Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:10]([P:12]([S:19][CH2:20][Cl:21])([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[S:13])[CH3:11].C(P(=S)=S)C.C(S)(C)(C)C.BrCCl>C(O)C.O.C(N(CC)CC)C>[CH2:10]([P:12]([S:19][CH2:20][Cl:21])([S:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[S:13])[CH3:11].[CH2:10]([P:12]([S:19][CH2:20][S:3][C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[S:2])([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[S:13])[CH3:11]
Reactant: C1COCCN1
Reactant: S=C=S
Agent: CCP(=S)(SCCl)SC(C)(C)C
Agent: CCP(=S)=S
Agent: ClCBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)(C)S
Product: CCP(=S)(SCSC(=S)N1CCOCC1)SC(C)(C)C

Procedure:
To a solution of 0.274 ml (0.347 g, 0.0046 mole) of carbon disulfide in 20 ml of ethanol was added 0.80 ml (0.80 g, 0.0091 mole) of morpholine. A white mixture resulted. The mixture was heated to reflux and a solution of 1.0 g (0.0038 mole) of S-t-butyl S-chloromethyl ethylphosphonotrithioate in 3 ml at ethanol was added. (The S-t-butyl S-chloromethyl ethylphosphonotrithioate was prepared according to the procedure of Example I, steps (a) and (b), from ethylthionophosphine sulfide, t-butyl mercaptan, triethylamine, and bromochloromethane.) The mixture was refluxed for 16 hours. After cooling, 20 ml of water was added and the mixture was twice extracted with ether. The ethereal solution was washed with 20 ml of water and 20 ml of brine, dried with magnesium sulfate, and evaporated to a viscous oil. Purification by a preparative, centrifugally accelerated, thin-layer (4 mm, silica gel) chromatograph, with 9:1 hexane-acetone as eluent, afforded 0.39 g (28% of theoretical yield) of the title compound, a clear, viscous oil. The structure was confirmed by nuclear magnetic resonance, infrared and mass spectroscopy.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:44]([CH3:45])=[CH:43][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:53]1([C:59]([NH2:61])=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C@@H:6]([C:12]1[C:44]([CH3:45])=[CH:43][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([NH:61][C:59]([CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)=[O:60])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(OS(=O)(=O)C(F)(F)F)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: NC(=O)C1CCCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC(=O)C6CCCCC6)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-(trifluoromethylsulfonyloxy)quinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (28.4 mg, 0.037 mmol) in anhydrous dioxane (0.6 mL) was added cyclohexanecarboxamide (7.0 mg, 0.055 mmol), Xantphos (2.0 mg, 0.004 mmol), Cs2CO3 (36.0 mg, 0.111 mmol) and Pd2(dba)3 (2.0 mg, 0.002 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. for 2 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C43H44ClN4O4S: 747.3; found: 747.2.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]([CH2:18][CH2:19][CH3:20])([NH:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:11])[CH2:6][CH2:7][CH3:8])C>Cl>[CH2:18]([C:5]1([CH2:6][CH2:7][CH3:8])[NH:9][C:10](=[O:11])[N:12]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[C:4]1=[O:21])[CH2:19][CH3:20]
Reactant: CCCC(CCC)(NC(=O)Nc1nccs1)C(=O)OCC
Agent: Cl
Product: CCCC1(CCC)NC(=O)N(c2nccs2)C1=O
Yield: 42.5 %

Procedure:
1.71 g of 2-propyl-2-(3-thiazol-2-ylureido)pentanoic acid ethyl ester (product from Example lA, stage 4) were combined with 30 ml of 30% hydrochloric acid. The mixture was refluxed for three hours. Once the mixture had cooled, the pH was adjusted to an alkaline value with potassium carbonate, extraction was performed three times with ethyl acetate, the mixture washed twice with a saturated common salt solution and dried over sodium sulphate. The crude product obtained by the subsequent removal of the solvent by distillation was purified by passage through a silica gel column with ethyl acetate. 