Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:28]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C@@:4]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)([CH2:1][CH2:2][CH2:3][OH:28])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: C[C@H](N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.1 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (90 mg, 0.28 mmol) in dry THF (5 mL) was added dropwise 1 M BH3.THF (0.56 mL, 0.564 mmol) at 0° C. After stirring for 2 h at rt, the reaction mixture was cooled to 0° C. and water (1 mL), 3 M aqueous NaOH (0.5 mL) and 30% H2O2 (0.5 mL) were successively added. The mixture was stirred for 2-3 h at rt and was then diluted with water (6 mL). The pH was adjusted to 6-7 with 0.5 N HCl. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (8 mL) and brine (8 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford (R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (2 mg, 2%). LC-MS Method 1 tR=1.179, min, m/z=338.1; 1H NMR (CDCl3) 0.65 (s, 9H), 0.99-1.06 (d, 3H), 1.18 (m, 1H), 1.29 (m, 1H), 1.61-1.71 (m, 1H), 1.83-2.08 (m, 3H), 2.21-2.28 (m, 1H), 2.62-2.73 (m, 1H), 3.06-3.13 (m, 1H), 3.47-3.53 (m, 2H), 4.36-4.43 (m, 1H), 6.98-7.06 (m, 2H), 7.22-7.26 (m, 2H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:32])(=[O:31])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1>>[CH2:24]([N:22]([CH3:23])[S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=2)[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1)(=[O:31])=[O:32])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCNCC2)cc1

Procedure:
Using general procedure H with the above amine (790 mg, 1.72 mmol) and α-bromo-m-tolunitrile (660 mg, 3.37 mmol) and then using general procedure C gave N-benzyl-4-[(3-cyano-benzyl)-piperidin-4-yl-amino]-N-methyl-benzenesulfonamide as a white foam (202 mg, 25% over 2 steps).
Reaction SMILES: C(=O)([O-])[O-].[Ba+2].[C:6]([OH:11])(=[O:10])[C:7]([OH:9])=[O:8].[CH3:12][CH2:13][CH2:14][CH2:15][CH:16]1[C:51](=[O:52])[O:50][CH:49]([CH:53]([CH:55]([OH:63])[CH2:56][CH2:57][CH2:58][NH:59][C:60]([NH2:62])=[NH:61])[CH3:54])[CH:48]([CH3:64])[CH:47]=[C:46]([CH3:65])[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]([OH:66])[CH2:40][CH:39]([OH:67])[CH2:38][CH:37]([OH:68])[CH2:36][CH:35]([OH:69])[CH2:34][CH:33]([OH:70])[CH:32]([O:71][C@H:72]2[O:76][C@H:75]([CH2:77][OH:78])[C@@H:74]([OH:79])[C@@H:73]2[OH:80])[CH:31]=[C:30]([CH3:81])[CH:29]([OH:82])[CH2:28][CH2:27][CH2:26][CH:25]([OH:83])[CH2:24][CH2:23][CH2:22][CH:21]([OH:84])[CH2:20][CH2:19][CH:18]([CH3:85])[CH:17]1[OH:86].S([O-])([O-])(=O)=O>CO>[CH3:12][CH2:13][CH2:14][CH2:15][CH:16]1[C:51](=[O:52])[O:50][CH:49]([CH:53]([CH:55]([OH:63])[CH2:56][CH2:57][CH2:58][NH:59][C:60]([NH2:62])=[NH:61])[CH3:54])[CH:48]([CH3:64])[CH:47]=[C:46]([CH3:65])[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]([OH:66])[CH2:40][CH:39]([OH:67])[CH2:38][CH:37]([OH:68])[CH2:36][CH:35]([OH:69])[CH2:34][CH:33]([OH:70])[CH:32]([O:71][C@H:72]2[O:76][C@H:75]([CH2:77][OH:78])[C@@H:74]([OH:79])[C@@H:73]2[OH:80])[CH:31]=[C:30]([CH3:81])[CH:29]([OH:82])[CH2:28][CH2:27][CH2:26][CH:25]([OH:83])[CH2:24][CH2:23][CH2:22][CH:21]([OH:84])[CH2:20][CH2:19][CH:18]([CH3:85])[CH:17]1[OH:86].[C:6]([O-:11])(=[O:10])[C:7]([O-:9])=[O:8]
Reactant: O=C(O)C(=O)O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)/C=C(\C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)/C=C(\C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)C=C(C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)C=C(C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: O=C([O-])[O-]
Solvent: CO
Product: O=C([O-])C(=O)[O-]
Reaction time: 0.33 h

