Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:35])[C@H:16]([N:21]2[C:27](=[O:28])[C@H:26]3[C@@H:22]2[O:23][C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]3)[C:17]([CH2:19]I)=[CH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:36]>>[C:1]1([CH:7]([O:14][C:15](=[O:35])[C@H:16]([N:21]2[C:27](=[O:28])[C@H:26]3[C@@H:22]2[O:23][C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]3)[C:17]([CH2:19][OH:36])=[CH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CI)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Reactant: O
Product: C=C(CO)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
To a mixture of (2R)-2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-3-iodomethyl-3-butenoic acid diphenylmethyl ester (1) in an organic solvent and inorganic base in water is added a peracid portionwise under nitrogen gas, and the mixture is stirred for the given time at the given temperature under nitrogen. The reaction mixture is washed with water, aqueous 5% sodium thiosulfate, aqueous sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated under reduced pressure. The residue is crystallized from ethanol to give (2R)-2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl]-3-hydroxymethyl-3-butenoic acid diphenylmethyl ester (2). mp. 100°-104° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH:13]([CH3:17])[NH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][CH:11]1[NH:12][CH:13]([CH3:17])[CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CC1CNCC(C)N1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Temperature: 120 °C
Yield: 56.9 %

Procedure:
A mixture of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol), 2,6-dimethylpiperazine (2.2 g, 19.3 mmol), and K2CO3 (2.7 g, 19.3 mmol) in DMF (10 mL) was heated at 120° C. for 4 hours. Then, the reaction was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 3% to 10% MeOH/CH2Cl2 afforded 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (2.0 g, 57%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18](=[O:46])[N:19]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[N:32]=1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18](=[O:46])[N:19]([C:31]1[CH:36]=[CH:35][C:34]2[NH:37][C:1](=[O:2])[N:39]([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[CH2:38][C:33]=2[N:32]=1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNC3CCCCC3)n2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C2CCCCC2)C(=O)N3)c(OC)c1
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol, 1.2 equiv) in THF (5 mL) was added a solution of (5-amino-6-cyclohexylaminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (390 mg, 0.83 mmol, 1.0 equiv) in THF (5 mL) and the reaction mixture was stirred for 2 h. The solvent was evaporated, the residue was dissolved in EtOAc, washed with water, brine, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from methanol to afford (3-cyclohexyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (282 mg) as a white solid. MS: [M+H]+=496.
Reaction SMILES: P(=O)([O-])O[C:3]([CH2:13][C:14](F)(F)F)(CC(F)(F)F)[C:4]([O:6][CH3:7])=[O:5].C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:48]([C:50]1[CH:51]=C([CH:55]=[CH:56][CH:57]=1)C=O)#[N:49]>C1COCC1.CCOC(C)=O.CCCCCC>[C:48]([C:50]1[CH:51]=[C:14]([CH:55]=[CH:56][CH:57]=1)[CH:13]=[CH:3][C:4]([O:6][CH3:7])=[O:5])#[N:49]
Reactant: COC(=O)C(CC(F)(F)F)(CC(F)(F)F)O[PH](=O)[O-]
Reactant: N#Cc1cccc(C=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (1.00 g, 3.14 mmol) and 18-crown-6 (4.14 g, 15.7 mmol) in THF (50 mL) at −78 C, potassium bis(trimethylsilyl)amide (6.3 mL, 0.5 M in toluene, 3.15 mmol) was added dropwise. After the addition was completed, 3-cyanobenzaldehyde (0.412 g, 3.14 mmol) in THF (8 mL) was added. The mixture was stirred at −78 C for 30 min before it was quenched with aq. NH4Cl. Water and ether were added. Aqueous phase was separated, extracted with ether once more. The combined organic solutions were dried over Na2SO4, concentrated in vacuo to give a solid, which was purified by a silica gel column, first eluted with EtOAc/hexane (5/95), then with EtOAc/hexane (10/90) to give the titled compound (0.40 g) (yield: 68%). 1H NMR (CDCl3) 7.85 (s, 1H), 7.77 (d, 1H, J=8 Hz), 7.60 (d, 1H, J=8 Hz), 7.45 (t, 1H, J=8 Hz), 6.91 (d, 1H, J=12 Hz), 6.06 (d, 1H, J=12 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=[C:30]([CH3:32])[C:29]2[C:28](=O)[CH2:27][CH:26](C3C=CC=CC=3C3C=CC=CC=3)[CH2:25][C:24]=2[N:23]=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[NH:23][CH:32]=[CH:30]4)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1Br)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1cccc3cc[nH]c13)C2

