Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:37]=[C:31]4[C:30]([CH3:29])=[CH:35][C:34]([CH3:36])=[CH:33][N:32]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1cnc(N)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Yield: 14.7 %

Procedure:
500 mg (1.13 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 137.5 mg (1.13 mmol) 3,5-dimethyl-pyridin-2-yl-amine and molecular sieves (4 Å, dried over night at 120° C. in a drying oven) were heated in 10 mL ethanol in a Dean-Stark apparatus for 23 hours. The reaction mixture had been sucked off via a glass fibre filter and evaporated to dryness. The residue was redissolved in dichloromethane, washed with an 1 M hydrochloric acid, saturated sodium bicarbonate and brine and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 142.6 mg (25.8%) of the pure title compound and 77.5 mg (14.7%) of the title compound which was slightly contaminated.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[N:4]([CH2:9][C:10]([O:12]C)=[O:11])[N:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[N:4]([CH2:9][C:10]([OH:12])=[O:11])[N:3]=1
Reactant: COC(=O)Cn1nc(C)n(C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(CC(=O)O)c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
593 mg of methyl (3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate (Va-6) are dissolved in 5 ml of tetrahydrofuran, and 134 mg of lithium hydroxide in 2 ml of water are added. The mixture is stirred at room temperature for 16 hours, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 167 mg of (3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetic acid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CN(C)C=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CN(C)C=O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 168 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of dimethyl formamide. The stirred mixture is heated to reflux (168° C.) and held 15 minutes; then cooled to about room temperature. Then 150 ml 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried overnight in a vacuum oven. There is obtained 11.4 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 81.2% pure, or a 59.7% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([O:13][CH2:24][O:25][CH3:26])([CH3:11])[CH3:12]
Reactant: COCCl
Reactant: Cc1cc(F)c(C(C)(C)O)c(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(C)(C)c1c(F)cc(C)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of 2-(2-bromo-6-fluoro-4-methylphenyl)propan-2-ol (12 g, 48.56 mmol) in DCM (120 mL) and diisopropylethylamine (6.9 g, 53.42 mmol) in DCM (120 mL) was added dropwise chloromethylmethylether (4.3 g, 53.42 mmol) at 0° C. under argon and the mixture was then stirred at rt for 15 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give 1-bromo-3-fluoro-2-(2-(methoxymethoxy)propan-2-yl)-5-methylbenzene (10 g, 70.73% yield) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 6.71-6.75 (m, 1H), 4.54 (s, 2H), 3.33 (s, 3H), 2.20 (s, 3H), 1.72 (d, J=5.2 Hz, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:27]4[CH:28]=[CH:29][C:24]([C:22]([NH:21][CH3:20])=[O:23])=[CH:25][CH:26]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Yield: 68.7 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 0.300 g, 0.777 mmol) and 4-(methylcarbamoyl)phenylboronic acid (0.174 g, 0.971 mmol) according to the procedure described for Example 94, Step A. Purified by trituration from hot MeOH to obtain the product (210 mg, 96%) as a brown solid. LRMS (APCI pos) m/e 394 (M+1).
Reaction SMILES: C([N:8]1[C:20]2[C:19]([CH3:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:18]1[C:19]([CH3:21])=[C:20]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([F:37])=[CH:13][C:14]=4[C:15]3=[CH:16][C:17]2=1
Reactant: Cc1c2c(cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c13)c1cc(F)ccc1n2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Yield: 89 %

