Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27](B(O)O)=[C:28]2[CH2:33][CH2:32][CH2:31][N:29]2[N:30]=1>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:27]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[N:30][N:29]4[CH2:31][CH2:32][CH2:33][C:28]=34)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cccnc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2cccnc21

Procedure:
Using Preparation 3A, 1-benzene-sulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine (Preparation 5) is reacted with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 2) to provide the titled product. MS (ES) m/z=442 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH2:17][CH3:18])[N:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=1)[C:8]2=[O:56])(=[O:3])[CH3:2].[NH4+].[OH-].C(O)(=O)C>CO.Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH2:17][CH3:18])[N:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:22][CH:21]=1)[C:8]2=[O:56])(=[O:3])[CH3:2]
Reactant: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of 0.073 g (0.099 mmol) of the product from Example 42 in 2 mL of MeOH was added 4 drops of conc. HCl. The reaction mixture was stirred for 5 minutes and then made basic by addition of conc. NH4OH. The pH of the solution was adjusted to 5.0 by addition of acetic acid. The reaction mixture was concentrated in vacuo and the residue was taken up in 20 ml of EtOAc. The solution was washed with water (2×5 mL) and brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The crude product was very insoluble and was consequently purified by trituration with CHCl3, EtOAc and hexanes to give 32 mg of an off white solid, 65% yield. 1H-NMR (CD3OD 300 MHz): 0.83 (t, 3H, J=7.3 Hz), 1.32 (m, 2H), 1.62 (2H, m), 2.09 (s, 2H), 2.68 (3 line m, 2H, J=8.1 Hz), 5.37 (bs, 2H), 7.00-7.10 (m, 4H), 7.42-7.61 (m, 5H), 7.89 (dd, 1H, J=2.4, 8.8 Hz), 8.39 (d, J=2.5 Hz). FABMS m/e: 494(M+ +1) calc. for C28H27N7O2.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-:27].[NH4+]>C1COCC1.O.CCOCC>[ClH:27].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [Cl-]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: OC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of 180 g of magnesium in 2670 ml of THF is heated to 30° C. and admixed with 33 ml of a solution of 1670 g of 1-bromo-3-(trifluoromethyl)benzene in 1330 ml of THF and then, slowly, with the remainder of the solution so as to bring about and subsequently maintain reflux of the THF, and is left at reflux with stirring for 2 hours. Subsequently a solution of 1000 g of 1-benzyl-4-piperidinone in 3200 ml of THF is added slowly and the mixture is heated at reflux for 2 hours. After cooling to AT, the reaction mixture is introduced over 30 minutes into a solution of 1870 g of ammonium chloride in 6700 ml of water and the mixture is left with stirring at 20-25° C. for 2 hours. After decanting, the organic phase is washed with 5330 ml of water and the solvent is evaporated under vacuum. The residue is taken up in 5330 ml of ether, a solution of 210 g of HCl gas in 800 ml of propan-2-ol is added slowly, the temperature being kept below 25° C., the mixture is left with stirring for 40 minutes and the crystals formed are isolated with suction. The crystals are taken up in 2000 ml of ether and again isolated with suction. 1080 g of the expected product are obtained following recrystallization from a propan-2-ol/EtOH (70/30; v/v) mixture.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([I:22])=[C:7]([C:16]([I:21])=[C:17]([NH2:20])[C:18]=1[I:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:4].[CH3:23][C:24](N(C)C)=[O:25]>>[CH3:1][NH:2][C:3]([C:5]1[C:6]([I:22])=[C:7]([C:16]([I:21])=[C:17]([NH:20][C:24](=[O:25])[CH3:23])[C:18]=1[I:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:4]
Reactant: CC(=O)N(C)C
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCCC(=O)O)c1I
Product: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)NCCC(=O)O)c1I
Yield: 66 %

