Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH2:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH:23]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccccc5S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
[8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.074 g, 62%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 m (d, J=6.6 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H), 7.29-7.25 (m, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.73 (s, 1H), 6.57 (d, J=8.2 Hz, 1H), 3.24-3.19 (m, 4H), 2.96 (s, 3H), 2.59-2.54 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:30]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OO
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:22])=[O:21]
Reactant: OCC(Cc1ccccc1)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(Cc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 15.8 parts of β-(2,4-dichlorophenyl)benzene-propanol, 12.15 parts of methanesulfonyl chloride, 50 parts of pyridine and 70 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated. The residue is triturated in methanol. The product is filtered off and crystallized from ethanol, yielding 7.28 parts of β-(2,4-dichlorophenyl)benzenepropanol methanesulfonate; mp. 87.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[O:10])=[C:4]([CH:11]=[O:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[O:10])=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=CNc1ccc(Br)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C=O)c1ccc(Br)cc1C=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To 4-bromo-2-formylphenylformamide (18.07 g), ethyl 4-bromobutyrate (30.9 g) and potassium carbonate (21.9 g) was added DMF (160 ml), and the mixture was stirred at 70° C. for 24 hours. The mixture was dilute with ethyl acetate (1400 ml), washed with water (300 ml×3) and saturated brine (150 ml), and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (300 g, hexane:ethyl acetate=4:1→1:1) to give ethyl 4-(4-bromo-2,N-diformylanilino)butyrate (21.56 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:17]=[C:16]([NH2:18])[N:15]=[CH:7]2
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ncc2cc(Cl)ccc2n1
Yield: 50 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzaldehyde (109) (5 g, 31.6 mmol) and guanidine carbonate (7.5 g, 41.1 mmol) was heated at 140° C. in DMA (50 mL) for 3 h. 100 ml water was added and after refrigeration, a solid was isolated by filtration, and dried under vacuum to give the product (110) (2.8 g, 15.8 mmol, 50% yield). ESI-MS (M+1): 180 calc. for C8H6ClN3 179.
Reaction SMILES: Br[CH:2]([CH:5]=O)[CH:3]=[O:4].C([O-])(=O)C.[Na+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]2[S:28][C:2]([CH:3]=[O:4])=[CH:5][N:29]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Yield: 56 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 78 mg (0.5 mmol) bromomalonaldehyde, 82 mg (1 mmol) sodium acetate and 131 mg (0.5 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated. The reaction was diluted with water and extracted twice with ethyl acetate and twice with methylene chloride/methanol 9/1. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was stirred diethyl ether to yield 88 mg (56%) of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde as a yellow solid. MS ISP (m/e): 315.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=11.35 (br s, 1H), 9.80 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.33 (d, 1H), 7.07 (s, 1H), 3.82 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15](OCC)=[O:16])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C([Mg]Cl)(C)C>C1COCC1>[CH3:24][O:23][N:22]([CH3:21])[C:15]([C:10]12[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:14][CH2:13]1)[CH2:8][CH2:9]2)=[O:16]
Reactant: CNOC
Reactant: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C12CCC(c3ccccc3)(CC1)CC2
Temperature: -20 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a mixture of ethyl 1-phenylbicyclo[2.2.2]octane-4-carboxylate (Intermediate 4; 15 g, 58.06 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.87 g, 89.99 mmol) in anhydrous THF (130 mL) cooled to −20° C. was added isopropylmagnesium chloride (2M solution in THF; 87 mL) dropwise over 30 mins maintaining the internal temp at −10° C. The mixture was stirred at −10° C. for 1 hr and then quenched by adding 20% ammonium chloride solution. The mixture was extracted into EtOAc (2×200 mL), the organic phase was separated and dried and evaporated to leave a white solid. This was purified on a 330 g Crawford silica cartridge, loading in DCM and eluting with 20-40% EtOAc-isohexane, to provide the title compound as a white solid (8.66 g, 31.67 mmol, 55%); 1H NMR (CDCl3) δ 1.75-1.90 (6H, m), 2.01-2.06 (6H, m), 3.19 (3H, s), 3.70 (3H, s), 7.15-7.20 (1H, m), 7.28-7.36 (4H, m); GC-MS EI+ m/e 243 (M−CH2O), MH+ not seen
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23][C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:21][C:22](=[O:31])[CH2:23]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: O=C1CNc2ccccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(=O)Nc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (105 mg) and 3,4-dihydro-1H-quinoxalin-2-one (R. E. TenBrink et al., J. Med. Chem., 1994, 37, pp. 758-768) (267 mg) in dimethylformamide (0.75 mL) was heated at 140° C. for 45 hours. The resulting mixture was poured into water and extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 30% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (67.8 mg), m.p. 69° C.-71° C.
