Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:15])=[O:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH2:26](Br)[CH:27]=[CH2:28].Cl>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH2:28]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:15])[C:3](=[O:4])[C:2]([F:16])([F:1])[F:17])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CCN(CCc1ccc(Cl)cc1I)C(=O)C(F)(F)F
Reaction time: 3.5 h
Yield: 75.8 %

Procedure:
A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (0.94 g, 2.4 mmol) in toluene (25 mL) was treated with K2CO3 (0.43 g, 3.12 mmol), KOH (0.40 g, 7.2 mmol), n-Bu4NBr (0.077 g, 0.24 mmol) and allyl bromide (0.43 g, 3.6 mmol) sequentially. The mixture was stirred at 80 C for 3.5 hours, cooled to 20 C and acidified with 10% aqueous HCl. The phases were separated, the aqueous phase extracted with ether (100 mL), the combined organic phases were washed with brine (50 mL), dried with Na2SO4 and concentrated to give 0.76 g of a clear oil. MS calculated for C13H12ClF3INO+H: 418, observed: 418.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([NH:21][C:22](=[O:24])[CH3:23])[CH:5]=1.[CH:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:6]([NH:21][C:22](=[O:24])[CH3:23])[CH:5]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)c(NC(C)=O)c1
Reactant: C#CCCCCC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O

Procedure:
This product was prepared from 3-acetylamino-4-(toluene-4-sulfonyloxy)-benzoic acid methyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 55%); 1H NMR δ (CDCl3): 8.96 (d, J=1.51 Hz, 1H), 7.92 (br s, 1H), 7.66 (dd, J=1.57, J=8.33 Hz, 1H), 7.38 (d, J=8.15 Hz, 1H), 3.89 (s, 3H), 2.53 (t, J=7.09 Hz, 2H), 2.21 (s, 3H), 1.63 (p, J=7.16 Hz, 2H), 1.48-1.3 (m, 4H), 0.92 (t, J=7.26 Hz, 3H); LCMS m/z: 287.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccncc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-(pyridin-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.031 g, 0.09 mmol), and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.020 g, 0.14 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was triturated with water, and the precipitate was collected by filtration, washed with water, ethanol, and diethyl ether. This material was further purified on a 10 g isolute silica column using a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v/v; 1:1) as eluant. The title compound was obtained as a pale yellow solid (0.007 g, 18%); 1H-NMR (500 MHz, DMSO-d6) 2.61 (br s, 4H, piperazine N(CH2)2), 3.71 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2), 3.83 (s, 3H, OMe), 7.09 (d, J=8.85 Hz, 2H) and 8.12 (d, J=8.80 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4—OMe), 7.40 (d, J=5.86 Hz, 2H), and 8.54 (d, J=4.48 Hz, 2H) (pyrid-4-yl protons), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.37 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH:51]([N:58]([CH3:60])[CH3:59])[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:59][N:58]([CH3:60])[CH:51]([C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)[CH2:50][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: CN(C)C(CN)c1cccnc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and (2-Amino-1-(3-pyridyl)ethyl)dimethylamine (0.055 g, 0.334 mmol). The mixture was stirred at rt for 2 h then sodium triacetoxyborohydride (0.177 g, 0.835 mmol) was added and it was stirred at rt for three days. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e 748.3 (M+H)+, 3.47 min (method 6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH:31]=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N.CO>ClCCCl.C(Cl)Cl>[NH3:8].[CH3:20][OH:21].[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH2:31][NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][C@H:10]([N:13]4[CH2:17][CH2:16][CH2:15][C@@H:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(CCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2C)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.5 %