Procedure:
From 100.0 g. (0.155 mole) of N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-β-alanine (IX c), m.p. about 190° C., in 190 ml. of dimethylacetamide, 70.1 g. (66.0%) of the above product, m.p. 295°-297° C. (under decomposition) is obtained with the addition of 28.7 ml. of acetyl chloride analogously to Example 14 and after reprecipitation from aqueous ammonia with hydrochloric acid.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16](=[O:34])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29](I)[CH:28]=1)=[O:26].[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37](B(O)O)[CH:36]=1>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.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:37]3[CH:36]=[N:35][C:44]4[C:39]([CH:38]=3)=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:28]=2)=[O:26])=[C:17]([CH:22]=1)[C:16]([O:15][CH3:14])=[O:34]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(I)c1
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: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2cnc3ccccc3c2)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
Under an Ar atmosphere, 9 mL of toluene, 2.5 mL of methanol, 2.5 mL of 2M aqueous sodium carbonate solution were added to 500 mg (1.20 mmol) of 5-chloro-2-{[(3-iodophenyl)carbonyl]amino}benzoic acid methyl ester and 330 mg (1.91 mmol) of quinolin-3-ylboronic acid, and the mixture was degassed. Further, 100 mg (0.087 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was heated under stirring at 90° C. for 6 hours. After the mixture was cooled to room temperature, water was added thereto, followed by collection by filtration, water-washing, and drying. Thereafter, the resultant was dissolved in chloroform, followed by filtration. The filtrate was condensed, thereby giving 340 mg of methyl 5-chloro-2-({[3-(quinolin-3-yl)phenyl]carbonyl}amino)benzoate (yield: 67%).
Reaction SMILES: [C:1]([C:3]1[CH:51]=[CH:50][C:6]([C:7](/[N:9]=[C:10]2/[N:11]([C@@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([N:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C@H:37]4[CH3:49])=[O:35])[CH2:30][CH2:29]3)[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:15]=[CH:14][C:13]=3[NH:27]/2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7](/[N:9]=[C:10]2/[N:11]([C@H:28]3[CH2:29][CH2:30][C@@H:31]([C:34]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][C@H:37]4[CH3:49])=[O:35])[CH2:32][CH2:33]3)[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[N:15]=[CH:14][C:13]=3[NH:27]/2)=[O:8])=[CH:50][CH:51]=1)#[N:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(C#N)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Agent: Cl
Product: C[C@@H]1CNCCN1C(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(C#N)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
A suspension of (R)-tert-butyl 4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate (0.07 g, 0.100 mmol) in HCl (4M in dioxanes) (1.252 mL, 5.01 mmol) was stirred at RT for 16 hours. The mixture was concentrated under reduced pressure, and the residue was suspended in DCM (20 mL) and washed with aqueous NaHCO3 solution (10 mL). The organic layer was collected, dried over sodium sulfate and concentrated to afford a brown solid. This material was purified by silica gel chromatography to afford (E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (10 mg, 16.7% yield). MS m/z=599.4 [M+H]. Calc'd for C33H42N8O3: 598.3.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]([CH3:23])[CH3:22])[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>>[CH:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:3])([CH3:23])[CH3:22]
Reactant: CON(Cc1ccccc1OC(C)C)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CS(N)(=O)=O
Product: CON(Cc1ccccc1OC(C)C)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 52.1 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(2-isopropoxy-benzyl)-N-methoxy-acetamide (0.234 g, 0.67 mmol) with methanesulfonamide (0.064 g, 0.67 mmol) as described in the preparation of compound 22 gave 0.135 g (53% yield) of the title amide as a light yellow solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 1.25 and 1.30 (2×3H, 2 d, J=6 Hz, CH3), 2.86 and 2.88 (3H, 2 S, SO2CH3), 3.63 and 3.67 (3H, 2 s, OCH3), 4.62 (1H, m, CH), 4.76 (2H, s, NCH2), 6.19 and 6.23 (1H, 2 s, CH), 6.8-7.2 (4H, m, aromatics). HRMS (ESI/neg) calculated for C16H21N2O7S: [M−H]−: 385.106948; found: 385.106655.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([C:19]([F:22])([F:21])[F:20])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:19]([F:22])([F:20])[F:21])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1c(C(F)(F)F)[nH]c2ncc(C#N)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.7 %