Procedure:
0.087 g (0.444 millimoles) of barium carbonate are suspended in 15 ml of mthanol whereupon 0.04 g (0.444 millimoles) of oxalic acid are added. The suspension thus obtained is heated to boiling until all the solid is dissolved (about 10 minutes). The solvent is removed in vacuo. The residue is added to a solution of 1.0 g (0.887 millimoles) of primycin sulfate and 80 ml of methanol and the reaction mixture is heated to boiling for 20 minutes under constant stirring. The precipitated barium sulfate is filtered hot over Celite. The filtrate is evaporated in vacuo. The solid residue is treated with ether and filtered. The solid is washed on the filter with a 2:1 mixture of acetone and water. Thus 0.93 g of white primycin oxalate is obtained, yield 92.2%. Mp.: 186°-187° C., /α/D25 =+40°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:19][C:20]([O:22]CC)=[O:21])([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:7][CH2:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:19][C:20]([OH:22])=[O:21])([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(OC)ccc2C1=O
Agent: Br
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Yield: 91.3 %

Procedure:
Aqueous HBr (100 mL) was added to 1D (10 g, 29 mmol), and the reaction mixture was refluxed overnight. The reaction mixture was then brought to room temperature and extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was removed under reduced pressure to afford crude compound (8 g) as a solid, which was carried on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 12.4 (s, 1H), 10.4 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 6.75 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 3.0-2.85 (m, 3H), 2.73 (d, J=16.4 Hz, 1H), 2.7-2.61 (m, 1H), 2.48 (m, 1H), 2.38 (m, 1H), 2.11 (m, 1H). ESI-MS m/z: 301 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]([CH3:20])[C:16]([CH3:19])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:20][N:15]1[C:16]([CH3:19])=[CH:17][N:18]=[C:14]1[N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Cc1cnc(N2CCC(c3ccc(N)cc3)CC2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cnc(N2CCC(c3ccc(NS(C)(=O)=O)cc3)CC2)n1C

Procedure:
Treatment of the product from part (ii) above (0.46 g) with methanesulphonyl chloride (0.22 g) in pyridine (12 ml) according to the method fo Example 1(iii) gave the title compound, (0.40 g), m.p. 225°-226°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li][CH3:14].[NH4+].[Cl-]>C(OCC)C>[OH:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [Li]C
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C1CCC(C)(O)CC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (4.00 g, 23.5 mmol) in diethyl ether (80 mL) was added MeLi (37.6 mL, 1M in diethyl ether) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at −60° C. for 30 min. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (150 mL) and water (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (1.8 g, 41% yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:39])=[CH:47][CH:48]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 64.7 %

Procedure:
A mixture of 0.0636 g (0.21 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0609 g (0.32 mmole) of toluenesulfonic acid monohydrate, 0.0463 g (0.21 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0661 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-17) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:34][C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6-chloropyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-chloropyridin-3-yl)terephthalamide. MS (Q1) 497 (M)+.
Reaction SMILES: NC1C2C(Cl)=CN(C(OCC3C=CC=CC=3)=O)C=2C=CN=1.C(N(CC)CC)C.C1(C(Cl)=O)CC1.[CH:35]1([C:38]([N:40](C(C2CC2)=O)[C:41]2[C:46]3[C:47]([Cl:60])=[CH:48][N:49](C(OCC4C=CC=CC=4)=O)[C:45]=3[CH:44]=[CH:43][N:42]=2)=[O:39])[CH2:37][CH2:36]1.C1(C(NC2C3C(Cl)=CN(C(OCC4C=CC=CC=4)=O)C=3C=CN=2)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[Cl:60][C:47]1[C:46]2[C:41]([NH:40][C:38]([CH:35]3[CH2:36][CH2:37]3)=[O:39])=[N:42][CH:43]=[CH:44][C:45]=2[NH:49][CH:48]=1
Reactant: O=C(C1CC1)N(C(=O)C1CC1)c1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Agent: Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Agent: O=C(Cl)C1CC1
Agent: O=C(Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Nc1nccc2[nH]cc(Cl)c12)C1CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Benzyl 4-amino-3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (350 mg, 1.16 mmol) was stirred in tetrahydrofuran and triethylamine (0.32 mL, 2.3 mmol) was added. The mixture was cooled to −10° C. and cyclopropanecarbonyl chloride (0.2 mL, 1.73 mmol) was added drop wise. The reaction mixture was stirred at room temperature for about 1 hour, followed by concentration under vacuum to remove tetrahydrofuran. The residue was dissolved in ethyl acetate and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude mixture of benzyl 4-[bis(cyclopropylcarbonyl)amino]-3-chloro1H-pyrrolo[3,2-c]pyridine-1-carboxylate and benzyl 4[(cyclopropylcarbonyl)amino]-3-chloro1H-pyrrolo[3,2-c]pyridine-1-carboxylate. The mixture was treated with saturated potassium carbonate solution in methanol (1 mL) and stirred at room temperature. After completion, methanol was removed under vacuum at room temperature. The residue was treated drop wise with saturated aq. sodium bicarbonate solution and the precipitated solid was filtered, washed with water and dried to obtain N-(3-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (176 mg, 69%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br-:23]>C(Cl)(Cl)Cl>[Br:23][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:18]
Reactant: [Br-]
Reactant: COc1ccc(C(=O)CCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)C(Br)Cc2ccccc2)cc1
Yield: 93.9 %

