Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[C:21]([CH3:24])=[N:22][O:23][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])[NH2:3].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:4][C:2]1([CH3:1])[NH:3][C:33](=[O:35])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:20]4[C:21]([CH3:24])=[N:22][O:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[C:5]1=[O:6]
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cc3)c12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1noc2cccc(Oc3ccc(N4C(=O)NC(C)(C)C4=O)cc3)c12
Reaction time: 0.08 h

Procedure:
2-methyl-N1-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}alaninamide (Intermediate 25, 18 mg) was dissolved in 4 ml of ethyl acetate. Triethylamine (0.017 ml, 0.12 mmol) was then added followed by a solution of triphosgene (8.21 mg, 0.028 mmol) in 1.0 ml of ethyl acetate. After stirring for 5 minutes, DMAP (3.4 mg, 0.028 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated aqueous solution of NaHCO3, the mixture was extracted two times with ethyl acetate and the collected organic layers were dried over sodium sulphate, filtered and evaporated. The crude obtained was charged on a silica gel column and eluted with c-Hex/EtOAc as eluents (from all 100:0 to 0:100). This afforded 10 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:17]([O:19][C@H:20]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[CH:22]([C:23](=[O:40])[CH2:24][C@@H:25]4[C@@H:34]3[CH2:33][CH2:32][C@@:30]3([CH3:31])[C@H:26]4[CH2:27][CH2:28][C:29]3=[O:39])[CH2:21]2)=[O:18])C=CN=C1.O>C(Cl)Cl.CC(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:17]([O:19][C@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[CH:22]([C:23](=[O:40])[CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C:29]2=[O:39])[CH2:21]1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@]12CC[C@H](OC(=O)n3ccnc3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Yield: 76 %

Procedure:
N-(tert-Butoxycarbonyl)ethylendiamine (0.20 mL) was added to a solution of 3β-(1-imidazolylcarbonyloxy)androstane-6,17-dione (200 mg) in CH2Cl2 (10 mL) and 2-propanol (1 mL). After heating under reflux for 9 hr, the mixture was cooled to room temperature and water was added. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2; CH2Cl2:EtOAc 1:1) to give 3β-[N-(2-tert-butoxycarbonylaminoethyl)-carbamoyloxy]androstane-6,17-dione (184 mg, 76%). 1H-NMR (300 MHz, CDCl3, ppm from TMS): δ 5.02 (1H, bb), 4.84 (1H, bb), 4.56 (1H, m), 3.27 (4H, m), 2.50-1.20 (20H, m), 1.45 (9H, s), 0.87 (3H, s), 0.80 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][C:2]1[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 3,4-dihydroxy-benzaldehyde (2.76 g, 20 mmol) in dry acetone (50 ml), potassium carbonate (5.52 g, 40 mmol) and benzylbromide (5 ml, 42 mmol) was heated at reflux for 12 hours. The mixture was cooled to room temperature, potassium carbonate was removed by filtering the solution and the filtrate was concentrated to a powder which was recrystallized from acetone to yield (5.4 g, 81%) ether as prisms, mp 89°-90° (lit. mp 90°) IR νmax 1685, 1595, 1483, 1508, 1454, 1434, 1269, 1132, 695, 650 cm-1 ; 1H-NMR (90 MHz), 5.21 (2H, s, ArCH2O), 5.26 (2H, s, ArCH20), 7.02 (1H, d, J=7.9 Hz), 7.30-7.50 (12H, ArH), 9.81 (1H, s, CHO). Anal. calcd for C21H18O3 : C, 79.23; H, 5.70. Found: C, 79.26; H, 5.68.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:31]=[C:30]([CH2:32][S:33][C:34]2[C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=[CH:28][N:27]=1.[NH2:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[CH:45]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:51][C:46]1[CH:45]=[C:44]([NH:43][C:40]([C:39]2[C:34]([S:33][CH2:32][C:30]3[CH:29]=[CH:28][N:27]=[C:26]([F:25])[CH:31]=3)=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:42])[CH:49]=[C:48]([CH3:50])[CH:47]=1
Reactant: O=C(O)c1cccnc1SCc1ccnc(F)c1
Reactant: Cc1cc(C)cc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(F)c2)c1
Yield: 44 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 g, 7.9 mmol) was added to a solution of 2-(2-fluoropyridin-4-ylmethylthio)pyridine-3-carboxylic acid (Reference compound No. 2-1, 1.5 g, 5.7 mmol), 3,5-xylidine (0.90 g, 7.4 mmol) and N,N-diisopropylethylamine (2.0 mL, 11 mmol) in N,N-dimethylformamide (20 mL) at room temperature, and the mixture was stirred for 12 hours. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with brine (50 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 0.91 g of the title reference compound as a colorless solid. (Yield 44%)
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)([O-:5])=[O:4].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[N:27]=[C:26]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][CH2:9][C:8]3[CH:18]=[CH:19][CH:20]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=3)[CH:12]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 128.1 %