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])[CH2:3][N+:4]([O-:6])=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[N+:4](/[CH:3]=[CH:2]/[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-:6])=[O:5]
Reactant: N#Cc1cccc(C(O)C[N+](=O)[O-])c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(/C=C/[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(1-Hydroxy-2-nitroethyl)benzonitrile (3.32 g, 17.3 mmol) and triethylamine (4.37 g, 43.2 mmol) were stirred in anhydrous dichloromethane (100 mL) at 0° C. To the resulting solution was added methanesulfonyl chloride (2.77 g, 24.2 mmol) dropwise via syringe, after which time the reaction was warmed to ambient temperature and stirred for 15 min. The resulting reaction mixture was diluted with additional dichloromethane (200 mL) and partitioned with H2O (100 mL). The dichloromethane layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was filtered through silica gel eluting with hexane:EtOAc (4:1) to afford 3-[(E)-2-nitroethenyl]benzonitrile as a yellow solid.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:37]=[C:38]=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:38]([NH:37][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 125 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-octyl isocyanate (1.55 g; 10 mmole). Recrystallization from methanol/ethanol/water provided the title compound (3.1 g; 62% yield) as colorless crystals, m.p. 229°-230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>CCO>[CH3:17][O:16][N:18]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95.5 %

Procedure:
7-Nitro-tetralone (1.00 g, 5.23 mmol) was suspended in EtOH (10 mL), cooled by an ice water bath and treated with methoxylamine hydrochloride (0.52 g, 6.23 mmol) and sodium bicarbonate (0.57 g, 6.78 mmol). The mixture was stirred at room temperature for 1 h before ice water (50 mL) was added. A precipitate formed which was filtered off to give a white solid (1.10 g, 95% yield). This solid contained two geometric isomers in a ratio of 7:1. It was dissolved in CCl4 /CHCl3 and flash chromatographed over silica gel (50 g) elutlng with EtOAc/hexane (1:20) to afford the major isomer as a white solid. It was recrystallized from hot EtOAc to give colorless crystals (556 mg): mp 128-131° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:7]1([C:5](=[O:6])[CH2:4][CH2:3][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]2=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCCC1
Reactant: CN(C)CCC(=O)c1ccccc1
Product: O=C(CCC1CCCCC1=O)c1ccccc1
Yield: 39.9 %

Procedure:
2-(3'-Phenyl-3'-oxopropyl)cyclohexanone was prepared accordinf to the method of W. Hahn and J. Epsztain (Roozniki Chem. 1963, 37, 403-12): A mixture of β-dimethylaminopropiophenone (27 gm.) and cyclohexanone (37.5 g.) were heated at reflux for 5 hours under nitrogen and the solvent removed in vacuo. The residual oil was distilled giving 2-(3'-phenyl-3'-oxopropyl)cyclohexanone (14 g.) which was cyclised to the title compound according to the method of Hahn and Epsztain by dissolving the diketone (12 g.) in ethanol (65 ml.), treating with hydroxylamine hydrochloride (9 g.) and heating under reflux for 1 hour. The cooled reaction mixture was poured onto water (300 ml.), extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was made basic with K2CO3 and extracted with ether (3 × 50 ml.). The combined ether extracts were dried and the solvent removed in vacuo. The residual oil was distilled to give the title compound as a colourless oil (7 g.) b.p. 134°-8° C/15 mm. Found: C, 85.40; H.7.5; N, 6.9%, C15H15N requires: C, 86.00; H, 7.2; N, 6.7%
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:12]([CH3:13])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Cl)c1C(=O)O
Product: Cc1nc2cccc(Cl)c2c(=O)o1
Temperature: 120 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
2-amino-6-chlorobenzoic acid (25 g) dissolved in acetic anhydride (100 ml) was stirred at 120° C. for 2 hours. The mixture was cooled to room temperature and filtered off. The precipitate was washed with water and Na2CO3 (10%) and dissolved in CH2Cl2. The solution was dried with Na2SO4, filtered off and evaporated. The residue was crystallized twice from benzene, yielding 13 g (46%) of 5-chloro-2-methyl-4H-3,1-benzoxazin-4-one; mp. 148.7° C. (interm. 14).