Procedure:
A solution of 5,7-diBOC-2,10-difluoro-6-methylindolo[2,3-b]carbazole (4.45 g, 8.8 mmol) was stirred with a solution of 20% trifluoroacetic acid in dichloromethane (100 mL) at room temperature for two hours. The solvents were evaporated and the residue dissolved in ethyl acetate (200 mL). This was washed with saturated sodium bicarbonate solution (100 mL) and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel, eluting with a gradient of dichloromethane and hexane (50% dichloromethane to 100% dichloromethane) to give 2,10-difluoro-6-methyl-5,7-dihydro-indolo[2,3-b]carbazole (2.4 g, 90% yield). 1H NMR (300 MHz) (DMSO-d6) δ 11.05 (2H, s, —NH), 8.67 (1H, s, arom), 7.89 (2H, dd, J=9.5, 2.6 Hz, arom), 7.43 (2H, dd, J=8.9, 4.4 Hz, arom), 7.17 ppm (2H, dt, J=9.5, 2.6 Hz, arom) and 2.70 ppm (3H, s, —CH3).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[C:20]([O:22][CH3:23])=[O:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[CH:9]([CH2:10][CH2:11]2)[CH2:8][CH:7]=[CH:6][CH2:5]1.[CH:25](=O)[CH2:26][CH:27]([CH3:29])[CH3:28].[BH4-].[Na+]>CO>[CH3:28][CH:27]([CH3:29])[CH2:26][CH2:25][NH:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[C:20]([O:22][CH3:23])=[O:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][CH:7]=[CH:6][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4CC=CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.5 h

Procedure:
Methyl 11α-amino-androst-2-ene-17β-carboxylate (1.46 g) was dissolved in methanol (20 ml) and isovaleraldehyde (1.29 ml) was added in three portions. After stirring for 1 h at room temperature sodium borohydride (0.45 g) was added in several portions to avoid excessive gas evolution and the reaction mixture was stirred for 1/2 h. The methanol was removed at reduced pressure and the residual gum was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with M--H2SO4, water and saturated brine, dried and concentrated to about 15 ml. Petrol was added to incipient cloudiness and the solution was allowed to crystallise to give the title compound (1.15 g), m.p. 150°-152° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]1=2>CN(C=O)C.C1(C)C=CC=CC=1>[S:5]1[C:9]([C:10]([Cl:3])=[O:11])=[CH:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2s1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
The Benzo[b]thiophene-2-carbonyl chloride was prepared by adding toluene (2 mL), DMF (2 drops) and thionyl chloride (50 μL) to benzo[b]thiophene-2-carboxylic acid. Heating the mixture to reflux for 5 hours followed by removal of the solvent afforded the crude product, which was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:36]=[S:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(N3CCSCC3)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(N3CCS(=O)CC3)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
20.1 mg (0.0515 mmol) of the 7-thiomorpholin-4-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 104 was dissolved in 2.3 ml of methylene chloride, and 9.8 mg (0.0566 mmol) of m-chloroperbenzoic acid was further added to the solution. The obtained mixture was stirred at 0° C. for 2 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 16.6 mg (79%) of 7-(1-oxothiomorpholin-4-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH:15]=[CH2:16].C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH2:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH:15]=[CH2:16]
Reactant: C=CCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (3.5 g, 1.78×10-2 mol) and 2-(allylthio)-2-methylpropanal (3.85 g, 2.67×10-2 mol, 150 M%) were dissolved in 200 ml methanol. Glacial acetic acid (2.05 ml, 3.56×10-2, 200 M%) and sodium cyanoborohydride (3.36 g, 5.35×10-2 mol, 300 M%) were then added. The reaction was stirred at room temperature for 18 hr, then 100 ml 0.5 M HCl was added and the mixture was extracted with 2×100 ml diethyl ether. The combined organic extracts were washed with 100 ml saturated NaHCO3, then with 100 ml saturated NaCl. The ether layer was dried over anhydrous Na2SO4, and the solvent was removed on the rotary evaporator. The crude product (6.7 g) was purified by filtration through a 600 ml sintered glass funnel filled silica bed, using 95% hexane/diethyl ether as the eluting solvent to give 4 g (70% yield) of 1-(2-allylthio-2-methylpropylamino)-2-(2-mercapto-2-methylpropylamino]benzene as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: COC[C@H](C)OC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
Sodium hydride (23.17 mg, 0.58 mmol) was added in one portion to a stirred solution of (S)-2-hydroxy-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y3) (78 mg, 0.29 mmol) in anhydrous THF (5 mL) at 0° C. The resulting mixture was stirred for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (115 mg, 0.43 mmol) in dry THF (2 mL) added dropwise over 1 minute and the reaction was allowed to warm up to ambient temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (115 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 1.20 (d, 3H), 2.53 (s, 3H), 3.35-3.50 (m, 5H), 3.79-3.88 (m, 1H), 4.08-4.16 (m, 1H), 4.21-4.28 (m, 1H), 5.94-5.99 (m, 1H), 7.43-7.55 (m, 3H), 7.60-7.63 (m, 1H), 8.12-8.13 (m, 1H), 8.40 (s, 1H), 8.58 (s, 1H), 9.18 (s, 1H), 9.42 (d, 1H). m/z (ESI+) (M+H)+=498.36; HPLC tR=2.25 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[O:17]=[C:18]1[NH:23][CH:22]=[C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:20]=[CH:19]1>>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:28]([C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:20]=[CH:19][C:18](=[O:17])[NH:23][CH:22]=5)=[CH:32][CH:31]=4)=[O:29])[CH2:13][CH2:12]3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: Clc1nccc2[nH]c(C3CCNCC3)cc12
Product: O=C(c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CCC(c2cc3c(Cl)nccc3[nH]2)CC1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part K, but with 4-chloro-2-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine and 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoic acid as starting materials. Purification was by flash column chromatography on silica gel. 1H NMR (d4-MeOH) δ 7.99 (dd, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.66-7.63 (m, 2H), 7.54-7.50 (m, 2H), 7.30 (dd, 1H), 6.65 (d, 1H), 6.41 (s, 1H), 3.96-3.84 (m, 1H), 3.45-3.05 (m, 4H), 2.22-2.01 (m, 2H), 1.92-1.71 (m, 2H). ESI MS (M+1)+: 433, 435 (Cl).
Reaction SMILES: O=C1O[C:5]([CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=O)([C:7]([F:10])([F:9])[F:8])[N:4]=C1C(C)C.Cl.[NH2:24]N.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:5]1[CH2:11][CH2:12][C:13](=[O:15])[NH:24][N:4]=1
Reactant: NN
Reactant: CC(C)C1=NC(CCC(=O)OC(C)(C)C)(C(F)(F)F)OC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(C(F)(F)F)=NN1

