Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12](=[O:21])[N:13]([CH3:20])[CH:14]=[C:15](B(O)O)[N:16]=3)=[CH:6][C:5]=12.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:40][CH2:39][N:38]3[C:31](=[CH:32][C:33]4[CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][C:37]=43)[C:30]2=[O:43])[C:24]=1[CH:44]=[O:45].C([O-])(=O)C.[K+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:41][C:35]1([CH3:42])[CH2:34][C:33]2[CH:32]=[C:31]3[N:38]([CH2:39][CH2:40][N:29]([C:25]4[C:24]([CH:44]=[O:45])=[C:23]([C:15]5[N:16]=[C:11]([NH:10][C:7]6[CH:8]=[CH:9][N:4]7[CH:3]=[CH:2][N:1]=[C:5]7[CH:6]=6)[C:12](=[O:21])[N:13]([CH3:20])[CH:14]=5)[CH:28]=[CH:27][N:26]=4)[C:30]3=[O:43])[C:37]=2[CH2:36]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cn1cc(B(O)O)nc(Nc2ccn3ccnc3c2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)nc(Nc2ccn3ccnc3c2)c1=O
Temperature: 80 °C
Yield: 29.3 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 185b (400 mg, 1.40 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (192 mg, 0.56 mmol), potassium acetate (220 mg, 2.24 mmol), acetonitrile (20 mL), and water (0.5 mL). After bubbling nitrogen through the suspension for 30 minutes, 1,1′-bis(diphenylphosphino)Ferrocenedichloropalladium(II) (49 mg, 0.054 mmol) was added. The system was subjected to three cycles of vacuum/argon flush and heated at 80° C. for 3 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×20 mL). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1 to 10:1) to afford 185c (90 mg, 29%) as a light yellow solid. MS-ESI: [M+H]+ 549
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:30])[C:26]([OH:29])([CH3:28])[CH3:27])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[CH3:31]I>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:30])[C:26]([O:29][CH3:31])([CH3:28])[CH3:27])[CH2:22][CH2:23]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(O)C(=O)NC1CCC(CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CI
Product: COC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (3 mg, 13.1%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 62 from N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide (20 mg, 47.9 mmol) and methyl iodide.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C([Al](CC)CC)C.[C:20]([C:22]1[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=1)#[N:21]>ClC(Cl)C>[CH3:28][C:23]1[C:22]([C:20](=[NH:21])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1ncccc1C#N
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: CC(Cl)Cl
Product: Cc1ncccc1C(=N)Nc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6.85 g, 0.040 mol) in dichloroethane (400 mL) was added triethylaluminum (1.9M solution in toluene, 32.0 mL, 60 mmol) over 15 minutes at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 3-cyano-2-methylpyridine, from step 2, in 70 mL of dichloroethane was added over 10 minutes and the mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and treated with 50 g of silica gel. The mixture was stirred for 30 minutes and filtered. The filtrate and washings were concentrated under reduced pressure and the residue was washed with ether to give 7.3 g of crude 2-methyl-N-[4-(methylsulfonyl)phenyl]-3-pyridinecarboximidamide (60%). To a mixture of the above crude amidine (7.0 g, 0.024 mol) and sodium bicarbonate (4.0 g, 0.048 mol) in isopropanol (350 mL) was added 3-bromo-1,1,1-trifluoroacetone (6.9 g, 0.036 mol) rapidly at room temperature. After heating the reaction mixture at 75–80° C. for 16 hours, the solvent was removed and the residue was partitioned between water and methylene chloride. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give 4.02 g of pure 2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (25%): mp (DSC) 237–239° C. Anal. Calc'd. for C17H16F3N3O3S: C, 51.12, H, 4.04, N, 10.52, S, 8.03. Found: C, 50.92, H, 4.12, N, 10.04, S, 7.83.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])=O)(C)(C)C.[Li+].[OH-].O1CCOCC1.[ClH:44]>O>[ClH:44].[NH2:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NC(C)(C)C
Temperature: 110 °C

