Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:30]2=[O:57])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[C:30]2=[O:57])=[O:27])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3S(=O)C2)cc1

Procedure:
A solution of 85% pure m-chloroperbenzoic acid (55.22 g) in methylene chloride (600 cc) is added dropwise, in the course of 2 hours, to a solution, cooled to -10° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (or -3-ene) (mixture of the E and Z forms) (180.56 g) in methylene chloride (1.4 liters). The mixture is washed with a 5% strength solution of sodium bicarbonate (1.5 liters) and water (2×1.5 liters), dried over sodium sulphate and concentrated at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa) to a volume of 300 cc. This solution is chromatographed on a column of Merck silica gel (0.05-0.2) (3 kg) (diameter of the column: 9.2 cm; height: 145 cm). Elution is carried out successively with the following mixtures of cyclohexane and ethyl acetate: 80/20 (by volume) (15 liters) and 70/30 (by volume) (32 liters), 600 cc fractions being collected. Fractions 27 and 28 are collected and evaporated and this yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5.56 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:20]1[CH:21]=[C:16]([F:15])[C:17](=[O:23])[NH:18][C:19]1=[O:22])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCCN=C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 3-t-butoxycarbonylaminopropyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° C. and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(3-t-butoxycarbonylaminopropyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[O:14][N:13]=[C:12]([C:15](=[O:17])[CH3:16])[CH:11]=1)(C)(C)C.COC(OC)OC.C([O-])(O)=O.[Na+]>C(O)CO>[OH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15](=[O:17])[CH3:16])[CH:11]=1
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)on1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: OCCO
Product: CC(=O)c1cc(CO)on1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-isoxazol-3-yl]-ethanone (1.99 g, 7.79 mmol) in ethylene glycol (8.69 mL) was treated with trimethylorthoformate (1.71 mL, 15.58 mmol) followed by LiBF4 (146 mg, 1.56 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (2×50 mL). The combined org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (40:60 EA-Hept) gave the title compound as a yellow oil. TLC:rf (40:60 EA-Hept)=0.25. LC-MS-conditions 02: tR=0.54 min.
Reaction SMILES: [CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Mg].II.[C:22](=[O:24])=[O:23].Cl>O1CCCC1.O>[CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCSc1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCSc1ccc(C(=O)O)cc1
Temperature: -70 °C

Procedure:
A solution of 4-(decylthio)bromobenzene (32.9 g) in dry tetrahydrofuran (100 ml) was added over about 30 minutes to a stirred, refluxing suspension of magnesium turnings (2.64 g) and one crystal of iodine in dry tetrahydrofuran (100 ml). The mixture was then stirred at reflux for 2 hours after which it was cooled to -70° C. Carbon dioxide was passed through the stirred solution at -70° C. for about 2 hours. The solution was warmed to room temperature and was then poured into a mixture of ice and water (1.251). Hydrochloric acid was added to bring the pH to 1, the precipitate was collected and washed with water, dried and then crystallized from cyclohexane to yield 4-(decylthio)benzoic acid (20.29 g) in the form of white crystals, m.p. 108°-109° C. [Elemental analysis: C,69.2; H,8.9; S,11.1%; calculated: C,69.34; H,8.9; S,10.88%].
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[Li][CH2:8][CH2:9][CH2:10]C.CCCCCC.BrCC#C.OS([O-])(=O)=O.[K+]>C1COCC1>[O:5]=[C:4]1[NH:6][CH2:1][CH2:2][N:3]1[CH2:10][C:9]#[CH:8]
Reactant: O=C1NCCN1
Reactant: [Li]CCCC
Agent: C#CCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCN1CCNC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a suspension of ethylene urea (2.0 g, 23.2 mmol) in THF (80 mL) was added dropwise 1.47 N n-BuLi in hexane (15.8 mL, 23.2 mmol) at room temperature. 3-Bromopropyne (2.0 mL, 22.4 mmol) was added and the mixture was stirred for 30 min at room temperature then for 2 h at 50° C. Aqueous 5% KHSO4 was added and the mixture was extracted with ethyl acetate. The Organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 1:1 to 0:1 hexane/ethyl acetate to give the title compound (641 mg, 22%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=O)C.[OH-].[Na+].[ClH:34]>C(Cl)Cl.CO.CO>[ClH:34].[OH:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccsc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 66 %

