Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(SCCOC3C=C(C#N)C=CN=3)=N2)C=CC=CC=1.[C:37]([N:56]1[CH:60]=[N:59][C:58]([O:61][CH2:62][C:63]2[CH:64]=[C:65]([C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]#[N:76])[CH:70]=3)[CH:66]=[CH:67][CH:68]=2)=[N:57]1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:37]([N:56]1[CH:60]=[N:59][C:58]([O:61][CH2:62][C:63]2[CH:64]=[C:65]([C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][NH2:76])[CH:70]=3)[CH:66]=[CH:67][CH:68]=2)=[N:57]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N#Cc1cccc(-c2cccc(COc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2)c1
Agent: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: NCc1cccc(-c2cccc(COc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2)c1

Procedure:
By a method similar to that in Reference Example 20 and using, instead of 2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridine-4-carbonitrile, 3′-{[(1-trityl-1H-1,2,4-triazol-3-yl)oxy]methyl}biphenyl-3-carbonitrile obtained in Reference Example 134, the title compound was obtained as a colorless oil (1.12 mg, 74%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.S1C=CC=C1CC([NH:21][CH:22]1[C:54](=[O:55])[N:24]2[C:25]([C:38]([O:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])=[C:26]([C:29]3[S:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][N:33]=3)[CH2:27][S:28][C@H:23]12)=O.C(O)CCC>ClCCl>[NH2:21][CH:22]1[C:54](=[O:55])[N:24]2[C:25]([C:38]([O:40][CH:41]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])=[C:26]([C:29]3[S:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][N:33]=3)[CH2:27][S:28][C@H:23]12
Reactant: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCCCO
Solvent: ClCCl
Product: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: -40 °C
Yield: 40.6 %

Procedure:
To a suspension of 1.5 g of phosphorous pentachloride in 13 ml of dichloromethane is added 1.2 g of pyridine in 13 ml of dichloromethane under stirring at -40° C. To the resulting mixture is added 1.6 g of benzhydryl 7-thienylacetamido-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate in 32 ml of dichloromethane at -40° C. After stirring for one hour at 0° C., to the reaction mixture is added 6 g of n-butanol under stirring at -40° C. After working up as described in Example 26, the obtained residue is chromatographed on a column of silica gel [eluting with ethyl acetate-dichloromethane (1:1)] to give 0.522 g of benzhydryl 7-amino-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate as pale yellow needles.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][C@@H:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.O.[OH-].[Li+]>C(O)C.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][C@@H:6]2[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: COC(=O)[C@H](C[C@@H]1CCC(F)(F)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(C[C@@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
(R)-2-(3-Chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid methyl ester (224 mg, 0.59 mmol) was dissolved in ethanol (8 mL) and treated with a solution of lithium hydroxide monohydrate (62 mg, 1.47 mmol) in water (2 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC (˜1 hr). The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid (210 mg, 97%) as a mixture of two diastereomers as a clear colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][N:8]([CH:28]2[CH2:30][CH2:29]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([N:17]1[CH2:27][CH2:26][C:19]3([O:23][CH:22]([CH2:24][NH2:25])[CH2:21][O:20]3)[CH2:18]1)[N:10]=2)=[O:5])C.[ClH:31]>O>[ClH:31].[NH2:25][CH2:24][CH:22]1[CH2:21][O:20][C:19]2([CH2:26][CH2:27][N:17]([C:11]3[N:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH2:7][N:8]4[CH:28]4[CH2:29][CH2:30]4)=[CH:13][C:12]=3[F:16])[CH2:18]2)[O:23]1
Reactant: CCOC(=O)C1=Cc2cc(F)c(N3CCC4(C3)OCC(CN)O4)nc2N(C2CC2)C1
Agent: Cl
Solvent: O
Product: NCC1COC2(CCN(c3nc4c(cc3F)C=C(C(=O)O)CN4C3CC3)C2)O1
Reaction time: 2 h

Procedure:
