Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:40][CH2:41][CH2:42][CH2:43][CH:44]=O>C1COCC1>[Br:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=1
Reactant: O=CCCCBr
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C=CCCCBr)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Add (4-cyanophenylmethyl)triphenylphosphonium bromide (27.25 g) to dry THF (65 ml) and cool to -20° C. under an argon atmosphere. With stirring, dropwise add 65 ml of a solution of 1 molar lithium bis(trimethylsilyl)amide in THF, maintaining the temperature at -20° C. Stir for 30 minutes at -20° C.; then for 30 minutes at 0° C. Cool to -20° C. and add freshly distilled 4-bromobutanal (10.50 g) dropwise with stirring. Stir at -20° C. for 1 hour, then at room temperature for 16 hours. Remove the solid material by filtration and wash with THF. Vacuum evaporate the solvent from the filtrate and purify the resultant residue by chromatography on silica gel, eluting with CH2Cl2 :hexane(4:1). Combine the desired fractions and vacuum evaporate the solvent to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[CH3:7])=[CH:2]1.[N-:9]=[N+:10]=[N-:11].[Na+].O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([N:9]=[N+:10]=[N-:11])[CH3:7])=[CH:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Cl)c1ccsc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])c1ccsc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
A mixture of 1-(thien-3-yl)chloroethane (5.0 g, 34 mmol) and sodium azide (2.65 g, 41 mmol) in DMF was stirred at room temperature for three days. The reaction mixture was poured into H2O (500 ml) and extracted with CH2Cl2 (3×200 ml). The organic extracts were washed with H2O (5×100 ml), dried over MgSO4 and concentrated in vacuo to give the product (5.02 g, 96% yield) as a brown oil; IR (neat) 2110 cm-1 ; 1H NMR (CDCl3) δ1.55 (d, J=7 Hz, 3H, CHCH3), 4.67 (q, J=7 Hz, 1H, CHCH3), 6.98-7.43 (m, 3H, thiophene-H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:10]=3[NH:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:10]=3[N:9]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:19])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1sc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2c(C)c(C)sc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
A 0.6 g quantity of 3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound III-1) was dissolved in 20 ml of anhydrous N,N-dimethylformamide. To the solution were added at room temperature 0.1 g of 50% sodium hydride and then 0.4 g of ethyl bromoacetate. The mixture was stirred at room temperature for 17 hours, concentrated and acidified by adding diluted hydrochloric acid with ice-cooling. The crystals precipitated were collected by filtration and recrystallized from ethanol, giving 0.7 g of 3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having a melting point of 151° to 152° C. in a yield of 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:15][C:16]1[C:17]([NH2:21])=[N:18][O:19][N:20]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8]([NH:21][C:17]2[C:16]([CH3:15])=[N:20][O:19][N:18]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1nonc1N
Reactant: O=C(O)c1ncc(Cl)cc1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nonc1NC(=O)c1ncc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
300 mg (1.33 mmol) of 5-chloro-3-(trifluoromethyl)pyridine-2-carboxylic acid and 132 mg (1.33 mmol) of 4-methyl-1,2,5-oxadiazol-3-amine are dissolved at RT in 10 ml of CH2Cl2, and 0.19 ml (1.33 mmol) of triethylamine, 32 mg (0.27 mmol) of DMAP and 1.27 g (2.00 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 10 ml each time of water. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield: 250 mg (61%).
