Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].[N:17]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][N:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: COC(=O)CS(=O)(=O)c1cc(C)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1=NNc2ccc(C)cc2S1(=O)=O
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of methyl ((2-amino-5-methylphenyl)sulfonyl)acetate (Preparation 38, 1.5 g) in glacial acetic acid (20 mL) is added dropwise with vigorous stirring to a mixture of sodium nitrite (0.47 g) in water (6 mL) at room temperature. The mixture is stirred for 1 h. The resulting precipitate is filtered and washed with excess water. The solid is collected and placed under high vacuum overnight to obtain 1.05 g (67%) of the title compound as a green powder. Physical characteristics: MS (ESI−) m/z 253 (M−H).
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:16]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:17]([C:21]([N:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])=[O:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Val-Pro-OBzl was prepared by dissolving H-Pro-OBzl (20 g, 83 mmol) in 50 mL of chloroform and adding Boc-Val-OH (18.0 g, 83 mmol), HOBt (23.0 g, 165 mmol), NMM (9.0 mL, 83 MMOL) and DCC (17.0 g, 83 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was filtered and solvent was evaporated. Ethyl acetate was added and insoluble material was removed by filtration. The filtrate was washed with 0.2N HCl, 5% NaHCO3, and saturated aqueous NaCl. It was dried over Na2SO4, filtered and evaporate to give a white solid (30 g, 75 mmol, 90%). ESI/MS calculated for C22H32N2O5+H: 405.2. Found 405.6.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH2:15][N:16]1[C:22](=[O:23])[C@@H:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][O:19][C:18]3[C:32]([C:36]([O:38]C)=[O:37])=[CH:33][CH:34]=[CH:35][C:17]1=3)=[C:10]([O:40][CH3:41])[CH:9]=[CH:8]2>CO>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH2:15][N:16]1[C:22](=[O:23])[C@@H:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][O:19][C:18]3[C:32]([C:36]([OH:38])=[O:37])=[CH:33][CH:34]=[CH:35][C:17]1=3)=[C:10]([O:40][CH3:41])[CH:9]=[CH:8]2
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2cc(Br)ccc12
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 47.5 °C
Reaction time: 7 h
Yield: 90.7 %

Procedure:
A 0.1 M aqueous solution of LiOH.H2O (5.98 mL, 598 μmol, Eq: 1.00) was added to a solution of (S)-methyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-(tert-butoxycarbonylamino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (0.35 g, 598 μmol, Eq: 1.00) in MeOH (20 mL) and the mixture was warmed to 45-50° C. After 7 h, the MeOH was removed in vacuo and the mixture diluted with sat. NaHCO3 then extracted with EtOAc. The aqueous mixture was cooled to 0° C., acidifed to pH 3.0 with 3 N HCl and extracted with EtOAc. The combined organic extracts were washed with brine and concentrated a to give a material that was purified by silica gel chromatography to afford (S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-(tert-butoxycarbonylamino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (310 mg, 90%) as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)C(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon atmosphere, a mixture of 6.55 g (39.7 mmol) of 15, 10.9 g (79.3 mmol) of K2CO3, 1.0 g (5.94 mmol) of KI and 80 mL of anhydrous DMF was stirred for 10 min at room temperature. After that 7.52 g (59.5 mmol) of benzyl chloride was added in one portion. The resulting mixture was stirred for 2 hr at 70° C. and then evaporated to dryness. To the residue, 70 mL of water and 30 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed by 2×50 mL of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The residue was washed by 50 mL of cold ether and dried in vacuum. Yield 9.71 g (96%) of a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][O:20][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (ESI) m/z 421 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5]([Cl:23])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reaction time: 8 h
Yield: 109.3 %

Procedure:
To a solution of 2-(methyloxy)-4,6-bis(trifluoromethyl)benzoic acid (20.2 g; 70.14 mmol) in dry DCM (400 mL), at 0° C., was added dropwise oxalyl chloride (13.4 mL; 154.31 mmol) followed by dry DMF (5 drops). The reaction was allowed to reach room temperature. After overnight stirring the solvent was evaporated in vacuo to get the title product (23.5 g) as a yellow slurry used without further purification.