Procedure:
To a solution of N-(3-nitrobenzyl)benzene-1,3-diamine dihydrochloride (6.58 g, 0.021 mol) and 2,4,5-trichloropyrimidine (2.38 mL, 0.021 mol) in N,N-dimethylformamide (70 mL) was added potassium carbonate (10.1 g, 0.073 mol). The resultant mixture was stirred for 60 h at room temperature. The reaction mixture was filtered first to remove K2CO3, and then quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue (10.5 g), which was purified by silica gel column chromatography to give the desired product as a light yellow powder (6.19 g, 76%). LCMS for C17H14Cl2N5O2 (M+H)+: m/z=389.9.
Reaction SMILES: C(Cl)Cl.[NH2:4][C@@H:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([O:34]C)[CH:25]=1)[CH2:6][NH:7][C:8]1[S:9][C:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][N:19]=[CH:20]3)=[CH:15][CH:14]=2)=[CH:11][N:12]=1.B(Br)(Br)Br>>[NH2:4][C@H:5]([CH2:6][NH:7][C:8]1[S:9][C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:13]=2)[CH:20]=[N:19][CH:18]=[CH:17]3)=[CH:11][N:12]=1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[C:26]([OH:34])[CH:25]=1.[NH2:4][C@H:5]([CH2:6][NH:7][C:8]1[S:9][C:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][N:19]=[CH:20]3)=[CH:15][CH:14]=2)=[CH:11][N:12]=1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[C:26]([OH:34])[CH:25]=1
Reactant: COc1cc(C[C@H](N)CNc2ncc(-c3ccc4ccncc4c3)s2)ccc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N[C@H](CNc1ncc(-c2ccc3ccncc3c2)s1)Cc1ccc(C(F)(F)F)c(O)c1
Product: N[C@H](CNc1ncc(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)c(O)c1
Temperature: -78 °C
Yield: 94.2 %

Procedure:
To a 50 mL round-bottomed flask was added anhydrous DCM (25 mL, 383 mmol) and N—((S)-2-amino-3-(3-methoxy-4-(trifluoromethyl)phenyl)-propyl)-5-(isoquinolin-7-yl)thiazol-2-amine (0.040 g, 0.086 mmol). The suspension was stirred at −78° C. and treated drop wise via syringe with boron tribromide (0.082 mL, 0.86 mmol). The solution was stirred at −78° C. for 1 hour and warmed to −12° C. and stirred for 1 hour and then stirred for 3 hours at room temperature. The reaction was quenched with NaHCO3 and ether, and the separated aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with saturated sodium chloride, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography ((5%→20% MeOH in DCM) to obtain the desired product as an off white solid of 5-((S)-2-amino-3-(5-(isoquinolin-7-yl)thiazol-2-ylamino)propyl)-2-(trifluoromethyl)phenol (0.018 g, 46% yield). m/z (%): 445.4 (100%, M++H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH2:18](N(CC)CC)[CH3:19].CN(C)[CH:27]=[O:28]>>[C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@:3]([CH:18]=[CH:19][CH:27]=[O:28])([OH:4])[CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Product: Cc1cn([C@H]2C[C@@](O)(C=CC=O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
Thymidine (488 mg, 2 mmol) is dissolved in dimethylformamide (4 ml), triethylamine (280 μl; 2 mmole) is added and the mixture is stirred for 1 hr. then cooled to -78°. Propargyl aldehyde (200 μl; 4 mmole) is added and the mixture is stirred at this temperature for 2 hrs. and then allowed to come to room temperature over a period of 3 hrs. The solvent and triethylamine are removed under reduced pressure at room temperature. The residue is dissolved in methanol and applied to two preparative tic plates (20×20 cm; silica gel, 2 mm thick). The plates are developed with ethyl acetate containing 5% methanol. The desired product has Rf 0.65 and is detected by means of a thiobarbituric acid coloration test (pink). The starting material has an Rf of 0.4. Removal of the appropriate band from the plates, followed by extraction with methanol affords the title compound as an almost colorless glass (220 mg, 35%) which crystallized on standing m.p. 121°-2°. The infrared spectrum shows bands at 3425 (OH), 1733 (CHO), 1690, 1660, 1295, 1260, 1150, 1095, 1040 cm-1. The NMR spectrum has absorption bands at (DMSO) 1.85 (S, 3H, CH3) 6.19 (t, J=6.1 Hz, 1H, O--CH--N) 7.06 (q,J,=7.8 Hz J2 =14.8 Hz 1H, CH=CH--CHO) 7.95 (s, 1H, 4H) 8.16 (d, J=14.6 Hz, 1H, CH=CH--CHO) 9.60 (d, J=7.8 Hz, 1H, CHO) in addition to the peaks usually observed for thymidine the NH at 11.28 excepted. Mass spectrum m/z (intensity % of base peak), ion: 296 (0.4)M+, 242(2.0) (M-54)+, 180 (4.0) (M-117)+, 117 (100) (M-180)+ , 73 (71)C3H3O.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].O.[Cl-].[NH4+]>C(O)C.C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH2:11][C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(F)c(CC(=O)O)c1
Temperature: 80 °C

