Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[Br:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:4][CH:5]=1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Fc1ccc(C(OCCCBr)c2ccc(F)cc2)cc1
Yield: 68.8 %

Procedure:
A mixture of 36.9 g (0.130 mole) of bromobis(4-fluorophenyl)methane, 21.7 g (0.156 mole) of 3-bromopropanol, 16.6 g (0.156 mole) of sodium carbonate and a few potassium iodide crystals were heated to 130° C. for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with ether. The ethereal phase was washed with water, dried on sodium sulfate and then concentrated to dryness. Distillation of the residue yielded 30.5 g (yield: 68%) of the desired propane.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:9](N[C@@H](C(N[C@H](C(N(CC1C=CC=CC=1)C)=O)CC1C=CC=CC=1)=O)CC1C2C(=CC=CC=2)N(C=O)C=1)=[O:10])CC1N=CNC=1.C1(OC)C=CC=CC=1.[ClH:62].[NH2:63][C@H:64]([C:71]([NH:73][C@@H:74]([C:87]([NH:89][C@H:90]([C:98]([N:100]([CH2:102][C:103]1[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=1)[CH3:101])=[O:99])[CH2:91][C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)=[O:88])[CH2:75][C:76]1[C:84]2[C:79](=[CH:80][CH:81]=[CH:82][CH:83]=2)[N:78]([CH:85]=[O:86])[CH:77]=1)=[O:72])[CH2:65][C:66]1[N:70]=[CH:69][NH:68][CH:67]=1.CC(OC(C)=O)=O>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[NH:63]([C:9]([CH3:2])=[O:10])[C@H:64]([C:71]([NH:73][C@@H:74]([C:87]([NH:89][C@H:90]([C:98]([N:100]([CH2:102][C:103]1[CH:104]=[CH:105][CH:106]=[CH:107][CH:108]=1)[CH3:101])=[O:99])[CH2:91][C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1)=[O:88])[CH2:75][C:76]1[C:84]2[C:79](=[CH:80][CH:81]=[CH:82][CH:83]=2)[N:78]([CH:85]=[O:86])[CH:77]=1)=[O:72])[CH2:65][C:66]1[N:70]=[CH:69][NH:68][CH:67]=1.[ClH:62]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of Boc-His-D-Trp(CHO)-Phe-NMeBzl (0.70 g) and anisole (0.7 ml) in methylene chloride (5 ml) was added 4N-HCl/DOX (5 ml). The solution was stirred for an hour at room temperature. After evaporation, the residue was pulverized with diisopropyl ether, filtered, washed with diisopropyl ether and dried to give 2HCl.H-His-D-Trp(CHO)-Phe-NMeBzl. The powder (0.70 g) was dissolved in a mixture of methylene chloride (10 ml) and DMF (1 ml) and ice-cooled. To the solution, triethylamine (0.41 ml) and Ac2O (0.09 ml) were added. After stirring for an hour and twenty minutes, triethylamine (0.12 ml) and Ac2O (0.09 ml) were added and stirred for additional half an hour. The mixture was evaporated and the residue was extracted with ethyl acetate. The organic layer was washed successively with water, 2% hydrochloric acid, water and saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residue was dissolved in DMF (10 ml). To the solution, pyridinium chloride (1.16 g) was added and the mixture was stirred for an hour. After evaporation the residue was solidified with water, filtered, washed with water, and dried. The powder was subjected to column chromatography on silica gel (20 g) and eluted with a mixture of chloroform and methanol (9:1). The fractions containing the object compound were combined and evaporated. The residue was pulverized with diethyl ether and filtered. The powder was dissolved in a mixture of chloroform and methanol. To the solution was added 4N-HCl/DOX (0.25 ml) and evaporated. The residue was pulverized with diethyl ether, filtered, washed with diethyl ether and dried to give Ac-His-D-Trp(CHO)-Phe-NMeBzl.HCl (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Sc1ccc(Cl)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 3.55 g of methyl α-(p-chlorophenylthio)-α-[p-(phenoxy)phenyl]acetate, 20 ml of 20% KOH and 5 ml of methanol is refluxed overnight. The mixture is acidified and worked up to afford a light green solid which is crystallized from chloroform to yield the product as white crystals, mp 121°-125° C.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[N:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1)SC)(=[O:9])=[O:8].[CH3:31][O:32][NH2:33]>O1CCOCC1>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1)=[N:33][O:32][CH3:31])(=[O:9])=[O:8]
Reactant: CON
Reactant: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Solvent: C1COCCO1
Product: CON=C(Nc1nc(OC)nc(OC)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 69.8 %