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[F:6][C:7]1[C:8](/[C:17](/I)=[CH:18]/[C:19](=O)[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2>C1COCC1.[Cu]I>[CH:1]([C:17]1[CH:18]=[C:19]([C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[C:10]2[C:11](=[O:16])[NH:12][C:13]3[C:9]=2[C:8]=1[C:7]([F:6])=[CH:15][CH:14]=3)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: [Li]C(C)CC
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC(C)c1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) iodide (Aldrich, 190 mg, 1.0 mmol) in dry THF (2 mL) was added sec-butyllithium (Aldrich, 1.3 M solution in ether, 1.53 mL, 2.0 mmol), under argon, at 0° C. and the reaction mixture was stirred for 30 minutes. To the resulting brown solution obtained was added dropwise a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (39.6 mg, 0.1 mmol) in THF (2 mL). After stirring at 0° C. for 45 minutes, the reaction mixture was stirred at room temperature for another 2 hours, then quenched with a saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product which was further purified by preparative TLC (silica gel, 20% ethyl acetate in hexanes) to afford (rac)-5-sec-butyl-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 3.6 mg, 11.7%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.FC(F)(F)S([O-])(=O)=O.[N:18]1([S:23](N2C=C[NH+](C)C2)(=[O:25])=[O:24])[CH:22]=[CH:21][N:20]=[CH:19]1>>[CH3:2][N:3]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[S:23]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)(=[O:25])=[O:24]
Reactant: CNC1CCOCC1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CCOCC1)S(=O)(=O)n1ccnc1

Procedure:
Imidazole-1-sulfonic acid methyl-(tetrahydro-pyran-4-yl)-amide was prepared in accordance with step A of the general method described in example 76 from methyl-(tetrahydro-pyran-4-yl)amine hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=246.8 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[CH2:14][N:15]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN>CN(C=O)C.C(OCC)(=O)C>[NH2:12][C:8]1[C:9]([F:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([NH:15][CH3:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(C(=O)O)c(F)cc1F
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N)c(F)cc1F
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 2,4-difluoro-5-aminobenzoic acid (1.73 g, 10.0 mmol) in DMF (40 mL) were successively added EDCI (1.62 g, 12.0 mmol), HOBt (2.30 g, 12.0 mmol) and methylamine (6.0 mL, 12.0 mmol, 2 M in MeOH) in that order at RT. After stirring for 2 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with NaHCO3 (3×50 mL) followed by 10% LiCl (50 mL). The organic layer was dried, filtered and concentrated to afford 5-amino-2,4-difluoro-N-methylbenzamide (0.76 g, 41%) as a light brownish solid. MS (M+H)+=187. It was used without further purification (>92% pure by HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:18])=[O:6].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[C:8]2[CH3:18])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(C(=O)c2c(C)[nH]c3ccccc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2c(C)n(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 57 mg (0.20 mmol) of 3-(3,4-dimethyl-benzoyl)-2-methyl-1H-quinolin-4-one, 9 mg (0.24 mmol) of 60% sodium hydride, 59 mg of 2-bromo-6-bromomethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 44 mg of a white solid: LC-MSD, m/z for C25H21BrN2O2 [M+H]+=461.1, 463.1; HPLC retention time: 2.7 min.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(O)(=O)C.[Cl:28][C:29]1[C:34]([CH2:35][N:36]2[CH2:56][CH2:55][C:39]3([O:44][CH2:43][CH2:42][N:41]([C:45]([C:47]4[N:48]=[C:49]([CH:52]([CH3:54])[CH3:53])[S:50][CH:51]=4)=[O:46])[CH2:40]3)[CH2:38][CH2:37]2)=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:57][CH:58]=O.C([BH3-])#N.