Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][NH:1][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)NCc1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of 4-(aminomethyl)benzonitrile (5.0 g, 0.038 moles) in 100 mL chloroform is added 3.82 g (0.038 moles) triethylamine. A solution of nonanoyl chloride (6.68 g, 0.038 moles) in 10 mL chloroform is then added dropwise with stirring over a 10 min period and the final mixture stirred at room temperature for 18 hrs. The mixture is extracted with water (100 mL), saturated NaHCO3 (50 mL), 2N HCl (50 mL), dried over Na2SO4 and evaporated to leave 10.2 g crude N-(4-cyanobenzyl)nonanamide. This crude product is taken up in 50 mL dimethylformamide, to which is added 2.47 g (0.038 moles) sodium azide and 2.03 g (0.038 moles) ammonium chloride. The final mixture is heated at 90°-110° C. for 4 hrs after cooling, the mixture is diluted with water (350 mL) and the resultant precipitate recovered by suction filtration, washed with water, and vacuum dried. Recrystallization from ethyl acetate left N-[[4-(1H-tetrazol-5-yl)phenyl]methyl]nonanamide (2.6 g), m.p. 185°-187° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH:19](OC)OC)[CH3:18]>>[CH:1]1([CH2:4][C:5](=[O:15])/[C:6](/[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:16]\[N:17]([CH3:19])[CH3:18])[CH2:3][CH2:2]1
Reactant: CSc1nccc(CC(=O)CC2CC2)n1
Reactant: COC(OC)N(C)C
Product: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Yield: 69.2 %

Procedure:
A solution of 1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2) (216.3 mg, 0.973 mmol) in DMF-DMA (1303 μl, 9.73 mmol) was stirred at 80° C. for 2 hours. The reaction was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [25 g ISOLUTE column, 100% DCM to 10% MeOH/DCM] to obtain the desired product as a orange-yellow solid (186.8 mg, 69.2% yield). MS (ES+): m/z=278.2/279.2 (100/50) [MH+]. HPLC: tR=0.99 minute over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].N>Cl>[Br:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[CH:8]=1)[N:4]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: C/C=C/C=O
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Agent: N
Product: Cc1ccc2cc(Br)cc(F)c2n1
Yield: 46.8 %

Procedure:
2-Fluoro-4-bromoaniline (10 g, 0.053 mol) was slurried in 6M HCl (100 ml). The mixture was heated to reflux and crotonaldehyde (14.9 g, 0.212 mol) was added dropwise over 1 hour. The resulting mixture was heated for an additional 90 minutes, then cooled down to room temperature and neutralized by careful addition of concentrated ammonia solution. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 15-10% ethyl acetate/petrol. The product containing fractions were combined and concentrated to ca 60 ml. The product was then isolated by filtration. The filter cake was washed with petrol and air dried to afford the title compound as a solid (5.96 g, 47% yield). 1H NMR (CDCl3, 400 MHz) 2.80 (3H, s), 7.38 (1H, d), 7.53 (1H, d), 7.76 (1H, s), 8.00 (1H, d); MS (ES+) 240/242.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][NH2:38]>>[OH:1][CH:3]([CH2:4][NH:38][CH2:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1CCN
Reactant: COc1cc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2cc1OC
Product: COc1ccccc1CCNCC(O)COc1ccc(-c2nc3cc(OC)c(OC)cc3c(=O)n2C)cc1

Procedure:
This compound was prepared analogous to Example 2 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one and 2-(2-methoxy-phenyl)-ethylamine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cn1)cc(-c1cc(NC(=O)c3ccccc3)ccc1C)c(=O)n2C
Temperature: 65 °C

