Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:3]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5])#[CH:2].[Li]CCCC.[CH3:18][N:19]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]1>O1CCCC1.CCOC(C)=O>[CH3:18][N:19]1[CH2:23][CH2:22][C:21]([C:2]#[C:1][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[CH:10]([CH3:12])[CH3:11])([OH:24])[CH2:20]1
Reactant: CN1CCC(=O)C1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](C#CC1(O)CCN(C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. Into a solution of Ethynyl-triisopropyl-silane (1.1 g, 6 mmol) in tetrahydrofuran (10 mL) was dropped in n-BuLi (2.4 mL, 6 mmol) at −78° C. The solution was stirred for 0.5 h. Then 1-Methyl-pyrrolidin-3-one (0.5 g, 5 mmol) was added. The solution was allowed to warm up to room temperature and stirred for 3 h. Then the reaction mixture was added in 50 mL EtOAc and washed with water three times. The solvent was removed under vacuum to afford 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (0.55 g, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 5.53 (s, 1H), 2.74-2.63 (m, 2H), 2.46-2.44 (m, 1H), 2.23 (s, 3H), 2.13-1.96 (m, 2H), 1.07-0.97 (m, 21H). A solution of 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (1.0 g, 3.6 mmol) in tetrahydrofuran (10 mL) was treated with Tetrabutyl-ammonium fluoride (0.94 g, 3.6 mmol). The solution was stirred overnight at room temperature. Then the reaction mixture was purified by column (eluent: CH2Cl2: MeOH=10:1) to afford 3-Ethynyl-1-methyl-pyrrolidin-3-ol (0.26 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 1H), 3.31 (s, 1H), 2.74-2.56 (m, 3H), 2.49-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.91 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>CN(C)C=O>[CH2:8]([N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCN(C#N)C(C)=O
Temperature: 70 °C

Procedure:
221 g (2.085 mols) of sodium acetylcyanamide are dissolved in 500 ml of dimethylformamide at 90° C., the mixture is allowed to cool to 70° C. and 285.6 g (2.085 mols) of n-butyl bromide are then added dropwise at 70° C. in the course of 11/2 hours. The mixture is allowed to after-react at 70° C. for 10 hours, and the NaBr which has precipitated is filtered off with suction and the entire distillable constituent is removed from the filtrate by vacuum distillation. Fractional distillation of this distillate over a packed column 60 cm high gives 216.4 g (74.1% of theory) of pure product of boiling point 105° C./34 mbar.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N:14]=[C:15]2[NH:19][C@@H:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:17][S:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N:14]=[C:15]2[N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[C@@H:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:17][S:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1
Reactant: CC(C)CBr
Product: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (1S)-1-(hydroxymethyl)-3-methylbutylamine to Method C2a to give (4S)-2-(4-nitro-1-naphthylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1-naphthylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH2:6][O:7][CH2:8][CH3:9])[CH3:2].Cl.[NH2:12][OH:13]>>[CH2:1]([O:3][CH2:4][C:5](=[N:12][OH:13])[CH2:6][O:7][CH2:8][CH3:9])[CH3:2]
Reactant: NO
Reactant: CCOCC(=O)COCC
Agent: Cl
Product: CCOCC(COCC)=NO

Procedure:
1,3-Diethoxy-propan-2-one oxime was prepared from 1,3-diethoxy-propan-2-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (1H, s), 4.18 (2H, s), 3.96 (2H, s), 3.41 (4H, quin, 7.0 Hz), 1.10 (6H, q, 7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:18](=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(Cl)c1

Procedure:
Dissolved in toluene were 2.5 g (0.02 mole) of m-chloroaniline and a catalytic amount of pyridine, followed by dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the dropwise addition, the resultant mixture was heated under reflux for 3 hours. Under ice-cooling, ligroin was added, and precipitated crystals were collected by filtration and were then washed first with ligroin and then with hexane. The crystals were then dried under reduced pressure to obtain 3'-chloroacetoacetanilide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=O)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C[Si](Br)(C)C.CO>CN(C=O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1/[CH:18]=[CH:16]/[C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=[N:10][N:9]2[CH:13]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: CN(C)C=O
Product: C(=C/c1cn2nccc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of compound 5e (10 g, 43 mmol) and 2-methylquinoline (4.6 g, 32 mmol) in DMF (10 mL) was added TMSBr (2.9 g, 19 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. MeOH (10 mL) was added. The solids formed were collected by filtration and washed with Et2O (2×50 mL) to obtain compound 57c as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H19N5O: 358.2 (M+H). Found: 358.3.
