Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34](Cl)(Cl)=[O:35].[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH3:14][CH:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:34]([N:45]3[CH2:46][CH2:47][C:42]4([O:41][CH2:40][CH2:39][O:38]4)[CH2:43][CH2:44]3)=[O:35])[CH:7]=[CH:6][CH:5]=2)([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: CC1CCC(c2cccc(N)c2)(N2CCN(c3ccccc3)CC2)CC1
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(c2cccc(NC(=O)N3CCC4(CC3)OCCO4)c2)(N2CCN(c3ccccc3)CC2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-aminophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane (cis isomer, 246 mg, 0.705 mmol) and triethylamine (147 μL, 1.06 mmol) in dry CH2Cl2 (15 mL) was brought to 020 C. using an ice bath. Phosgene (1.93 M in toluene, 438 μL, 0.846 mmol) was added dropwise and the resulting mixture was stirred at 020 C., under a dry N2 atmosphere, for 30 minutes. 1,4-dioxa-8-azaspiro[4.5]decane (181 μl 1.41 mmol) was added via syringe and the reaction was allowed to come to room temperature. After 2 h the reaction mixture was diluted with an equal volume of CH2Cl2, washed with H2O, dried (Na2SO4) and concentrated to give an off-white solid. The solid was washed with 30% EtOAc/hexanes to give the free base of N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)cyclohexyl]phenyl]-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxamide (cis isomer) as a white solid. mp=245-247° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[CH:22][C:21]=1[Cl:37].[CH:38]1[C:43]([N:44]=[C:45]=[S:46])=[CH:42][C:41]2[C:47]([O:49][C:50]3([C:60]4[CH:61]=[CH:62][C:63]([OH:65])=[CH:64][C:59]=4[O:58][C:52]4[CH:53]=[C:54]([OH:57])[CH:55]=[CH:56][C:51]3=4)[C:40]=2[CH:39]=1)=[O:48]>CN(C=O)C>[Cl:37][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])[CH:24]=[C:25]([Cl:26])[C:20]=1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:45]([NH:44][C:43]1[CH:42]=[C:41]2[C:40](=[CH:39][CH:38]=1)[C:50]1([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][C:52]=3[O:58][C:59]3[C:60]1=[CH:61][CH:62]=[C:63]([OH:65])[CH:64]=3)[O:49][C:47]2=[O:48])=[S:46]
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Reactant: NCCOCCOCCOc1c(Cl)cc(Nc2ccccc2C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Nc1cc(Cl)c(OCCOCCOCCNC(=S)Nc2ccc3c(c2)C(=O)OC32c3ccc(O)cc3Oc3cc(O)ccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N,N-Diisopropylethylamine (10 μL, 0.057 mmol) was added to a solution of the compound 4 (1.9 mg, 0.0035 mmol) and fluorescein isothiocyanate (FITC) (1.2 mg, 0.003 mmol) in DMF (1.0 ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography (silica gel, 1-20% methanol/methylene chloride) to give the desired compound 5 (1.5 mg, 52% yield); 1H NMR (CD3OD, 400 MHz) δ 8.14-8.10 (m, 1H), 7.88 (dd, 1H, J=2.0 Hz, 8.0 Hz), 7.80-7.62 (m, 2H), 7.34-7.30 (m, 1H), 7.24-7.18 (m, 1H), 7.18-7.12 (m, 3H), 6.86-6.78 (m, 1H), 6.72-6.64 (m, 3H), 6.54-6.50 (m, 2H), 4.21-4.04 (m, 4H), 3.92-3.66 (m, 8H); HRMS (ESI+) m/z: calcd for C40H33Cl2N3O10S+H+ 818.1342; found 818.1328 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9][CH2:8]2.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([N:15]1[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]1=[O:21])[CH2:9][CH2:8]2
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: O=C1OC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a stirred suspension of 60% NaH (6 g; 0.182 mmol) in DMF (400 mL) is added 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (30 g; 0.140 mol), portionwise at 0° C. The reaction mixture is warmed to RT and stirred for an additional 1 h. Phthalic anhydride (20.7 g; 0.139 mol) is added in 1-portion at RT, upon which the reaction mixture is stirred for an additional 1 h followed by 18 h at 120° C. The reaction was allowed to cool to RT, diluted with H2O and extracted several times with EtOAc. The combined organic extracts are washed with water, brine, dried over Na2SO4, and the solvent removed under reduced pressure. The crude solid was triturated with MeOH, filtered, and dried under vacuo to afford 29.1 g (67%) of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[N:13]=[C:16]([CH3:18])[CH:15]=[C:14]([OH:19])[N:11]2[N:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(-c3ccccc3Cl)cc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-1A-1a; 1.51 g, 7.80 mmol) in acetic acid (10 ml) was added ethyl acetoacetate (1.1 ml, 8.6 mmol). The reaction was heated at reflux for 17 hours. Upon cooling to room temperature a solid precipitate formed which, after standing for 2 days, was isolated by vacuum filtration and washed with additional acetic acid. The solids were stirred in ether and then isolated by vacuum filtration to afford I-1A-3f as a colorless solid (1.52 g, 75%): +ESI MS (M+1) 260.2; 1H NMR (400 MHz, DMSO-d6) δ 12.18 (br s, 1H), 7.85–7.81 (m, 1H), 7.57–7.54 (m, 1H), 7.46–7.41 (m, 2H), 6.49 (s, 1H), 5.61 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.Cl.