Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:32]([O-:34])=[O:33])=[C:14]([CH:31]=1)[C:15]([NH:17][C:18]1[CH:23]=[C:22]([C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:30])=[O:16]>>[CH:27]1([NH:26][C:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:30])=[C:18]([NH:17][C:15](=[O:16])[C:14]3[CH:31]=[C:10]([N:6]4[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]4)[CH:11]=[CH:12][C:13]=3[N+:32]([O-:34])=[O:33])[CH:23]=2)=[O:25])[CH2:29][CH2:28]1
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1, which is concerned with the preparation of starting materials, N-ethylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-ethylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 1.02 (t, 3H), 2.30 (s, 3H), 2.37 (m, 2H), 2.48 (m, 4H), 2.83 (m, 1H), 3.49 (m, 4H), 7.06 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.04 (d, 1H), 8.35 (d, 1H), 9.91 (s, 1H);
Reaction SMILES: [O:1]=[C:2]1[C:10]2[N:9]([CH2:11][C:12](=[O:19])[NH:13][CH2:14][C:15](=O)[CH2:16][CH3:17])[N:8]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:16]([C:15]1[O:19][C:12]([CH2:11][N:9]2[C:10]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=3[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:8]2)=[N:13][CH:14]=1)[CH3:17]
Reactant: CCOC(=O)c1nn(CC(=O)NCC(=O)CC)c2c1CCCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(Cc2ncc(CC)o2)c2c1CCCC2=O
Temperature: 90 °C
Yield: 59.5 %

Procedure:
A solution of 506 mg (1.51 mmol) of ethyl 7-oxo-1-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in toluene (45 mL) was treated with 0.422 mL (4.53 mmol) of phosphoric trichloride and heated at 90° C. for 15 hours. The mixture was cooled to room temperature, poured into ice and neutralized with NaOH 5N. The aqueous phase was extracted with dichloromethane and the organic layer afforded 425 mg of crude that was purified on silica gel (eluant hexane/ethylacetate 7/3). 285 mg of the title compound were thus isolated (60% yield).
Reaction SMILES: C([O:4][CH:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:6]1=[O:24])(=O)C.[OH-].[K+].O>CC(C)=O.CO>[OH:4][CH:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:6]1=[O:24]
Reactant: COc1ccc(N2C(=O)C(OC(C)=O)C2c2ccccc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(N2C(=O)C(O)C2c2ccccc2Cl)cc1
Yield: 96.9 %

Procedure:
To a solution of β-lactam 23 (8.00 g, 23.1 mmol) in 50 ml of acetone was added KOH (1.30 g, 23.1 mmol) in 20 ml of methanol at 0° C. The resultant mixture was stirred for 5 minutes, and 50 ml of water was added. The product was precipitated and isolated by filtration to yield 6.8 g (96%) of 24 as a white solid, mp 178-180° C. 1H NMR (250 MHz) δ 7.48 (d, J=7.3 Hz, 1H), 7.34-7.24 (m, 5H), 6.85 (d, J=9.0 Hz, 2H), 5.63 (d, J=5.1 Hz, 1H), 5.34 (d, J=5.1 Hz, 1H), 3.78 (s, 3H), 1.74 (bs, 1H). 13C NMR (63 MHz, DMSO-d6), δ 166.6, 156.1, 133.1, 132.9, 131.0, 129.8, 129.6, 128.9, 127.4, 118.6, 115.0, 77.2, 60.0, 55.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1>>[CH3:9][C@H:10]1[N:15]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1
Reactant: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1
Reactant: O=Cc1cccnc1
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1Cc1cccnc1
Yield: 58 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(3R)-3-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5, to give 6-[(3R)-3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:17]C)(OC)[CH2:13][OH:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19]I.[OH-].[K+].S(=O)(=O)(O)O>O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[O:17])[CH2:13][O:14][CH3:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(CO)(OC)C1(c2ccc(Cl)cc2)CCC1
Reactant: CI
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 0.08 h

Procedure:
2-[1-(4-Chlorophenyl)cyclobutyl]-2,2-dimethoxyethanol (1.48 g) and then methyl iodide (1.86 g) were added to a mixture of powdered potassium hydroxide (1.23 g) and dry dimethylsulphoxide (10 ml) which had been stirred for 5 minutes. The mixture was stirred for 30 minutes and was then poured into water (100 ml). The resulting mixture was acidified with concentrated sulphuric acid and extracted with dichloromethane. The extract was washed with water and dried and then evaporated to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methoxyethanone as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:11])[CH:9]=O)=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.[NH:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH:8]([CH3:11])[CH2:9][N:39]2[CH2:42][CH:41]([OH:43])[CH2:40]2)=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)C=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: OC1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CN4CC(O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