Reaction SMILES: C([O:5][CH2:6][CH:7]1[CH2:12][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9][N:8]1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][N:8]2[CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:12][CH:7]2[CH2:6][OH:5])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: CC(C)(C)OCC1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(CO)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butoxymethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine (30 mg) in DCM (2 mL) was added TFA (2 mL). The reaction was allowed to stir at 25° C. for 2 hours. LC showed complete removal of the tert-butyl group. The solvents were removed under reduced pressure, and the residue was collected without further purification. LC-MS (IE, m/z): 415 [M+1]+. (0.26 μM)
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43](O)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:65][N:66]1[CH2:72][CH:71]2[NH:73][CH:68]([CH2:69][CH2:70]2)[CH2:67]1>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43]([N:73]4[CH:68]5[CH2:69][CH2:70][CH:71]4[CH2:72][N:66]([CH3:65])[CH2:67]5)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)=Cc1ccccc1-3
Reactant: CN1CC2CCC(C1)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1C2CCC1CN(C)C2)=Cc1ccccc1-3

Procedure:
TBTU (115 mg, 0.361 mmol) was added at rt, in one portion, to a solution containing 13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (100 mg, 0.241 mmol), DIEA (0.17 mL, 0.964 mmol), 3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (115 mg, 0.289 mmol), and DMF (2.4 mL). The solution was maintained for 18 h and concentrated. The resultant residue was charged with dichloromethane (30 mL), washed with water (4×15 mL), washed with brine (15 mL), dried (magnesium sulfate), filtered and concentrated to afford a yellow solid which was used without further purification in the next step. LCMS: retention time: 2.272 min LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode: m/z 524 (MH+). Crude 1H NMR (300 MHz, CDCl3) δ ppm: 8.19 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.78 Hz, J=1.46 Hz, 1H), 7.61 (m, 1H), 7.49 (m, 3H), 6.96 (s, 1H), 5.2 (s, 1H), 4.41 (s, 1H), 2.81 (m, 4H), 2.51 (s, 1H), 1.95 (m, 15H), 1.29 (m, 11H), 0.76 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[C@H:26]([N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)[C@H](Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 70.7 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg, 1.21 mmol, 1 equiv), (R)-methyl 2-bromo-2-phenylacetate (276.6 mg, 1.21 mmol, 1 equiv) and potassium carbonate (418.1 mg, 3.025 mmol, 2.5 equiv) in N,N-dimethylformamide was stirred at 65° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature and the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, gradient—5%-20% ethyl acetate/hexanes) to afford (R)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (410 mg, 71.1%). MS for C27H33N3O5 m/z 479.57 (M+H)+.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CO>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Temperature: 65 °C

Procedure:
KOH (2.12 g, 37.8 mmole), indole (1.0 g, 8.54 mmole) and 1-benzyl-3-piperidone hydrochloride (4.82 g, 21.34 mmole) were suspended in methanol (20 ml) and heated for 8 hours at 65° C. under argon. Water (40 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The methanol was distilled off and the aqueous phase was extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. 3-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-indole was purified by chromatography with cyclohexane/EE (1:1). The product was obtained as a yellow solid in a yield of 860 mg (35%) and an m.p. of 105°-107° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])[C@@H:17]([CH3:29])[CH2:16]3)=[C:11]3[CH:30]=[N:31][CH:32]=[CH:33][C:10]=23)=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:36]([N:38]=C=O)=[O:37]>C(Cl)(Cl)Cl>[C:36](=[O:37])([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:22])[C@@H:17]([CH3:29])[CH2:16]3)=[C:11]3[CH:30]=[N:31][CH:32]=[CH:33][C:10]=23)=[CH:5][CH:4]=1)[NH2:38]
Reactant: C[C@H]1CN(c2nnc(-c3ccc(CO)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(c2nnc(-c3ccc(COC(N)=O)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(4-(1-(4-(hydroxymethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 9 (100 mg, 224 μmol) in chloroform (2 mL) was added 2,2,2-trichloroacetyl isocyanate (39 μl, 314 μmol). The reaction was stirred at RT for 1 h and deposited on 3 g of Alumina (Brockmann II). After 1 h, the product was eluted from the alumina with 10% MeOH in dichloromethane. The crude reaction product was concentrated and purified by column chromatography to afford (S)-(4-(4-(3-methyl-4-(piperidine-1-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)phenyl)methyl carbamate 10. MS 489.2 (calc'd) 490.1 (M+H, found).