The 0.394 g of the ester from Step 2 was hydrolyzed by the procedure of Step 2 Example 387. The residue was poured into water and conc. HCl was added to adjust the acidity to pH 1. The product was filtered off, stirred in 1:1 methanol/methylene chloride for 2 hours, filtered, and the filtrate dried to afford 0.252 g of the title compound, mp 179°-181° C.; MS (DCl) M/Z 405 (M+H). NMR (TFA/AA) d 1.40 (m, 4H), 4.10 (m, 12H), 8.08 (d, 1H, J=12 Hz), 9.12 (s, 1H). Analysis calculated for C19H22ClFN4O5 ·H2O: C, 47.85; H, 5.50; N, 11.75. Found: C, 48.54; H, 5.12; N, 11.23.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3]>C(Cl)Cl.O=[Mn]=O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2[nH]ccc2c1
Yield: 97.5 %

Procedure:
A solution of 5-methanesulfonyl-indoline (4.11 mmol) and MnO2 (20.55 mmol) in DCM (20 mL) is stirred at rt overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo to afford 5-methanesulfonyl-1H-indole (782 mg, 100%) as a solid. MS: 196 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.09 (s, 3H), 6.71 (s, H), 7.39 (s, H), 7.53 (d, H), 7.74 (m, H), 8.30 (s, H), 8.66 (br, N—H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:2][CH2:3]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: ClCCCN1CCOCC1
Temperature: 70 °C

Procedure:
A mixture of morpholine (52.2 ml), 1-bromo-3-chloropropane (30 ml) and toluene (180 ml) was heated to 70° C. for 3 hours. The solid was removed by filtration and the filtrate was evaporated under vacuum. The resultant oil was decanted from the additional solid which was deposited and the oil was purified by vacuum distillation to yield 3-morpholinopropyl chloride (37.91 g); NMR Spectrum: (DMSOd6) 1.85 (m, 2H), 2.3 (t, 4H), 2.38 (t, 2H), 3.53 (t, 4H), 3.65 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH3:24]
Reactant: CCc1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: CCc1cccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: Cl.O=[C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:16][C:4]1=2>O1CCOCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[CH2:3][C:4]3[CH:16]=[C:15]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:13][C:5]=3[S:6][C:7]=12
Reactant: CC(C(=O)O)c1ccc2sc3ncccc3c(=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1S2
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
A mixture of 3.7 g of zinc, 0.22 g of mercuric chloride, 0.22 ml of concentrated hydrochloric acid and 3.7 ml of water is stirred for 5 minutes, and the aqueous solution is removed by decantation. To the zinc amalgam thus obtained are added 6 ml of dioxane and 6 ml of concentrated hydrochloric acid. 1.5 g of 2-(5-oxo-5H-[1]benzothiopyrano[2,3-b]pyridin-7-yl)propionic acid is added to the mixture with stirring at 50°-60°C over a period of about 15 minutes. The whole mixture is stirred at 60°C for 1 hour. The excess zinc is removed by filtration, and the filtrate is evaporated under reduced pressure. The residue is dissolved in water, and the solution is adjusted to pH 2-3 by addition of 10% sodium hydroxide. The resulting crystalline precipitate is filtered off, and recrystallized from aqueous dioxane to give 0.8 g of 2-(5H-[1]benzothiopyrano[2,3-b]pyridin-7-yl)propionic acid as pale yellowish white crystals melting at 203°-204°C.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-2].[Na+].[Na+].Cl.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[NH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][C:13]([OH:16])=[N:12][N:11]4[C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:23][CH:22]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC1(c2ccc(-c3nc4ccc(O)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-5 (0.25 g, 0.53 mmol) in N-methylpyrrolidone (5 mL) was warmed to 100° C., then sodium sulfide (0.21 g, 2.66 mmol, 5.0 equiv) was added and the mixture was heated to 160° C. for 10 minutes. The resulting mixture was added to ice water (15 mL). The aqueous mixture was made acidic with an aqueous 2 N HCl solution, then was buffered with a saturated aqueous sodium bicarbonate solution. The resulting precipitate was removed by filtration, washed with water, and dried at 50° C. under vacuum to give 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-ol (0.10 g, 53%):