Procedure:
To a 500 ml three-necked flask equipped with a thermometer were added 23.0 g (95.7 mmol) 1-(4-methoxy-phenyl)-3-phenyl-propan-1-one prepared in the step 2, 0.30 g (2.25 mmol) anhydrous AlCl3 and 150 ml chloroform, the resulting mixture was agitated, upon the completion of the dissolution, to the mixture was added dropwise a bromide dissolved in 30 ml chloroform maintaining at 5-10° C. in an ice-bath, the dripping was controlled to make the color of bromide disappear quickly. Upon the completion of addition, the mixture was agitated at room temperature for 30 minutes, and then placed into a separating funnel, washed with water, then with saturated aqueous sodium bicarbonate solution, and then with water, dried over anhydrous sodium sulfate, filtrated and concentrated under a reduced pressure to a obtain a crude product, which was subjected to a silica gel column chromatography eluted with petroleum ether/ethyl acetate (13:1) to obtain a 28.7 g colorless liquid product, which was recrystallized with anhydrous ethanol to obtain a white solid in a yield of 93.9%, mp: 57-58□. 1H-NMR (CDCl3, 400 MHz) δ: 3.34 (1H, dd, J=14.28, 7.00 Hz), 3.66 (1H, dd, J=14.28, 7.00 Hz), 3.13 (3H, s, OCH3), 5.29 (1H, t, J=7.32 Hz, CHBr), 6.91 (2H, d, J=9.00 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.94 (2H, d, J=9.00 Hz, ArH); ESI-MS m/e (%): 320.8 (M+1, 100), 239.2 (M-Br, 18).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: CNC(=O)CC(c1ccccc1)c1c[nH]c2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a RT suspension of N-methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide (54 mg, 0.19 mmol) in THF (5 ml) was added LiAlH4 (0.38 ml, 1M in THF) at room temperature. The resulting mixture was refluxed for 4 h, then the same amount of LiAlH4 was added. The resulting mixture was refluxed overnight, cooled to RT, quenched by addition of Na2SO4.10H2O. The mixture was stirred for 30 min and the solid was filtered off and washed with EtOAc. The filtrate was concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording N-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]amine as a white foam (28 mg, 56% yield); MS M+H=266.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[NH2:33][C@H:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36]>CN1C(=O)CCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:33][C@H:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)C(=O)O
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(=O)O
Temperature: 160 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (151 mg, 0.5 mmol) was dissolved in NMP (5 mL) and DBU (1.5 mL, 10 mmol). (R)-(−)-2-Aminobutyric acid (99% ee/GLC; 1.03 g, 10 mmol) was then added and the mixture was stirred under N2 at 160° C. for 1 h. After cooling, the mixture was diluted with citric acid (10% aq solution) and CH2Cl2 (25 mL each). The phases were separated and the organic fraction was extracted with brine (2×10 mL), dried over MgSO4, filtered, and evaporated. The residue was redissolved in MeCN and was fractionated by preparative RP-HPLC (Vydac 218TP1022, 9 mL/min, 22.5-32.5% MeCN in H2O containing 0.1% CF3COOH over 40 min). Appropriate fractions were pooled and lyophilised to afford the pure title compound (137 mg, 74.4%) as an amorphous off-white solid. Anal. RP-HPLC (Vydac 218TP54, 1 mL/min): tR=16.04 min (0-60% MeCN), 15.95 min (22.5-32.5% MeCN in H2O containing 0.1% CF3COOH over 20 min), purity: >98% (λ=214 nm). 1H-NMR (d6-DMSO, 300 MHz) δ: 0.95 (t, J=7.3 Hz, 3H, CH2CH3); 1.51 (d, J=6.7 Hz, 6H, CH(CH3)2); 1.78 (m, J=7.3 Hz, 2H, CH2CH3); 4.27 (m, 1H, CHCH2); 4.64 (hept., J=6.7 Hz, 1H, CH(CH3)2); 4.69 (m, 2H, CH2Ph); 7.25-7.41 (m, 6H, ArH). DE-MALDI-TOF MS (α-cyano-hydroxy-cinnamic acid matrix): [M+H]+=369.41. FAB-MS: [M+H]+=369.2033 (C19H25N6O2 requires 369.2039).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[CH2:2]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>CCOCC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1COc2ccccc21
Solvent: CCOCC
Product: Fc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To an ice-cold solution of 3-coumaranone (10 mmol, 1.34 g) in ether (20 mL) was added 4-fluoro-phenyl magnesium bromide (2 M in ether, 20 mmol, 10 mL) and the reaction stirred for 3.5 hours. The reaction was quenched with H2O (10 mL), the pH was adjusted to 7 with sufficient 10% HCl and extracted with ether (3×10 mL). The ether extract was collected, dried, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (eluent: hexanes) to obtain 4-fluorophenyl-benzofuran.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[C:20]1([C:19]2[N:5]3[C:6]4[CH:18]=[CH:17][CH:16]=[N:15][C:7]=4[NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:4]3=[N:3][C:2]=2[C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1nc2n(c1-c1ccccc1)-c1cccnc1Nc1ccccc1-2
Reactant: OB(O)c1ccncc1
Product: c1ccc(-c2c(-c3ccncc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1