Procedure:
N-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)benzamide A6 (70 mg, 0.17 mmol) is treated with sodium methoxide (0.8 mL of a 0.5 M solution in methanol) and heated to 65° C. for 3 h. The reaction is cooled to rt and partitioned with EtOAc and aqueous ammonium chloride. The organic layer is washed with brine, dried over magnesium sulfate, filtered and solvent removed. Crude product is dissolved in DMF (1 mL) and purified by preparative LCMS to afford the desired product. 1H NMR 400 MHz (MeOD) δ 8.56 (s, 1H), 7.92 (d, J=8 Hz, 2H), 7.88 (s, 1H), 7.64-7.46 (m, 5H), 7.28 (d, J=8 Hz, 1H), 6.84 (1H), 4.05 (s, 3H), 3.71 (s, 3H), 2.20 (s, 3H); MS m/z 400.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>CN(C)C=O>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: FC(F)(F)c1cccc(CBr)c1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cccc(C(F)(F)F)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 35.8 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-trifluoromethyl-benzyl bromide (75 μL, 0.49 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3-trifluoromethyl-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (64 mg, 36%) as an off-white solid. APCI-MS (M+H) 365.
Reaction SMILES: [C:1]([C:3]([C:17]#[N:18])=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)#[N:2].Cl.[CH3:20][NH:21][CH3:22].NC1C=CC=CC=1>>[C:17]([C:3]([C:1]#[N:2])=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][C:8]([N:21]([CH3:22])[CH3:20])=[O:10])#[N:18]
Reactant: CNC
Reactant: N#CC(C#N)=C(CCCC(=O)O)c1ccccc1
Agent: Cl
Solvent: Nc1ccccc1
Product: CN(C)C(=O)CCCC(=C(C#N)C#N)c1ccccc1

Procedure:
The desired product was prepared by substituting 6,6-dicyano-5-phenyl-5-hexenoic acid (prepared by substituting 5-oxo-5-phenylpentanoic acid for Example 1A in Example 1B) and dimethylamine hydrochloride for Example 66B and aniline, respectively, in Example 66C. MS (ESI(−)) m/e 266 (M−H)−.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.[OH:21]O>C(O)(=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11](=[O:21])[C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1
Reactant: c1ccc2c(c1)CCc1ccc(-c3nnn[nH]3)cc1S2
Reactant: OO
Solvent: CC(=O)O
Product: O=S1c2ccccc2CCc2ccc(-c3nnn[nH]3)cc21

Procedure:
A mixture of 600 mg. of 10,11-dihydro-3-(5-tetrazolyl)dibenzo[b,f]thiepin, 25 cc. acetic acid and 5 cc. 30% hydrogen peroxide is stirred for 6 hours. The suspended solid is filtered, washed with acetic acid, then water and dried to yield 575 mg. of pure material, m.p. 278° C. dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=2)[N:7]=1)=[O:5])C.[Li+].[OH-].O>C1COCC1>[C:11]1([C:9]2[N:8]([C:17]3[CH:18]=[CH:19][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:21][CH:22]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cc1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of compound 3b (0.37 g, 1 mmol) in THF (10 mL) was added LiOH (35 mg, 1.5 mmol) followed by 2 mL of water at room temperature. The reaction mixture was stirred overnight. The reaction was quenched by adding 1N HCl. The solvent was evaporated in vacuo. The resulting white solids were collected by suction filtration and washed with water. The crude product was recrystallized from MeOH to give the titled compound (0.33 g, 96% yield) as a white solid. mp 188.5-190.9° C. 1H NMR (300 MHz, DMSO-d6): δ 13.10 (s, 1H), 7.87 (d, J=8 Hz, 2H), 7.55-7.48 (m, 4H), 7.44-7.37 (m, 3H), 7.34-7.26 (m, 2H), 7.10 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:11]([O:18][N:19]=[CH:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCc1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C(Cc1ccccc1)=NOCc1ccccc1
Yield: 85.3 %

Procedure:
A mixture of 5 g of phenylacetaldehyde, 6.7 g of O-benzylhydroxylamine hydrochloride, and 3 g of potassium carbonate in 30 ml of aqueous methanol (1:1) was refluxed for 2 hours. The aqueous solution was extracted with ethyl acetate and the organic solution was dried and evaporated to give 8 g of crude product which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:26]CC)[C@@H:9]([CH3:10])[C@H:8]([NH:11][C:12](=[O:14])[CH3:13])[C:7]([C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:6]([CH3:25])[O:5]1)[CH3:2]>O1CCCC1.Cl.O>[CH3:10][CH:9]([CH:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]([C:15](=[O:24])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:6](=[O:5])[CH3:25])[C:4]([O:3][CH2:1][CH3:2])=[O:26]
Reactant: CCOC1(OCC)OC(C)=C(C(=O)Nc2ccc(Cl)cc2)[C@@H](NC(C)=O)[C@@H]1C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(NC(C)=O)C(C(C)=O)C(=O)Nc1ccc(Cl)cc1