Procedure:
To a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (200 mg, 0.45 mmol) in methylene chloride/methanol (1/1) (20 ml) was added, a 2M aqueous sodium hydroxide solution (0.67 ml , 1.35 mmol). The mixture was stirred for 35 minutes at ambient temperature, the solvents were evaporated, water was added to the residue and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, then dried (MgSO4) and evaporated to give a white solid. This solid was then dissolved into a saturated solution of hydrochloric acid in methanol (10 ml) and stirred for 10 minutes. The solid product was filtered and dried under a vacuum, to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline hydrochloride (127 mg, 66%). m.p. 246-248° C. 1H NMR Spectrum: (DMSOd6) 2.15(s, 3H); 3.98(s, 3H); 5.32(s, 2H); 6.98(dd, 1H); 7.10(s, 1H); 7.14(d, 1H); 7.25(d, 1H); 7.40(s, 1H); 7.61(dd, 1H); 7.70(d, 1H); 8.12(s, 1H); 8.74(s, 1 H); 9.60(s, 1H) MS−ESI: 394 [MH]+
Reaction SMILES: C(O[N:5]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:55]([C:65]([OH:67])=O)[C:54]([CH:68]([CH3:70])[CH3:69])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:42])=[O:41])[CH:36]=[CH2:37]>>[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:59])[C@H:55]([C:65](=[O:67])[NH2:5])[C:54]([CH:68]([CH3:70])[CH3:69])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:41])=[O:42])[CH:36]=[CH2:37]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 43.7 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (0.260 g, 43.7%) was prepared a similar manner as described in Intermediate 83 as a pale yellow oil, using (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 93, 0.595 g, 1.13 mmol) as a starting material.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[CH:35]=[N:34]2)[CH:21]=[CH:22][C:23]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.Cl>C(OCC)C.C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[CH:35]=[N:34]2)[CH:21]=[CH:22][C:23]=1[C:24]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)([OH:32])[C:14]1[S:15][CH:16]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1
Reactant: c1ccc(-c2cscn2)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1cnn(-c2ccc(C(O)(c3ccc(Cl)cc3)c3nc(-c4ccccc4)cs3)c(Cl)c2)c(=O)[nH]1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 10.6 %

Procedure:
n-Butyl lithium (0.045 mol) was added at −70° C. under N2 flow to a solution of 4-phenyl-thiazole (0.045 mol) in diethyl ether (50 ml). The mixture was stirred at −70° C. for 90 minutes. A solution of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione (0.015 mol) in THF (10 ml) was added at −70° C. The mixture was stirred at −70° C. for 1 hour, then poured out into ice water, neutralized with HCl 3N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH2Cl2/CH3OH 98/2). The desired fraction was repurified by HPLC (eluent: CH3OH/(NH4OAc 1% in H2O) 80/20). The pure fractions were collected and the solvent was evaporated, yielding 0.83 g (11%) of (±)-2-[3-chloro-4-[(4-chlorophenyl)hydroxy(4-phenyl-2-thiazolyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (interm. 71).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C)ccc4N3)c2)cc1
Yield: 31.9 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 4-methyl-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 16 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 67 mg of 4-methyl-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 32%). MS (ESI+APCI) M+1=421.2.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH2:3][C:4]2[N:8]=[CH:7][NH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ClCc1nc[nH]n1
Reactant: C1CCNCC1
Agent: Cl
Product: c1nc(CN2CCCCC2)n[nH]1

Procedure:
3-Chloromethyl-1,2,4-triazole hydrochloride (0.5 g.) was added to piperidine (10 ml.) and the mixture was heated at 100° for 16 hours, then evaporated to dryness. The residue was dissolved in water (10 ml.) and basified with sodium bicarbonate. The resulting solution was evaporated to dryness and the residue was extracted twice with ethanol (50 ml.). The combined extracts were evaporated to dryness and the residual gum was subjected to MPLC on K60 silica gel using methanol/chloroform, 3/97 v/v, as solvent to give 3-(piperidinomethyl)-1,2,4-triazole with NMR data as follows: solvent--CDCl3 : 8.05 ppm (singlet, 1H), 3.75 ppm (singlet, 2H), 2.5 ppm (multiplet, 4H) and 1.6 ppm (multiplet, 6H).
Reaction SMILES: O1C=CC=N1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: c1cnoc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)-isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:30]2[CH2:35][CH2:34][N:33]3[N:36]=[C:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH:38]=[C:32]3[C:31]2=[O:44])=CC=1>O.C(#N)C>[O:44]=[C:31]1[NH:30][CH2:35][CH2:34][N:33]2[N:36]=[C:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH:38]=[C:32]12
Reactant: COc1ccc(CN2CCn3nc(COC(C)=O)cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1cc2n(n1)CCNC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
A solution of ammonium cerium (IV) nitrate (0.7 g, 1.29 mmol) in water (1.1 mL) was added to a stirred solution of acetic acid 5-(4-methoxy-benzyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (142 mg, 0.43 mmol) in ACN (4.3 mL). The mixture was stirred at room temperature for 30 minutes and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield acetic acid 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (56 mg, 62% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:13]([CH3:14])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:33][C:29]2[CH:28]=[C:27]3[C:32]([C:24]([C:22]([NH:21][CH3:20])=[O:23])=[C:25]([CH3:35])[N:26]3[CH3:34])=[CH:31][CH:30]=2)[CH:8]=1)=[O:12]
Reactant: CN(C)CCN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)CCN(C)C)sc34)ccc12
Yield: 14.9 %