Procedure:
4.45 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea were dissolved in 50 ml of dioxane, and 2.35 g of O-methylhydroxylamine were added to the solution. The mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 3.1 g of N-(2-biphenylylsulfonyl) N'-(4,6-dimethoxy-1,3,5-triazin-2-yl) N"-(methoxy)guanidine represented by the following formula: ##STR30##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
To a solution of methyl 2-(2-methoxy-4-nitrophenyl)acetate (step 3, 1.2 g, 5.5 mmol) in methanol (10 ml) was added 10% Pd/C (130 mg, 0.12 mmol) and stirred under hydrogen atmosphere for 3 h at room temperature. The catalyst was filtered off through a pad of celite and well washed with ethanol and ethyl acetate. The filtrate was concentrated to give 1.1 g of title compound as pink oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[C@@H:21]([C:22]#[CH:23])[CH2:20][CH2:19][C:18]1=[O:24].O>C(N(CC)CC)C.[Cu](I)I.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>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:23]#[C:22][C@@H:21]2[N:17]([CH2:16][C:15]3[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:14]=3[O:13][CH3:12])[C:18](=[O:24])[CH2:19][CH2:20]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: C#C[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(C(C)(C)C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Copper iodide (74 mg) and bis(triphenylphosphine)palladium(II) dichloride (135 mg) were added to a solution of 4-tert-butyliodobenzene (3.0 g) in triethylamine (10 mL), and the mixture was stirred at room temperature for 15 minutes. (5R)-1-(2,4-Dimethoxybenzyl)-5-ethynylpyrrolidin-2-one (1.0 g) was added thereto over one hour, and the mixture was stirred at room temperature for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-[(4-tert-butylphenyl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless powder (1.25 g, 84%).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH3:52])[CH2:50][CH2:49][C@H:48]1[C:53]([OH:55])=[O:54])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:55][C:53]([C@@H:48]6[CH2:49][CH2:50][C@H:51]([CH3:52])[N:47]6[C:45]([O:44][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:46])=[O:54])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(OC(=O)[C@@H]2CC[C@H](C)N2C(=O)OC(C)(C)C)C4=O)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 53.1 %

Procedure:
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (700 mg, 1.17 mmol) was treated with a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (375 mg, 1.64 mmol) in acetone (6 mL) and Cs2CO3 (267 mg, 0.82 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (464 mg, 53%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][NH:13][CH3:14].[NH2:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18](O)=[O:19].C(Cl)CCl>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([N:13]([O:12][CH3:11])[CH3:14])=[O:19]
Reactant: CNOC
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)ccc1N
Reaction time: 2 h

Procedure:
To a 0° C. mixture of diisopropylethylamine (34.36 mL, 197.25 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (19.24 g, 197.25 mmol) in CHCl3 (300 mL) was added 2-amino-5-fluorobenzoic acid (25.50 g, 164.38 mmol) followed by EDC (31.51 g, 164.38 mmol). The reaction was stirred from 0° C. to ambient temperature over 2 h and then diluted with CH2Cl2 (100 mL), washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (3-8% MeOH/CH2Cl2) yielded 2-amino-5-fluoro-N-methoxy-N-methylbenzamide as a yellow oil. 1H NMR (CDCl3, 400 MHz) 7.12 (m, 1H, ArH); 6.93 (m, 1H, ArH); 6.65 (m, 1H, ArH); 3.63 (s, 3H, CH3); 3.35 (s, 3H, CH3); MS (Electrospray): m/z 199.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C>[Cl:22][C:23]1[C:28]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[O:9])=[CH:4][CH:3]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(c1ccc(O)cc1)c1ccccn1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1ccccn1
Temperature: 80 °C

