Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:3]=1.Br[C:13]1[CH:26]=[C:25]2[C:16]([O:17][CH2:18][CH2:19][N:20]3[C:24]2=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)=[CH:15][CH:14]=1>CS(C)=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][C@@:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:14]=[CH:15][C:16]2[O:17][CH2:18][CH2:19][N:20]3[C:24](=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)[C:25]=2[CH:26]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc([C@@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1
Reaction time: 1 h

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (515 mg, 3.41 mmol, 3.50 equiv), 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (300 mg, 0.97 mmol, 1 equiv) and Pd(PPh3)2Cl2 (205 mg, 0.29 mmol, 0.3 equiv) in DMSO (2 mL) and triethylamine (2 mL). The final reaction mixture was irradiated with microwave radiation for 2 h at 70° C. The resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN. The solids were collected by filtration. The residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003; Phase A:MTBE Phase B:EtOH (0.2% DEA)-HPLC (10.0% EtOH for 60 min, then down to 0%); Detector, uv 254/220 nm. This resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z): 379[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.536 (s, 1H), 7.802 (s, 1H), 7.558 (br s, 1H), 7.340-7.300 (m, 1H), 7.143 (br s, 1H), 7.040 (d, 1H), 6.504 (s, 1H), 6.360 (s, 1H), 4.492 (s, 4H), 2.365 (s, 3H), 1.920 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[S:10]([O-:13])([O-:12])=[O:11].[Na+:14].[Na+]>>[CH:3]1([CH2:2][S:10]([O-:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:14]
Reactant: O=S([O-])[O-]
Reactant: BrCC1CCCCCC1
Agent: [Na+]
Product: O=S(=O)([O-])CC1CCCCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 61 from 1-(bromomethyl)cycloheptane [Preparation 66] and sodium sulfite. The crude product was purified by recrystallisation from water to afford sodium cycloheptylmethanesulfonate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)cn1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)nc3)cccc2c1N
Yield: 70.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.49 mmol) and (6-methoxypyridin-3-yl)boronic acid (153 mg, 1.00 mmol) were reacted to afford the title compound (117 mg, 72% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.55 (bs, 1H), 8.43 (d, J=1.65 Hz, 1H), 8.05 (dd, J=8.5, 1.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.71-7.81 (m, 2H), 6.89 (d, J=8.5 Hz, 1H), 4.01 (s, 3H), 3.46 (apparent q, J=6.6 Hz, 2H), 1.67 (apparent sextet, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=338 (M+H) HPLC 1.73 min.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([CH2:33][O:34][CH2:35][C:36](O)=[O:37])[C:29]=3[CH:39]=2)[C:15]1=[O:40].[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([CH2:33][O:34][CH2:35][C:36]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:37])[C:29]=3[CH:39]=2)[C:15]1=[O:40]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)O)c3c2)c1=O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)NS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
1,1'-Carbonyldiimidazole (1.17 g, 0.00722 mol) is added to a solution of {{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}methoxy}acetic acid (1.50 g, 0.00361 mol) in tetrahydrofuran. The mixture is stirred one hour at reflux and cooled to room temperature. Methylsulfonamide (0.755 g, 0.00794 mol) is added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 ml, 0.00794 mol). The resultant mixture is stirred overnight at room temperature, poured into 10% hydrochloric acid, and filtered. The resultant white solid is triturated in tetrahydrofuran, and filtered to give the title compound as an off-white solid (1.00 g, 56.2%, mp >240° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccccc1NN1C(=O)c2[nH]c3cc(Cl)ccc3c(=O)c2C1=O
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccccc1-n1nc(O)c2c(=O)c3ccc(Cl)cc3[nH]c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A stirred suspension of 6-chloro-2-(2-methoxyanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.78 g, 4.81 mM) in a solution of methanol (285 mL) and methanesulfonic acid (89 mL) was refluxed for 8 hours during which time a tan precipitate formed. The resulting suspension was cooled to room temperature and stirred for 16 hours. The suspension was filtered (the filtrate was saved for use in Example 30) and the collected solids were washed with methanol and then ether to give the title compound (0.889 g, 50%) as a yellow powder, mp 356-359° C.; MS(CI): 370 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[OH:16])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:14]([CH2:25][O:26][Si:27]([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28])[CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[O:16][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of N-benzyl-N-[(2RS,3SR)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(3,4-dichlorophenyl)-3-hydroxypropyl]-2-chloroacetamide (12.5 g) in THF (470 ml) was added sodium tert-butoxide (2.71 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (11.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:26])[CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[Cl:18])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>>[Cl:18][CH:17]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:16]([NH:15][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=2)(=[O:37])=[O:38])[CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:26]
Reactant: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Corresponding to Example 3c, 900 mg of (5b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 1.18 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCCC1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: c1ccc(CN2CCc3nc(NCCN4CCCC4)ccc3C2)cc1
Temperature: 150 °C