2-((2-chloro-5-cyano-3-(1-oxopropan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.047 mmol) was taken up in THF (0.5 mL) and a solution of azetidin-3-ol (6.94 mg, 0.095 mmol) in MeOH (0.333 mL) was added. A drop of AcOH was added and the solution was stirred for 10 min. Next, sodium cyanoborohydride (5.96 mg, 0.095 mmol) was added and the reaction was stirred for 1 h. The reaction was diluted with EtOAc and washed with 2M K3PO4 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOHiDCM; 12 g column). 2-((2-chloro-5-cyano-3-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (17.5 mg) was obtained as a yellow glass.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-].[H][H]>[Pd].C1COCC1>[NH2:1][CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate (2.1 g, 7.04 mmol, 1.0 equiv) and Pd/C (10%, ˜200 mg) were added to a flask. THF (30 mL) was added and the flask fitted with a gas inlet connected to a balloon of hydrogen gas. The flask was evacuated and back-filled with H2 from the balloon. This was repeated twice and the reaction mixture stirred for 17 h at ambient temperature. Analysis by LC/MS showed complete conversion to the desired amine. The catalyst was removed by filtration through a pad of Celite and the mixture evaporated. This provided 1.82 g (94%) of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate.
Reaction SMILES: [F:1][C:2]1[C:7]([Si](C)(C)C)=[C:6]([F:12])[C:5]([F:13])=[C:4]([CH3:14])[C:3]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1.[F-].[Cs+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[C:6]([F:12])[C:5]([F:13])=[C:4]([CH3:14])[C:3]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1
Reactant: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1C1=NC(C)(C)CO1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)c(F)cc(F)c1C1=NC(C)(C)CO1
Yield: 98.5 %

Procedure:
A solution of 12.0 g (38.0 mmol) of 2-[2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)phenyl]-4,4-dimethyl-2-oxazoline, 5.85 g (38.5 mmol) of cesium fluoride, 110 mL of dimethylformamide, and 15 mL of water was stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate; the organic phase was washed with water, dried over magnesium sulfate, and concentrated to give 9.1 g of liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].I[CH2:20][CH3:21].C(=O)([O-])O.[Na+]>CN(C=O)C.C1COCC1.C(OCC)(=O)C.O>[CH2:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:21]
Reactant: COC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNc1cc(-c2ccncc2)sc1C(=O)OC
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a stirred solution of methyl 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylate (1.21 g, 5.00 mmol) in DMF (25 mL) was added sodium hydride (60%, 0.220 g, 5.50 mmol). After 10 min, iodoethane (0.44 mL, 5.5 mmol) was added and stirring was continued for 4 h. The mixture was poured into water (60 mL) and sat. aqueous sodium hydrogen carbonate (60 mL). Ethyl acetate (120 mL) and THF (60 mL) were added to the mixture for extraction and the insoluble precipitate was removed by filtration. The organic layer was washed with brine, dried over magnesium sulfate, filtrated and concentrated at reduced pressure. The obtained residue was purified by column chromatography (Combiflash, 40 g silica gel, hexanes to 30:70 hexanes/ethyl acetate) to afford the title compound (0.636 g, 48%) as an orange solid:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[N+:24]([O-])([OH:26])=[O:25].[K+].[Br-]>C(O)(=O)C>[OH:1][C:2]1[CH:3]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[C:4]2[S:10][CH:9]([N+:24]([O-:26])=[O:25])[CH2:8][C:5]=2[O:6][CH:7]=1
Reactant: O=C(NC1c2sccc2OCC1O)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(NC1C(O)=COC2=C1SC([N+](=O)[O-])C2)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared as described in Example 9 starting with 5,6-dihydro-6-hydroxy-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol) and 90% nitric acid (2.5 mL) in acetic acid (20 mL) to give a yellow solid, 0.165 g (10%): mp 219°-220° C.; IR (KBr): 3310, 1661, 1538 and 1504 cm-1, MS: m/z 417 (MS+) 1H NMR (DMSO-d6): δ 1.26 (s, 3H), 1.45 (s, 3H), 3.92 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 4.98 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.99 (d, 1H, exchanges with D2O), 7.74 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H) and 9.30 (d, 1H, exchanges with D2O).