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (334b) (0.27 g, 0.56 mmol), LiOH hydrated (0.12 g, 2.82 mmol), dioxane (3 mL), and water (1 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 3 h. The reaction mixture was acidified with HCl (1 N, 5 mL) and the orange solid obtained was filtered, washed with water, ether, and dried in a vacuum oven at 50° C. for 3 h. The orange solid was suspended in dioxane (2 mL), treated with HCl (2 mL of 4 N in dioxane), and stirred at RT for 4 h. The mixture was concentrated to half of its volume and the orange solid obtained was filtered, washed with ether and dried to give 2-(aminomethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (334c), which was used as crude material and based on theoretical yield.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C=O.O>[N:23]1([CH2:22][CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=Cc1ccccc1O
Reactant: ClCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCN1CCOCC1

Procedure:
Salicylaldehyde (17 g) is treated first with 6.7 g of 50% sodium hydride in 110 ml of dimethylformamide and then with 92 ml of a 2 N toluene solution of N-(3-chloropropyl)morpholine. The mixture is heated at 105°-110° C. for 4 hours, cooled and poured into 300 ml of water. The product is extracted three times with ether. The extracts are combined, dried, concentrated on a rotary evaporator and the residue distilled to give 32.3 g of product as an oil, boiling point 155°-160° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][CH2:23][CH2:24][CH:25](NN)[CH2:26][CH2:27][CH3:28].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH2:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]2)[C:14]1=[O:21])[CH2:23][CH3:22]
Reactant: CCCC(CCC)NN
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCCCCCCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CC=CC[C@@H]2C1=O

Procedure:
Prepared from compound 3 and 4-heptylhydrazine as described for compound 8. Purified by chromatography and crystallized from petroleum ether (60-80° C.) M.p. 71-73° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:17]([CH3:18])=[C:16]([Cl:19])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10](O)=[O:11]>>[Cl:5][C:6]1[C:17]([CH3:18])=[C:16]([Cl:19])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Cl)ccc(OC(C)C(=O)O)c1Cl
Product: Cc1c(Cl)ccc(OC(C)C(=O)Cl)c1Cl
Yield: 106.2 %

Procedure:
Thionyl chloride (17.9 g; 0.15 mole) was added to 12.5 g (0.05 mole) of 2-(2,4-dichloro-3-methylphenoxy)-propionic acid, and the mixture was heated under reflux for 3 hours. The excess of thionyl chloride was distilled off from the reaction mixture to give 14.2 g of crude 2-(2,4-dichloro-3-methylphenoxy)propionyl chloride. A solution of 14.2 g of the crude chloride in 50 ml of diethyl ether was added dropwise to a mixture of 4.65 g (0.05 mole) and 40 g (0.05 mole) of a 5% aqueous solution of sodium hydroxide with stirring over the course of 15 minutes. The mixture was then stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water and dried. Recrystallization from hexane yielded 10.7 g of the desired product as colorless needles. Yield: 66.0%; melting point 147.5 to 148.0° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: CN1CCCC1=O
Product: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 170 °C