Procedure:
To a stirred solution of (4-hydroxy-phenyl)-pyridin-2-yl-methanone (2.5 g, 0.0125 mol) in DMF (35 mL) was added cesium carbonate (6.14 g, 0.0188 mol). The resulting mixture was stirred for 15 minutes before addition of 2,3-dichloro pyrazine(1.87 g, 0.0125 mol) at 0° C. The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×100 mL). The organic layer was dried over sodium sulphate and concentrated to afford the product. MS (ESI, pos. ion) m/z: 312 (M+1). IC50 (uM) 30.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][OH:31])[C:24](OC)=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[CH2:28][CH2:29][CH2:30][O:31][C:24]1=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCCO)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H]1CCCOC1=O)OCc1ccccc1
Yield: 75.8 %

Procedure:
In benzene (100 ml ) was dissolved methyl (S )-2-[[N-benzyloxycarbonyl-(L )-phenylalanyl]amino]-5-hydroxyvalerate (2.85 g) followed by addition of p-toluenesulfonic acid (0.09 g), and the mixture was stirred under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure to provide (S)-3-[[N-benzyloxycarbonyl-(L)-phenylalanyl]amino]-2-oxotetrahydropyran (chemical formula below) (2.0 g, 77%) m p 167°-169° C. optical rotation [α]D +43. 6° (c=0.50, CHCl3) ##STR36##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl[CH2:16][CH:17]=[CH2:18]>CS(C)=O>[CH3:16][CH:17]1[CH2:18][C:3]2[C:2]([Cl:1])=[C:7]([CH3:8])[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=2[O:12]1
Reactant: C=CCCl
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(C)O2
Temperature: 190 °C
Reaction time: 8 h

Procedure:
A mixture of 93.4 g of 2B, 750 ml of DMSO, 48 g of 50% aqueous sodium hydroxide and 45.9 g of 3-chloropropene was stirred for 8 hours at 75°-80° C., then for 16 hours at room temperature, The resulting mixture was added to 3 liters of ice water and the resulting mixture was extracted with methylene chloride. The extract was washed with water, dried (MgSO4) and evaporated to dryness. The residue, in a nitrogen atmosphere, was heated slowly to 190° C. (one hour) and held at 185°-195° C. for two hours, cooled to room temperature, and dissolved in 250 ml of acetic acid. 150 ml of 48% aqueous hydrogen bromide solution was added. The mixture was stirred at reflux for three hours, then mixed with 2 liters of ice water, and the resulting mixture was extracted with a 1:1 v:v mixture of hexane and ether. The extract was washed with water, 5 % aqueous sodium bicarbonate solution, dried (MgSO4), charcoaled and concentrated to dryness. The residue was crystallized from 500 ml of 9:1 v:v hexane/ether mixture, giving 2,3-dihydro-2,5-dimethyl-4-chloro-7-nitrobenzofuran (2C), m.p.: 114°-116° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:32][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOCCOCCOCCBr)(c1ccccc1)c1ccccc1

