Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CCC[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:29][CH2:30]1
Reactant: OC1CCN(CCCCl)CC1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCC(O)CC3)cc2)CCOCC1
Yield: 60.9 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (533 mg, 2.62 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (750 mg, 4.22 mmol), DMF (10 ml) and K2CO3 (1.44 g, 10.42 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (550 mg, 61%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.13-4.04 (m, 2H), 4.02 (t, 2H), 3.89 (td, 2H), 3.70 (m, 1H), 2.87-2.71 (m, 2H), 2.50 (t, 2H), 2.23-1.84 (m, 10H), 1.68-1.49 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cn1
Solvent: ClCCl
Product: Cc1ccc(CCl)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In a 250 ml round-bottomed flask at room temperature under nitrogen, (6-methyl-3-pyridinyl)methanol (4.32 g, 35.1 mmol, D8) was dissolved in dry dichloromethane (45 ml) to give a yellow solution, which was cooled down to 0° C. Thionyl chloride (3 ml, 41.1 mmol) was then added. The resulting pale-orange mixture was stirred at 0° C. for 15 minutes and at room temperature for 2 hours. The mixture was concentrated in vacuum and the brown residue was partitioned between DCM (150 ml) and saturated NaHCO3 (100 ml). Phases were separated and the organic was washed with saturated NaHCO3 (2×100 ml), dried over Na2SO4, filtered and concentrated to give the desired compound as brown oil (4.26 g), that was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[C:23]([C:24](=[O:25])[NH:36][CH:33]3[CH2:35][CH2:34]3)=[CH:27][CH:28]=[CH:29][N:30]=2)[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)O)OC1(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)NC2CC2)OC1(C)C

Procedure:
Using general reaction procedure 5 with 2-[(4R,5S)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid (0.3 g, 0.67 mmol) and cyclopropylamine (0.23 mL, 3.4 mmol) gives the title compound.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[F:7][CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10]>C(O)C>[F:7][C:8]1[C:9]([OH:10])=[N:5][C:4]([NH2:6])=[N:3][C:14]=1[OH:15]
Reactant: N=C(N)N
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(O)c(F)c(O)n1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Sodium (257 mg, 11 mmol) was dissolved in absolute ethanol (50 ml) with stirring under argon. When the sodium had thoroughly dissolved, guanidine hydrochloride (2) (502 mg, 5 mmol) and diethyl fluoromalonate (1) (790 mg, 4.4 mmol) were added. The solution was left to stir at room temperature overnight. A condenser was then attached to the flask and the solution was refluxed under argon for 4.5 hours. The solution was cooled to room temperature and concentrated. The residue was redissolved in 20 ml hot H2O and acidified to pH 4. The mixture was cooled on ice and the precipitate was collected, yielding (3) as a peach colored solid (618 mg, 96%): MS (70 eV, EI)m/z (relative intensity) 146(M+, 100), 18 (95), 172 (26), 17 (24), 300 (21); IR (mull, cm-1) 3363, 1695, 1601, 1420, 1208, 677, 666; UV (MeOH, nm) 206(3,840), 235(3,380), 270(11,600). Exact Mass Calcd for C4H4N3O2F: 146.0366. Found: 146.0371.
Reaction SMILES: N[C:2]1([NH2:16])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]1=[N:4][CH:5]=[N:6]2.C([O-])([O-])=O.[K+].[K+].[O:23]1[CH2:32][CH:24]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[NH2:16][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:32][CH:24]([OH:23])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: COCCOC1=NC(N)(N)C2=NC=NC2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(CC(O)Cc3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 34.6 %

Procedure:
To a suspension of 6-amino-2-(2-methoxyethoxy)adenine Compound (15) (300 mg, 1.43 mmol) in DMF (3 ml) was added K2CO3. Then (2,3-epoxypropyl)benzene (285 μl, 34 mmol) was added and the reaction mixture was stirred at 70° C. for 5 h. The solvent was removed under vacuum and the residue was washed with brine. The aqueous phase was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (eluting a linear gradient of 0-10% MeOH in DCM) to give 170 mg of Compound (22). 1H NMR (CDCl3) δ 2.82-2.85 (dd, 2H), δ 3.43 (s, 3H), δ 3.74 (t, 2H), δ 4.00-4.10 (m, 1H), δ 4.25-4.29 (m, 2H), δ 4.42 (t, 2H), δ 5.76 (bs, 2H), δ 7.21-7.34 (m, 5H), δ 7.50 (s, 1H); MS: 494.2 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33]N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(F)ccc3F)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,5-difluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=428.6 (M+H)+
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:26]([O:28]C)=[O:27])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2cc(C(=O)OC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
N-(1-Octyl-5-methoxycarbonyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide (580 mg) was dissolved in methanol (10 ml) and a solution of NaOH (290 mg) in water (5 ml) was added, which was followed by stirring at 60° C. for 4 hr. Methanol was evaporated under reduced pressure. Water (50 ml) was added to the residue and the mixture was washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 6-7 with 2N sulfuric acid and extracted with chloroform (100 ml). The chloroform layer was washed with water and dried over anhydrous sodium sulfate. Chloroform was evaporated under reduced pressure to give 380 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[O:33]1[C:37](=[O:38])[CH2:36][CH2:35][C:34]1=[O:39].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([OH:39])=[O:33])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)CCC(=O)O)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) was dissolved in DMF (4 ml), and dihydrofuran-2,5-dione (50 mg) and K2CO3 (125 mg) were added thereto, followed by stirring at room temperature for 1 hour. Water and 1 M hydrochloric acid were added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-4-oxobutanoic acid (168 mg).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:11].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[CH:12]1([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[F:11])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(F)c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-1-fluoro-3-nitrobenzene (2.0 g, 9.1 mmol), cyclopropanamine (1.26 mL, 18.2 mmol) in THF (10 mL) under N2 was heated at 60° C. for 4 days. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using hexane-EtOAc (8.5:1.5) as eluent to give N-cyclopropyl-2-fluoro-6-nitroaniline.
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[C:3]([C:5]([O-:7])=[O:6])=O.[Na+].[Na+].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C(OCC)(=O)C>Cl.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][N:21]=[C:3]([C:5]([OH:7])=[O:6])[C:2]([OH:9])=[O:8]
Reactant: NNc1ccccc1F
Reactant: O=C([O-])C(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C(=NNc1ccccc1F)C(=O)O
Reaction time: 8 h