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][N:2]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.[I-].[K+]>CC(C)=O>[CH3:11][N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2sccc12
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc2sccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a solution of 3H-thiopheno[2,3-d]1,2,3-triazin-4-one (80 mg, 0.522 mmol) in acetone (50 mL) was added sequentially potassium carbonate (144 mg, 1.04 mmol), iodomethane (0.04 mL, 0.627 mmol) and potassium iodide (catalytic) at rt and the mixture was stirred at rt for 3 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure, diluted with ice cold water and stirred for 10 min. The solution was extracted with chloroform (4×75 mL) and the combined CHCl3 layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as an off-white solid (50 mg, 57%), mp 104-108° C. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (1H, d, J=5.6 Hz), 7.64 (1H, d, J=5.6 Hz), 3.95 (3H, s); 13C NMR (100 MHz, CDCl3): δ 159.4, 153.9, 130.7, 125.6, 121.7, 37.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:22](C)C=O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:22])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.25 g (20 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid in 30 ml of ether containing one drop of N,N-dimethylformamide is added dropwise 3.81 g (30 mmol) of oxalyl chloride. The solution is stirred at RT until gas evolution ceases. The solvent and excess oxalyl chloride ae removed in vacuo and the residue is taken up in 30 ml of ether. This solution is then added dropwise at 0°-5° to 4.86 g (40 mmol) of a 14% w/w aqueous solution of ammonia. After stirring the mixture for 30 minutes at 0°-5°, the aqueous layer is removed. The ethereal solution is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-chlorophenyl)-3-methylbutyramide.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:42])[C@H:14]([C:18]([N:20]([CH3:41])[C@H:21]([C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[NH2:1][C@H:2]([C:11]([N:13]([CH3:42])[C@H:14]([C:18]([N:20]([CH3:41])[C@H:21]([C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[F:53][C:52]([C:50]([OH:56])=[O:51])([F:55])[F:54]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)[C@@H](N)Cc1ccc(F)cc1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a solution of Boc-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-t-Bu)-NHSO2Me (208 mg, 0.294 mmol) in methylene chloride (6 ml), TFA (3 ml) was added and stirred for 1.5 hours. The reaction mixture was evaporated under reduced pressure; the thus obtained residue was dissolved in a mixture of acetonitrile/water (1:10) (80 ml), which mixture containing 0.1% TFA, and lyophilized to give the titled compound (0.20 g, 94%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([N:17]2[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=4)[N:27]=3)[CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>>[C:11]1([N:17]2[C:21]([C:22]([F:23])([F:24])[F:25])=[C:20]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[CH:35][CH:36]=4)[N:27]=3)[CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A 50 mL round bottom flask was flame dried and cooled under a stream of dry nitrogen. DCM (25 mL) followed by oxalyl chloride (6.79 mL, 13.59 mmol) (2M in DCM) were added to the flask and it was cooled in an acetone/dry ice bath. Dimethyl sulfoxide (1.47 mL, 20.71 mmol) was added dropwise. After 10 minutes, (4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (2.5 g, 6.47 mmol) was added in small portions over 5-10 minutes providing a pale yellow slurry. After stirring for 5 minutes, DIPEA (9.27 mL, 53.1 mmol) was added dropwise. The cloudy mixture began to clear up, then became cloudy again with the color fading from pale yellow to off-white during the course of the addition. After 5 minutes, the cooling bath was removed and the reaction was allowed to slowly warm to room temperature. After stirring at room temperature for 3 hours the solvents were evaporated and the residue was partitioned between EtOAc (100 mL) and 0.5 N KHSO4 (70 mL). The EtOAc phase was washed with 50 mL each 1N HCl, water, sat. aq. NaHCO3, water and brine, then dried over MgSO4, filtered and evaporated. The solid was slurried in hexanes (with ˜5% EtOAc) with sonication and heating, then cooled to room temperature and filtered. The solids were washed with hexanes, air dried and placed under vacuum to afford 4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (1.55 g). The compound had an HPLC retention time=2.04 min.−Column: PHENOMENEX® Luna 5u C18 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=385.17.
