Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])#[N:4]
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of 75 ml. of 33% methylamine in ethanol was added to a solution of 10.1 g. of N-cyano-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-S-methylisothiourea in 30 ml. of ethanol. The reaction mixture was set aside at ambient temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallized twice from isopropanol-petroleum ether to give N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p. 141°-143°.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:58])[CH2:16][N:17]([CH2:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:45])=[O:37])[CH2:18][C:19](=[O:34])[NH:20][CH2:21][CH2:22][O:23][C@@H:24]2[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]2[OH:26])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].Cl.[NH2:60][CH2:61][C@@H:62]([C:81]([OH:83])=[O:82])[NH:63][C:64]([O:66][CH2:67][CH:68]1[C:80]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:74]2[C:69]1=[CH:70][CH:71]=[CH:72][CH:73]=2)=[O:65].CCN(C(C)C)C(C)C>CN(C=O)C>[O:58]=[C:15]([NH:14][CH2:13][CH2:12][O:11][C@@H:1]1[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3])[CH2:16][N:17]([CH2:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([NH:60][CH2:61][C@@H:62]([C:81]([OH:83])=[O:82])[NH:63][C:64]([O:66][CH2:67][CH:68]1[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][C:74]=2[C:75]2[C:80]1=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:65])=[O:45])=[O:37])[CH2:18][C:19]([NH:20][CH2:21][CH2:22][O:23][C@@H:24]1[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]1[OH:26])=[O:34]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCCCCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCCCCC(=O)NC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of pentafluorophenyl 6-[({bis[2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}acetyl)amino]hexanoate (270 mg, 0.318 mmol) in DMF at 0° C. was added 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine hydrochloride (303 mg, 0.306 mmol) and, 5 min later, DIPEA (111 μL, 0.636 mmol). After stirring at 0° C. for 2 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (22 g), eluting first with 100 mL of EtOAc and then 0-20% of Solvent B in Solvent A (Solvent A: v/v EtOAc/MeOH/AcCN/H2O: 6/1/1/1; Solvent B v/v EtOAc/MeOH/AcCN/H2O: 2/1/1/1) to afford the title compound. LC-MS Method A: m/e=991.66 [M+1]; Rt=1.84 min.
Reaction SMILES: [C:1]1([C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])=[N:2]O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:2][C:1]1[C:4]([OH:5])=[N:6][C:7]([OH:8])=[N:9][C:10]=1[OH:11]
Reactant: O=C1NC(=O)C(=NO)C(=O)N1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1c(O)nc(O)nc1O
Temperature: 70 °C
Yield: 82.3 %