Procedure:
8.44 g (26.1 mmol) of tert-butyl 3-[5-oxo-4-(propan-2-yl)-2-(trifluoromethyl)-2,5-dihydro-1,3-oxazol-2-yl]propanoate [CAS Reg. No. 87341-14-8] and 13.44 g (130.5 mmol) of hydrazine hydrochloride were stirred in 100 ml of glacial acetic acid at 118° C. for 2 hours. The reaction solution was then evaporated to dryness under reduced pressure. The residue obtained was taken up in 100 ml of water and made basic using potassium carbonate. The basic solution was subsequently extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified chromatographically on silica gel (mobile phase dichloromethane/methanol 50:1→10:1). This gave 2.65 g (15.95 mmol, 61% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22](O)=[O:23])[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)=[O:23])[CH3:21])=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 5-amino-2-oxindole (800 mg, 5.4 mM) and N-tert-butoxycarbonylalanine (1020 mg, 5.4 mM) in dichloromethane (50 ml) were added benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (2800 mg, 5.6 mM) and N-methylmorpholine (1.2 ml, 11 mM). The mixture was stirred for 15 h at room temperature. Then the solvent was evaporated under vacuum, the residue suspended in water and extracted 3 times with ethyl acetate. The collected extracts were evaporated and then purified by flash chromatography on silica gel using as eluant cyclohexane/ethylacetate 1:9. Thus pure 5-(N-tert-butoxycarbonylalanylamino)-2-oxindole was obtained (600 mg). A solution of the above compound (250 mg, 0.97 mM) in trifluoroacetic acid (15 ml) was maintained for 1 h at room temperature. Then the solution was concentrated under vacuum and ether added to precipitate 5-(alanylamino)-2-oxindole.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]1=[O:11].[Br:12]N1C(=O)CCC1=O>CN(C)C=O.ClCCl>[Br:12][C:4]1[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: Cn1cc([N+](=O)[O-])ccc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc([N+](=O)[O-])cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution containing 0.55 g (3.57 mmol) of 1-methyl-5-nitropyridin-2(1H)-one in 10 ml of N,N-dimethylformamide under a nitrogen atm. was added 0.76 g (4.27 mmol) of N-bromosuccinimide. The reaction was allowed to stir at 25° C. overnight. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 70% ethyl acetate/hexanes gave 0.60 g (72.15%) of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:39])[C:30]3[CH:35]=[CH:34][C:33]4[O:36][CH2:37][O:38][C:32]=4[CH:31]=3)[CH2:25][CH2:24]2)[N:3]=1>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:39])[C:30]3[CH:35]=[CH:34][C:33]4[O:36][CH2:37][O:38][C:32]=4[CH:31]=3)[CH2:25][CH2:24]2)[N:3]=1
Reactant: Nc1nc(Cc2ccc(OCc3ccccc3)cc2)cc(C2CCN(C(=O)c3ccc4c(c3)OCO4)CC2)n1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1nc(Cc2ccc(O)cc2)cc(C2CCN(C(=O)c3ccc4c(c3)OCO4)CC2)n1
Yield: 54.3 %