Procedure:
Compound 10 (651 mg, 1.50 mmol) and carbon tetrabromide (628 mg, 1.88 mmol) were dissolved in tetrahydrofuran (THF, 0.5 mL). Triphenylphosphine (498 mg, 1.88 mmol) was added to this solution portionwise over 5 min with stirring and additional amount of THF (0.5 mL) was added to the mixture. Reaction was monitored by TLC, which indicated that it was over in 10 min Solvent was removed at room temperature and the crude product was chromatographed (SiO2, hexane/EtOAc 2:1) to give 767 mg (1.55 mmol, >100%, less dry) of 35 as a clear colorless oil. Rf 0.74 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.68 (m, 4H, H-2 of phenyl), 7.45-7.35 (m, 6H, H-3 and H-4 of phenyl), 3.81 (t, 2H, J=5.5 Hz, CH2CH2OSi), 3.79 (t, 2H, J=7.1 Hz, CH2CH2Br), 3.65 (m, 8H, (OCH2CH2)2OCH2CH2OSi), 3.61 (t, 2H, J=5.3 Hz, CH2CH2OSi), 3.45 (t, 2H, J=6.4 Hz, CH2CH2Br), 1.05 (s, 9H, C(CH3)3); MS (ESI) Calcd for C24H35BrO4SiNa (M+Na+): 517.1. Found: 517.1.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7](=[O:32])[C@@H:8]([NH:24]C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].FC(F)(F)C(O)=O>ClCCl>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7](=[O:32])[C@@H:8]([NH2:24])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of (2S)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylaminohexanoic acid 1,3,4-thiadiazol-2-ylamide (0.81 g, 1.75 mmol) in dichloromethane (8 mL) is added trifluoroacetic acid (2 mL). The resulting solution is stirred for 4 h at 25° C., is concentrated, diluted with 50 mL of EtOAc, and washed with 1 N aqueous sodium hydroxide solution. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide (2S)-6-benzyloxycarbonylamino-2-aminohexanoic acid 1,3,4-thiadiazol-2-ylamide as a solid (0.62 g, 98% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([C:14]([CH3:16])=O)[C:9](OCC)=[O:10])[CH:2]=1.[NH2:17][C:18]([NH2:20])=[S:19].[O-]CC.[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:10])[NH:17][C:18](=[S:19])[NH:20][C:14]=2[CH3:16])[CH:2]=1
Reactant: CCOC(=O)C(Cc1cccnc1)C(C)=O
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1[nH]c(=S)[nH]c(=O)c1Cc1cccnc1

Procedure:
A mixture of pyridine-3-carboxaldehyde (48 g), ethyl acetoacetate (52 g) aqueous piperidine acetate (40% 4.8 g) and 5% palladium on charcoal catalyst (50% wet, 2.48 g) was hydrogenated at 100 p.s.i. at 30° for 22 hours. The mixture was diluted with ether, filtered and the filtrate was evaporated and distilled under reduced pressure to give ethyl α-(3-pyridylmethyl)acetoacetate (b.p. 146°/1 mmHg). This ester was refluxed with thiourea and sodium ethoxide in ethanol, and the mixture was subsequently acidified to give 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 328°-331°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:35][CH2:34]4)[CH:30]=[CH:29][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[Br-].[O:85]1[CH2:89][CH2:88][O:87][CH:86]1[CH2:90][CH2:91][Zn+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([C:41]2[CH2:42][C:43]([CH3:46])([CH3:47])[CH2:44][CH2:45][C:40]=2[CH2:39][N:36]2[CH2:35][CH2:34][N:33]([C:31]3[CH:30]=[CH:29][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([CH2:91][CH2:90][CH:86]5[O:87][CH2:88][CH2:89][O:85]5)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[CH:3]5)[CH:32]=3)[CH2:38][CH2:37]2)=[CH:49][CH:50]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: [Zn+]CCC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(CCC5OCCO5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 187A (0.079 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.016 g), and palladium acetate (0.0045 g) in tetrahydrofuran (1 mL) was stirred at room temperature for 5 minutes. To this mixture was added (2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (0.6 mL). The reaction mixture was stirred overnight. The solvent was removed, and the residue was purified by reverse phase Prep HPLC. The desired fractions were combined, and the organic solvent was partially removed. The resulting mixture was treated with saturated aqueous NaHCO3, extracted with ethyl acetate, dried over MgSO4, filtered, and concentrated to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.14 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.55 (br s., 1H), 7.52 (d, 1H), 7.33-7.39 (m, 4H), 7.08 (br s, 1H), 7.04 (d, 2H), 6.83 (dd, 1H), 6.62 (d, 1H), 6.38 (s, 1H), 6.15 (d, 1H), 4.85 (t, 1H), 3.87-3.89 (m, 2H), 3.76-3.79 (m, 2H), 3.04 (s, 4H), 2.91-2.94 (m, 2H), 2.11-2.15 (m, 4H), 1.88-1.91 (s, 4H), 1.39 (t, 2H), 0.92 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[F:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[F:40])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 160 °C

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 231 mg, 0.75 mmol), 4-amino-N-(1-ethylpiperidin-4-yl)-3-fluorobenzamide (200 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (335 mg, 1.88 mmol) were suspended in 4-Methyl-2-pentanol (5 mL) and sealed into a microwave tube. The reaction was heated to 160° C. for 30 minutes in the microwave reactor and allowed to cool to room temperature.