Procedure:
The title compound was synthesized according to the procedure described in step 1 of example 19 using 2-bromo-3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine and pyridin-4-ylboronic acid. 1HNMR (CDCl3) 400 MHz δ: 8.50-8.47 (m, 2H), 8.18-8.14 (m, 1H), 8.06-8.03 (m, 1H), 7.49-7.46 (m, 2H), 7.44-7.31 (m, 5H), 7.29-7.22 (m, 1H), 7.20-7.16 (m, 1H), 6.98-6.94 (m, 1H), 6.83-6.78 (m, 1H), 6.64 (dd, J=8.0, 4.6 Hz, 1H), 6.28 (br s, 1H); LC/MS: 388 [M+H].
Reaction SMILES: C(OC([P:9]([CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>ClCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([CH3:16])=[CH:14][PH:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:22][CH:21]=1
Reactant: CCOC(C)(OCC)P(=O)(C=C(C)c1ccc(Cl)cc1)OCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCO[PH](=O)C=C(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 14.42 g of ethyl (1,1-diethoxyethyl)-2-(4-chlorophenyl)prop-1-enylphosphinate in 50 ml of anhydrous dichloromethane containing 10% of absolute ethanol is treated with 6.518 g of trimethylchlorosilane. After stirring at room temperature for 24 hours the volatile material is removed under reduced pressure. Chromatography of the resulting oil on silica-gel gives ethyl 2-(4-chlorophenyl)prop-1-enylphosphinate as a colourless oil; 1H-NMR (CDCl3): δ(ppm)=7.35 (4H, m, Ph), 7.05 (1H, d, t, J=549 and 1.5 Hz, P--H), 5.56 (1H, d, CH), 5.30 (1H, d, CH), 4.20-3.97 (2H, q, CH2OP), 3.07 (2H, d, t, J=17+1.5 Hz, P--CH2), 1.27 (3H, t, CH3).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C@@H:14]([CH2:19][C:20]([F:29])([F:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([O:17]C)=[O:16])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH2:4]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([NH:13][C@@H:14]([CH2:19][C:20]([F:29])([F:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([OH:17])=[O:16])=[O:12])[CH2:9][CH2:10]2)[CH2:1][CH2:2][CH2:3]1
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenylpentanoate (240 mg, 0.59 mmol) was dissolved in a mixture of 15 ml of THF and 5 ml of methanol. A solution of 42 mg of LiOH (1.76 mmol, 3 eq.) in 5 ml of water was added and the mixture was stirred at RT for 3 h. After the reaction had ended, the reaction mixture was acidified to pH=3 by adding a 2 M HCl solution. The organic solvent was removed under reduced pressure and the remaining aqueous phase was extracted with ethyl acetate. Subsequently, the organic phase was washed another three times with water and once with saturated NaCl solution, dried over MgSO4 and freed from the solvent under reduced pressure. The product was obtained in the form of a yellow solid which was used in the reaction which followed without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCO2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)c2c(c1)CCO2
Yield: 74.1 %

Procedure:
7-Bromo-5-nitro-2,3-dihydrobenzofuran (2 g) was suspended in acetic acid (5 ml) and water (12 ml). Iron powder (3.5 g) was added and the mixture was heated at reflux for 3hr. The cooled mixture was cooled and filtered through celite. The filtrate was concentrated and azeotroped with toluene. The residue was purified by chromatography on silica using 10% ethyl acetate in hexane as eluent to afford the title compound (1.3 g) as an oil. 1H NMR (250 MHz, CDCl3) δ 3.22 (2H, t, J=7.5 Hz), 3.38 (2H, br s), 4.58 (2H, t, J=8 Hz), 6.51-6.53 (1H, m), 6.63-6.64 (1H, m).