Procedure:
To a suspension of 2-(2-fluoro-5-nitrophenyl)acetic acid (15.0 g, 75.3 mmol) in ethanol (800 mL), THF (400 mL), and water (200 mL) was added ammonium chloride (4.46 g, 83.4 mmol) and ferrous powder (25.04 g, 405.4 mmol). The resulting mixture was heated at 80° C. for 1 hr and the progress of the reaction was monitored by TLC. Upon complete consumption of starting material, the reaction mixture was filtered off while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (200 mL) and washed with water (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum to afford 2-(5-amino-2-fluorophenyl)acetic acid as a grey solid which was used for the next step without further purification (6.13 g, 48%).
Reaction SMILES: IC.[NH:3]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[N:6][N:5]=[N:4]1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:35][N:6]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)=[O:23])=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)=[N:3][N:4]=[N:5]1
Reactant: O=C(Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnnc1-c1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Iodomethane (0.21 mL, 3.40 mmol, 1.5 equiv) is added to a cold (0° C.) mixture of 1-{4-[2-(1H-tetrazol-5yl)-pyridin-4-yloxy]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea (Example 122) (1.0 g, 2.27 mmol) and potassium carbonate (0.94 g, 6.80 mmol, 3.0 equiv) in DMF abs. (5.8 mL), under an argon atmosphere. The reaction mixture is stirred at 0° C. for 2 h, allowed to warm to rt and stirred for additional 20 h. The resulting brown suspension is filtered and concentrated in vacuo. MeOH (10 mL) and DMF (0.5 mL) are added to the residue and the resulting suspension is filtered. The white solid is washed with MeOH and dried in vacuo to afford the title compound as a white solid. The filtrate is concentrated in vacuo and the residue is purified by MPLC (CH3CN/H2O/TFA) to afford additional title compound as a beige solid: ES-MS: 455.9 [M+H]+; single peak at tR=9.15 min (System 2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[C:35]=[O:36].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:35]([NH:34][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)=[O:36])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.4 %