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[NH:22][C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1)[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH2:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[NH:25][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Part B. To a solution of lithium aluminum hydride (0.46 g, 0.012 mol) in dry tetrahydrofuran (15 mL) was added, dropwise, a solution of N-butyl-8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanamide (1.20 g, 0.0027 mol) in tetrahydrofuran (8 mL) and the reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to 0° C. and quenched by the slow and careful sequential addition of water (0.46 mL), 15% sodium hydroxide (1.38 mL), and water (1.38 mL) and then the reaction mixture was stirred at 0° for 30 minutes. The solution was dried over magnesium sulfate and concentrated under vacuum, and the residue was chromatographed with 1:1 hexane-ethyl acetate and then with a gradient of 1:0 to 8:2 to 1:1 ethyl acetate-methanol. The resulting solid was triturated with hexane to give N-butyl-8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanamine (0.45 g, 0.001 mol) as a white solid, mp 75°-78°. 1H NMR (CDCl3) δ7.6-7.1(m,10H), 3.1(t,2H,J=7Hz), 2.5(t,2H,J=7Hz), 1.7-1.0(m,16H), 0.9(t,3H,J=8Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.Cl.C([N:29]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:29])=[O:14])=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
A mixture of 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (0.9 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.95 g), 1-hydroxybenzotriazole (0.67 g) and N,N-dimethylformamide (15 mL) was stirred at 50° C. for 20 min. The mixture was cooled to room temperature, and 10% aqueous ammonium hydroxide solution (2 mL) was added to the mixture. After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. Water was added to the residue and the resulting yellow suspension was filtered to give the title compound (0.66 g, 74%) as a yellow solid. MS 362 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:16][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 79.7 %

Procedure:
Methyl (4S)-4-[(tert-butoxy)carbonylamino]-5-[(4-methylphenyl)sulfonyloxy]pentanoate (4.93 mmol, 1.98 g) was dissolved in DMF (15 mL) and sodium azide (14.8 mmol, 0.961 g) were added. The reaction was heated at 50° C. for 3 hours. The reaction mixture was filtered and the solvent was removed in vacuo. The crude was purified by flash chromatography (SiO2, ethyl acetate) to yield the title compound (1.07 g, 80% yield). ES-MS: 273 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.Cl[C:26]([O:28][CH3:29])=[O:27].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:28][C:26](=[O:27])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)Cl
Reactant: CCCC(CCC)NCCc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(CCC)N(CCc1ccccc1Br)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.85 g of N-[2-(2-bromophenyl)ethyl]heptan-4-amine in solution in 60 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 0° C. 2.76 cm3 of triethylamine are added to the reaction mixture, then 1.52 cm3 of methyl chloroformate are introduced over 10 min using a syringe. The reaction mixture is kept stirring for 1 h at 0° C., then 3 h at 20° C. 20 cm3 of a saturated aqueous solution of ammonium chloride are added, then 100 cm3 of ethyl acetate. The organic phase is washed with 4 lots of 30 cm3 of water, then 30 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered through a pellet (30 g) of silica (particle size: 40-63 μm), rinsed with 50 cm3 of ethyl acetate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 6.4 g of methyl[2-(2-bromophenyl)ethyl](1-propylbutyl)carbamate are obtained in the form of a colorless oil.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]4[CH3:41])[C:25]4[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.C(O)(=O)C>[Pd]>[C:32]([N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])=[N:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:17][CH:18]=3)=[N:27][C:26]=2[CH2:28]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCc2c(nc(-c3ccc(Nc4cccc(OCc5ccccc5)n4)cc3)nc2N2CCOC[C@@H]2C)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCc2c(nc(-c3ccc(Nc4cccc(=O)[nH]4)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound wf: (S)-1-(2-(4-(6-(benzyloxy)pyridin-2-ylamino)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone (0.098 g, 0.00018 mol), Palladium on Carbon 10% (0.1:0.9, Palladium:carbon black, 0.103 g), dry Methanol (5.00 mL, 0.123 mol) and Acetic acid (0.300 mL, 0.00528 mol) were combined under nitrogen then purged with hydrogen, heated at 65° C., and stirred overnight. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 9.13 (s, 1H), 8.21 (d, J=8.6, 2H), 7.78 (s, 2H), 7.42 (t, J=7.9, 1H), 6.32 (s, 1H), 5.99 (s, 1H), 4.71-4.43 (m, 2H), 4.10 (s, 1H), 3.88 (d, J=11.2, 1H), 3.82-3.56 (m, 5H), 3.44 (dd, J=26.9, 16.5, 2H), 2.75 (s, 1H), 2.62 (s, 1H), 2.13 (s, 3H), 1.26 (t, J=5.9, 3H). LC/MS-m/z+461.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29].C([O-])(O)=O.[Na+]>Cl.O.CCO.[Fe]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29]
