Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]1.[Mg]>CO>[N:10]1[CH:11]=[CH:12][C:7]([C@H:4]2[CH2:5][CH2:6][N:1]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:2][C@H:3]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1=C(c2ccncc2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Mg]
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccncc1

Procedure:
To a MeOH solution (0.2 M) of 1-(1,1-dimethylethyl) 3-ethyl 5,6-dihydro-4,4′-bipyridine-1,3(2H)-dicarboxylate (1 eq.) from the previous step was added magnesium turnings (3 eq.). The suspension was evacuated and back-filled with N2. Finally, the reaction mixture was sonicated at RT for 2 h during which the magnesium turnings disappeared. The reaction was then quenched with the addition of EtOAc and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a golden yellow oil.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:31]([CH:34]=[CH2:35])(=[O:33])=[O:32])[CH2:4]1)[CH3:2].CCN(C(C)C)C(C)C.[NH:45]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[N:46]1>C(O)CC.C(Cl)Cl>[C:50]([C:48]1[CH:49]=[N:45][N:46]([CH2:35][CH2:34][S:31]([NH:30][C@@H:5]2[CH2:6][C@H:7]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:3]([CH2:1][CH3:2])[CH2:4]2)(=[O:32])=[O:33])[CH:47]=1)#[N:51]
Reactant: C=CS(=O)(=O)N[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Reactant: N#Cc1cn[nH]c1
Solvent: ClCCl
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](NS(=O)(=O)CCn2cc(C#N)cn2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A mixture of N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethenesulfonamide (0.065 g, 0.13 mmol, prepared using K.1 from Example #8 Step M and 2-chloroethanesulfonyl chloride with TEA), DIEA (0.30 mL, 1.7 mmol) and 1H-pyrazole-4-carbonitrile (0.047 g, 0.51 mmol, American Custom Chemicals Corp) in n-PrOH (2.0 mL) was stirred for about 2 h at about 60° C. then at about 80° C. for about 18 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude residue was dissolved in DCM (10 mL), washed with saturated NaHCO3 (5 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide (0.024 g, 42%): LC/MS (Table 1, Method b) Rt=1.63 min; MS m/z: 454 (M+H)+.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:7][C:4]2[CH:3]=[CH:2][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3ccccc3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 72.3 %

Procedure:
To a solution of biphenyl-4-amine (338 mg, 2 mmol) in 10 mL of dry pyridine followed by 529 mg of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. After drying over Na2SO4, solvent was removed in vacuo. The crude product (0.79 g) was obtained as a glass which slowly crystallized. Addition of hexane caused complete solidification. The solid was taken up in EtOAc (11 mL), diluted with hexane (11 mL) and seeded to give 534 mg of white needles. The product had mp 171-173° C.
Reaction SMILES: Cl.CO.[CH2:4]([C@:8]12[CH2:16][CH2:15][C@@H:14]3[C:17]4[CH2:18][CH:19]=[C:20]([O:25]C)[CH2:21][C:22]=4[CH2:23][CH2:24][C@H:13]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[OH:27])[CH:5]([CH3:7])[CH3:6]>O>[CH2:4]([C@:8]12[CH2:16][CH2:15][C@@H:14]3[C@@H:17]4[C:22]([CH2:23][CH2:24][C@H:13]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[OH:27])=[CH:21][C:20](=[O:25])[CH2:19][CH2:18]4)[CH:5]([CH3:7])[CH3:6]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
Add to a mixture of concentrated hydrochloric acid (4.8 cc.), water (3.2 cc.) and methanol (.72 cc. ) 13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17β-ol (2.0 g.). Heat the resulting solution on a steam bath for 30 minutes with stirring. Cool to room temperature, dilute the solution with water (160 cc.) and extract with ether. Wash the ethereal solution with water, sodium bicarbonate, and water, dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to give a gum. Recrystallize from ethyl acetate to obtain the title compound (0.8 g., 43%, m.p. 124.0°-125.5°; ultraviolet absorption peak at 240 mμ (ε18,200).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(#N)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH:18]([CH3:20])[CH3:19])#[N:2]
Reactant: CC(C)N
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CC#N
Product: CC(C)NC(=NC#N)NC1CCCc2ccccc21
Reaction time: 154 h