[CH2:16]([O:19][NH2:20])[CH:17]=[CH2:18].C(N(CC)CC)C>O1CCOCC1>[CH2:16]([O:19][NH:20][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1)[CH:17]=[CH2:18]
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: C=CCON
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CCONc1nc(NC=O)nc(Cl)c1NC=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (3.75 g, 16 mmol), O-allylhydroxylamine hydrochloride (1.8 g, 16.4 mmol) and triethylamine (9.1 ml, 66 mmol) in dioxan (80 ml) was stirred at 100° C. for 6 hours. The cooled reaction mixture was filtered and evaporated to dryness under reduced pressure. The residue was on silica gel (eluted with chloroform chromatographed methanol, 10:1) and the product recrystallised from chloroform-methanol affording the title compound (2.1 g, 48%), m.p. 170°-181° C. IR: υmax (KBr) 3240, 1705, 1650, 1590, 1570, 1495, 1465, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 4.37 (2H, d, J=6 Hz, CH2ON), 5.28 (2H, m, CH=CH2), 6.00 (1H, m, CH=CH2), 8.17 (1H, s, CHO), 9.30 (1H, s, CHO), 9.45 (1H, br.s, NH), 10.87 (2H, br.s, 2×NH). Found: C, 39.64; H, 3.49; N, 25.34%, M+ 271.0469. C9H10ClN5O3 requires C, 39.79; H, 3.71; N, 25.78%, M+ 271.0469.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].C(O)(=O)C>C1C=CC=CC=1.N1CCCCC1=O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH:1]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:6]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C1CCCCN1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1C(=O)OC)C(=O)C(OCC)OCC
Yield: 116.3 %

Procedure:
2-(i) To a mixture of methyl 2-formylbenzoate (4.92 g), ethyl 4,4-diethoxyacetoacetate (7.2 g) and acetic acid (0.36 g) in benzene (15 ml) was added portionwise each one third portion of a solution of piperidone (306 mg) in benzene (5 ml) for each 20 minutes' interval, and the mixture was heated to reflux for 3 hours under removing off azeotropically the resulting water. After cooling, the reaction mixture was diluted with additional benzene (25 ml), washed three times with water and successively with diluted aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give reddish oil (12.7 g) of crude ethyl 2-(2-methoxycarbonylbenzyliden)-4,4-diethoxyacetoacetate which was used in the following reaction without any further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(-n2ccnn2)nc1
Reactant: C[Si](C)(C)Br
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-n2ccnn2)nc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
57.2 mg (corresponding to 0.304 mmol) of 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine was dissolved in 2.0 mL of dichloromethane and 127 μL of triethylamine, and then 78.9 μL (corresponding to 0.608 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then the reaction solution was supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 2.0 mL of tetrahydrofuran, and 54.1 mg (corresponding to 0.304 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 66.4 mg (corresponding to 0.249 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine (FIG. 1, step 2).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]([CH2:17][CH3:18])[C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=1.[C-:21]#[N:22].[Na+].O>CN(C=O)C>[CH2:17]([N:7]1[C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[C:3]([CH2:2][C:21]#[N:22])[CH:20]=[CH:19][C:6]1=2)[CH3:18]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CC#N)ccc21
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.11 g) in DMF (15 ml) was added sodium cyanide (0.59 g) at room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.84 g) as a pale yellow oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:11]([C:23]1[S:24][C:25]([CH:3]=[O:4])=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCc1cccs1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 75.8 %