Reaction SMILES: [CH3:1][C:2]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[C:22](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[C:22]2[C:3](=[C:2]([CH3:1])[C:25]([F:26])=[C:24]([F:27])[CH:23]=2)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(F)c(F)c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)c(C)c2c1=O
Yield: 67 %

Procedure:
Employing ethyl 2(2-methyl-3,4,6-trifluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate (1.1 g) and 60 sodium hydride (0.13 g), the procedure of Reference Example 9 is repeated to give ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[NH2:21].[S]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:20][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[C:15]=4[N:21]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1n[nH]c2ncc(Br)cc12
Reactant: Cc1cccc(N)c1N
Agent: [S]
Solvent: CN(C)C=O
Product: Cc1cccc2[nH]c(-c3n[nH]c4ncc(Br)cc34)nc12
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde Compound 5a (50 mg, 0.22 mmol) and 3-methyl-benzene-1,2-diamine Compound 5b (27 mg, 0.22 mmol) and sulfur (9 mg, 0.28 mmol) in DMF (1 mL) was heated to 100° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 50% of ethyl acetate in hexanes) to yield 5-bromo-3-(4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 5c (50 mg, 69% yield) as a grey powder. 1H NMR (400 MHz, MeOD) δ 9.03 (s, 1H), 8.68 (s, 1H), 7.18 (t, 1H, J=8.4 Hz), 7.09 (m, 2H), 2.69 (s, 3H); MS (ESI) m/z: 329 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:22]=3)=[CH:19][N:20]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH:22]=3)=[CH:19][N:20]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:33]
Reactant: CCc1cc(-c2ncc(-c3cc(C)nc(CC(C)C)c3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(-c2ncc(-c3cc(C)nc(CC(C)C)c3)o2)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 4-[2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-oxazol-5-yl]-2-isobutyl-6-methyl-pyridine (29 mg, 66 μmol) in THF (0.5 mL) and EtOH (0.5 mL), Pd/C (10 mg, 10% Pd) is added. The mixture is stirred at rt under 1 bar of H2 for 16 h. The catalyst is filtered off and the filtrate is concentrated. The residue is again treated with Pd/C and H2 at rt for 24 h as described before. The catalyst is filtered off and the filtrate is evaporated. The crude product is purified on prep. TLC using heptane:EA 1:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-oxazol-2-yl]-6-methyl-phenol (11 mg) as a pale yellow glass; LC-MS: tR=0.97*, [M+1]+=351.11; 1H NMR (CDCl3): δ 0.99 (d, J=6.5 Hz, 6 H), 1.33 (t, J=7.5 Hz, 3 H), 2.12-2.22 (m, 1 H), 2.37 (s, 3 H), 2.63 (s, 3 H), 2.66-2.79 (m, 4 H), 5.35 (s br, 1 H), 7.21 (s, 1 H), 7.29 (s, 1H), 7.58 (s, 1 H), 7.80 (s, 2 H).
Reaction SMILES: Br[CH:2]([CH3:19])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>COCCOC>[CH3:19][C:2]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: Nc1ccccn1
Reactant: CC(Br)C(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(CC(=O)OCc2ccc([N+](=O)[O-])cc2)nc2ccccn12
Yield: 26.9 %

Procedure:
4-Nitrobenzyl 4-bromo-3-oxopentanoate (1.02 g) and 2-aminopyridine (436 mg) were dissolved in 1,2-dimethoxyethane (20 ml). The solution was heated for 15 hours under reflux. The reaction mixture was concentrated, to which were added 1N HCl (10 ml) and ethyl acetate (10 ml). The mixture was shaken and left standing to form two layers. To the aqueous layer was added sodium hydrogencarbonate to adjust its pH to 7, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, which was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 30 g, developing: ethyl acetate) to afford the title compound (0.27 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: COC(=O)CBr
Reactant: Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C
Reaction time: 0.05 h
Yield: 82.1 %

Procedure:
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.24 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 48 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (82%) of the {9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.56 (br s, 1H), 7.5-7.1 (m, 9H), 6.9 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H). IR (KBr, cm−1) 3367, 3153, 1760, 1740, 1672, 1644, 1619, 1591, 1578, 1498, 1456, 1425, 1327, 1200, 1153, 1109, 1100, and 777. MS (FD) m/e 402.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH:21]=2)[CH:13]=1)[CH2:9][CH3:10].C=O.[C:35]([BH3-])#N.[Na+]>C(#N)C>[CH3:32][C:2]([CH3:31])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH:21]=2)[CH3:35])[CH:13]=1)[CH2:9][CH3:10]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N(C)Cc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
100 mg of the (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzylamino]benzylamine obtained in Example 175 was dissolved in 3 ml of acetonitrile. 0.1 ml of a 35% aqueous solution of formaldehyde and 22.7 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 5 g; eluting solvent: hexane/ethyl acetate=10/1→6/1] to give 55 mg (yield 53%) of the captioned compound as a pale yellow crystalline solid, m.p. 51°-52° C.