Procedure:
A solution of 30.0 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 40 ml of isopropylamine in 300 ml of acetonitrile was heated at reflux with stirring for 154 hours. The solvent and excess isopropylamine were removed by evaporation in vacuo, leaving the crude product as a tacky, white solid. Crystallization from isopropyl acetate followed by a recrystallization from a mixture of isopropyl acetate and 2-propanol gave 5.13 g of N"-cyano-N-isopropyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 170.5°-172.5° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13](C(N=[N+]=[N-])=O)=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Na+].C[N:30](C=O)C>>[NH2:30][C:13]1[N:12]=[CH:11][C:10]([O:22][CH3:23])=[C:9]2[C:14]=1[CH2:15][CH2:16][N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]2=[O:24]
Reactant: COc1cnc(C(=O)N=[N+]=[N-])c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cnc(N)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.33 h

Procedure:
To a solution of sodium azide (0.24 g, 3.69 mmol) in water (2.5 mL) was added 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl chloride (1.17 g, 3.36 mmol) in acetone (15 mL). After 20 minutes, the product mixture was concentrated under vacuum to provide 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl azide. The crude azide (1.19 g, 3.35 mmol) in DMF (20 mL) was heated to 110° C. After 20 minutes, the product mixture was cooled for 10 minutes, then 1N NaOH (3.3 mL) was added. After 20 minutes, the mixture was concentrated under vacuum, re-dissolved in toluene and CHCl3 and evaporated. The residue was partitioned between CHCl3 and saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C)=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][OH:48])=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Yield: 85.8 %

Procedure:
A sol. of compound E1 (7.93 g, 9.45 mmol) and TBAF (1.0 M in THF, 14.5 mL, 14.5 mmol) in THF (115 mL) was stirred at 0° C. for 1 h. The mixture was diluted with EtOAc (115 mL) and was then washed with brine (4×115 mL). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→1:1→3:2→7:3) yielded the title compound (5.54 g, 76%). LC-MS: tR=1.08 min, ES+: 683.27.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][C:4]=1[C:5](OC)=[O:6].C[CH2:18][N:19](CC)CC.CN.CCO.Cl>CO.CCOC(C)=O>[Cl:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][N:19]([CH3:18])[C:5]2=[O:6])=[CH:12][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1CBr
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CN1Cc2cc([N+](=O)[O-])c(Cl)cc2C1=O
Temperature: 70 °C
Yield: 76.6 %

Procedure:
To methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (617 mg, 2 mmol) in methanol (18 mL) was added Et3N (0.34 mL, 2.4 mmol) and methylamine in EtOH (0.3 mL, ˜d 8 M in EtOH, 2.4 mmol). The mixture was heated to 70° C. for 3 h. and then EtOAc (30 mL) and 2M HCl(aq) (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-10% methanol in DCM) gave 6-chloro-2-methyl-5-nitroisoindolin-1-one (347 mg, 77%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=227 at 2.89 min. 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.90 (s, 1H), 4.46 (s, 2H), 3.24 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: Cc1c(F)cc(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(C)c(I)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
3-Fluoro-5-iodo-4-methylbenzoic acid (1.3 g, 4.6 mmol, 1 eq) was dissolved in Methanol and treated with conc. Sulphuric acid (0.49 ml, 9.2 mmol, 2 eq). The above solution was stirred at 50° C. for 15 h. Later on solvent was removed and to the resulting residue diethylether was added and the organic layer was washed with 10% sodium bicarbonate solution and water. Finally, the organic layer was concentrated and purified by flash silica gel column chromatography using 240-400 silica gel and using 10% EtOAc in hexane as the eluent. Yield: 1 g (77%). 1HNMR (400 MHz CDCl3). δ 2.39 (s, 3H), 3.90 (s, 3H), 7.64 (d, 1H, J=8 Hz), 8.25 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:20][C:18]1([CH3:21])[CH2:17][O:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:19]1
Reactant: [H][H]
Reactant: CC1(C)COC(c2ccc(OCc3ccccc3)cc2)=N1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)COC(c2ccc(O)cc2)=N1
Yield: 95 %