0.62 g of 5,5-dipropyl-3-thiazol-2-yl-2,4-imidazolidinedione (42% of th.) were obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:15]1[C:20]2[CH2:21][C:22]([CH2:25][OH:26])([CH3:24])[O:23][C:19]=2[CH:18]=[C:17]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=1[O:31][Si:32]([CH3:35])([CH3:34])[CH3:33])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([C:15]1[C:20]2[CH2:21][C:22]([CH:25]=[O:26])([CH3:24])[O:23][C:19]=2[CH:18]=[C:17]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:16]=1[O:31][Si:32]([CH3:35])([CH3:34])[CH3:33])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC1(CO)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C=O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.43 ml of dimethyl sulfoxide in 12 ml of dichloromethane cooled to -78° C. under nitrogen was added dropwise 0.26 ml of oxalyl chloride. After 15 minutes, a solution of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran in 5 ml of dichloromethane was added dropwise. After further 15 minutes, 1.91 ml of triethylamine was added dropwise and then the mixture was slowly warmed to room temperature. After one hour, the reaction solution was poured into water and extracted with dichloromethane, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified on a short column of silica gel eluting with n-hexane containing 9% ethyl acetate to give 1.04 g of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran containing impurities.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:37])[CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])=[O:14])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:28]([N:25]1[C:20]2=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][CH2:9][C:4]3[CH:3]=[C:2]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=4)[C:7]([CH3:8])=[CH:6][CH:5]=3)=[O:37])[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]2[CH:27]=[N:26]1)[CH3:29]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(C)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(C)c(-c2cccc(C=O)c2)c1
Yield: 5.1 %

Procedure:
A mixture of N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (1.3 g, 2.275 mmol), (3-formylphenyl)boronic acid (0.428 g, 2.85 mmol), tetrakis (triphenylphosphine) palladium (0) (0.093 g, 0.080 mmol), sodium carbonate (0.610 g, 5.76 mmol), and 1,4-dioxane (14 mL) and water (5 mL), while stirring under N2, was microwaved at 140° C. for 30 min. The reaction mixture was diluted with EtOAc and water. The organic layer was recovered and washed with saturated NaCl, dried over Na2SO4, and then evaporated to viscous taffy. The viscous taffy was purified on a Chromatotron Plate Silica Gel (1000μ) eluting with CH2Cl2— MeOH (97:3) to afford N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]propanediamide (69.7 mg, 32.8%) as a viscous, nearly colorless, foam, taffy. LC-MS m/z 597.5 (M+H)+, 0.87 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=C[N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52](C#N)=[CH:51][CH:50]=2)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:52]3[CH:55]=[CH:56][C:49]([C:48]#[N:45])=[CH:50][CH:51]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: N#Cc1ccc(Cn2ccc(N)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C#N)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 4-(3-amino-pyrazol-1-ylmethyl)-benzonitrile (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(4-cyano-benzyl)-1H-pyrazol-3-yl]-3-cyclopentyl-propionamide (35 mg, 23%) as a white solid: ESI-LRMS m/e calcd for C26H27ClN4O3S [M+] 510.2, found 511.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.21 (m, 2H, CH2), 1.44-1.92 (m, 8H, 4×CH2), 2.09-2.35 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.56 (t, J=7.5 Hz, 1H, CH), 5.20 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 7.19 (d, Jo=8.4 Hz, 2H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.54-7.63 (m, 3H, Ar), 7.99 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1.Br[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]>ClCCl>[C:17]1([CH:15]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCNC1
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCC[C@H](C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