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/i stage 2/3), following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 5/a stage 1) using 7-boronic acid-1H-indole instead of phenyl-boronic acid.
Reaction SMILES: CS(C1C=CC(C2N=C(N)C=NC=2)=CC=1)(=O)=O.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]3[N:34]=[C:35]([NH2:37])[N:36]=[C:32]3[CH:31]=[N:30][CH:29]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20].Br[C:39]1[CH:40]=[C:41]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[CH:42]=[CH:43][CH:44]=1>>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:33]3[N:34]=[C:35]([NH2:37])[N:36]=[C:32]3[CH:31]=[N:30][CH:29]=2)=[CH:26][CH:27]=1)(=[O:20])=[O:21].[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:33]3[N:34]=[C:35]([NH:37][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([N:45]5[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]5)[CH:40]=4)[N:36]=[C:32]3[CH:31]=[N:30][CH:29]=2)=[CH:26][CH:27]=1)(=[O:20])=[O:21]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: CS(=O)(=O)c1ccc(-c2cncc(N)n2)cc1
Agent: CS(=O)(=O)c1ccc(-c2cncc3nc(N)nn23)cc1
Product: CN1CCN(c2cccc(Nc3nc4cncc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1

Procedure:
6-(4-Methanesulfonyl-phenyl)-pyrazin-2-ylamine was prepared from 6-chloro-pyrazin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford an off-white solid (99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.39 (s, 1H), 8.25 (d, 7.6 Hz, 2H) 8.02 (d, 7.6 Hz, 2H), 7.95 (s, 1H), 6.70 (bs, 2H), 3.26 (s, 3H). 107b) 5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine was prepared from 6-(4-methanesulfonyl-phenyl)-pyrazin-2-ylamine in a manner analogous to Steps 2a-b. (37%), MS=291.1 (MH)+. 107c) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a pale orange lyophilate (3% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.0 (s, 1H), 9.62 (bs, 1H), 9.14 (s, 1H), 8.42-8.40 (m, 3H), 8.20 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.18 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.72 (bd, 2H), 3.52 (bd, 2H), 3.39 (s, 3H), 3.17 (m, 2H), 2.93 (m, 2H), 2.87 (s, 3H). MS=464.1 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:24]#[N:25])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1oc2cccc(C#N)c2c1C
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (721 mg, 2.0 mmol, 1 eq) in 10 mL of DMF under nitrogen was added 322 mg of Zn(CN)2 (2.74 mmol, 1.37 eq), and 123 mg of Pd(PPh3)4 (0.1 mmol, 0.05 eq). The reaction mixture was heated to 85° C. The reaction was complete in 2.5 h by TLC. After work up and column chromatography eluting with 5% ethyl acetate/hexane, 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 80% yield (367 mg). 1H NMR (400 MHz, CD3OD) δ ppm 1.6 (t, J=7.1 Hz, 3 H) 3.0 (s, 3 H) 4.6 (q, J=7.2 Hz, 2 H) 7.8 (dd, J=8.3, 7.6 Hz, 1 H) 7.9(m, 1 H) 8.1 (dd, J=8.3, 1.0 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 85.7 %