Procedure:
To a solution of 2-(4-benzyloxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole ax4 (4.0 g, 140 mmol, 1 eq) in ethanol (200 ml) is added 1.5 g of 10% Pd/C (1.42 mmol, 0.1 eq). The mixture is stirred for 48 h at room temperature, under 40 psi of a hydrogen atmosphere. The mixture is then filtered on celite and the solvent removed under vacuum. The residual solid is triturated in hexane to give 2.6 g of 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenol ax7.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:51])=[C:8]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:29]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:30]=4[C:31]([CH3:48])=[CH:32][N:33]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[C@H:20]([CH3:28])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[NH4+].[OH-].[OH-].[K+]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:51])=[C:8]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:29]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:30]=4[C:31]([CH3:48])=[CH:32][NH:33]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[C@H:20]([CH3:28])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(C)(=O)=O)[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3cccc4[nH]cc(C)c34)nc(N3CCN(S(C)(=O)=O)[C@H](C)C3)c2C1
Temperature: 100 °C

Procedure:
A mixture of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (52 mg, 0.080 mmol), prepared in a manner similar to that described in Example 25, methanesulfonyl chloride (0.01 mL, 0.096 mmol) and DIEA (0.042 mL, 0.240 mmol) in DCM (3 mL) was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc, washed successively with sat NaHCO3, and brine, dried over Na2SO4 and concentrated. The resulting residue was purified via FCC (5-50% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 727.4 (M+H)+. To a solution of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.055 mmol) in MeOH (4 mL), NH4OH (0.325 mL, 8.25 mmol) and KOH (27.8 mg, 0.495 mmol) was added. The mixture was heated in a microwave reactor 100° C. for 1 h. The mixture was then filtered and concentrated. The resulting residue was purified via FCC (0-45% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (d, J=2.02 Hz, 1 H) 7.40-7.43 (m, 1 H) 7.24 (dd, J=7.33, 1.01 Hz, 1 H) 7.09-7.16 (m, 3 H) 7.02 (d, J=1.26 Hz, 1 H) 6.87 (dd, J=7.83, 1.26 Hz, 1 H) 4.03-4.16 (m, 3 H) 3.70-3.84 (m, 2 H) 3.56 (d, J=12.88 Hz, 1 H) 3.33-3.42 (m, 2 H) 3.23-3.28 (m, 1 H) 3.14 (dd, J=12.88, 3.54 Hz, 1 H) 2.92-3.06 (m, 6 H) 2.79-2.90 (m, 1H) 2.22 (s, 3 H) 2.03 (s, 3 H) 1.32 (d, J=6.82 Hz, 3 H) 1.19 (dd, J=6.95, 1.89 Hz, 6 H); MS (ESI+) m/z 573.4 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=[NH:12].[N+:14]([C:17]1[CH:28]=[CH:27][C:20]([CH:21]=[CH:22][S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[CH:22][S:23]([NH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[NH:13])(=[O:25])=[O:24])=[CH:27][CH:28]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Reactant: N=C(N)c1ccc2ccccc2c1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc2ccccc2c1

Procedure:
Reaction of β-naphthamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)-β-NAPHTHAMIDINE, m.p. 180°-182.5° C., by triturating with isopropanol.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2].N[C:24]1[CH:25]=C2C(=C[CH:32]=1)NC(CCC(C)C)=C2>>[CH3:32][CH:24]([CH3:25])[CH2:2][CH2:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2
Reactant: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1
Reactant: CC(C)CCc1cc2cc(N)ccc2[nH]1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c(CCC(C)C)cc3c2)cc1

