Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH2:29])[CH:15]=2)=[N:11][CH:12]=1>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:25]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of acryloyl chloride (0.049 mL, 0.60 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 112, 260 mg, 0.54 mmol) in CH2Cl2 (9 mL). This mixture was stirred for 1 h and then loaded onto a SCX column. The column was washed with CH3OH and the desired product was then eluted from the column using 2M methanolic ammonia. Appropriate fractions were concentrated in vacuo to give a brown gum. Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 (containing 1% concentrated aqueous ammonia) gave the title compound (214 mg, 74%) as a yellow solid after trituration with CH3OH (0.5 mL) using an ultrasound bath for 2 mins; 1H NMR: 2.10 (6H, s), 3.03-3.14 (1H, m), 3.59 (2H, t), 3.77 (3H, s), 3.90 (3H, s), 3.97 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.23 (1H, s), 6.46 (1H, dd), 7.12 (1H, t), 7.23 (1H, t), 7.44-7.54 (2H, m), 8.20-8.38 (3H, m), 8.51 (1H, s), 9.21 (1H, s); m/z: ES+ MH+ 532.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]([NH2:28])=O)[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]#[N:28])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Reaction time: 0.83 h
Yield: 72.5 %

Procedure:
To a solution of 6-(6-cyclopropyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamide (137 mg) in N,N-dimethylformamide (1.5 mL) was added dropwise phosphoryl chloride (0.051 mL) under ice-cooling. This mixture was stirred for 50 minutes under ice-cooling. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (94.4 mg). 1H-NMR (CDCl3) δ ppm: 0.69-0.77 (2H, m), 0.92-1.03 (2H, m), 1.97-2.07 (1H, m), 4.46 (2H, s), 6.86 (1H, dd, J=1.5, 8.3 Hz), 7.11-7.17 (1H, m), 7.21-7.32 (2H, m), 7.33-7.64 (7H, m), 8.09 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 61 %

Procedure:
Following General Procedure I, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethyl(methyl)carbamate (400 mg, 0.86 mmol) was reacted with NBS (184 mg, 1.03 mmol) to afford the desired product (285 mg, 61%) as a yellow solid: ESI MS m/z 543 [C26H30BrN2O4S+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13](OCC)([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH2:2][P:13](=[O:14])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Temperature: 150 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (25 g, 109 mmol) and triethyl phosphate (24.3 ml, 142 mmol) was stirred at 150° C. for 24 h. The resulting mixture was purified by distillation (165-172° C., 1 mmHg) to obtain diethyl 4-(methoxycarbonyl)benzylphosphonate (21.5 g, 69%). To a mixture of diethyl 4-(methoxycarbonyl)benzylphosphonate (20.5 g, 71.5 mmol), 15-crown-5 (1.4 ml, 7.1 mmol) and THF (120 ml) was added sodium hydride (60% in oil, 2.9 g, 71.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11.9 g, 59.6 mmol) in THF (45 ml) was added dropwise to the resulting mixture over period of 10 min at 0° C. The mixture was stirred at room temperature for 20 h. The resulting mixture was poured into ice-water (200 ml) and the whole was extracted with ethyl acetate (100 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate(100 ml), saturated sodium chloride solution (100 ml) successively. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 200 g, ethyl acetate/hexane=1/10) followed by recrystallization from hexane to give tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6.9 g, 35%) as a colorless crystalline powder. A mixture of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was hydrogenated over 10% palladium carbon (50% wet, 1 g) for 5 h at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to obtain the title compound (6.1 g, 100%) as pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[C@H:3]1[CH2:23][CH3:24].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:23]([C@H:3]1[C:2](=[O:1])[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]1[C:5](=[O:22])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:21])[CH3:24]
Reactant: CC[C@@H]1C2C(=O)C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC[C@H]1O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC[C@H]1C(=O)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 3α,17β-dihydroxy-4β-ethylandrostan-6-one and 3β-17β-dihydroxy-4β-ethylandrostan-6-one (179 mg) in DCM (6.7 ml) under N2, NMO (190 mg), TPAP (9.5 mg) and 4 Å molecular sieves (270 mg) were added. The mixture was stirred for 15 min and then SiO2 was added. The mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc 70/30) to give the title compound (140 mg, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH2:12][CH:13]1[CH2:18][CH:17]2[CH2:19][CH:14]1[CH2:15][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:14]12[CH2:19][CH:17]([CH2:16][CH2:15]1)[CH2:18][CH:13]2[NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NC1CC2CCC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NC2CC3CCC2C3)nc1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), 2-aminonorbornane hydrochloride (147 mg, 1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness to yield 220 mg. ES-MS calcd for C12H15N3O2 (m/e) 233.21, obsd 234.1 (M+H).
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:28])[CH2:13][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:16](OCC)=[O:17])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:28][CH:12]1[NH:11][C:16](=[O:17])[CH2:15][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13]1
Reactant: CCOC(=O)CN(CC(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of ethyl 2-[[2-[[(benzyloxy)carbonyl]amino]propyl](tert-butoxycarbonyl)amino]acetate (2.3 g) and 10% Pd/C (0.23 g) in methanol (46 ml) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was stirred at 50° C. for 1 hour, concentrated under reduced pressure to obtain the title compound (1.1 g) as a colorless non-crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].OO>C(O)C.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.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)[O:22][C:23]=3[CH3:24])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)cc2)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
4-Methoxy-benzeneboronic acid (1.44 g, 7.19 mmol) in ethyl alcohol (5 mL) was added into a mixture of 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (2.5 g, 6.54 mmol), sodium carbonate (2N, 6.5 mL), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.196 mmol), and toluene (200 mL). The reaction mixture was refluxed for 12 hours, cooled to room temperature, and treated with hydrogen peroxide (30%, 5 mL) for 1 hour. Then, the mixture was poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and crystallization from hexanes/ethyl ether gave a white solid (2.2 g, 82% yield): mp 167-168° C.; MS m/e 409 (M+);
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([F:16])([F:15])[F:14].[S:17]([O-:20])([O-:19])=[O:18].[Na+].[Na+].C(O)C>O>[F:14][C:13]([F:16])([F:15])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:17]([OH:20])(=[O:19])=[O:18]
Reactant: O=S([O-])[O-]
Reactant: FC(F)(F)OCCCCCCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)CCCCCCCCCCOC(F)(F)F