In a flask, dichloromethane (0.432 mL) was added to (S)-tert-butyl piperidine-3-carboxylate (0.020 g, 0.108 mmol). At 0° C., (1-bromoethyl)benzene (0.030 g, 0.162 mmol) was added to the reaction. The solution was allowed to stir from 0° C. to room temperature for 3 hrs. The reaction was quenched using water (1 mL) and extracted using dichloromethane (3×1 mL). The extractions were combined and dried using sodium sulfate. The extracts were concentrated in vacuo, and the crude product was progressed to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:37]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]([Br:37])[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 8-(benzyloxy)-2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (8.0 g, 18.9 mmol) and sodium bicarbonate (4.8 g, 56.8 mmol) in dichloromethane (100 mL) at room temperature, a solution of bromine (3.5 g, 21.7 mmol) in dichloromethane (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide the titled product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:17][C:14]([F:15])([F:16])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[S:21]([N:20]([CH3:25])[CH3:19])(=[O:23])=[O:22])=[CH:8][CH:7]=1)([OH:18])[C:10]([F:12])([F:13])[F:11]
Reactant: CNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To 5.4 g (20 mmole) N-methyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline in 50 ml pyridine add 4.3 g (30 mmole) dimethylsulfamoyl chloride. Stir 16 hours, pour onto water, acidify and extract with Et2O. Wash with 1N NaOH, acidify the aqueous layer, and extract with Et2O. Dry, concentrate and recrystallize first from CCl4, and then from Et2O-hexane to obtain the product; m.p. 63°-65° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].Br[CH2:23][C:24]1[C:25]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C1C=CC=CN=1)C>CS(C)=O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:23][C:24]3[C:25]([N:30]4[C:31](=[O:40])[C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:38]4=[O:39])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1CBr
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N3C(=O)c4ccccc4C3=O)c3ccc(C#N)cc23)C1

Procedure:
Dissolve (S)-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (20 g, 70.59 mmoles; ee>98%, 2nd isomer on Chiracel OJ, 0.2% DMEA in Hexane/EtOH [80:20]) in dimethyl sulfoxide (160 mL) and add 2-(3-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (29.8 g, 84.71 mmol). Stir the mixture until a clear solution is obtained. Add cesium carbonate (46.4 g, 141.18 mmoles) and dimethylaminopyridine (875.5 mg, 7.06 mmol) in one portion. Stir the resulting mixture at 22/24° C. for 2 h. Add the mixture onto water (1.4 L). Stir the resulting suspension for 30 min and filter. Wash the resulting cake with water (100 ml). Dissolve the isolated wet solid in dichloromethane (750 mL) and separate the organic layer. Wash the organic layer with brine and evaporate the organic solvent. Purify the resulting material by silica gel chromatography, eluting with hexanes/acetone/CH2Cl2 (3/1/1) to obtain 24 g (58%). MS (m/z): 520 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24])([OH:3])=[O:2].[N+](=[CH2:27])=[N-]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24])([O:3][CH3:27])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CCCCCCCC(O)[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O
Product: CCCCCCCC(O)[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC

Procedure:
To a solution of 0.5 g. (1.47 mmol) of trans-2-(6-carboxyhexyl)-3-(1-hydroxyoctyl)cyclopentanone is added on etheral solution of diazomethane until a permanent yellow color remains. The solvent and excess diazomethane are removed un a stream of nitrogen. After removing traces of solvent at reduced pressure, 0.52 g. of trans-2-(6-carbomethoxyhexyl)-3-(1-hydroxyoctyl)cyclopentanone is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([N:30]=[N+:31]=[N-:32])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 g (97.45 mmol) of 5-(2-pyridyl)-thiophene-2-carboxylic acid are dissolved in 200 ml of acetone, and the solution is treated with 15.94 ml (115 mmol) of Et3N and cooled to 0° C. A solution of 14.85 ml (115 mmol) of isobutyl chloroformate in 88 ml of acetone is slowly added dropwise with stirring to the reaction solution thus obtained. After 1 h at 0° C., a solution of 9.5 g (146 mmol) of sodium azide in 44 ml of water is added dropwise, and the mixture is stirred at 0° C. for 1 h and allowed to come to room temperature. The reaction mixture is tipped onto ice water and the precipitate is filtered off with suction and reacted further as it is.