Procedure:
Refer to 45a) using 5-amino-2-(3-methyl-n-butyl)indole.
Reaction SMILES: C1COCC1.[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9].[N:13]1([C:19]2[N:20]=[CH:21][C:22]3[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:23]=3[N:24]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(N(CC)CC)C>[CH2:6]([NH:10][C:11]([CH:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:19]1[N:20]=[CH:21][C:22]2[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:23]=2[N:24]=1)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CN1C(=O)Cc2cnc(N3CCNCC3)nc21
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCNC(=O)C1CNCCN1c1ncc2c(n1)N(C)C(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
THF (30 ml), 1 ml of triethylamine and 0.43 g (4.34 mmoles) of n-butyl isocyanate were added to 0.5 g (2.14 mmoles) of 2-piperazino-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo[2,3-d]pyrimidine, and the mixture was stirred at room temperature for 3 hours. It was concentrated under reduced pressure, and after addition of water, extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue purified by silica gel column chromatography to give 0.15 g (yield 21%) of the desired product.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(OC([CH2:15][NH:16][CH2:17][C:18]([O:20][CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1)=[O:19])=O)(C)(C)C>C(OCC)(=O)C>[ClH:7].[CH3:15][NH:16][CH2:17][C:18]([O:20][CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1)=[O:19]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)CNCC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)CNC)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A 4N hydrogen chloride ethylacetate solution (1 ml) was added to an ethyl acetate solution (2 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (tert-butoxycarbonylmethylamino)acetate (100 mg, 0.19 mmol) and stirred at room temperature for 3 hours. The deposited insoluble matter was collected by filtration, washed with acetone, and then dried, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl methylaminoacetate hydrochloride (78.3 mg, yield: 88%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ncc1N
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COc1ccc(F)c(-c2cc(C)c(N)cn2)c1
Yield: 76 %

Procedure:
Obtained (1.225 g, yield 76%) following the procedure described in Intermediate 27, starting with 6-chloro-4-methylpyridin-3-amine (7.01 mmol, 1.000 g), 2-fluoro-5-methoxyphenylboronic acid (7.01 mmol, 1.191 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CCCCC1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a 20 mL scintillation vial equipped with a stirring bar and a septum screw cap, a solution of 3-piperidin-1-yl-propan-1-ol (0.500 g, 3.49 mmol) in DCM (5 mL) was cooled down to 0° C. Then, triethylamine (10 eq.) was added to the vial via a syringe followed by a solution of methanesulfonyl chloride (5 eq.) in DCM (1 mL). The resulting reaction mixture was allowed to slowly warm up to room temperature and stirring was maintained for additional 2 h. The volatiles were removed in vacuo and the resulting crude methanesulfonic acid 3-piperidin-1-yl-propyl ester was used in the next step of the synthesis without further purification (the material was found to contain 30% of the title compound by weight according to 1H NMR).
Reaction SMILES: [CH2:1]([CH2:7][C:8]([NH2:10])=[S:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:11]([NH:10][C:8](=[S:9])[CH2:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=S)CCc1ccco1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NC(=S)CCc1ccco1)c1ccccc1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
12.11 g (0.07 mol) of 2-furfurylthioacetamide was dissolved in 30 ml of pyridine. To the above solution, 9.94 g (0.07 mol) of benzoylchloride was added, and the mixture was stirred at 60° C. for 15 hours. The solvent was distilled away from the reaction mixture, and a residue thus obtained was added to ethyl acetate and washed successively with water twice, 1N hydrochloric acid, water three times, and brine. A resultant organic extract layer was dried, and the solvent was distilled away therefrom.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][N:13]([CH3:15])[CH2:12][C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(O)C>[OH:16][CH:11]1[CH2:12][N:13]([CH3:15])[CH2:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][CH:7]=2)=[CH:10]1
Reactant: Cc1ccc(C2=CC(=O)CN(C)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: Cc1ccc(C2=CC(O)CN(C)C2)cc1
Reaction time: 2 h
Yield: 58.5 %

Procedure:
A solution of 1,6-dihydro-5-(4-methylphenyl)-1-methyl-3[2H]pyridone hydrochloride (18 g) in 50% aqueous ethanol (500 ml) was treated with sodium bicarbonate (6.4 g) followed by sodium borohydride (4 g) in portions. After 2 hours, the solvent was removed under reduced pressure and the residue extracted with ether (2×250 ml). Drying (MgSO4) followed by removal of the solvent under vacuum gave an oil which crystallised and was recrystallised from pentane to give the title compound (9 g) m.p. 67°-69°.