Procedure:
6.8 g of bromide from Example 5b (22.35 mmol) and 3.7 g (29 mmol; 1.3 eq) of sodium sulfite are dissolved in 40 ml of deionised water and 40 ml of ethanol in a 250 ml one-necked flask, and the mixture is heated at 100° C. for 20 h. The cooled reaction mixture is extracted with methyl t-butyl ether/heptane (1:1). The aqueous phase is acidified (pH=0) and extracted with methyl t-butyl ether. The combined organic phases are dried over sodium sulfate and evaporated.
Reaction SMILES: C([N:3](CC)CC)C.ClC(OC)=O.[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31](O)=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N>O1CCCC1>[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31]([NH2:3])=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: O=C1C2C3C=CC(C(=O)O)(C3)C2C(=O)N1Cc1ccccc1
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 0 °C

Procedure:
1.1 g (11 mmol) of triethylamine and then 1.15 g (12 mmol) of methyl chloroformate are added dropwise to 3 g (10 mmol) of 4-benzyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6 ]dec-8-ene-1-carboxylic acid in 20 ml of absolute tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for a further hour and the solution is poured onto 20 ml of ammonia solution. The mixture is stirred at room temperature for 1 hour and extracted several times with chloroform, and the extracts are dried over MgSO4 and concentrated, whereupon the product crystallizes.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1)[CH3:2].C(O)(=O)C.[CH3:28][C:29]1[N:30]=[CH:31][C:32]([CH:35]=O)=[N:33][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH2:1]([C@@H:3]1[CH2:7][N:6]([CH2:28][C:29]2[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: Cc1cnc(C=O)cn1
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(Cc2cnc(C)cn2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (4.4 g) in dimethylformamide (62 mL) was added acetic acid (2.4 mL), 5-methylpyrazine-2-carbaldehyde (2 g) and sodium triacetoxyborohydride (5.27 g). The reaction mixture stirred for 2 h at ambient temperature and was carefully quenched with saturated sodium bicarbonate solution, extracted 3× with methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC chromatography eluting with 1-4% methanolmethylene chloride/0.5% saturated ammonium hydroxide provided the title compound (3.9 g). 400 MHz 1H NMR (CDCl3) δ 8.52-8.48 (m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 4.81-4.75 (m, 1H), 4.11-4.01 (m, 3H), 3.79-3.75 (m, 1H), 3.60-3.53 (m, 2H), 3.40-3.32 (m, 1H), 3.10-3.08 (m, 1H), 2.94 (m, 1H), 2.63-2.57 (m, 1H), 2.53 (d, J=7.5 Hz, 1H), 2.37-2.18 (m, 4H), 1.90-1.83 (m, 2H), 1.67-1.60 (m, 1H), 1.54-1.47 (m, 1H), 0.95-0.92 (m, 3H). MS: (M+H m/z 424.2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]3[C:17]=1[CH:16]=[C:15]([C:18](OCC)=[O:19])[C:14]3=[C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=1)[C:24]=2[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:12](=[CH:11][CH:10]=1)[C:24]([CH2:25][CH3:26])=[C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:29][CH:28]=1)[C:14]3=[C:15]([CH2:18][OH:19])[CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)ccc3c(CC)c(-c4ccc(OCc5ccccc5)cc4)c1n23
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(CO)cc3c(OCc4ccccc4)ccc1n32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-2-carboxylate (15.79 g, 30 mmol) was dissolved in 250 ml of dry tetrahydrofuran under a nitrogen atmosphere. Lithium aluminium hydride (1.8 g, 50 mmol) was added in small portions, and the mixture was stirred at room temperature for 21/2 hours. Water was added until effervescence terminated and solid potassium carbonate was added until a white suspension was formed. Diethyl ether (200 ml) was added and the reaction mixture was stirred vigorously. The reaction mixture was filtered through celite and the organic material was extracted into 3×100 ml of diethyl ether and 3×100 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude product was recrystallized from hot ethyl acetate and petroleum ether. This gave 13.06 g (89%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-hydroxymethyl-pyrrolo[2,1,5-cd]indolizine as yellow crystals. M.p. 133-134° C. MS(SP): m/z 487 (M+). 1H-NMR (DMSO-d6, 400 MHz) δ: 1.34 (t, 3H); 3.04 (q, 2H); 4.81 (s, 2H); 5.18 (m, 3H); 5.57 (s, 2H); 7.20 (d, 2H); 7.31-7.64 (m, 14H); 7.92 (d, 1H). The structure has been proven by COSY, ROESY and NOESY, 400 MHz.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([SH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(N(C)C)=O.C[O-].[Na+]>CO>[CH2:10]([S:24][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CCCCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCSc1ccc(C(=O)O)s1