Procedure:
Sodium mesoxalate monohydrate (2.21 g, 12.3 mmol) was dissolved in 1 M hydrochloric acid (50 ml) to give a colourless cloudy solution. 2-Fluoro-phenylhydrazine hydrochloride (2.00 g, 12.3 mmol) was added portionwise at room temperature to the stirred mixture. A yellow precipitate formed, the mixture was diluted with water (50 ml) and stirring continued overnight. Ethyl acetate (150 ml) was added, the phases were mixed vigorously until the solids had dissolved. The phases were separated and the aqueous phase was washed with ethyl acetate (50 ml). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed under vacuum. The title compound was isolated as a yellow powder (2.55 g, 11.7 mmol, 92%). LCMS: m/z 227 [M−H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([NH2:10])[C:8]#[CH:9].CN(C1C=CC=CN=1)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[C:3]([NH:10][CH2:7][C:8]#[CH:9])=[O:4]
Reactant: C#CCN
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CCNC(=O)N(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dimethyl carbamylchloride (0.84 mL, 9.1 mmol) was added to a stirred solution of propargylamine (0.62 mL, 9.1 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (5 mL) at room temperature. The resulting suspension was stirred at ambient temperature for approximately 15 h. The reaction mixture was diluted with ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (i-5), which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1)=[O:5].CC([O-])(C)C.[K+].CC(O)(C)C>C1COCC1>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[F:32])[NH:25][C:10]1[C:9]2[C:14](=[CH:15][C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:7]([NH:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:23]#[N:24]
Reactant: N#Cc1cnc2cc(N3CCOCC3)c(NC(=O)CCCl)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1N1CCOCC1
Yield: 101.6 %

Procedure:
To a stirred solution of 3-chloro-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-(4-morpholinyl)-6-quinolinyl]propanamide (0.30 g, 0.61 mmol) in 1.2 ml of THF at 0° was added 1.2 ml of 1.0 M KOtBu/tBuOH dropwise during 1 m. After 2 h at 0° the reaction was quenched with solid CO2 and partitioned with DCM-water. The organic layer was washed with water, dried, and evaporated to give 0.28 g of the title compound as a white amorphous solid; ms 452.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1.[Cu][C:21]#[N:22].NCCN>CN(C)C=O>[C:21]([C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1)#[N:22]
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 160 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
35 g of the product of Example 24 were dissolved in 75 ml of dimethylformamide, and 10.5 g of copper(I) cyanide were added. The mixture was stirred for 8 hours at 160° C. The hot mixture was then discharged into 100 ml of ice-water, and 30 g of 1,2-diaminoethane were added. After stirring for 30 minutes, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with a solution of 30 g of 1,2-diaminoethane in 75 ml of water, dried over magnesium sulphate and distilled under high vacuum to give 20.5 g of product (=69% of theory). The. boiling point was 110° C. at 0.02 mbar. =19F NMR: -58.1 and -84.6 ppm. 1H NMR: 3.08 ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42]([NH2:44])=O)C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:42]([NH2:44])=[NH:37])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: NC(=O)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Reaction time: 16 h
Yield: 14.7 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (60 mg, 0.089 mmol) and pyrazole-1-carboxamide hydrochloride (16 mg, 0.11 mmol) in DMF (3 mL) was added DIPEA (45 μL, 0.27 mmol). After stirring for 16 h, the solution was concentrated and washed with ether. The crude residue was purified by reverse phase prep HPLC (XBridge, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (7.5 mg, 15%) as a white solid. LCMS: m/z=571.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.55 (s, 1H), 6.78 (s, 1H), 5.38 (d, J=5.2 Hz, 1H), 4.82-4.76 (m, 1H assumed; obscured by solvent residual peak), 4.76-4.72 (m, 2H assumed; obscured by solvent residual peak), 4.32 (s, 2H), 1.15 (s, 3H), 1.14 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[C:16]([F:45])[CH:15]=1>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:17]3[C:16]([F:45])=[CH:15][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:19]([O:20][CH3:21])[CH:18]=3)[C:30]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) in dichloromethane (0.3 mL) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL) at 0° C. After 5 minutes the ice-water bath was removed and the reaction mixture was stirred at room temperature for 3 hours. More trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) was added to ensure the reaction went to completion. Solvent was evaporated and the residue was purified by flash column chromatography to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamide (93 mg, 88%). 1H NMR (DMSO-d6) δ 1.35 (m, 1H), 1.50 (m, 3H), 1.98 (m, 6H), 2.19 (s, 3H), 2.37-2.68 (m, 11H), 3.87 (s, 3H), 4.64 (m, 1H), 7.09 (m, 1H), 7.21 (m, 3H), 7.31 (m, 2H), 8.21 (m, 2H), 9.82 (m, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=599.3, Rt=1.97 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].C(Cl)(=O)C(Cl)=O.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C=O)C.Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)(C)N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-bromo-3-fluorobenzoic acid (19 g, 87 mmol) in DCM (200 mL) was added oxalyl chloride (9.10 mL, 104 mmol), followed by 1 drop of DMF. The mixture was allowed to stir at rt for 2 h. Upon clarification of the suspension, the solution was concentrated to dryness. The residue was redissolved in DCM (200 mL) and cooled to 0° C. Next the solution was treated with TEA (30.2 mL, 217 mmol) followed by tert-butyl amine (12.0 mL, 113 mmol). The solution was allowed to stir for 12 h. The reaction was diluted with 1N HCl (200 mL). The organic layer was then removed and washed with 1N NaOH. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[K+].Cl>CS(C)=O.O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cccc(Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.8 %