Procedure:
A mixture of 4-(3-bromopyridin-2-yloxy)aniline (1.73 g, 6.53 mmol) and 2-chlorobenzoxazole (1.00 g, 6.51 mmol, TCI America) in NMP (3 mL) was sealed in a screw-cap flask and heated at 170° C. for 20 h. The reaction was cooled to rt and partitioned with water/EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→1:2) a tan amorphous solid. MS (ESI, pos. ion) m/z: 382.0, 383.9 (M+1).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Br:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Br:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(Br)cc2C1=O
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2ccc(Br)cc2C1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 9.86 g of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone in 150 ml of anhydrous dichloro-methane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.09 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 1 50 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was recrystallized from ethyl acetate/hexane. 7.5 g (80%) of (RS)-2-(2-oxoethyl)-6-bromo-1-indanone were obtained as a light yellow solid with m.p. 84°.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[N:43]1[CH:48]=[CH:47][N:46]=[CH:45][C:44]=1[C:49](Cl)=[O:50]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:49]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][N:43]=4)=[O:50])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cnccn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnccn2)C3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0493 g, 0.000129 mol) in dry N,N-Dimethylformamide (0.610 mL, 0.00788 mol) was added N,N-Diisopropylethylamine (0.0684 mL, 0.000393 mol) cooled at 0° C., added Pyrazine-2-carbonyl chloride (0.0312 g, 0.000219 mol), warmed to room temperature, and stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.98-8.91 (m, 1H), 8.80 (dd, J=5.3, 2.6, 1H), 8.74 (d, J=1.4, 1H), 8.64 (d, J=12.3, 1H), 8.18 (dd, J=34.9, 8.7, 2H), 7.47 (dd, J=20.0, 8.8, 2H), 6.20-6.09 (m, 1H), 4.75 (d, J=25.1, 2H), 3.88 (t, J=5.0, 1H), 3.79-3.60 (m, 5H), 3.49 (d, J=4.0, 4H), 3.18-3.02 (m, 2H), 2.77 (s, 2H), 1.06 (dd, J=13.3, 7.0, 3H). LC/MS-m/z+489.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:10][NH2:11]>CCO>[NH:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[NH2:11]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Product: N#Cc1ccc(NN)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
To a suspended mixture of 6-chloronicotinonitrile (7 g, 50.8 mmol) in EtOH (50 mL), was added NH2NH2 (10 g, 310.2 mmol). The mixture was stirred at room temperature for 10 min, and then 60° C. for 5 h. The mixture was cooled to room temperature. The solids were filtered out, washed with water and dried under high vacuum to give 6-hydrazinylnicotinonitrile (3.5 g). Compound 6 was prepared from 6-hydrazinylnicotinonitrile following the procedure of the synthesis of compound 4. 1H NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 11.37 (s, 1H), 8.70 (t, J=1.2 Hz, 1 H), 8.14 (s, 1 H), 8.11(dd, J=1.04 and 9.52 Hz, 1 H), 7.96 (dd, J=1.12 and 9.52 Hz, 1 H), 7.61 (dd, J=1.52 and 9.48 Hz, 1 H), 7.38 (d, J=9.0 Hz, 1 H), 1.77 (m, 1 H), 1.06 (m, 2 H), 0.90 (m, 2H) ESI-MS:m/z 377.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([OH:24])[C@H:11]([CH3:25])[O:10][C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30].O>N1C=CC=CC=1>[C:28]([O:24][C@@H:12]1[C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][O:15][CH2:16][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:27])[C:9](=[O:26])[O:10][C@H:11]1[CH3:25])(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To a solution of tert-butyl-(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-ylcarbamate (72 mg, 0.19 mmol) in pyridine (1 mL) at 0° C. was added isobutyryl chloride (80 μL, 0.76 mmol) and the solution was stirred at 0° C. for 2 h. The crude reaction mixture was warmed to room temperature, water (1 mL) was added, and the solution was stirred for 30 min. The reaction mixture was extracted with Et2O (3×) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexanes, TLC Rf=0.5) to furnish (3S,6S,7R,8S)-8-benzyl-3-(tert-butoxycarbonylamino)-6-methyl-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white foam (45 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.31-7.11 (m, 5H), 5.14 (d, J=8.0 Hz, 1H), 5.03 (m, 1H), 4.94 (t, J=9.2 Hz, 1H), 4.66 (d, J=7.7 Hz, 1H), 3.89 (dd, J=11.7, 7.2 Hz, 1H), 3.56 (d, J=10.7 Hz, 1H), 3.46 (m, 1H), 3.35 (dd, J=11.4, 6.8 Hz, 1H), 2.71 (dd, J=13.9, 3.6 Hz, 1H), 2.58 (dt, J=13.9, 7.0 Hz, 1H), 2.25 (t, J=12.6 Hz, 1H), 2.04 (s, 1H), 1.43 (s, 9H), 1.32 (d, J=6.2 Hz, 3H), 1.21 (dd, J=7.0, 0.9 Hz, 6H); ESIMS m/z 471.9 ([M+Na]1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([F:18])=[C:13]([F:17])[C:14]=2[F:16])[C:9](=[O:20])[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7]1.Cl>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([F:18])=[C:13]([F:17])[C:14]=2[F:16])[C:9](=[O:20])[C:8]([C:21]([OH:23])=[O:22])=[CH:7]1
Reactant: CCOC(=O)c1cn(-c2cccs2)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1cccs1
Yield: 95.9 %

Procedure:
Employing ethyl 1-(2-thienyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3-carboxylate (1.05 g), conc. hydrochloric acid (10 ml) and 90% acetic acid (40 ml), the procedure of Reference Example 23 is repeated to give 1-(2-thienyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.93 g), as white powder, m.p. 221°-222.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15](OCC)(=O)[C:16]([NH2:18])=[O:17].C[O-].[Na+]>C(O)CO>[N:1]1[C:2]2=[N:3][C:4]3[C:9]([CH:10]=[C:11]2[C:12](=[O:13])[NH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: NC(=O)c1cc2ccccc2nc1N
Reactant: CCOC(=O)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: OCCO
Product: NC(=O)c1nc2nc3ccccc3cc2c(=O)[nH]1
Temperature: 170 °C