Procedure:
In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser were placed fluorobenzene (117 g, 1.2 mol) and 4-bromobenzoyl chloride (39.8 g, 0.181 mol). The mixture was cooled to 0° C. and aluminum chloride (27 g, 0.20 mol) was added. The mixture was stirred for 15 minutes at 23° C., followed by heating to reflux for 4 h. The reaction was then cooled to 23° C. and stirred for 16 h. The resulting slurry was poured into 2 L of acidic (HCl) water. The organics were extracted with methylene chloride, and dried over magnesium sulfate. The slurry was filtered and the methylene chloride was removed under reduced pressure to yield an off white powder. Recrystallization from ethanol afforded 43.3 g (86%) of 4-bromo-4'-fluorobenzophenone as white crystals: m.p. 106°-107° C., (Lit. 107°-108° C.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1>C(#N)C>[CH3:13][C:14]1[O:15][C:16]([CH:8]=[CH:9][CH:10]=[O:11])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1
Reactant: CN(C)C=CC=O
Reactant: Cc1cc(-c2ccc(F)cc2)co1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(F)cc2)c(C=CC=O)o1
Temperature: -23 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 1.1 mL (11.9 mmol) of phosphorus oxychloride in 15 mL of acetonitrile was allowed to react with 1.2 mL (11.9 mmol) of 3-dimethylaminoacrolein at -23° C. After 0.25 hour at -23° C., 1.4 g (7.9 mmol) of 2-methyl-4-(4'-fluorophenyl)furan in 10 mL of acetonitrile was added dropwise. The reaction mixture was stirred at -23° C. for 0.15 hour then at 24° C. for 2 hours. The reaction was quenched upon treatment with 20 mL of 1M NaOH and extracted three times with CHCl3. The CHCl3 layers were combined, dried (MgSO4) and concentrated under reduced pressure. Column chromatography (3:1 hexanes-diethyl ether) of the residue on silica gel produced 1.76 g (97%) of 3-(5-methyl-3-p-fluorophenyl-furan-2-yl)acrylaldehyde as a solid (m.p. 89°-90° C.), homogeneous by TLC and spectroscopic criteria; Rf 0.58 (1:1 hexanes-diethyl ether); IR (KBr) 1655, 1600, 1205, 1118, 1095 cm-1 ; 1HNMR (300 MHz, CDCl3) 9.60 (d, 1H, J=10.5 Hz), 7.41 (m, 2H), 7.27 (d, 1H, J=15 Hz), 7.18 (t, 2H, J=9.0 Hz), 6.64 (dd, 1H, J=10.5 Hz, 15 Hz), 6.32 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][CH:19]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:20]([OH:31])[CH2:21][CH:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[C:36]1([CH2:46][C@H:47]([CH2:51][C:52]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:53])C(O)=O)[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[C:36]1([CH2:46][C@H:47]([CH2:51][C:52]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: CNC(=O)C(CC(O)C(CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(C)(C)O
Yield: 94 %

Procedure:
4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-4-hydroxy-2-(1-hydroxy-1-methylethyl)-7-methyl-N-methyl octanamide [prepared as described in Example 16(a)], 119 mg (0.36 mmoles) of 2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionic acid, 0.06 ml (0.40 mmoles) of diethyl cyanophosphate, and 0.14 ml (1.00 mmoles) of triethylamine were used, to obtain 205 mg (yield 94%) of the title compound as a white amorphous substance.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>>[ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)([OH:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CC1CC(CCC2CCCC2)CCC1=O
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Yield: 54 %

Procedure:
The base of compound (56) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with diisopropyl ether via a silica gel column and was taken up in ether. After adding trimethylchlorosilane/water, compound (52) was obtained in a yield of 54% theoretical.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].Cl[C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[NH:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18]
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)Cl
Product: COC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-carbamic acid methyl ester was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and Methyl chloroformate in an analogous manner to Example 1271d. Title compound is an off white solid. (94 mg, 38%) LCMS 308 (M+H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[Cl:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15].[C:18](O)([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:12][C@@H:13]([CH3:17])[C:14]([O:16][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15]
Reactant: C[C@H](Cl)C(=O)O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: C[C@H](Cl)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.1 %

Procedure:
Prepared according to Wright et al. Tetrahedron Lett. 1997, 38, 7345. A 500 mL glass bomb was charged with magnesium sulfate (21.7 g, 181 mmol) and DCM (182 mL). To this suspension was added sulfuric acid (2.5 mL, 45 mmol), drop-wise with vigorous stirring. After 15 min of stirring, (S)-2-chloropropanoic acid (5.0 g, 45 mmol) was added followed by tert-butanol (21.6 ml, 226 mmol). The bomb was sealed and stirred at rt for 19 h, whereupon it was cooled to 0° C. and sodium bicarbonate (aq satd, 350 mL) was carefully added, at which point all solids had dissolved. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organics layers were washed with brine, dried over Na2SO4 and concentrated in vacuo (20° C. bath, 50 mBar) to afford the title compound (7.64 g, 96%) as a light yellow oil (93% purity). 1H NMR data was an identical match to the previously prepared enantiomer.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH:30]1([NH:36][C:21]([C:15]2[CH:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=3)[C:16]=2[S:17][CH2:18][CH2:19][CH3:20])=[O:23])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCCC1
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate#35) (220 mg, 0.66 mmol) was dissolved in DCM (5 mL) and 1 drop of DMF added. Oxalyl chloride (176 μL, 1.96 mmol) was added and the mixture stiffed at ambient temperature for 3 h. Volatiles were removed by evaporation under reduced pressure and the resulting gum re-dissolved in DCM (2 mL) and added at ambient temperature to a solution of cyclohexylamine (66 mg, 0.66 mmol) and DIPEA (230 μL, 1.32 mmol) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 2 h, diluted with EtOAc (50 mL) and washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution gradient 0-100% EtOAc in isohexane) to afford methyl 2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate as a white solid. (220 mg, 88%)
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:8][CH:7]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([C:19](Cl)=[O:20])=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:6][C:5]([CH3:24])([CH3:23])[NH:4]1.[CH3:26][C:27]1([CH3:36])[CH2:32][CH:31]([OH:33])[CH2:30][C:29]([CH3:35])([CH3:34])[NH:28]1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:2][C:3]1([CH3:25])[CH2:8][CH:7]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([C:19]([O:33][CH:31]4[CH2:32][C:27]([CH3:36])([CH3:26])[NH:28][C:29]([CH3:35])([CH3:34])[CH2:30]4)=[O:20])=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:6][C:5]([CH3:24])([CH3:23])[NH:4]1
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)Cl)cc3C2=O)CC(C)(C)N1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(OC(=O)c2ccc3c(c2)C(=O)N(C2CC(C)(C)NC(C)(C)C2)C3=O)CC(C)(C)N1