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:45]COCC[Si](C)(C)C)=[CH:5][C:6]([CH2:43][OH:44])=[C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[N:30](COCC[Si](C)(C)C)[C:29]5[CH:39]=[CH:40][CH:41]=[CH:42][C:28]=5[N:27]=4)=[N:14][N:15]3COCC[Si](C)(C)C)=[CH:11][CH:10]=2)[CH:8]=1.COC1C(OCOCC[Si](C)(C)C)=CC(C)=C(C2C=C3C(C(C4N(COCC[Si](C)(C)C)C5C=CC=CC=5N=4)=NN3COCC[Si](C)(C)C)=CC=2)C=1>>[NH:30]1[C:29]2[CH:39]=[CH:40][CH:41]=[CH:42][C:28]=2[N:27]=[C:26]1[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([OH:45])=[CH:5][C:6]=3[CH2:43][OH:44])=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: COc1cc(-c2ccc3c(-c4nc5ccccc5n4COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c3c2)c(CO)cc1OCOCC[Si](C)(C)C
Agent: COc1cc(-c2ccc3c(-c4nc5ccccc5n4COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c3c2)c(C)cc1OCOCC[Si](C)(C)C
Product: COc1cc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c(CO)cc1O

Procedure:
Example 24(n) was prepared in a similar manner to that described for Example 24(a), except that 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole, prepared as described below, was used instead of 6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole. 1H NMR (300 MHz, DMSO-d6) δ 13.59 (s, 1H), 12.95 (s, 1H), 9.05 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.72 (dd, 1H, J=6.3, 2.1 Hz), 7.60 (s, 1H), 7.51 (dd, 1H, J=6.3, 2.1 Hz), 7.31 (d, 1H, J=8.4 Hz), 7.20–7.24 (m, 2H), 7.02 (s, 1H), 6.87 (s, 1H), 5.02 (t, 1H, J=5.4 Hz), 4.32 (d, 2H, J=5.4 Hz), 3.80 (s, 3H). MS (ES) [m+H]/z calc'd 387. found 387. [m−H]/z calc'd 385. found 385.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH3:37].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2)[CH3:37]
Reactant: CCc1ccccc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Temperature: 100 °C
Yield: 32.1 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.0 g, 2.39 mmol), 1-bromo-2-ethylbenzene (572.0 mg, 3.11 mmol, Aldrich), Pd2(dba)3 (218 mg, 0.23 mmol, GLR), Xantphos (276 mg, 0.46 mmol, GLR) and sodium-tert-butoxide (458 mg, 4.784 mmol) in toluene (20 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 100° C. for 1 h under microwave irradiation. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane) to obtain 4-(2-ethylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (400 mg, 33%) as a brown solid. MS (ESI, positive ion) m/z; 522.1 (M+1)
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([Cl:21])=[C:15]([CH3:22])[C:14]=1Br)([CH3:9])(C)C.C(=O)C.[Cl-].[NH4+]>C1COCC1.O>[Cl:21][C:16]1[CH:17]=[C:18]([O:19][CH3:20])[C:13]2[NH:12][C:11](=[O:24])[O:10][CH:6]([CH3:9])[C:14]=2[C:15]=1[CH3:22]
Reactant: COc1cc(Cl)c(C)c(Br)c1NC(=O)OC(C)(C)C
Agent: CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(C)c2c1NC(=O)OC2C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (1.6M in hexane, 5.1 ml, 8.1 mmol) was added dropwise under nitrogen at −78° C. to a solution of (2-bromo-4-chloro-6-methoxy-3-methyl-phenyl)-carbamic acid tert-butyl ester (1.3 g, 3.7 mmol) in THF (22 ml). The reaction was stirred for 15 minutes at −78° C., and acetaldehyde (480 ul, 8.4 mmol) was added. The reaction was warmed overnight to r.t. Saturated aqueous ammonium chloride solution (10 ml) was added, the reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was treated with heptane and little methylene chloride. The title compound was filtered off as a yellow solid. The filtrate was purified by column chromatography (silica gel, heptane/ethyl acetate=1/1) to yield another batch of product, which gave a combined yield of 708 mg (79%).