[Na+]>CO>[Si:5]([O:4][C@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[CH2:2][NH:1][CH2:58][CH2:57][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][N:36]2[CH2:37][CH2:38][C:39]3([O:44][CH2:43][CH2:42][N:41]([C:45]([C:47]4[N:48]=[C:49]([CH:52]([CH3:53])[CH3:54])[S:50][CH:51]=4)=[O:46])[CH2:40]3)[CH2:55][CH2:56]2)[C:29]=1[Cl:28])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4Cl)CC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4Cl)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.261 g) in methanol (2 mL) was treated with acetic acid (0.030 mL) and stirred for 10 minutes. A solution of 2-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)acetaldehyde (example 80, step f) (0.247 g) in methanol (3 mL) was then added, and the resulting mixture was stirred at room temperature for 10 minutes, before cooling in ice-water and treating with sodium cyanoborohydride (0.102 g). The cooling bath was removed and the mixture was stirred at room temperature overnight. More sodium cyanoborohydride (0.101 g) was added, and the mixture was stirred over a second night. The solution was then concentrated onto flash silica in vacuo, and the resulting powder was purified by flash chromatography on silica eluted with 1:3:96 to 1:5:94 triethylamine:methanol:dichloromethane to afford the subtitled compound as a yellow oil. Yield 0.130 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:16]([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C@H:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC2CC2)cc1Cl
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(cyclopropylmethyl)amino]benzonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z 335 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 52.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), isobutyryl chloride (0.56 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (30 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-isobutyramide (0.67 g). Mp 206.5-208.0° C.;MS m/z 258 ([M+H]+); Anal. Calcd. for C15H17NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.43; H, 7.39; N, 5.50.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OCc3ccccc3)c2s1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6 (0.050 g, 0.16 mmol) and potassium carbonate (0.023 g, 0.17 mmol, 1.05 eq) in anhydrous DMF (1.6 mL) was stirred at about 20° C. for about 0.5 hour, and was cooled down to about 0° C. The reaction mixture was treated with benzyl bromide (0.019 mL, 0.16 mmol, 1.0 eq), and was stirred at about 0° C. for about 16 hours. To the reaction mixture was added methanol (10 mL). The solid was filtered off and rinsed with methanol (3 mL). The solvent was evaporated and the residue was dissolved in DMF (2 mL). The crude reaction solution was purified by LC/MS to give 0.029 g (45%) of the desired compound 9. 1H NMR (DMSO) δ 10.86 (br s, 1H, NH), 7.59–7.34 (m, 7H, ArH), 6.72 (br s, 1H, NH), 5.17 (s, 2H, CH2), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3); LC/MS 406 (MH+); RP-HPLC RT 3.8 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.[CH3:34][N:35]=[C:36]=[O:37]>ClCCCl>[CH2:12]([O:11][C:10]1[C:6]2[C:5](=[O:25])[N:4]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:3]=[C:2]([NH:1][C:36]([NH:35][CH3:34])=[O:37])[C:7]=2[N:8]2[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Reactant: CN=C=O
Solvent: ClCCCl
Product: CNC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 4-amino-2-(4-fluorobenzyl)-10-benzyloxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (75 mg, 168 μmol) and methylisocyanate (24 mg, 419 μmol) in anhydrous 1,2-dichloroethane (3 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The product mixture was concentrated under vacuum. The intermediate dicarbonimidic diamide was dissolved in methanol, treated with an aqueous solution of KOH (0.1 mL, 2 M), and stirred at room temperature for one hour, and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. ES MS M+1=505
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[Br:11]Br>Br>[BrH:11].[OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:10])[CH2:9][Br:11])[N:7]=1
Reactant: CC(=O)c1c[nH]c(CO)n1
Reactant: BrBr
Agent: Br
Product: O=C(CBr)c1c[nH]c(CO)n1
Yield: 112.8 %

Procedure:
