)C(c4ccccc4)OC3=O)c3ccccc3)[nH]c2c1

Procedure:
Using general procedure C, 4-hydroxy-5-phenyl-5H-furan-2-one (Lit. 14) was reacted with benzaldehyde and 2-(6-ethyl-1H-indol-3-yl)-ethylamine (Lit. 8) to give the title compound as a white solid; MS: 453.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29](=[O:32])[CH2:30]Br)=[CH:27][C:26]=1[F:35]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:29](=[O:32])[C:28]1[CH:33]=[CH:34][C:25]([Cl:24])=[C:26]([F:35])[CH:27]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)c(F)c1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)c(F)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-chloro-3-fluorophenacyl bromide* .
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9].CO[CH:19](OC)[N:20](C)[CH3:21]>CN(C)C=O.O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH:9][N:20]([CH3:21])[CH3:19]
Reactant: C=C(C(=O)c1sccc1Cl)c1ccncc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=C(C(=O)c1sccc1Cl)c1ccncc1
Yield: 74.6 %

Procedure:
To a solution of 1-(3-chlorothiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one (1 eq, 27 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added N,N-dimethylformamide dimethyl acetal (4 eq, 108 mmol). The reaction mixture was stirred under reflux for 1.5 h. The mixture was diluted with water (600 mL) and extracted with dichloromethane (4×200 mL) and ethylacetate (4×200 mL). The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The obtained residue was purified by column chromatography on silica gel (DCM:MeOH, 40:1 to 20:1) to afford intermediate 5.9 g of 1-(3-chlorothiophen-2-yl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one (74% yield).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].N>C(Cl)Cl.C(O)(=O)C>[CH3:31][O:32][CH2:33][C:34]([NH:21][C:17]1[CH:16]=[C:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:20]=[CH:19][N:18]=1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a stirred solution of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (10) (40.0 g, 135 mmol) and DIPEA (48.1 mL, 270 mmol) in DCM (600 mL) at 0° C., under nitrogen, was added dropwise methoxyacetyl chloride (18.53 ml, 203 mmol). The mixture was warmed to RT and after 1 hr a solution of ammonia (100 mL, 7 M in MeOH) was added and stirring continued for 30 min, during which time a precipitate formed. The mixture was evaporated in vacuo and water (1 L) was added to the residue to provide a red suspension. Glacial acetic acid was added dropwise until a yellow colour persisted (˜5 mL). The solid was collected by filtration and washed with water (300 mL) to afford 2-methoxy-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)acetamide (11) (44.1 g, 90%) as a yellow solid: m/z 354 (M+H)+ (ES+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[C:22]1([C:28]2[N:29]=[N:30][N:31]([CH:33]3[CH2:37][CH2:36][NH:35][CH2:34]3)[CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:35]4[CH2:36][CH2:37][CH:33]([N:31]5[CH:32]=[C:28]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)[N:29]=[N:30]5)[CH2:34]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1ccc(-c2cn(C3CCNC3)nn2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cc(-c5ccccc5)nn4)C3)c(F)cc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg, 0.53 mmol), 3-(4-phenyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (252 mg, 1.05 mmol) and diazobicycloundecane (160 mg, 1.05 mmol) in pyridine (5 ml) was heated at 110° C. for 20 hrs, concentrated and diluted with water. The separated solid was filtered, washed with water and crystallized from methanol. Yield: 55 mg (22.3%), m.p. 241.4° C. 1H NMR (TFA) δ: 1.34-1.73 (m, 4H), 2.82-3.09 (m, 2H), 4.20-4.95 (m, 5H), 5.73-5.92 (m, 1H), 7.5-7.92 (m, 4H), 8.15 (d, 1H), 8.80 (s, 1H), 9.30 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:15]3[N:31]=[CH:30][S:29][C:16]=3[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:24](=[O:26])[C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH:8]=3)[C:15]3[N:31]=[CH:30][S:29][C:16]=3[N:17]=2)=[CH:28][CH:27]=1
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3ccc(C(=O)NCCN(C)C)cc3)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
To a solution of (S)-4-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (80 mg, 0.19 mmol) and N1,N1-dimethylethane-1,2-diamine (18 mg, 0.2 mmol) in DCM (20 mL) was added 1-methyl-1H-indozole (92 mg, 1.12 mmol) and EDCI (217 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography (DCM:MeOH=50:1) and product treated with conc. HCl to give (S)—N-(2-(dimethylamino)ethyl)-4-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (22 mg, 24%) as HCl salt. 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 7.97-7.91 (m, 3H), 7.63-7.57 (m, 1H), 7.41 (d, 1H, J=8.1 Hz), 4.06-3.93 (m, 2H), 3.77-3.68 (m, 3H), 3.37-3.33 (m, 2H), 2.91 (s, 6H), 2.53-2.42 (m, 1H), 2.35-2.18 (m, 2H), 2.06-1.87 (m, 1H), 1.36 (d, 3H, J=6.6 Hz). LC-MS: 502 [M+H]+, tR=1.344 min. HPLC: 97.57% at 214 nm, 97.17% at 254 nm, tR=4.793 min.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5].[Br:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>CN(C=O)C>[Br:16][CH2:17][CH2:18][NH:19][C:20]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5])=[O:21]
Reactant: NCCC(=O)NC(=O)c1ccccc1S
Reactant: O=C=NCCBr
Solvent: CN(C)C=O
Product: NCCC(=O)NC(=O)c1ccccc1SC(=O)NCCBr
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of N-(2-mercaptobenzoyl)-β-alaninamide (0.90 g, 4.0 mmol) in DMF (20 ml) was added 2-bromoethyl isocyanate (0.91 g, 6.0 mmol). The reaction mixture was stirred for 6 h. The solvent was evaporated to dryness, and the residue was treated with ethyl ether (20 ml) with vigorous stirring. The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield: 87%. 1H NMR (DMSO-d6): 2.36(t, 2H, CH2), 3.42(q, 2H, CH2), 3.54(s, 4H, 2CH2), 6.88(brs, 1H, NH2), 7.36-7.66(m, 5H, Ar—H, NH2), 8.26(t, 1H, NH), 8.66(brs, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][CH:14]=1>CC#N.[Cu]I>[F:1][CH:2]([F:10])[O:11][CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CCOC(=O)c1cccc(CO)n1
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(=O)c1cccc(COC(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.7 %

Procedure:
2,2-Difluoro-2-(fluorosulfonyl)acetic acid (495 mL, 4.79 mmol) was added dropwise to a solution of ethyl 6-hydroxymethylpyridine-2-carboxylate (800 mg, 4.79 mmol) and CuI (91 mg, 0.479 mmol) in MeCN (10 mL) at room temperature at a rate to maintain the internal temperature <30° C. The mixture was stirred for a further 20 min at room temperature, poured onto brine/water and extracted with EtOAc (×3). The combined extracts were dried (MgSO4), filtered, evaporated and purified by column chromatography (4:1 to 2:1, isohexane:EtOAc) to give the title compound (130 mg, 13%) as a colorless oil; NMR δH (400 MHz, CDCl3) 8.01 (1H, d, J 7.5 Hz), 7.89 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 7.5 Hz), 6.41 (1H, t, J 74.0 Hz), 5.14 (2H, s), 4.49 (2H, q, J 7.0 Hz), 1.44 (3H, t, J 7.0H); (M+H)+ 232.