Procedure:
This material was prepared by the reaction of 7-chloro-N-[2-(dimethylamino)ethyl]-N-methylthieno[3,2-b]pyridine-2-carboxamide 29a (0.167 g, 0.56 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.123 g, 0.56 mmole) and Cs2CO3 (0.182 g, 0.56 mmole) in a manner as previously described for example 1 to give a yellow solid (0.040 g, 13%). 1H NMR (400 MHz, CD3OD) δ 8.71 (1H, d, J=6.8 Hz), 8.06 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.46 (1H, d, J=2.0 Hz), 7.09 (1H, d, J=6.8 Hz), 7.05 (1H, dd, J=2.0, 8.6 Hz), 3.90 (2H, t, J=5.8 Hz), 3.64 (3H, s), 3.42 (2H, t, J=5.8 Hz), 3.23 (6H, s), 2.93 (3H, s), 2.88 (3H, s), 2.58 (3H, s). HRMS (MH+): Calcd: 480.2090. Found: 480.2069.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@@H:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C@@H:45]([NH2:52])[CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@@H:29]5[CH2:30][CH2:31][CH2:32][N:28]5[CH3:27])=[N:34][N:35]=4)[CH:38]=3)[CH2:44]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 33a (190 mg, 0.454 mmol), Intermediate 37a (132 mg, 0.378 mmol) and DIPEA (132 μL, 0.756 mmol) in anhydrous DMF (3 mL) was stirred at 100° C. for 3 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give an off-white solid after freeze-drying (143 mg, 61%). LCMS (Method 5): Rt 3.23, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.22 (9H, s), 1.95-1.97 (3H, m), 2.07 (3H, s), 2.20-2.23 (3H, m), 2.52-2.53 (1H, m), 3.10 (1H, m), 3.92 (1H, t, J 8.1), 4.51 (2H, d, J 5.6), 5.25-5.27 (2H, m), 5.83 (1H, d, J 5.8), 6.25 (1H, s), 6.99 (1H, d, J 7.9), 7.18 (1H, dd, J 9.9, 2.2), 7.24-7.32 (2H, m), 7.35-7.41 (6H, m), 7.67 (1H, d, J 9.9), 8.10 (1H, s), 8.20 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C#N)c1ccc(Br)cc1Cl
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (2.85 g, 11.0 mmol) in anhydrous THF (60 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (6.1 mL, 12.1 mmol). The reaction mixture is stirred at this temperature 10 min., then N-methoxy-N-methyl-acetamide (2.34 mL, 22.0 mmol) is added neat and the solution is stirred 10 min. at −78° C. and then warmed up to room temperature for another hour. Acidic brine (60 mL) is then slowly added and the solution is extracted with EtOAc (3×60 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 1:0 to 7:3) to provide the expected product 2-(4-acetyl-2-chlorophenyl)-2-methylpropanenitrile (1.57 g, 64%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.96 (1H, d, J=1.9 Hz), 7.81 (1H, dd, J=8.3, 1.9 Hz), 7.55 (1H, d, J=8.3 Hz), 2.56 (3H, s), 1.85 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:8]([CH:12]=O)=[CH:9][S:10][CH:11]=1)=[O:5])[CH3:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH3:26][C:24]([CH3:27])([O:23][C:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][CH2:12][C:8]2[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][S:10][CH:9]=2)[CH2:20][CH2:19]1)=[O:22])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)Nc1cscc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1cscc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of 28.2 g (0.142 mol) of 4-(ethoxycarbonyl-amino)-thiophene-3-carboxaldehyde, 28.2 g (0.141 mol) of 4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine and 300 ml of toluene was refluxed using a water separator until water formation had ceased. The solvent was removed in vacuo, the residue was dissolved in 300 ml of methanol and at room temperature combined batchwise with 5.5 g (0.145 mol) of sodium borohydride. The mixture was stirred for a further hour at room temperature, then evaporated down in vacuo and the residue was distributed between water and tert. butyl-methylether. The organic phase was dried over sodium sulphate and freed from solvent in vacuo. The oily residue was further processed without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 30.0 gm (0.176 mole) of o-chlorophenylacetic acid and 40.0 mL of thionyl chloride was stirred at ambient temperature for 18 hours. The volatiles were then removed in vacuo to give 32.76 gm (99.0 %) of o-chlorophenylacetyl chloride as a transparent, pale yellow, mobile liquid.