Reaction SMILES: Cl[C:2](OCC)=[O:3].[NH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1>O1CCOCC1>[NH:7]1[C:2](=[O:3])[NH:15][C:13](=[O:14])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]12
Reactant: NC(=O)c1cccn1N
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2cccn2[nH]1
Temperature: 155 °C
Yield: 63 %

Procedure:
Ethyl chloroformate (4.9 ml, 51 mmole) was added dropwise to a stirred mixture of 1-amino-1H-pyrrole-2-carboxamide (5.85 gm, 46.7 mmole, Journal of Heterocyclic Chemistry, 1994, 31, 781) and dry pyridine (4.2 mL, 51 mmole) in dry dioxane (48 mL) under N2 at RT. This was heated at reflux for 1 hr and then the solvent was removed. The residue was heated at 155° C. for 17 hr and then allowed to cool to RT. This was triturated with methanol and the solid was collected by filtration and washed with cold methanol to give the product, 4.43 gm (63% yield): MS: 152 (M+H)+; HPLC Ret Time: 0.36 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:19][C:20](=O)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:19]=[C:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: CCOC(=O)Cc1cc(NC(N)=S)ncc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A flask was charged with ethyl 2-(5-bromo-2-thioureidopyridin-4-yl)acetate (2.200 g, 6.914 mmol), 1-bromo-4-phenylbutan-2-one (1.884 g, 8.297 mmol), DIEA (1.806 mL, 10.37 mmol) and ethanol (100 mL). The mixture was heated stirred at 70° C. for 2 hours, then cooled. The reaction was concentrated, and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from hexane/ethyl acetate to give the desired product (1.815 g, 58.81% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]([S:39]([CH3:38])(=[O:41])=[O:40])[S:39]([CH3:38])(=[O:41])=[O:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) was added triethylamine (0.48 ml), methanesulfonyl chloride (0.07 ml) was added and the mixture was stirred at room temperature for 3 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1-+2/3) to give the title compound (110 mg, 59%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1Oc1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[2-(4-Trifluoromethyl-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01063, 1.0 g, 2.16 mmol) was dissolved in DCM (20 ml), and cooled to 0° C., and to this was added TFA (5 ml). Allowed to warm to room temperature and stirred for 1 h. The solution was poured over solid potassium carbonate (12 g), and extracted with DCM and water. Organic layers dried over MgSO4 and evaporated to dryness, to afford a cream coloured solid. 0.85 g, 100%, R.f. 0.4 (5% MeOH in DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.65 (2H, m, CHCH2), 1.79 (2H, m, CHCH2), 2.30 (1H, m, CH), 2.64 (2H, td, J=12.4, 2.7 Hz, NCH2), 3.10 (2H, m, NCH2), 6.97 (1H, dd, J=6.4, 30.5 Hz, Ar HD), 7.05 (2H, m, Ar HF), 7.06 (1H, m, Ar HB), 7.17 (1H, t, J=7.2 Hz, Ar HC), 7.58, D, J=8.6 Hz, Ar HE), 8.39 (1H, d, J=7.9 Hz, Ar HA).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34]CC)=[O:33])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[NH2:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(O)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Yield: 86 %

Procedure:
A homogeneous solution of 0.175 of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 3 mL of 1N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Addition of 2 mL of acetic acid followed by centrifugation gave 0.125 g (86%) of the title compound, which can be alternatively named as 5,10-dideazafolic acid, as a microcrystalline colorless solid, mp>200° C.; NMR (TFA-d1) delta 2.3-2.7(m, 2H), 2.7-3.0(m, 2H), 3.25(s, 5H), 4.9-5.25(m, 1H), 7.35, 7.85(AB q, 4H, J=9 Hz), 8.50(s, 1H), 8.90(s, 1H).