Reaction SMILES: I.CS[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[NH:14][C:15]([C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)=[NH:5].C([N:32](CC)CC)C>CO.O>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[NH:14][C:15]([C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)(=[NH:32])[NH2:5]
Reactant: CCN(CC)CC
Reactant: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(=N)SC)cc2)cc1
Agent: I
Solvent: O
Solvent: CO
Product: N=C(N)c1ccc(NC(=O)NC(=O)c2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of the product of Example 1 (100 mg) in methanol (25 ml) was added a 1% (by volume) solution of triethylamine in water (25 ml). The reaction mixture was stirred at ambient temperature for 24 hours and filtered. The collected solid was washed thoroughly with methanol and dried to give the title compound (60 mg) as a cream solid; m.p. 285°-288° C. (decomposes); NMR Spectrum (TFA+DMSO-d6) 4.90 (2H, s), 7.14 (2H, d), 7.90 (8H, m), 8.07 (2H, d); Mass Spectrum m/Z 357 (M+H)+ ; Elemental Analysis: calculated for C17H16N4O5 : C, 53.5%; H, 4.97%; N, 14.7; found: C, 53.6%; H, 4.8%; N, 14.6%.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[K].[SH:13][C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>CC(C)=O>[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[S:13][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: Sc1nc2cccnc2s1
Reactant: O=C(O)C(Br)c1ccccc1
Agent: [K]
Solvent: CC(C)=O
Product: O=C(O)C(Sc1nc2cccnc2s1)c1ccccc1

Procedure:
6.5 g. (0.03 moles) α-bromophenylacetic acid and 6.2 g. (0.03 moles) potassium salt of 2-mercaptothiazolo[5,4-b]pyridine are suspended in 200 ml. acetone and the mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate concentrated to dryness. The resulting compound is an oil and is not isolated.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.[Cl:22][C:23]1[CH:41]=[CH:40][C:26]([CH:27]=[C:28]2[C:32](=[O:33])[C:31]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=3[O:29]2)=[CH:25][CH:24]=1.[K+].[Br-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:27]=[C:28]2[O:29][C:30]3[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=3[C:32]2([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:9]3[CH2:10][CH2:11][O:6][CH2:7][CH2:8]3)=[CH:16][CH:17]=2)[OH:33])=[CH:40][CH:41]=1
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Reactant: COc1ccc2c(c1)OC(=Cc1ccc(Cl)cc1)C2=O
Agent: [Br-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OC(=Cc1ccc(Cl)cc1)C2(O)c1ccc(OCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (2.87 mi of a 1.28M solution, 3.68 mmol) was added dropwise to a solution of 4-[2-morpholinoethoxy]phenyl bromide (0.80 ml, 3.68 mmol) in THF (10 ml) at -78° C. under nitrogen atmosphere. After stirring for 1 hour at -78° C., 2-(p-chlorobenzylidene)-6-methoxy-3(2H)-benzofuranone (1.0 g, 3.50 mmol) in THF (5 m was added dropwise to the mixture at -78° C. The reaction mixture was left overnight at room temperature. It was quenched with saturated ammonium chloride, THF was evaporated off to yield an oil which was extracted with ethyl acetate (2×20 ml). The ethyl acetate extract was washed with water followed by brine (2×20 ml), dried (anhydrous magnesium sulfate) and the solvent was evaporated to give an oil which was chromatographed on silica gel. Elution with (chloroform:hexane:triethylamine=1:1:0.2) yielded a solid of the free base (Rf =0.3). Yield (56%); m.p. 69-70° C.; 1H-NMR (CDCl3) δ 1.55 (brs, 1H, OH), 2.54-2.58 (m, 4H, N(CH2CH2)20 (ring)), 2.79 (t, 2H, OCH2CH2N), 3.7-3.74 (m, 4H, N(CH2CH2)2 (ring)), 3.84 (3H, OCH3), 4.09 (2H, OCH2CH2N), 5.64 (benzylidene proton), 6.72-7.60 (m, 11H, ArH). 