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C:7]2[O:11][CH:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]\1=2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.Cl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][N:2]=[C:3]2[C:8]3[C:9]([C:12]([OH:14])=[O:13])=[CH:10][O:11][C:7]=3[CH2:6][CH2:5][CH2:4]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=C(O)c1coc2c1/C(=N/O)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCCc3occ(C(=O)O)c32)cc1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a partial solution of 2.8 g of (E)-4,5,6,7-tetrahydro-4-(hydroxyimino)-3-benzofurancarboxylic acid in 7 ml of pyridine is added portionwise at 0° C., 3.01 g of p-toluene sulfonyl chloride under argon. The mixture is stirred for 1 hour then diluted with 40 ml of cold 1N HCl, filtered, washed with water and dried with Na2SO4. The filtrate is concentrated in vacuo to give 4.78 g of the desired product as an off-white solid, m.p. 155°-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:27](=[O:29])[CH3:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(C)c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (150.3 mg, 0.3998 mmol) in dichloromethane (15 mL) were added acetyl acetate (81.5 mg, 0.798 mmol) and N,N-diethylethanamine (81.3 mg, 0.803 mmol). The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow solid (120.0 mg, 71.82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)=[CH2:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:19]=[CH2:20])=[CH:22][CH:23]=2)[N:3]=1
Reactant: C=Cc1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: C=Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-vinylbenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 318 (M+H+, 100).
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:5]=1)(=O)[CH3:2].C([BH3-])#N.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:30]([S:27]([N:24]1[CH2:23][CH2:22][CH:21]([C:12]2[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:6]4[CH:5]=[C:4]([C@@H:1]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH3:2])[S:8][CH:7]=4)[CH:10]=3)[NH:14][CH:13]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28])[CH3:31]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(C)=O)c4)cc23)CC1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc([C@H](C)N5CCCC5)c4)cc23)CC1

Procedure:
To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (10 mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave for 40 min at 150° C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:17][C:5]1[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1c(F)ccc(N)c1Nc1ccccn1
Yield: 54.3 %

Procedure:
6-Fluoro-3-nitro-2-(pyridin-2-ylamino)benzonitrile (1.3 g, 5.0 mmol), iron powder (1.12 g, 20.1 mmol), and ammonium chloride (1.55 g, 30.2 mmol) in methanol (20 mL) and water (7 mL) were heated at 90° C. for 3 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow solid (620 mg, 54%). 1H NMR 400 MHz δ (CDCl3): 9.05 (1H, ddd, J=7.5, 1.1, 0.8 Hz), 9.00-8.89 (1H, m), 7.34 (1H, ddd, J=9.1, 6.2, 1.7 Hz), 7.23-7.19 (1H, m), 6.83 (1H, s), 6.80 (1H, d, J=2.8 Hz), 6.65 (1H, ddd, J=7.6, 6.4, 1.4 Hz), 4.53 (2H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[O:4].C(O[C:21](=[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=2)[NH:30][C:29]1=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15]/[C:21](=[C:28]2\[C:29](=[O:40])[NH:30][C:31]3[C:36]\2=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: COC(=O)C1CCCN1Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN1Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared from 4-(2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-aniline and 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone in DMF.
Reaction SMILES: CC(C)([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]/[C:16](/[CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6])C.Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]/[C:16](/[CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:17]\[C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: CCOC(=O)c1ccc(/C=C(/CCCc2ccc(C(=O)OC(C)(C)C)cc2)Cn2ccnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(/C=C(\CCCc2ccc(C(=O)O)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution containing ethyl 4-[5-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]-2-(1H-imidazol-1-ylmethyl)-1E-pentenyl]benzoate (prepared as in Example 15; 3.5 g, 0.0074 mol) in acetic acid (45 ml) was treated with aqueous hydrochloric acid (5% of 35.4%). The solution was stirred at room temperature for three hours after which time the solution was basified with sodium hydrogen carbonate, diluted with water (500 ml) and extracted with dichloromethane (4×300 ml). The extracts were combined, dried over sodium sulphate, and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel, 10% ethanol in chloroform) to yield ethyl 4-[5-(4-carboxyphenyl)-2-(1H-imidazol-1-ylmethyl)1E-pentenyl]benzoate as a colorless crystalline solid having a melting point of 167°-170° C. (chloroform/benzene) and the following structural characteristics:
Reaction SMILES: [C:1]([C:5]1[NH:6][NH:7][C:8](=[O:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:18][N:19]=[C:20]=[O:21]>O1CCCC1>[C:1]([C:5]1[N:9]=[C:8]([OH:10])[N:7]([C:20](=[O:21])[NH:19][CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(=O)[nH][nH]1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(C(C)(C)C)nc1O
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a mixture of 1.41 g (0.01 mole) of 3-tert-butyl-1H-1,2,4-triazole-5-one and 0.5 g of triethylamine was added 50 ml of tetrahydrofuran, to the mixture was added 2.28 g (0.04 mole) of methylisocyanate while stirring, and the reaction was carried out at 60° C. for 2 hours. By concentration of the reaction mixture under a reduced pressure a white powder was obtained, which was washed with n-hexane to give 1.6 g of white powder of 3-tert-butyl-1-N-methylcarbamoyl-5-hydroxy-1,2,4-triazole. (yield 81%)