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed 5.0 g (0.013 mol) of the acid chloride of Example 2 and 50 ml of 2% dimethylformamide in methylene chloride. This mixture was stirred during the addition of 2.1 g (0.013 mol) 2,2,6,6-tetramethyl-4-piperidinol and 2.8 g (0.028 mol) triethylamine. The reaction was then refluxed for 3 hours. The mixture was cooled and transferred to a separatory funnel with 100 ml methylene chloride, 25 ml water and 50 ml 5% sodium hydroxide. The mixture was shaken, allowed to separate and the organic phase drawn off. The aqueous phase (and interfacial solid) was extracted with an additional 25 ml solvent. The combined organic solutions were dried with anhydrous magnesium sulfate and the solvent stripped using aspirator vacuum. The product was 4.1 g of slightly yellow crystals (melting at 196°-200° C.). The infrared spectrum (chloroform) showed the carbonyl absorption at 1705 cm-1 (imide and ester). The NMR spectrum showed the anticipated aromatic ring (7.7-7.9 ppm, doublet, 1H; 8.3-8.5, multiplet, 2H) and two HALS groups [5.2-5.7 ppm, multiplet, 1H; 4.4-4.9 ppm, multiplet, 1H; 1.0-2.3 ppm, several multiplets including two singlets (1.2 and 1.3 ppm)]. The UV spectrum showed an absorbance maximum (THF) at 296 nm, molar absorptivity 300.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:19](Cl)(=[O:21])=[O:20])[C:5]([C:8]2[C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O>[C:23]1([S:19]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[S:15]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:17])=[O:16])(=[O:21])=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1-c1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(c1ccccc1)c1cc(Cl)ccc1-c1ccc(Cl)cc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 154.8 %

Procedure:
Inside a glove box, a 125 mL round-bottom flask equipped with a stirring bar, reflux condenser, and gas inlet was charged with 4,4′-dichlorobiphenyl-2,2′-disulfonyl dichloride (15.4 g, 36.7 mmoles), benzene (25 mL, 280 mmoles), and anhydrous nitromethane (75 mL). Aluminum chloride (11 g, 81 mmoles) was added and the mixture stirred until dissolved under nitrogen. The solution was heated to 100° C. for 8 hours. The solution was cooled to room temperature and poured onto 200 g ice mixed with 100 mL hydrochloric acid. The mixture was extracted several times with dichloromethane. The organic extracts were washed with water, dried with sodium carbonate, filtered to give a dark solution. The solution was treated with decolorizing carbon and heated to a reflux, then filtered through filter aid, evaporated, and the solids dried at 150° C. in a vacuum oven for 8 hr to give 18.02 g (97% crude yield). The mixture was purified by column chromatography using silica gel and dichloromethane (Rf 0.28) to give 14.3 g (77% yield) of 2,2′-bis-benzenesulfonyl-4,4′-dichlorobiphenyl. The solids were recrystallized from xylenes to give 13.08 g (71%). 1H NMR (DMSO-d6): 6.96 (d, 8.2 Hz, 2H), 7.55 (bs, 4H), 7.56 (m, 8.1 Hz, 4H), 7.69 (m, 2H), 7.74 (dd, 8.2, 2.2 Hz, 2H), 8.13 (d, 2.2 Hz, 2H). 13C NMR (CDCl3): 128.42 (4CH), 129.14 (4CH), 129.58 (2CH), 132.21 (2CH), 133.84 (2CH), 134.13 (2CH), 134.68 (2C), 135.61 (2C), 140.42 (2C), 141.42 (2C). MS (M+H+): m/e 502.99 (100%), 504.99 (75%), exact mass for C24H17O4Cl2S2, 502.99 (100%), 504.99 (72.9%).