Procedure:
2-Methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (4.56 mmol) was dissolved in DCE (20 mL); to this solution was transferred a solution of 4-(2-Oxo-ethyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.85 g, 4.56 mmol) in DCE (50 mL). To this clear solution was then added acetic acid (0.86 g, 14.3 mmol, 3.1 equiv), followed by addition of powder NaBH(OAc)3 (CSN: 56553-60-7, mw=211.94): 2.9 g, 13.6 mmol, 3 equiv.) in one portion under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS showed m/z 429.35/430.40 at t=2.123 min. TLC (5% of 7N NH3/MeOH in DCM) showed no SM. The reaction was diluted with DCM (40 mL) and quenched with 30 mL of conc. NH4OH in 70 mL of water. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (15 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The product was purified on a 25 g-silica gel column (0-20%, 0-4 min; 20-40: 4-13 min; 40%: 13-25 min (A is % of 7N NH3/MeOH in DCM) to get 1.17 g (60%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO.[Cl-].[Na+].O>[C:11]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
A solution of 6-bromoindole (2.0 g, 10.20 mmol) in anhydrous toluene (20 mL) under a nitrogen atmosphere was treated with Pd[P(Ph3)]4 (10% mol). After stirring the mixture for 30 min., phenylboronic acid (1.87 g, 15.30 mmol) in anhydrous EtOH (10 mL) was added followed by the addition of sat'd NaHCO3 (6 mL). The bi-phasic mixture was heated to reflux for 24 h. After cooling to room temperature, the mixture was added to a sat'd brine solution and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 CH2Cl2/heptane) to give the desired material as white powder (900 mg, 45%): 1H NMR (DMSO-d6, 300 MHz) δ 11.15 (br s, 1H), 7.58-7.66 (m, 4H), 7.41-7.47 (m, 2H), 7.36 (m, 1H), 7.26-7.31 (m, 2H), 6.42 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[S:12][CH2:11][N:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: COC(C1=CN(C)CS1)c1ccccc1CO
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(C1=CN(C)CS1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylthiazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylthiazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[OH-].[Na+]>O>[CH2:8]([NH:11][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH:9]=[CH2:10]
Reactant: BrCC1OCCO1
Reactant: C=CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and allylamine (70 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27](O)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:65][CH2:66][CH2:67][CH:68]([O:72][CH2:73][CH3:74])[O:69][CH2:70][CH3:71].Cl>C(#N)C.O>[CH2:70]([O:69][CH:68]([O:72][CH2:73][CH3:74])[CH2:67][CH2:66][NH:65][C:27]([C:25]1[S:26][C:19]2[C:20](=[N:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])=[CH:31][CH:30]=2)[CH:24]=1)=[O:28])[CH3:71]
Reactant: CCOC(CCN)OCC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (600 mg, 1.37 mmol) in 10 ml of anhydrous acetonitrile were added HATU (608 mg, 1.6 mmol) and N,N-diisopropylethylamine (388 mg, 3.0 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294 mg, 2.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 680 mg, 88%.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]1[N:32]=[CH:31][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:19]([CH3:30])[CH:18]=4)[C:10]=3[CH:9]=1)[CH2:6]2.C(N(CC)CC)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:30][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[CH:9]=[C:8]([N:5]4[CH2:4][CH:3]5[CH:7]([CH:2]5[NH:1][C:43]([CH:40]5[CH2:42][CH2:41]5)=[O:44])[CH2:6]4)[N:32]=[CH:31][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncnc3cnc(N4CC5C(C4)C5NC(=O)C4CC4)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 107.4 mg (0.25 mmol) of [6-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine and 35.2 μL (0.25 mmol) of triethylamine in 0.5 mL of methylene chloride in an ice/brine bath was treated with 24.1 μL of cyclopropanecarbonyl chloride. The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with chloroform and washed with 2×50 mL of saturated sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was recrystallized from ethyl acetate to afford 91.7 mg (73%) of the title compound. 1H NMR (CDCl3): δ 8.78 (s, 1), 8.37 (s, 1), 7.63 (m, 1), 7.53 (m, 1), 7.26 (m, 2), 6.95 (m, 1), 6.89 (m, 3), 6.79 (s, 1), 3.87 (d, 2), 3.48 (m, 2), 2.38 (m, 1), 2.21 (s, 3), 184 (m, 2), 1.33 (m, 1), 0.89 (m, 2), 0.72 (m, 2). M.S. (m+1): 493; HPLC retention time (minutes): 6.672.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].O1CC1C[C:15]1[C:16]([O:34][CH3:35])=[C:17]([O:21][C:22]2C=CC=[C:24](CC3OC3)[C:23]=2[O:32]C)[CH:18]=[CH:19][CH:20]=1.CO>C1(C)C=CC=CC=1>[CH3:35][O:34][C:16]1[CH:15]=[CH:20][CH:19]=[CH:18][C:17]=1[O:21][CH2:22][CH:23]([OH:32])[CH2:24][N:8]1[CH2:7][CH2:6][C:5]2([O:1][C:2](=[O:11])[NH:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: COc1c(CC2CO2)cccc1Oc1cccc(CC2CO2)c1OC
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccccc1OCC(O)CN1CCC2(CC1)CNC(=O)O2
Yield: 86.7 %