Procedure:
A mixture of 18.6 g (0.090 mole) of 5-bromo-2-thiophenecarboxylic acid, 25.0 g (0.109 mole) of 1-tetradecanethiol and 500 ml of dried dimethyl acetamide is stirred at room temperature after which 10.8 g (0.200 mole) of sodium methoxide is added. The mixture is heated and the methanol formed is allowed to distill off. The mixture is refluxed for 24 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with 10% aqueous hydrochloric acid, filtered, and the precipitate washed with water and dried. The solid obtained is crystallized from the methanol then recrystallized from hexane to give 5-(tetradecylthio)-2 -thiophene carboxylic acid, M.P. 106°-108° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[C:15]([CH3:16])=[N:14][C:13]2[O:12][CH:11]([CH2:17][CH2:18]Cl)[CH2:10][N:9]([CH3:20])[C:8](=[O:21])[C:7]=2[CH:6]=1.CO.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)(C)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:4][C:5]1[C:15]([CH3:16])=[N:14][C:13]2[O:12][CH:11]([CH2:17][CH2:18][N:2]([CH3:3])[CH3:1])[CH2:10][N:9]([CH3:20])[C:8](=[O:21])[C:7]=2[CH:6]=1
Reactant: Cc1nc2c(cc1Cl)C(=O)N(C)CC(CCCl)O2
Reactant: CNC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CO
Product: Cc1nc2c(cc1Cl)C(=O)N(C)CC(CCN(C)C)O2
Reaction time: 48 h

Procedure:
To 70 ml of freshly collected dimethylamine was added 5.0 g (0.017 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one and 5 ml of methanol. The reaction flask was sealed tightly and left standing at room temperature for 2 days. The reaction flask was cooled and opened and the solvent evaporated in a stream of air. The residue was taken up in 100 ml of methylene chloride and the solution was washed with 3×50 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was treated with 2 equivalents of fumaric acid in isopropyl alcohol which yielded 5.3 g (59%) of white analytically pure crystals, m.p. 153°-56° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccncc4)c3F)cnc2n1
Temperature: 80 °C
Yield: 5 %

Procedure:
A mixture of 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (0.10 g, 0.38 mmol), 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid (0.14 g, 0.58 mmol) and sodium carbonate (950 μL of a 2 M solution) in ethylene glycol dimethyl ether (2 ml) was degassed by bubbling nitrogen through for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added and the mixture was degassed for a further 20 min before heating at 80° C. for 18 h. The mixture was filtered through glass fibre paper, and partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. Purification by chromatography (silica gel, 5% MeOH/CH2C12), then recrystallisation from EtOAc/CH2C1 2, gave 7.0 mg (5%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 7.19–7.24 (1H, s), 7.47 (2H, d, J 4.6), 8.14–8.21 (1H, m), 8.28 (1H, d, J 2.5), 8.77 (3H, dd, J 4.6, 6.0).