Procedure:
A mixture of 2-aminoquinoline-3-carboxamide (2.0 g., 1.15 millimoles) ethyl oxamate (2.71 g., 23.1 millimoles), ethylene glycol (10 ml.) and sodium methoxide (10 mg.) is heated at 170° C. for 1 hour. The product is precipitated by slow addition of ice methanol (50 ml.) to the hot reaction mixture followed by chilling in an ice bath. It is filtered off, washed with cold methanol and dried in vacuo. Yield = 0.768 g. (28%). M.P. 320° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]#[C:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:18][CH:17]=[C:16]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=3)[N:15]2[CH:39]=1.C(O)(C(F)(F)F)=O.O>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]#[C:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:18][CH:17]=[C:16]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[N:15]2[CH:39]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C#Cc4nc5ccccc5s4)cn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C#Cc4nc5ccccc5s4)cn23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 81c (49 mg, 0.09 mmol) in dichloromethane (4 mL), TFA (1 mL, 13 mmol) was added. The mixture was stirred at rt for 18 h and concentrated under reduced pressure. The oil obtained was dissolved in dichloromethane and water was added. The resultant precipitate was collected by filtration to afford the title compound 11. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 13.18 (s, 1H), 8.60 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.13-8.11 (m, 3H), 7.85 (d, J=8.3 Hz, 2H), 7.66-7.57 (m, 3H), 4.29 (m, 4H), 3.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H20N5O3S: (M+H) 482.1. Found 482.4.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[CH:15]([NH:16][C:17](=[O:27])[CH2:18][S:19]([CH2:22][C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:20])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:29]([S:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)[CH2:30][CH2:31][NH:32][C:33]([NH2:35])=[O:34])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(#N)C>[F:25][C:23]([F:24])([F:26])[CH2:22][S:19]([CH2:18][C:17]([NH:16][CH:15]1[C:14](=[O:28])[N:13]2[C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH:29]([S:36][C:37]3[NH:41][N:40]=[N:39][N:38]=3)[CH2:30][CH2:31][NH:32][C:33]([NH2:35])=[O:34])[CH2:10][S:11][C@H:12]12)=[O:27])(=[O:20])=[O:21]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 3 h

Procedure:
The ester is dissolved in acetonitrile and trifluoroacetic acid is added. The solution is stirred for 3 hours, then evaporated to dryness to give the title compound.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH2:5][CH:6]2[CH2:7][CH2:8][CH:9](/[C:27]/2=[N:28]/[S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[CH2:10][C:11]=1/[CH:12]=[CH:13]/[C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:16]([CH3:26])[N:15]=1>CO>[Cl:3][C:4]1[CH2:5][CH:6]2[CH:27]([NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[CH:9]([CH2:10][C:11]=1/[CH:12]=[CH:13]/[C:14]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:16]([CH3:26])[N:15]=1)[CH2:8][CH2:7]2
Reactant: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)/C3=N/S(=O)C(C)(C)C)cc1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)C3NS(=O)C(C)(C)C)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
Sodium borohydride (0.83 g, 22 mmol) was added portionwise into a stirring solution of the product of Step 4 (5.19 g, 11 mmol) in methanol (150 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at ambient temperature for a further 2 hrs. The reaction mixture was concentrated in vacuo and diluted with water and extracted with ethyl acetate (3×100 ml). The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo to afford N(3-chloro-4-{(E)2-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]vinyl}bicyclo[4.2.1]non-3-en-9-yl)-2-methylpropane-2-sulfinamide (5.71 g, 79%). δH (400 MHz, CDCl3) 1.20-1.27 (9H, m), 1.86-1.91 (2H, m), 2.40-2.50 (1H, m), 2.56-2.67 (4H, m), 3.06-3.18 (1H, m), 3.30-3.39 (1H, m), 3.67-3.77 (2H, m), 3.82 (3H, s), 6.47 (1H, d, J 5.5), 6.63 (1H, d, J 16.0), 7.15 (2H, t, J, 8.5), 7.38-7.42 (2H, m), 7.47 (1H, d, J 16.0).