Procedure:
A mixture of 3.12 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 5.4 g 2,3-epoxypropyl-o-methoxyphenyl ether, 5 ml methanol and 10 ml toluene is heated at reflux for 24 hours. The solvent is evaporated and the residue filtered through 20 g silica gel with 10% methanol/methylene chloride. Evaporation of solvent and crystallization from diethyl ether affords 4.6 g 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 124°-125°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:10]=3[N:11](CC3C=CC(OC)=CC=3)[C:12](=[O:23])[CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:10]=3[NH:11][C:12](=[O:23])[CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cncc(N)c3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: Nc1cncc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
5-(5-Aminopyridin-3-yl)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (90 mg) was dissolved in anisole (5 mL) and aluminum chloride (90 mg, 4 eq) was then added. The suspension was heated to 85° C. under nitrogen gas for two hours, and then it was cooled to room temperature and poured onto ice water/EtOAc 1:1 (30 mL:30 g). The slurry was stirred vigorously for 1 hour, and the organic phase was then separated and washed with brine. The organic phase was dried over sodium sulfate, then concentrated, and purified by chromatography (gradient: DCM to 8:2 DCM:MeOH) delivering the title compound as a solid (23 mg, 34% yield). 1H-NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.98 (d, 1H), 7.65 (m, 2H), 7.47 (dd, 2H), 7.30-7.20 (m, 4H), 6.85 (s, 1H) 5.47 (bs, 2H), 3.77 (t, 1H), 3.45 (d, 2H). HRMS (ES+) m/z calcd for C21H16Cl2N4O [M+H]+, 411.0779. found, 411.0770.
Reaction SMILES: OB1C2C=CC(OC3C=CC(C#N)=C(N4CCOCC4)N=3)=CC=2CO1.[CH2:26]([O:28][C:29]1[N:36]=[C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([B:44]3[O:48][C:47](C)(C)C(C)(C)[O:45]3)=[C:40](C=O)[CH:39]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:27].[BH4-].[Na+]>>[CH2:26]([O:28][C:29]1[N:36]=[C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]3[B:44]([OH:45])[O:48][CH2:47][C:42]=3[CH:43]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:27]
Reactant: CCOc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reaction time: 8 h

Procedure:
Experimental procedure for synthesis of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile (D107) is the same as that described in synthesis of (D46). The reaction of 2-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (6) (2.71 g, 7.81 mmol) with NaBH4 (886 mg, 23.4 mmol) gave an orange oil containing D107 upon workup. The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with 30% MeOH/CH2Cl2 (400 mL) followed by the addition of silica gel (80 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (160 g, 230-400 mesh) and eluted with 1:1:100 acetic acid:MeOH:CH2Cl2. The fractions containing D107 were collected and concentrated to give a light yellow coloured oil. The oil was freeze dried by first diluting with methanol (30 mL) followed by the addition of deionised water (400 mL), the resultant white suspension was frozen in a dry-ice acetone bath and placed overnight on freeze-dryer. A white solid of D107 was obtained (1.82 g, with 30 mol % pinacoldiol present as established by H NMR). To increase purity of D107, it was resubjected to column chromatography and freeze-dried following the same conditions as before to give D107 (402 mg, 17% isolated yield) as a white solid. 1H NMR 400 MHz (d6-DMSO) 89.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20 (dd, J=7.8, 2.0 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H); Mass Spectrum [M+H+]=297; HPLC purity 97.18% (Maxplot), 97.65% (220 nm).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:41])=[C:7]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([C:31](OC(C)(C)C)=[O:32])([CH3:30])[CH3:29])=[CH:16][CH:15]=3)=[C:11]([C:38]#[N:39])[CH:10]=[N:9][N:8]2[CH:40]=1)=[O:4].Cl.[C:43]([O:47][C:48](=[O:51])[CH2:49][NH2:50])([CH3:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl.O.ClCCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:41])=[C:7]2[C:12]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([C:31](=[O:32])[NH:50][CH2:49][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:51])([CH3:30])[CH3:29])=[CH:18][CH:19]=3)=[C:11]([C:38]#[N:39])[CH:10]=[N:9][N:8]2[CH:40]=1)=[O:4]
Reactant: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCC(=O)OC(C)(C)C)cc3)c2c1C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of ester 388D (482 mg, 0.866 mmol) in TFA/CH2Cl2/H2O (5 ml, 48/48/4) was stirred for 1 h at rt, concentrated, the resulting residue was rotavaped with chloroform twice and CH2Cl2 once to give acid intermediate as a yellow solid. The solid was dissolved in 1,2-dichloroethane (5 ml), glycine t-butyl ester hydrochloride (203 mg, 1.21 mmol), DMAP (52.9 mg, 0.433 mmol) and DIEA (528 μl, 3.03 mmol) were added. The mixture was stirred 3 min until homogeneous, then EDC.HCl (249 mg, 1.30 mmol) was added. The reaction mixture was stirred for 2 h, concentrated, partitioned between EtOAc (50 ml) and 1N HCl (50 ml). The organic layer were washed with 1N HCl (30 ml), the combined aqueous wash layer was extracted with EtOAc (3×50 ml), the combined organic layer was washed with brine (100 ml), dried with Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography to afford a yellow crystalline solid 388 (372 mg, 70%)(10%-25% EtOAc—CH2Cl2). LCMS Found: (M+H)+=613.6; (M−tBu+2H)+=558.2