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (18.18 mg, 0.18 mmol) in dichloromethane (6 ml) was added 1-isocyanato-4-methoxybenzene (26.82 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound Yield: 25 mg (22.82%); 1H NMR (DMSO-d6, 300 MHz): δ 8.785 (s, 1H), 7.81-7.94 (m, 4H), 7.62-7.69 (m, 3H), 6.95 (s, 1H), 6.47-6.63 (m, 4H), 3.51 (s, 3H), 1.79 (s, 6H); MS: m/z 556 (M+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][C@@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1.C(N(CC)CC)C.[F:26][C:27]1[CH:47]=[C:46]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:45]=[CH:44][C:28]=1[O:29][C:30]1[C:35]([CH3:36])=[C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[N:33]=[CH:32][N:31]=1>C1COCC1>[O:16]1[CH2:17][CH2:18][C@@H:14]([O:13][C:1]([N:41]2[CH2:42][CH2:43][CH:38]([O:37][C:34]3[C:35]([CH3:36])=[C:30]([O:29][C:28]4[CH:44]=[CH:45][C:46]([S:48]([CH3:51])(=[O:49])=[O:50])=[CH:47][C:27]=4[F:26])[N:31]=[CH:32][N:33]=3)[CH2:39][CH2:40]2)=[O:2])[CH2:15]1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)O[C@@H]2CCOC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (54.8 mg, 0.338 mmol) in 1 mL THF was added (R)-(+)-3-hydroxytetrahydrofuran (32 μl, 0.38 mmol). After stirring for 30 minutes at room temperature, 1 mL triethylamine, 1 mL THF, and 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (70 mg, 0.166 mmol) were added. The resulting mixture was stirred at 60° C. for 48 hours and purified by HPLC to give Compound C177 as a white solid (35.3 mg, 42%). 1H NMR (CDCl3, 400 MHz) δ 1.81-1.88 (m, 2H), 1.96-2.09 (m, 3H), 2.12-2.20 (m, 4H), 3.10 (s, 3H), 3.42-3.48 (m, 2H), 3.75-3.81 (m, 2H), 3.84-3.97 (m, 4H), 5.27-5.31 (m, 1H), 5.34-5.38 (m, 1H), 7.41-7.45 (m, 1H), 7.77-7.82 (m, 2H), 8.20 (s, 1H). Exact mass calculated for C22H26FN3O7S 495.15, found 496.3 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.O.[OH-].[Na+]>C(O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[C:21]([CH3:29])[CH:22]=1)(=[O:28])[NH2:27]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]propanoic acid ethyl ester (86 mg, 0.216 mmol) was dissolved in ethanol (4 mL). Water (0.5 mL) was added to the ethanolic solution followed by the addition of 1N NaOH (0.51 mL, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 h and then at 45° C. for an additional hour. After removal of the solvent in vacuo, the residue was diluted with water (6 mL) and extracted with ethyl acetate (2×6 mL). The pH of the aqueous layer was adjusted to 2 with 1 N HCl and then extracted with ethyl acetate (6 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent removed in vacuo to obtain 3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propanoic acid as the product (68 mg, 85%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].C(O)(=O)C>O>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[O:20])[NH:21][C:22]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2NC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 50.6 %

Procedure:
A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde (7.0 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), μ-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 48 hours the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed with water three times, and dried. Recrystallization from acetonitrile gave the pure product (4.8 g), mp 251°-252° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1)C)C1C=CC=CC=1.[CH2:35](O)C>[Pd]>[CH3:1][NH:8][CH:10]([CH3:35])[CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1
Reactant: CCO
Reactant: CN(CCN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O)Cc1ccccc1
Agent: [Pd]
Product: CNC(C)CN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O

Procedure:
4 g of 2-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a] [1,5]benzodiazepine-1,5-dione in 100 ml of ethanol containing 0.4 g of 5% palladium on charcoal is hydrogenated at 50 p.s.i. hydrogen pressure until 1 molar equivalent of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Brc1cccc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
To a solution of 3-bromoaniline (1.00 g, 5.81 mmol) in anhydrous DMF (20 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (1.62 g, 6.18 mmol) and DIPEA (2.25 g, 17.4 mmol). The solution was heated to 100° C. for 16 h, cooled and concentrated. The residue was purified by preparative HPLC purification. (230 mg, yield 16.4%) MS (ESI+) e/z: 242.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[CH3:27][C:28]1[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:33]([C:31]3[S:32][C:28]([CH3:27])=[CH:29][CH:30]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: Cc1ccc(C=O)s1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Product: COC(=O)c1cc(N)c2nc(-c3ccc(C)s3)nn2c1

Procedure:
The title compound, MS m/e (%): 289.2 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and 5-methylthiophene-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 0 °C

Procedure:
95.7 g of finely pulverised aluminium chloride are suspended in 180 ml of absolute methylene chloride. While stirring and cooling, 35 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester, dissolved in a small amount of methylene chloride, are added dropwise in such a manner that the temperature remains below 30°. At the same temperature, 50.5 g of benzoyl chloride are added dropwise thereto and the whole is subsequently heated at reflux for 4 hours. After cooling, the reaction mixture is poured onto 600 g of ice. The organic phase is separated off and the aqueous phase is extracted 3 times with 150 ml of methylene chloride each time. The combined organic phases are washed once with 250 ml of water, dried over magnesium sulphate and concentrated by evaporation. The excess benzoyl chloride is distilled off under a high vacuum and the residue is crystallised from ether/petroleum ether. 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of yellow crystals having a melting point of 75°-76°.