Procedure:
Trans-2,2-diethoxy-3,6-dimethyl-4-acetylamino-5-(4'-chlorophenylcarbamoyl)-3,4-dihydro-2H-pyran (76.5 g) (Example 18) was stirred at room temperature in a mixture of tetrahydrofuran (200 ml) and 1N hydrochloric acid (10 ml) for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate and the organic extract dried in anhydrous magnesium sulphate and evaporated to dryness. The residual solid was triturated with diethyl ether to give ethyl 2-methyl-3-acetylamino-4-(4'-chlorophenylcarbamoyl)-5-oxohexanoate, 66 g, m.p. 169°-73° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: C1COCCN1
Product: COc1cc(N2CCN(C(=O)CN3CCOCC3)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), and morpholine (575 μL, 6.60 mmol, 10.00 equiv). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone (24): HPLC retention time, 0.32 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 353.9, found, 354.5.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:15]=[C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:24])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[S:4][N:3]=1.[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:15]=[C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:24])[CH:13]=[CH:12][C:9]=2[C:10]([NH2:11])=[O:31])[S:4][N:3]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-(3-methylisothiazol-5-ylamino)-4-(2-oxoazepan-3-ylamino)benzonitrile (143 mg, 0.263 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 3 h. HOAc (1 mL) was added. The mixture was then purified by HPLC to give the titled compound (72 mg). MS 360.3 (M+H); UV 202.1, 300.7 nm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:23])[N:9]=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:23])[N:9]=1
Reactant: Cn1nc(NC(=O)OC(C)(C)C)c(Cc2cccc(Cl)c2Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(N)c(Cc2cccc(Cl)c2Cl)c1O
Yield: 64.3 %

Procedure:
To a solution of tert-butyl(4-(2,3-dichlorobenzyl)-5-hydroxy-1-methyl-1H-pyrazol-3-yl)carbamate (15 g, 40 mmol) in DCM (150 mL), TFA (10 mL) was added dropwise at room temperature with stirring. The reaction mixture was stirred at room temperature overnight. Then the pH of the reaction mixture was adjusted to 10 with aq. Na2CO3, and extracted with DCM (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (7 g, 63%), as a white solid; LC/MS: MS (ES+) m/e 272 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.90 (s, 3H), 3.45 (s, 2H), 6.06 (s, 2H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 8.95 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (11.2 g, 0.052 mol) in anhydrous DMF (40 mL) and anhydrous dioxane (40 mL) was added, dropwise, bromoacetyl bromide while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~25 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice water. The precipitate which formed was filtered, washed with water, and then dried in a vacuum oven for 20 h at 40°-45° C., affording 9.9 g (57%) of the title compound: mp 203°-204° C.; 1H NMR (CDCl3) δ11.67 (s, 1H, NH), 8.64 (d, 1H, J=8.8), 8.55 (d, 1H, J=2.4), 7.71 (dd, 1H, J=2, J=6.8), 3.72 (s, 2H ); 13C NMR (CDCl3): 200.55, 138.06, 134.22, 134.20, 122.06, 107.46. 67.08; MS (EI, m/z) 337 (M+). HRMS (EI) calcd for C9H7NO3Br2 334.8792, found 334.8791.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH2:24][CH3:25])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)(=[O:22])=[O:21])=[C:16]([CH2:24][CH3:25])[CH:15]=1
Reactant: Cn1ncc2cc(CN)ccc21
Reactant: CCc1cc(Br)ccc1S(=O)(=O)Cl
Product: CCc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from (1-methyl-1H-indazol-5-yl)methanamine and 4-bromo-2-ethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:17]1[C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[NH:20][CH:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:1]1([NH:7][C:8]([N:24]2[CH2:25][CH2:26][C:21]3([N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:18](=[O:34])[CH:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:20]3)[CH2:22][CH2:23]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CCC2(CC1)NC(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C