Procedure:
100 g of violuric acid was added to 1 liter of water with vigorous overhead stirring, and heated to 70° C. 200 g of sodium hydrosulfite was added in portions aver 15 min. After 2.5 hours the reaction was filtered and the precipitate rinsed with water. The solid was dried under vacuum at 98° C. for 3 hours to yield 75 g of 5-amino-2,4,6-trihydroxypyrimidine.
Reaction SMILES: [C:1](=[O:58])([O:6][CH:7]([C@:9]12[O:16][C@:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)([O:14][CH2:15]1)[C@H:12]([O:34]CC1C=CC=CC=1)[C@@H:11]([O:42]CC1C=CC=CC=1)[CH:10]2[O:50]CC1C=CC=CC=1)[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[C:1](=[O:58])([O:2][CH:3]([CH3:5])[CH3:4])[O:6][CH:7]([C@:9]12[O:16][C@:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)([O:14][CH2:15]1)[C@H:12]([OH:34])[C@@H:11]([OH:42])[CH:10]2[OH:50])[CH3:8]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a solution of isopropyl 1-[(1R,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethyl carbonate 13a (244 mg, 0.3 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.16 mL, 1.5 mmol) and 10% Pd/C (36 mg, 0.03 mmol) in turn at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=4/1 to give the title compound 13 as a white solid (120 mg, 75.0%, HPLC: 92.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 537.3[M+H]+; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.40 (m, 2H), 7.29 (m, 1H), 7.11 (d, 2H), 6.84 (m, 2H), 5.58 (brs, 1H), 5.04 (brs, 2H), 4.93 (m, 1H), 4.73 (m, 1H), 4.50-3.98 (m, 5H), 3.54 (m, 2H), 3.44 (m, 2H), 1.31 (m, 6H), 1.23-1.20 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[NH2:29][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(CO)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(CO)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(hydroxymethyl)piperidin-1-yl]quinolin-7-yl) ethanone (0.030 g, 0.094 mmol) and ammonium acetate (0.0725 g, 0.941 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.235 mL, 0.235 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.1.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](O)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:28]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C29H26N4O, 446.56; m/z found, 447.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]([N:14]([CH2:18][C:19]1[CH:20]=[C:21]([CH:54]=[CH:55][CH:56]=1)[C:22]([NH:24][C:25]1[S:26][C:27]2[CH2:53][CH2:52][CH2:51][CH2:50][C:28]=2[C:29]=1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:31])=[O:23])[CH:15]([CH3:17])[CH3:16])=[O:13])([O:6]CC)=[O:5])[CH3:2].Br[Si](C)(C)C.C(Cl)(Cl)Cl>O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]([N:14]([CH2:18][C:19]1[CH:20]=[C:21]([CH:54]=[CH:55][CH:56]=1)[C:22]([NH:24][C:25]1[S:26][C:27]2[CH2:53][CH2:52][CH2:51][CH2:50][C:28]=2[C:29]=1[C:30]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]([OH:47])=[O:46])=[CH:48][CH:49]=2)=[CH:37][CH:38]=1)=[O:31])=[O:23])[CH:15]([CH3:17])[CH3:16])=[O:13])([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1)C(C)C)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(O)CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of 180 mg of 4-[2-(4-{[(2-{[3-({[4-(diethoxyphosphoryl)butanoyl](isopropyl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoic acid, 0.040 mL of bromotrimethylsilane, and 3.6 mL of chloroform was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 42 mg of 4-(2-{4-[({2-[(3-{[{4-[ethoxy(hydroxy)phosphoryl]butanoyl}(isopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][NH2:14])[C:6](=O)[C:5]12[O:20][CH2:19][CH2:18][CH2:17][O:16]1.N.C1COCC1>CCOC(C)=O>[N:14]1[CH2:13][CH2:12][CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][C:4]=3[C:5]3([O:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:6]=12
Reactant: NCCCN1C(=O)C2(OCCCO2)c2cc(N)ccc21
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 25 °C
Yield: 76 %

Procedure:
5′-Amino-1′-(3-aminopropyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (1.56 g, 5.63 mmol) was dissolved in 2M EtOAc.NH3 (1.90 mL) and THF (10 mL) and heated in a steel pressure vessel at 135° C. for 16 hr. The reaction mixture was cooled to room temperature and combined with silica gel and concentrated. The adsorbate was purified on Biotage KP silica gel eluting with a step gradient of CH2Cl2/CH3OH/NH4OH (95/3/2) to (85/10/5) to give the title compound as a bright yellow-orange solid (1.11 g, 76% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:25]5[NH:24][C:32]6[C:27]([CH:26]=5)=[CH:28][CH:29]=[CH:30][CH:31]=6)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc2ccccc2[nH]1
Yield: 69.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 1H-indole-2-carboxylic acid (93 mg, 0.581 mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (3 mL) as starting materials and in the same manner as in Example 412, the title compound (153 mg, 70%) was obtained as a white powder.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[Bi](Br)(Br)Br.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][O:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])[CH2:13][CH2:14]2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@H]1CC[C@H](OCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution in acetonitrile (11 mL) of the compound (1.00 g) obtained in step (2) above, triethylsilane (579 mg) was added. Bismuth tribromide (104 mg) and 4-fluorobenzaldehyde (617 mg) were added under cooling with ice and the mixture was stirred at room temperature for two hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added and the insoluble matter was removed by filtration through Celite (registered trademark). The organic layer in the filtrate was separated and washed with saturated brine. The washed organic layer was dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (0.61 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1([CH2:28][CH2:29][CH2:30][C:31]2[N:36]=[C:35]3[CH2:37][O:38][C:39](=O)[C:34]3=[CH:33][CH:32]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:39]1[C:34]2[C:35](=[N:36][C:31]([CH2:30][CH2:29][CH2:28][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[CH2:37][O:38]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CCCN3CCOCC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCCN3CCOCC3)ccc21
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (190 mg, 1.26 mmol.) in THF (1 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (4 mL of a 1M in THF, 4 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is then removed and a solution of 2-(3-Morpholin-4-yl-propyl)-7H-furo[3,4-b]pyridin-5-one (220 mg, 0.84 mmol) in THF (15 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4.5 h and then poured into an aqueous 10% HCl solution (50 mL). The resulting solution is stirred for 70 h at room temperature. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH, EtOAc, and Et2O and dried under vacuum give the title compound (110 mg, 33%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:26][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:2][CH:3]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 92.9 %