13C-NMR δ(ppm) 104.4 (benzylidene carbon), 133.1 (C-2), 81.0 (C-3), 54.1 (OCH3); IR (KBr) 1680 cm-1 (C=C), 3400 cm-1 (broad OH); m/z (%) 495(5), 493(10), 100(100). (Found: C, 68.14, H, 5.89, N, 2.75, Cl, 7.30. C28H28ClO5N required C, 68.15, It, 5.68, N, 2.84, Cl, 7.10).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]>C(Cl)Cl>[C:5]([O:4][C:3]([NH:2][O:1][C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19])=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: COCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)ONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-hydroxycarbamate (1.5 g, 11.3 mmol) in DCM (50 ml) is added triethylamine (1.6 ml, 11.3 mmol) at 0° C. Chloro(2-methoxyethoxy)methanone (1.56 g, 11.3 mmol) is added dropwise. Reaction is stirred for 18 hours at room temperature before being washed with water (2×10 ml), NaHCO3 (2×10 ml), dried (MgSO4) and concentrated in vacuo to give the title product as an oil. (0.67 g, 25%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.74-8.46 (1H, m), 4.23-4.73 (2H, m), 3.45-3.84 (2H, m), 3.34 (3H, s), 1.41 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1>CN(C)C=O>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([F:19])[CH:13]=1)[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(F)cc(Br)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
Combine 1-methyl-piperidin-4-ol (5.97 g, 51.81 mmol) and N,N-dimethylformamide (100 mL) and treat, in portions, the resulting solution with 95% sodium hydride (1.31 g, 51.81 mmol) and stir. After 1 hr., add 1-bromo-3,5-difluoro-benzene (10.0 g, 51.81 mmol), stir and heat to 80° C. After 2 hr., cool to ambient temperature, partition between water (100 mL) and ethyl acetate (100 mL), separate and wash the water layer with ethyl acetate (100 mL). Combine the ethyl acetate layers and wash with water (5×75 mL). Wash the organic layer with aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate to an oil. Purify the residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain of the title compound (10.61 g, 71%). Mass spectrum (electrospray): m/z=288 (M+1−1), 290 (M+1+1); 1H NMR (CDCl3): 6.85 (s, 1H), 6.8 (m, 1H), 6.55 (m, 1H), 4.3 (m, 1H), 2.6 (m, 2H), 2.3 (m, 5H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])=[CH:4][CH:3]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]([C:13]1[C:12]([CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:42]=[N:41][C:40]([O:39][CH3:38])=[CH:45][CH:44]=3)=[CH:3][CH:4]=2)[N:19]2[C:14]=1[CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]2)=[O:28]
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccc(-c2ccc(OC)nc2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
A solution of ethyl 3-{3-[(4-bromophenyl)carbamoyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (55 mg, 0.097 mmol), 2-(methoxy)pyridine-5-boronic acid (15 mg, 0.097 mmol) and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.007 mmol) in 1,4-dioxane (4 mL) is heated in the microwave at 120° C. for 20 minutes then 100° C. for 16 h. The mixture is cooled to 23° C., poured into water and extracted with EtOAc. The combined organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 50% EtOAc in hexanes) gives ethyl 3-[1-(2,2-dimethylpropanoyl)-3-{[4-(6-methoxypyridin-3-yl)phenyl]carbamoyl}-7-(propan-2-yl)indolizin-2-yl]-2,2-dimethylpropanoate (22 mg, 38%) that is dissolved in 1,4-dioxane (3 mL) and water (0.5 mL). To this mixture is added 10M aqueous NaOH (5 drops) and solution is stirred at 23° C. until reaction is complete. The mixture is acidified with HOAc and resulting solid is filtered, washed with water, collected, and dried to give the title compound (14 mg, 67%).