Procedure:
Phenyl isocyanate (0.16 ml, 1.49 mmol) was added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (502 mg, 1.49 mmol) in toluene (12.4 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. After removal of the solvent, the desired product 1,3-dibenzyl-2-oxo-1,4,8-triaza-spiro[4,5]decane-8-carboxylic acid phenylamide was obtained by means of preparative HPLC.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]4[C:15](=[O:25])[N:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:18][S:19][CH2:20][CH:13]4[C:12]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([N:16]1[C:15](=[O:25])[CH:14]2[CH:13]([C:12]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:9]3[C:10]4[CH:11]=[C:2]([C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)[C:3]([O:31][CH3:32])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]32)[CH2:20][S:19][CH2:18][CH2:17]1)([CH3:23])([CH3:22])[CH3:24]
Reactant: COc1cc2c(cc1Br)C1=C(c3cccs3)C3CSCCN(C(C)(C)C)C(=O)C3N1CC2
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)C1=C(c3cccs3)C3CSCCN(C(C)(C)C)C(=O)C3N1CC2

Procedure:
A mixture containing 20 mg of 9j, 6 mg of pyridine-3-boronic acid and 10 mg of K2CO3 and 6 mg of Pd(PPh3)4 in 2 ml of degassed 90% aq. dimethoxyethane was heated under N2 for 16 h. The reaction mixture was cooled and diluted with water. The product was extracted with ethyl acetate. The extract was dried, concentrated and the residue was purified by chromatography over silica gel, using heptane/acetone as eluent. The isolated product was treated with ether/ethyl acetate (9/1 v/v) to give 14 mg of white crystalline 9k; Rf 0.50 (heptane/acetone 1/1);
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1([CH2:18][OH:19])[CH2:17][CH:16]=[CH:15][CH2:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:19][CH2:18][CH:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC=CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Nitrobenzoyl chloride (3.46 g, 18.7 mmol) was added to a dichloromethane solution (34 mL) of cyclopent-3-en-1-ylmethanol (1.67 g, 17.0 mmol) and triethylamine (3.55 mL, 25.4 mmol). The solution was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate solution was added, and the solution was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CHCl3) δ 2.21 (dd, J=4.9, 14.8 Hz, 2H), 2.57 (dd, J=8.6, 15.1 Hz, 2H), 2.71-2.82 (m, 1H), 4.28 (d, J=7.2 Hz, 2H), 5.69 (s, 2H), 8.19 (d, J=8.6 Hz, 2H), 8.27 (d, J=8.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>CC(O)=O.O.[Fe]>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1cc(Br)ncc1N
Reaction time: 6 h

Procedure:
A solution of 2-bromo-N-isopropyl-5-nitropyridin-4-amine (intermediate 258, 4.5 g, 16.61 mmol) in HOAc (59 ml) was added dropwise to a mixture of iron powder (3.75 g, 66.4 mmol) in HOAc (59 ml) at 70° C. After stirring vigorously for 6 h, the reaction mixture was diluted with H2O and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 80 g RediSep® silica column and purified by normal phase chromatography, eluting with a gradient from 5% to 100% EtOAc/heptanes. Product-containing fractions were combined and evaporated to give the title compound as a brown solid. (UPLC-MS 6) tR 0.56; ESI-MS 230.0/232.0 [M+H]+.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]1[CH2:9][CH:10]([CH3:12])[CH3:11])=O.[P:13]([OH:16])([OH:15])[OH:14].P(Cl)(Cl)Cl>O>[CH2:9]([CH:4]1[CH2:5][S:6][CH2:7][CH2:8][N:3]1[CH:1]([P:13](=[O:14])([OH:16])[OH:15])[P:13](=[O:16])([OH:15])[OH:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CC1CSCCN1C=O
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CC(C)CC1CSCCN1C(P(=O)(O)O)P(=O)(O)O
Temperature: 100 °C

Procedure:
A mixture of N-formyl-3-isobutyl-thiomorpholine (18.7 g) and phosphorous acid (16.4 g) was heated at 100° C. for 2 hours. Phosphorus trichloride (30 ml) was added dropwise with stirring, and after reflux for 3 hours water (180 ml) was added slowly. The mixture was refluxed for 1 hour and filtered. Evaporation of the filtrate gave a residue which was triturated with ethanol to yield a crystalline compound which was isolated by filtration. M.p.: 237°-238° C. (dec.).