Reactant: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2N)cc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
Iron (324 mg) and conc. hydrochloric acid (1 drop) was added to a suspension of (R)-N-{2-chloro-3-nitro-4-[4-(N,N-dimethylcarbamoyl)phenyl]sulphonylphenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 63) (305 mg) in water (0.25 ml) and EtOH (1 ml). The mixture was stirred for 1.5 hours at 75° C. and allowed to cool to ambient temperature. Saturated NaHCO3 (10 ml) was added and the solution was extracted with EtOAc (100 ml). The extracts were washed with brine (40 ml) and dried. The volatile material was removed by evaporation. The reaction had not gone to completion, so additional iron (324 mg) and conc. hydrochloric acid (3 drop) was added to a suspension of the residue in water (0.25 ml) and EtOH (1 ml). The mixture was stirred for 3 hours at 75° C. After the mixture was allowed to cool to ambient temperature, saturated NaHCO3 (10 ml) was added and the solution was extracted with EtOAc (100 ml). The extracts were washed with brine (40 ml) and dried. The volatile material was removed by evaporation to give a foam. This was purified by chromatography on silica gel, eluted with 4% MeOH in DCM to give the title compound as a foam (250 mg). NMR: 1.58 (s, 3H), 2.81 (s, 3H), 2.95 (s, 3H), 6.31 (s, 2), 7.60 (m, 3H), 7.81 (d, 1H), 7.96 (m, 3H), 9.73 (brs, 1H), m/z 492.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](O)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:49]([O:51][C:52]([C@@:54]1([NH2:59])[CH2:56][C@H:55]1[CH:57]=[CH2:58])=[O:53])[CH3:50].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:36])[NH:59][C:54]1([C:52]([O:51][CH2:49][CH3:50])=[O:53])[CH2:56][CH:55]1[CH:57]=[CH2:58])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a stirred solution of 4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (48, 3.4 g, 6.20 mmol) in dry DMF (50 mL) was added (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester tosylate (2.23 g, 6.82 mmol) and diisopropylethylamine (2.70 mL, 17.1 mmol). Then, HATU (2.59 g, 6.82 mmol) was added at 0° C. under nitrogen. After 30 min at 0° C., the reaction mixture was successively allowed to warm up to room temperature for 4 h, then diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layers were combined and washed with a saturated solution of NaHCO3, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography (gradient EtOAc/CH2Cl2, 0:1 to 2:8) afforded 3.0 g (70%) of the title product 49: m/z=685 (M+H)+.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)N=C(Cl)[C:14]=12)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:1]=[C:2]([SH:3])[C:14]=12)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Reactant: NC(N)=S
Product: CCOC(=O)c1ncn2c1c(S)nc1ccccc12
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To an ethanolic solution (200 ml) of 4-chloroimidazo [1,5-a]quinoxaline 3-carboxylic acid ethyl ester (4.8 g) was added thiourea (1.5 g). The mixture was heated on steam bath for one hour. After cooling to room temperature, the precipitated product was collected as a yellowish crystalline solid (3.2 g, 67% yield). Recrystallized from methanol-chloroform, m.p. 251°-253° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH2:15][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CCC1CCCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC1CCCC1
Yield: 88.8 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.7 g, 5 mmol) was reacted with 2-cyclopentylacetaldehyde (Betapharma) (0.9 g, 8 mmol) in CH2Cl2 at room temperature for 20 h to give [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 90%).