Procedure:
3.1 g (10 mmol) of 9-(4-biphenylyl)carbazole was dissolved in 100 mL of chloroform, and 1.8 g (10 mmol) of N-bromosuccinimide was added thereto slowly. The mixture was stirred overnight (for about 24 hours) and then washed with water. Magnesium sulfate was added thereto to remove water and it was filtered. The filtrate was concentrated, collected, and dried. 3.7 g (yield: 95%) of 3-bromo-9-(4-biphenylyl)carbazole, which was beige powder, was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Yield: 33.5 %

Procedure:
N-(2-(5-Chloro-2-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.094 g; 0.382 mmol), HATU (0.132 g; 0.347 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.049 g (34%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)=O>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[CH2:18][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)n1c(Cc2cccc([N+](=O)[O-])c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example I from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromo-3′-nitroacetophenone.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:38])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:36])[C:23]([OH:35])([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=2)[C:24]([F:27])([F:26])[F:25])=[C:18]([Cl:37])[CH:17]=1)(C)(C)C>ClCCl.O>[Cl:37][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH:22]([CH3:36])[C:23]([OH:35])([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[C:24]([F:26])([F:27])[F:25])[O:15][CH2:14][C:13]([OH:38])=[O:12]
Reactant: Cc1cc(C(O)(C(C)c2ccc(OCC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(OCC(=O)O)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
Under an atmosphere of nitrogen, trifluoroacetic acid (1.5 ml) was added to a solution of {3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenoxy}-acetic acid tert-butyl ester (Example 78, 98 mg) in dichloromethane (1.5 ml). The reaction mixture was stirred for 1 h at r.t., and then diluted with water, and extracted (ethyl acetate). The combined organic layers were dried (Na2SO4), filtered, and evaporated. Flash chromatography provided the title compound (27 mg, 31%). MS (m/e)=404.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][CH2:12][C:10]4[CH:9]=[CH:8][C:5]5[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=5[N:11]=4)[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (48 mg, 44% yield) following Scheme 3 and in analogy to Example 40 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (40 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:94])[C@@H:85]([NH2:93])[C:86]3(C)[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:93][C@@H:85]([CH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]1)[C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)(=[O:59])=[O:60])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:94])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C1CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 3 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.15 g; 0.55 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.31 g; 0.82 mmol) in DCM (15 mL) was stirred for 30 min at ambient temperature. After addition of DIPEA (0.56 mL; 3.27 mmol) and (5R,8S)-7-[(S)-2-Amino-2-(4-methyl-tetrahydro-pyran-4-yl)-acetyl]-10,10-dimethyl-7-aza-dispiro-[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.412 g; 0.55 mmol) in DCM (5 mL) the reaction mixture was stirred for 3 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.78 min; M/z=859 [M+], HPLC (method A3) Rt=6.81 min
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH:13](OCC)=[O:14].[O-]CC.[Na+].O>C(O)C>[OH:14][CH:13]=[C:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]#[N:12]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(C#N)=CO)c(C)c1
Temperature: 60 °C
Yield: 52.2 %

Procedure:
A solution of 2,4,6-trimethylphenylacetonitrile (75 g) and ethyl formate (67 g) in 225 ml absolute ethanol was treated with solid sodium ethoxide (36 g) in small portions over 10 minutes, with good stirring. The mixture was heated to 60° C. under nitrogen for 16 hours and allowed to cool to room temperature. The reaction mixture was poured into 1.2 liters of water, extracted with diethyl ether (3×200 ml). The aqueous phase was acidified with 6 M HCl to pH=1 and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over MgSO4 and concentrated, yielding 46 g (98%) of 3-hydroxy-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 1).