Procedure:
1,1-Dimethylethyl 5-cyano-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (Intermediate 2, 2.77 g, 8.90 mmol) was dissolved in DCM (40 mL), treated with TFA (10 mL) and the resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give the title compound as a brown solid (2.49 g);
Reaction SMILES: CN(C)/[CH:3]=[CH:4]\[C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=1.C(O)(=O)C>CO.ClCCl.[Pd]>[NH:11]1[C:10]2=[CH:9][N:8]=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=[C:5]2[CH:4]=[CH:3]1
Reactant: CC(=O)Nc1cc(/C=C\N(C)C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2cc[nH]c2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of N-{4-[(Z)-2-(dimethylamino)ethenyl]-5-nitropyridin-2-yl}acetamide (0.7 g, 3 mmol, Step b) in methanol and dichloromethane (5:1, 120 mL), palladium on carbon (0.4 g) was added followed by addition of acetic acid (7 mL). The reaction mixture was then purged with hydrogen gas and stirred overnight at room temperature. The resulting mixture was filtered over celite bed, and the residue was washed with methanol (100 mL). The combined filtrate was concentrated under vacuum and purified by silica gel column chromatography using methanol in dichloromethane (2%) to afford N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (0.35 g, 71%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C@H:27]1[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][C@@H:30]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH:48][C:49](=[O:69])[C@H:50]([CH:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[NH:51][C:52]([O:54][CH3:55])=[O:53])[O:29][CH2:28]1.[C:70](O)(=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.N1C(C)=CC=CC=1C>CN(C=O)C.CCOC(C)=O>[CH3:55][O:54][C:52]([NH:51][C@H:50]([C:49]([NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][CH2:40][C@H:30]1[O:29][CH2:28][C@@H:27]([CH2:26][NH:25][C:70]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[O:77])[N:32]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31]1)=[O:69])[CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:53]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (1.4 eq) was added to a stirred mixture a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq), benzoic acid (1.2 eq) and 2,6-lutidine (2 eq) in DMF (0.05 M) and the mixture was stirred at room temperature for 16 hrs. The mixture was diluted in EtOAc, The organic layer was washed with aqueous saturated NH4Cl and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.Cl.[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CS(C)=O>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([CH3:14])[CH:24]=3)=[CH:33][CH:32]=2)=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Reactant: O=C(O)CC1NC(=O)NC1=O
Agent: Cl
Solvent: CS(C)=O
Product: Cc1cc(COc2ccc(NC(=O)CC3NC(=O)NC3=O)cc2)c2ccccc2n1

Procedure:
Commercially available (+/−) hydantoin-5-acetic acid (100 mg, 0.63 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (213 mg, 0.63 mmol) were warmed in 1 mL dry DMSO and coupled using GENERAL COUPLING METHOD A. Purified on silica gel using 5% MeOH in EtOAc to give 116 mg (46%) of a white waxy solid. MS found: (M+H)+=406.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[CH:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=[CH:24][C:15]=1[NH:14][C:4]1[C:5]2[C:9]3[CH2:10][N:11]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:13][C:8]=3[NH:7][C:6]=2[N:1]=[CH:2][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(Nc2ccc3c(c2)CCCC3)c2c3c([nH]c2n1)CCNC3
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)CCCC5)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
(6,7,8,9-Tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-(5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (75 mg, 0.24 mmol), acetic anhydride (25 μL, 0.24 mmol), and triethylamine (98 μL, 0.71 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 59 (22 mg, 26% yield) as a tan powder. LC-MS (M+H=361, obsd.=361).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([OH:10])=[O:9])=[CH:3]1.[C:11](Cl)(=O)[CH3:12]>C(O)C>[CH2:11]([O:9][C:8]([C:4]1[CH:5]=[N:6][NH:7][C:2](=[O:1])[CH:3]=1)=[O:10])[CH3:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cn[nH]c(=O)c1
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c(=O)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
The title compound from Example 18.3 (1.0 g, 7.13 mmol) was added to a solution of ethanol (16 mL) and acetyl chloride (4 mL) and the resulting suspension was heated to 75° C. and stirred overnight. The reaction mixture was concentrated, diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].P(O[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(OCC)(OCC)=O.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:6]2[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCOP(=O)(OCC)OCc1ccc(Cl)cc1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Product: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Yield: 48 %

Procedure:
The title compound was synthesized from 5-formylthiophen-2-ylboronic acid and diethyl 4-chlorobenzyl phosphate using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde (Example 1.1.a). Purification by flash chromatography (0-20% heptane/EtOAc) yielded 5-(4-chlorobenzyl)thiophene-2-carbaldehyde (730 mg, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 9.82 (s, 1H), 7.62 (d, 1H), 7.31 (m, 2H), 7.18 (m, 2H), 6.90 (m, 1H), 4.17 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[CH3:25][N:26](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:25]([C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:23])([C:19]([F:22])([F:20])[F:21])[C:4]([OH:3])=[O:24])=[C:11]([O:17][CH3:18])[CH:12]=1)#[N:26]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)cc1OC)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)ccc1C(C)(C)CC(O)(C(=O)O)C(F)(F)F