Procedure:
In a 1 liter-four-necked flask, 93.7 g (1.28 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 107.4 g (7.00×10-1 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 160 g (6.35×10-1 mol) of 2-dodecylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2.5 hours at 60° C. After the reaction, the reaction mixture was poured into 2 liter of iced water, subjected to 3 times of extraction with 500 ml of chloroform and washed 6 times with 500 ml of water. The organic layer was dried on CaCl2, followed by distilling-off of the solvent to obtain 237 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 135 g of a product (yield: 75.9%). b.p.: 160° C./0.6 mmHg
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)C(=O)[O:17][N:16]=2)=[N:12][O:13][N:14]=1.[S:29](N)([NH2:32])(=[O:31])=[O:30].[OH-].[Na+]>N1C=CC=CC=1.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:32][S:29]([NH:8][CH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)=[N:12][O:13][N:14]=1)(=[O:31])=[O:30]
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (30 mg, 0.07 mmol) and sulfamide (20 mg, 0.2 mmol) was dissolved in pyridine (1.0 mL) and heated at 120° C. for 3 min in a microwave. A solution of sodium hydroxide in water (0.5 mL, 1 N) was added and the solution was stirred for 30 minutes. Acidification with acetic acid and purification by preparative LCMS gave the desired product (17 mg, 50%). MF=C10H10ClFN6O4S; LCMS calculated for C10H11ClFN6O4S (M+H)+: m/z=364.9. 1H NMR (400 MHz, CD3OD): δ 7.02 (m, 2H), 6.76 (m, 1H), 4.50 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:41][C:42]#[N:43].[Na+]>O.C(O)CC.O1CCOCC1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][N:32]([C:42]([NH2:43])=[O:41])[CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[O-]
Reactant: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCNCC3)C2)CC1
Agent: [Na+]
Solvent: CCCO
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N1CCN(C(=O)[C@@H]2CCCN(C3CCN(C(=O)c4cc(-c5ccccc5)nc(-c5ccccc5)c4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
(3R)-(2,6-Diphenyl-pyridin-4-yl)-[3-(piperazine-1-carbonyl)-[1,4′]bipiperidinyl-1′-yl]-methanone (21.4 mg, 0.040 mmol) and sodium cyanate (0.060 mmol, 3.9 mg) were heated at 100° C. in a water-dioxane-n-propanol solution. After 2 h an additional aliquot of sodium cyanate (4 mg) was added and heating was continued for another 1 hour then the solution was allowed to stir at ambient temperature for an additional 42 h. The solvent was removed under vacuum and the product was purified by silica gel chromatography eluting with a 5% to 10% methanol-dichloromethane gradient to give the title compound (9.3 mg, 40%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=[O:10])=[O:9].O[CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:54])[NH:31][C:32](=[O:53])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=3)[CH:35]=2)=[N:21]1.Cl>C1COCC1>[CH3:7][S:8]([O:11][CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:54])[NH:31][C:32](=[O:53])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=3)[CH:35]=2)=[N:21]1)(=[O:10])=[O:9]
Reactant: O=C1NC(=O)C(c2nn(CCCO)c3ccccc23)=C1c1cn(-c2ccc3ccccc3c2)c2ccccc12
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCn1nc(C2=C(c3cn(-c4ccc5ccccc5c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Following the procedure of Example 26, pyridine (0.7 g, 8.35 mmol) and methanesulfonic anhydride (1.09 g, 6.26 mmol) were added to Compound 84 (1.07 g, 2.09 mmol) (prepared in Example 24) in THF (20 mL). The mixture was heated at 50° C. for 2 h, then cooled to rt. Another portion of THF (10 mL) was added, followed by addition of 1N HCl (10 mL). The mixture was stirred for 15 min, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), then dried (Na2SO4) and evaporated in vacuo to obtain a 3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione analog of Compound 26a (1.1 g, 92%) as a reddish solid. ES-MS m/z 591 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][N:23]4[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[NH:25][C:24]4=[O:31])[N:15]=3)=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:10]=2)=[CH:4][CH:3]=1.[OH:38]OS([O-])=O.[K+].