Reaction SMILES: [OH-].[K+].O.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.ClC(OCC)=O.[C:20](=S)=[S:21]>>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1([CH2:12][N:13]=[C:20]=[S:21])[CH2:11][CH2:10]1
Reactant: NCC1(c2cccs2)CC1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: S=C=NCC1(c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 parts of potassium hydroxide in 200 parts of water is cooled to about 10° C. and there are added successively 22.8 parts of carbon disulfide and then dropwise 42 parts of 1-(2-thienyl)cyclopropylmethylamine (exothermic reaction). Upon completion, the whole is stirred for 30 minutes at room temperature. Then there are added at 30° C., 29.8 parts of ethyl chloroformate (exothermic reaction: cooling is necessary). The whole is stirred for 3 hours while heating at 50° C. The reaction mixture is cooled and the product is extracted with benzene. The extract is dried, filtered and evaporated. The oily residue is distilled twice, yielding 40 parts of [1-(2-thienyl)cyclopropylmethyl]isothiocyanate; bp. 140°-150° C. at 10 mm pressure; nD20 :1.6008; d2020 :1.1911.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][N:27]([CH3:42])[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.Cl>O1CCCC1.CN(C)C=O>[CH3:26][N:27]([CH3:42])[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH2:33][CH2:32][CH:31]([CH:4]=[O:5])[CH2:30][CH2:29]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (254 mg, 6.36 mmol) was added to a suspension of methoxymethyltriphenylphosphonium chloride (2.18 g, 6.36 mmol) in anhydrous tetrahydrofuran (5 ml) and anhydrous N,N-dimethylformamide (5 ml) under argon. The mixture was stirred at room temperature for 2 h. A solution of 4-dimethylamino-4-(3-fluorophenyl)cyclohexanone (1.0 g, 4.24 mmol) in anhydrous tetrahydrofuran (5 ml) and anhydrous N,N-dimethylformamide (5 ml) was then added dropwise in the course of 30 min and the mixture was stirred at room temperature overnight. 2 M hydrochloric acid (25 ml) was then added dropwise, while cooling with ice, and the mixture was stirred at room temperature for 5 h. Thereafter, the mixture was extracted with ethyl acetate (5×20 ml) and diethyl ether (3×20 ml). The aqueous phase was adjusted to pH 11 with 4 M sodium hydroxide solution and extracted with ethyl acetate (4×20 ml). The combined organic extracts from the alkaline solution were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[CH:11]([NH:14][C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])=[O:16])([CH3:13])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 5.0 g. (37.6 mmole) of 2-oxindole in 50 ml. of toluene was added 8.0 g. (94.0 mmole) of isopropyl isocyanate, and the mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool and then it was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo, and the residue was dissolved in hot cyclohexane. The solution was allowed to cool and the solid was collected by filtration, giving 7.0 g. of the title compound, m.p. 84°-85.5° C., as pink crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([O:10][C@H:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:23]=2)[CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:19][C:18]1[CH:17]=[N+:16]([O-:20])[CH:15]=[C:14]([Cl:21])[C:13]=1[CH2:12][C@@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:23]=1)[O:10][C:8](=[O:9])[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:38][CH:37]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
A mixture of (S)-4-(2-(4-aminobenzylcarbamoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (190 mg, 0.334 mmol) and TEA (0.102 ml, 0.735 mmol) in DCM (7 ml) was cooled to 0° C., and methanesulfonyl chloride (0.051 ml, 0.669 mmol) was added. The cold bath was removed and the solution was stirred at RT for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude product (218 mg, 0.301 mmol, 90% yield, MS/ESI+ 646.3 [MH]+) was used in the next step without further purification.