Procedure:
From 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140° C. After saponification, the title acid is obtained as an amorphous powder.
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH:12]1[CH2:15][C:14](=[O:16])[CH2:13]1)C1C=CC=CC=1.N#N>C(OCC)(=O)C.[Pd]>[O:16]=[C:14]1[CH2:15][CH:12]([CH2:11][CH2:10][C:9]([OH:17])=[O:8])[CH2:13]1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Product: O=C(O)CCC1CC(=O)C1
Yield: 99.4 %

Procedure:
A solution of 3-(3-Oxo-cyclobutyl)-propionic acid benzyl ester (9) (8.12 g, 34.96 mmol) in ethyl acetate (80 ml) was purged 3× with N2 before 10% Pd/C (800 mg, 0.077 mmol, ˜2 mol %) was added. The reaction mixture was purged again 3× with N2 then twice with H2 before leaving the reaction under an atmosphere of H2. The reaction was monitored by LCMS until no more sign of starting material was observed (˜10 h). The reaction was purged with 3 times N2, filtered through celite and Pd/C was washed 3× with ˜25 ml of EtOAc. The combined organic were concentrated to yield 4.94 g (99%) of 10 as a light yellow oil. NMR analysis shows clean product, no further purification was required. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.46 (1 H, br. s.), 3.09-3.29 (2 H, m), 2.63-2.80 (2 H, m), 2.35-2.53 (3 H, m), 1.95 (2 H, q, J=7.57 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]CC(=O)C(C)(C)C)[CH2:10][C@@H:9]1[C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@@H:9]1[C@H:21]1[O:25][C:24]([CH3:26])([CH3:27])[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCC(=O)C(C)(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reaction time: 0.83 h
Yield: 95.4 %

Procedure:
Add sulfur trioxide pyridine complex (1.99 g, 12.46 mmol) to a solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3,3-dimethyl-2-oxo-butoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.83 g, 6.23 mmol) and triethylamine (3.5 mL, 24.9 mmol) in dimethyl sulfoxide (14 mL) at 10° C. Stir 50 minutes, dilute with ethyl acetate and wash with water, saturated aqueous sodium chloride, dry with magnesium sulfate. Purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound as a foam (2.69 g, 95%).
Reaction SMILES: I/[C:2](=[CH:5]\[CH2:6][CH3:7])/[CH2:3][CH3:4].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH2:14]=[CH:15]/[CH:16]=[CH:17]/[CH3:18]>>[CH2:3]([C:2]([CH2:14][CH:15]=[CH:16][CH:17]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:18])=[CH:5][CH2:6][CH3:7])[CH3:4]
Reactant: CC/C=C(\I)CC
Reactant: C=C/C=C/C
Reactant: C1COCCN1
Product: CCC=C(CC)CC=CC(C)N1CCOCC1

Procedure:
A reaction between Z-3-iodo-3-hexene, morpholine and E-1, 3-pentadiene gave 9% trienes and 63% of the expected adduct, 4-ethyl-8-morpholino-3,6-nonadiene. ##STR6##
Reaction SMILES: O[C:2]1([CH2:16][CH2:17][NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]21C[CH2:14][CH2:13][CH2:12]2.S(=O)(=O)(O)O.O.[C:30](O)(=O)C>>[N:18]1([C:19]([O:20][CH2:21][CH3:22])=[O:23])[C:17]23[CH2:30][CH2:6][CH2:7][CH2:8][C:9]2([CH2:10][CH2:11][C:2]2[CH:3]=[CH:12][CH:13]=[CH:14][C:16]=23)[CH2:4][CH2:5]1
Reactant: CC(=O)O
Reactant: CCOC(=O)NCCC1(O)CCc2ccccc2C12CCCC2
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)N1CCC23CCCCC12c1ccccc1CC3
Yield: 59 %

Procedure:
A solution of the product from Example 13 (1.68 g, 5.29 mmol) in 15 mL of 3:1 acetic acid/concentrated sulfuric acid (v/v) was stirred at room temperature for 18 hours. The reaction mixture was poured into water (50 mL) and the resulting mixture was extracted with CH2Cl2 (4×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was dissolved in CH2Cl2 (100 mL and washed with saturated aq. bicarbonate solution (30 mL). The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 9:1 heptane/ethyl acetate) to give the title compound (0.94 g, 59%) as a white solid mp 67°-69° C.