Procedure:
2-Amino-4-(4-benzyloxyphenylmethyl)-6-[1-(3,4-methylenedioxybenzoyl)-4-piperidinyl]pyrimidine (570 mg, 1.09 mmol) was dissolved in acetic acid (5 ml) and hydrogenated under 1 atm in the presence of 10% palladium on carbon (360 mg) for about 3.5 hours. The catalyst was filtered off. The filtrate was poured into aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (chloroform:methanol=97:3) to give the titled compound (256 mg) as a foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][S:10][C:9]1=[N:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-:17].[NH4+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][S:10][C:9]1=[N:13][C:14](=[O:17])[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN=C1SCCN1Cc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Product: NC(=O)N=C1SCCN1Cc1ccccc1

Procedure:
6.36 g (50 moles) of 3-benzyl-2-cyanimino-thiazolidine are boiled with 80 ml of a 10% hydrochloric acid for 10 minutes. A clear solution is obtained, which is cooled down and alkalized with a 25% aqueous ammonium hydroxide solution to yield 5.65 g of 3-benzyl-2-carbamoylimino-thiazolidine, melting at 143° to 145° C. After crystallization from ethanol the melting point is raised to 148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23](OC(C)=O)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:23](=[O:24])[CH3:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(4-Fluoro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.8 g; 9.51 mmol; 1 eq.) was dissolved in DCM (30 mL) and Ac2O (2.2 mL; 23.77 mmol; 2.5 eq.) was added. DMAP (1.51 g; 12.36 mmol; 1.3 eq.) was introduced and the reaction was stirred overnight (approx. 18 hours) at room temperature. The solution was diluted with DCM (150 mL) and washed with 1N HCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum to provide the product as an oil. The crude product was used without further purification. LC/MS M/Z 337.3, Retention time=2.95 minutes; 10-99% CH3CN/H2O gradient with 0.05% TFA). H NMR (400 MHz, CDCl3) δ7.16-7.05 (m, 4H), 4.77 (tt, J=12.2 Hz, 3.8 Hz, 1H), 4.13 (d, J=7.1 Hz, 2H), 2.81 (t, J=12.4 Hz, 2H), 1.82-1.73 (m, 2H), 1.77 (s, 3H), 1.41 (s, 9H), 1.26-1.16 (m, 2H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:25][CH:22]1[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC3CC3)c2)N1C

Procedure:
6.6 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of cyclopropyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. Fair yellow crystals, melting point: 180° C. (decomposition).