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH3:7][CH2:6][O:5][C:3]([CH:2]([P:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:16])[F:8])=[O:4]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(F)Br
Product: CCOC(=O)C(F)P(=O)(OCC)OCC
Yield: 67.2 %

Procedure:
Ethyl bromofluoroacetate (ex Fluorochem) (25 g) and triethyl phosphite (ex Aldrich) (29 g) were heated together at 140°-5° for 6 hours in a vessel equipped with a fractionating column. When all the ethyl bromide had distilled off the residue was distilled to give triethyl 2-fluoro-2-phosphonoacetate (22 g) (bp 98°-108° at 0.8 mm). The latter (20 g) was added dropwise to hexane washed sodium hydride (3.3 g of 60% dispersion) in dry ether (85 ml). After 3 hours at room temperature and 30 mins under reflux, acetone (6.1 ml) was added and the mixture stirred for 4 days at room temperature under nitrogen. After conventional work up the crude product was distilled to give ethyl 2-fluoro-3-methyl-but-2-enoate (4 g) (bp. 60°-2° at 15 mm). (Ref. Machledit & Wessendorf. Ann. 674, 1, (1964)).
Reaction SMILES: N1CCCCC1.[I-].[K+].Cl[CH2:10][CH:11]1[S:19][C:18]2[N:13]([C:14](=[O:24])[N:15]([CH2:21][CH2:22][CH3:23])[C:16](=[O:20])[CH:17]=2)[CH2:12]1>C(O)C>[CH2:10]=[C:11]1[S:19][C:18]2[N:13]([C:14](=[O:24])[N:15]([CH2:21][CH2:22][CH3:23])[C:16](=[O:20])[CH:17]=2)[CH2:12]1
Reactant: CCCn1c(=O)cc2n(c1=O)CC(CCl)S2
Agent: [I-]
Agent: [K+]
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C1Cn2c(cc(=O)n(CCC)c2=O)S1
Temperature: 60 °C
Reaction time: 42 h
Yield: 64 %

Procedure:
Piperidine (0.66 g) and potassium iodide (0.1 g) were added to a solution of 2-chloromethyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (1g) in ethanol (20 ml). The reaction mixture was stirred at 60° C. for 42 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in chloroform. After washing with water and drying, the organic layer was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The resulting crystals were recrystallized from methylene chloride-isopropyl ether-hexane to give colorless crystals (0.55 g, 64%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O>[N:1]([N:11]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: O=N[O-]
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN(C1CCCCC1)C1CCCCC1
Temperature: 95 °C

Procedure:
A solution of 20.7 g of sodium nitrite in 60 ml of water is slowly added dropwise at RT to a mixture of 36.2 g of dicylohexylamine, 18 ml of conc. HCl and 300 ml of water. After this, the mixture is heated to 95° C. for 7 h. The nitro compound is extracted by shaking with ether. After drying over Na2SO4 and evaporating the ether, an oily residue remains which immediately crystallises.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Br.[NH2:25][C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: C[C@H](N)C(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Br
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
To a solution of 5-nitro-isochromen-1-one (1.5 g, 0.0078 mol) in methanol (20 mL, 0.4 mol) was added triethylamine (2 mL, 0.02 mol) and (S)-2-aminopropanamide hydrobromide (1.6 g, 0.0094 mol) and the resulting mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature wherein the product precipitated out. The precipitate was filtered and dried to yield the pure product as a yellow solid. MS m/z=262.2 (M+H).