Procedure:
6-Chloropyridine-2-carboxylic acid (1.00 g, 6.347 mmol), 2,2,2-trifluoroethan-1-ol (0.683 mL, 9.520 mmol) and potassium hydroxide (1.424 g, 25.387 mmol) were dissolved in DMSO (25 mL) and heated at 100 C for 18 h. The reaction mixture was re-treated with potassium hydroxide (0.356 g, 6.347 mmol) and heated at 100 C for 18 h. The reaction mixture was then re-treated with 2,2,2-trifluoroethan-1-ol (1.367 mL, 19.040 mmol) and potassium hydroxide (0.356 g, 6.347 mmol) and heated at 110 C for 18 h. The reaction mixture was then further re-treated with potassium hydroxide (0.356 g, 6.347 mmol) and 2,2,2-trifluoroethan-1-ol (0.683 mL, 9.520 mmol) and the mixture was stirred at room temperature for 72 h. Water (10 mL) was added and acidified to pH 1 with 1M hydrochloric acid. The aqueous was extracted with EtOAc (3×15 mL) and the organic layer was washed with brine (15 mL). This was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown gum. The crude material was purified by FCC (DCM: MeOH, 90:10) to afford the title compound as a yellow solid (1.26 g, 90%). Method B HPLC-MS: MH+ requires m/z=222 Found: m/z=222, Rt=1.71 min (79%).
Reaction SMILES: [NH3:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:13])[C:8](OCC)=[O:9]>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:13])[C:8]([NH2:1])=[O:9]
Reactant: N
Reactant: CCOC(=O)C(=O)c1cccs1
Product: NC(=O)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.6 g of ammonia are passed into a cooled solution of 73.6 g of ethyl 2-thienylglyoxylate, and the resulting mixture is stirred at room temperature for 2 h. The solvent is stripped off in vacuo, and the residue is recrystallized from water:ethanol (80:20).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CO>O>[C:14]1([CH:13]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2cc(O)ccc21
Temperature: 25 °C

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and benzaldehyde 0.42 ml were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for two hours and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.756 g.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH:4]([CH3:5])CO1.[NH:8](CCO)[CH2:9][CH2:10][OH:11].[OH-].[Na+]>>[OH:11][CH2:10][CH2:9][N:8]1[CH2:5][CH2:4][O:6][C:1]1=[O:7]
Reactant: OCCNCCO
Reactant: CC1COC(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCO
Temperature: 100 °C

Procedure:
5.1 mol of propylene carbonate were provided as an initial charge at 23° C. under a nitrogen atmosphere. 5 mol of diethanolamine were added over 30 to 120 minutes with stirring, and the temperature of the reaction mixture rose. On completion of the addition the mixture was heated to 100° C. in the course of 10 to 120 minutes. At 100° C., 2.5 mol % of NaOH in solid form were added, and the batch was left to stir at 100° C. for 2 hours. Then a 10 to 20 mbar vacuum was applied, the temperature was raised from 100° C. to 160° C. and propylene glycol was distilled off. The N-(2-hydroxyethyl)-oxazolidin-2-one obtained almost quantitatively as undistilled bottom product comprised 96-98% by weight of product of value and had a Hazen color number in the range from 0 to 25.