[OH2:44]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][N:23]4[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[NH:25][C:24]4=[O:31])[N:15]=3)=[C:11]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:10]=2)(=[O:38])=[O:44])=[CH:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sc(Sc3ccc(F)cc3)cc2-c2ccccc2)n1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sc(S(=O)(=O)c3ccc(F)cc3)cc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-(4-(5-(4-Fluorophenylthio)-3-phenylthiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.100 g, 0.188 mmol) was dissolved in acetone (3.0 mL) and treated with a solution of Oxone (0.346 g, 0.563 mmol) in H2O (1.5 mL). The reaction mixture was allowed to stir at ambient temperature overnight and then diluted with 10 mL H2O. The suspension was filtered and the precipitate washed with additional portions of H2O. The solid was air-dried and then purified by flash chromatography, eluted with 1-10% MeOH/dichloromethane to afford the product as a bright yellow solid. MS (M+H)+ 566.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([F:24])[C:22]=1F>CN1CCCC1=O.O.Cl>[F:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([F:24])[C:22]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5.10 mL morpholine are dissolved in 1 mL 1-methyl-2-pyrrolidon and combined with 14.99 mL N,N-diisopropylethylamine and 1.85 mL 3,4,5-trifluoronitrobenzene. The reaction mixture is stirred for 1 h at 110° C. After cooling the reaction mixture is diluted with 70 mL water and 15 mL concentrated aqueous HCl solution are added. The precipitate formed is filtered off, with water washed and dissolved with ethyl acetate. Then the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([Si:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]3[N:19](CN(C)C)[CH:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[C:49]2=[CH:50][N:51]=[CH:52][C:53]([C:54]3[CH:59]=[C:58]([C:60](OC)=[O:61])[CH:57]=[CH:56][C:55]=3[C:64]#[N:65])=[C:48]2[CH:47]=[CH:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].[Li+].CC([N-]C(C)C)C>C1COCC1>[C:38]([O:42][C:43]([N:45]1[C:49]2=[CH:50][N:51]=[CH:52][C:53]([C:54]3[CH:59]=[C:58]([C:60]([C:20]4[NH:19][C:17]5=[N:18][C:13]([N:10]6[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([C:26]7[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=7)[C:32]7[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=7)[CH2:8][CH2:9]6)=[CH:14][CH:15]=[C:16]5[N:21]=4)=[O:61])[CH:57]=[CH:56][C:55]=3[C:64]#[N:65])=[C:48]2[CH:47]=[CH:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CN(C)Cn1cnc2ccc(N3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)nc21
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc3c2ccn3C(=O)OC(C)(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C(=O)c4nc5ccc(N6CCC(O[Si](c7ccccc7)(c7ccccc7)C(C)(C)C)CC6)nc5[nH]4)ccc3C#N)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of {5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-imidazo[4,5-b]pyridin-3-ylmethyl}-dimethyl-amine (574 mg, 1.12 mmol) and 4-(2-cyano-5-methoxycarbonyl-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (474 mg, 1.26 mmol, 1.1 eq) (Step 1 example 140) in THF (0.1M), cooled to −78° C., was slowly added 1M LDA (2 mol eq). After 1 hr, the reaction mixture was quenched with 50% acetic acid in water (0.25 vols.) at −78° C. The mixture was allowed to warm to room temperature and concentrated to remove most THF. The residue was diluted with EtOAc (20 mL) and basified with aqueous ammonium hydroxide (30%) until pH>8. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was then purified by trituration from Acetonitrile affording 4-(5-{5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine-2-carbonyl}-2-cyano-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester as a red solid (900 mg, 1.01 mmol, 90%). MS ESI m/z 802.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:50][CH2:49][C:46]3[CH:45]=[CH:44][C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:48][CH:47]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: NCc1ccc(CN2CCCC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(CN4CCCC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (75 mg, 0.21 mmol), CDI (41 mg, 0.25 mmol) and 1-[4-(pyrrolidin-1-ylmethyl)phenyl]methanamine (37 mg, 0.21 mmol) in THF (4.5 mL) and DMF (0.6 mL). A portion of the crude product was purified using prep method A.