Procedure:
Copper (II) sulphate (70 mg) was added to a solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (0.75 g, 2.9 mmol)(WO9830560 Example 33 b) in 2-pyrrolidin-1-yl-ethylamine (3 ml) and the mixture was heated in an autoclave to 150° C. for 24 hours. The reaction mixture was cooled to room temperature and was diluted with dichloromethane (50 ml). The solution was washed with 50% ammonium hydroxide solution (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ammonium hydroxide and methanol in dichloromethane as eluant (gradient from 0.5:5:95 to 0.7:7:93) to give the title compound as a yellow oil (0.9 g). LRMS: m/z (ES+) 337 [MH+]
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14].[C:16]1(C)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:19]1([S:22]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:15])[CH3:14])(=[O:24])=[O:23])[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccccc1OCCCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1OCCCOS(=O)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of N-[2-(3-hydroxypropoxy)phenyl]-acetamide (Example 113) (7.5 g, 36 mmol) in pyridine (90 ml), cooled to 0° C., was added p-toluenesulfonyl chloride (13.6 g, 56 mmol). After the tosyl chloride went into solution, the reaction was then allowed to stand at 5° C. for 16 hours. The reaction was poured onto ice, and a brown oil settled. The aqueous supernatant was decanted from the oil, and the residual oil taken up in diethyl ether. The diethyl ether was washed with cold (5° C.) 3N HCl and then with brine. The organic layer was dried (MgSO4), and concentrated to afford a thick, brown oil, 5.3 g.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[C:12]([C:16]([OH:18])=O)[NH:13]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N[CH2:20][C:21]([NH2:23])=[O:22]>>[C:5]([CH2:4][NH:23][C:21]([C@@H:20]1[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[NH:13][C:16]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH:15]=2)=[O:18])=[O:22])#[N:1]
Reactant: NCC(N)=O
Reactant: O=C(O)c1cc2ccc(Cn3ccnc3)cc2[nH]1
Product: N#CCNC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(Cn3ccnc3)cc2[nH]1

Procedure:
6-Imidazol-1-ylmethyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide was prepared from 6-imidazol-1-ylmethyl-1H-indole-2-carboxylic acid using the coupling procedure of Example 10 and replacing leucinamide with 2-aminoacetamide.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1.[C:29]1([NH2:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=[N:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1CCC(=Nc2ccccc2)CC1

Procedure:
To a stirred and refluxing mixture of 48 parts of 1-(1-methylethyl)-4-piperidinone, 1 part of 4-methylbenzenesulfonic acid and 540 parts of methylbenzene is added dropwise a solution of 30 parts of benzenamine in 90 parts of methylbenzene. Upon completion, the whole is stirred and refluxed for 3 hours with water-separator. The reaction mixture is evaporated, yielding 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine as a residue.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:12]#[N:13].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8][C:12]#[N:13])[CH:7]=1
Reactant: [C-]#N
Reactant: N#Cc1ncc(CCl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cnc(C#N)c(Cl)c1
Temperature: 130 °C