1.826 g (0.013 mol) of 2-hydroxymethyl-4- acetylimidazole was dissolved in 40 ml of 48% hydrobromic acid and 2.1 g (0.013 mol) of bromine was added. The reaction was warmed at 80° for 2 hours and then concentrated in vacuo to a solid. This material was triturated with isopropylether and the resultant solid was collected by filtration and was washed with ether and dried to give 2.2 g (56%) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide, mp 183° with decomposition. nmr (DMSO-d6) (δ): 8.8 (s, 1H); 4.8 (s, 2×2H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[Br:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[C:25](Cl)=[O:26].Cl>C(#N)C>[Br:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[C:25]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[O:26]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.9 g (0.167 mol) of magnesium chloride in 150 ml of anhydrous acetonitrile (dried over zeolite) are initially introduced into the reaction vessel and 26.9 g (0.167 mol) of diethyl malonate are added dropwise, while cooling. The mixture is cooled to 0° C., 46 ml (33.7 g=0.33 mol) of triethylamine are added dropwise and the mixture is subsequently stirred for 30 minutes. 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are then added dropwise and the mixture is subsequently stirred at 0° C. for a further hour and brought to room temperature overnight. 100 ml of 5N hydrochloric acid are added, the mixture is extracted three times with methylene chloride and the extract is dried with Na2SO4 and concentrated in vacuo.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[CH:11]=[C:12]([CH:45]=[C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:47]=1[OH:48])[C:13]([O:15][CH2:16][CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([NH:28][C:29](=[O:44])[CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=2)=[O:32])[CH:22]=1)=[O:19])=[O:14])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[CH2:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([C:31](=[O:32])[CH:30]([Cl:4])[C:29]([NH:28][C:23]2[CH:22]=[C:21]([O:20][C:18]([CH2:17][CH2:16][O:15][C:13](=[O:14])[C:12]3[CH:11]=[C:10]([C:6]([CH3:7])([CH3:8])[CH3:9])[C:47]([OH:48])=[C:46]([C:49]([CH3:51])([CH3:50])[CH3:52])[CH:45]=3)=[O:19])[CH:26]=[CH:25][C:24]=2[Cl:27])=[O:44])=[CH:38][CH:37]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCOc1ccc(C(=O)CC(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)C(Cl)C(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 99 %

Procedure:
Sulphuryl chloride (4.9 g, 36.2 mmole) in dichloromethane (10 ml) was slowly added to a solution of the 4 equivalent coupler from (f) (24.1 g, 36.2 mmole) in dichloromethane (140 ml). After stirring at room temperature for 21 hours, the volatiles were removed by rotary evaporation. The product was isolated as a yellow oil (25.1 g, 99%) and was used in the next reaction without further purification.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[O:21]>[Ni]>[C:11]([CH:9]([OH:10])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH2:2][NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[O:21])([OH:13])=[O:12]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: [Ni]
Product: NC(=O)NCCC[C@H](NCC(O)C(O)C(O)C(O)C(=O)O)C(=O)O

Procedure:
The product was made from D-glucuronic acid and L-(+)-citrulline using Raney nickel as a catalyst under the conditions of the above example. A brownish, highly viscous oil was obtained.
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][C:9]([OH:11])=O)[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.S(Cl)([Cl:14])=O>>[CH:1]12[CH:7]([CH2:8][C:9]([Cl:14])=[O:11])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1C2CCC1CC2
Product: O=C(Cl)CC1C2CCC1CC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.0455 Mole of bicyclo[2.2.1]hept-7-yl acetic acid is mixed with 20 ml. of thionyl chloride at room temperature and allowed to stand for 2 hours. The mixture is then warmed to 50° C and maintained at this temperature for another 2 hours. Excess thionyl chloride is then removed by distillation, under reduced pressure, affording a crude bicyclo[2.2.1]hept-7-yl acetyl chloride residue which is then dissolved in 50 ml. of ethyl ether and added dropwise to a concentrated aqueous ammonia solution (20 ml. of 58% wt. ammonia) at 0° C with rapid stirring. 200 Ml. of ethyl acetate is then added and the resulting mixture stirred. The organic layer is then decanted off and washed twice with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording bicyclo[2.2.1]hept-7-yl acetamide.