Procedure:
To a solution of 3-chloro-5-(chloromethyl)picolinonitrile (from the previous step) in DMSO (0.2 M) was added sodium cyanide (1.25 eq). The reaction mixture was heated at 130° C. under microwave irradiation. The reaction mixture taken up in water and EtOAc, and extracted with EtOAc. Organic phases were dried over anhydrous Na2SO4, and concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the crude afforded 3-chloro-5-(cyanomethyl)picolinonitrile.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:37]5[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 72.6 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 78 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (88 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 9.11 (t, J=5.8 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.35-7.41 (m, 2H), 7.16 (t, J=8.7 Hz, 2H), 4.50 (d, J=5.8 Hz, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][CH2:34][OH:35])[CH:32]=1)[CH2:5][N:6]1[CH2:29][CH2:28][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=CC=C[CH:23]=4)[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1.N.[CH3:37]O>>[C:22]([C:19]1[S:20][CH:21]=[C:17]([C:15]([N:11]2[CH2:10][C:9]3([CH2:28][CH2:29][N:6]([CH2:5][C:4]4[CH:30]=[C:31]([CH2:33][CH2:34][OH:35])[CH:32]=[C:2]([F:1])[CH:3]=4)[CH2:7][CH2:8]3)[O:14][CH2:13][CH2:12]2)=[O:16])[N:18]=1)([CH3:37])([CH3:23])[CH3:27]
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reactant: CO
Agent: N
Product: CC(C)(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,2-trifluoro-1-(9-(3-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone (example 41, step d) (0.21 g) in methanol (3 mL) was added to ammonia (35% aqueous solution, 15 mL) and the reaction mixture stirred at 20° C. for 1 hour. The mixture was evaporated to dryness under reduced pressure and the residue azeotroped three times with acetonitrile. The residue was dissolved in DMF (7 mL) and treated with 2-tert-butylthiazole-4-carboxylic acid (0.096 g) followed by triethylamine (0.290 mL) and then HATU (0.257 g) and the resultant mixture stirred at 20° C. for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.22 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][S:15]([NH:18][C:19](=[O:25])[C:20](OCC)=[O:21])(=[O:17])=[O:16])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[S:15](=[O:17])(=[O:16])[NH:18][C:19](=[O:25])[C:20]=3[OH:21])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(=O)NS(=O)(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NS(=O)(=O)C(c2nc(-c3ccc(Cl)c(Cl)c3)cs2)=C1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the 2-thiazolylmethyl substituted oxamate intermediate prepared in Step B above (1.0 g., 0.0024 mol) in dimethylformamide (5 ml) was added potassium tert-butoxide (0.55 g, 0.0048 ml) in several portions over 15 minutes. The mixture was stirred at room temperature for 24 hours. After diluting with water (30 ml) and acidifying to congo red indicator paper, a yellow gum (1.1 g.) was obtained. Recrystallization was achieved by dissolving in boiling ether (500 ml), filtering, concentrating to a small volume, and adding petroleum ether. The yield of the title product was 0.3 g., m.p. 250° C. (dec.).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][C@H:36]([C:39]([OH:41])=[O:40])[CH2:37][OH:38]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:35][CH:36]([CH2:37][OH:38])[C:39]([OH:41])=[O:40])=[O:18])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Product: O=C(NC(CO)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Yield: 36 %

Procedure:
Compound 231 was synthesized from Compound 201 as described for Compound 235, except L-serine was used instead of L-5-hydroxytryptophane. Yield: 36%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH2:19])([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)[CH3:2].Br.CN1CCOCC1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH:19][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:17])[CH3:18])[N:15]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(-c2nc(C(C)(C)N)cs2)cc1
Agent: Br
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2nc(C(C)(C)NC(=O)c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 4-[4-(1-Amino-1-methyl-ethyl)-thiazol-2-yl]-benzoic acid ethyl ester:hydrobromide (11.0 mmol) and n-methylmorpholine (2.0 mmol) in dichloromethane (0.10M), add benzoyl chloride (1.0 mmol) diluted in 2 mL dichloromethane. Stir at room temperature for 20 minutes. Wash the reaction with water while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify via radial chromatography eluting with ethyl acetate and hexane. MS (m/e): 395.2 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH2:32]([NH:34][CH3:35])[CH3:33]>>[CH2:32]([N:34]([CH3:35])[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[CH3:33]
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CCNC
Product: CCN(C)CCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(OC)cc4c3CC2(C)C1=O

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and N-ethyl methyl amine as starting materials. MS: m/z (MH+)=463.2
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7].Cl>O.CCOCC>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=1)[CH3:7]
Reactant: CCc1ccc(O)cc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 95 %

Procedure:
To a stirred mixture of 130 ml of water, 130 ml of ether, 7.66 g of sodium nitrate and 10.0 g of 4-ethylphenol was added 13 ml of concentrated hydrochloric acid, and the reaction was continued at room temperature for 3 days. To the reaction mixture was added 300 ml of water and the mixture was extracted with 500 ml of ether. The extract was washed with water, then a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure to give 13.0 g of 4-ethyl-2-nitrophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:20])[CH:15](Br)[CH2:16][CH2:17][CH3:18])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:20])[CH:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 mL) was heated at 140° C. for 1 h. After cooled to room temperature, the mixture was poured into water and the water phase was extracted with EtOAc thrice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).