Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:15])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])[O:2][CH2:3]Cl.[C:16]([O-:20])(=[O:19])[CH:17]=[CH2:18].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:15])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])[O:2][CH2:3][O:20][C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCOC(=O)OCCl
Reactant: C=CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)OCOC(=O)C=C
Yield: 91.1 %

Procedure:
Chloromethyl 4-acryloyloxybutyl carbonate (1.183 g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.24 g (91%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.82 (4 H, m, CH2 --CH2), 4.23 (4 H, m, 2×CH2 --O), 5.88 (2 H, s, O--CH2 --O), 5.7-6.8 (6 H, 2×CH=CH2).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14]>>[OH:12][CH:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: OC1CCCc2c(Br)cncc21
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Yield: 83 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-ol (intermediate A-2) was reacted with 4-cyanophenylboronic acid to give the title compound as light brown powder in 83% yield. MS: 251.1 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>N1CCCCC1.C(O)C>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)c(C)c21
Yield: 55 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (91 mg), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 95 mg of the title compound.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]([F:20])([F:19])[C:7](=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(O)C>[NH2:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[CH2:8][C:7]([C:6]([F:20])([F:19])[F:5])=[N:32]2)=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: O=C(C=Cc1ccc(F)cc1F)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2N=C(C(F)(F)F)CC2c2ccc(F)cc2F)cc1
Yield: 65 %

Procedure:
In a flask with an inert atmosphere sodium ethoxide (0.53 g, 7.72 mmoles) is dissolved in 45 ml of ethanol. 1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (prepared according to method E-1) (0.913 g, 3.86 mmoles) and 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.87 g, 3.87 mmoles) are added and the mixture was refluxed for 16 hours. The mixture was cooled, evaporated to dryness, cold water added, and the mixture acidified by adding acetic acid and the precipitated solid filtered. This solid was redissolved in ether, treated with active C, filtered and the solvent eliminated with a rotavapor. The resulting residue was crystallised from ethyl ether-petrol ether (50:50) to give 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole (1.02 g, yield: 65%) in the form of a solid m.p.=160-2° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S1C2C=CC=CC=2N=C1S([CH2:23][C@@H:24]1[NH:28][C:27](=[O:29])[CH2:26][CH2:25]1)(=O)=O.[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([O:53][CH3:54])[N:47]=2)=O)=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>O1CCCC1>[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41](/[C:44](/[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([O:53][CH3:54])[N:47]=2)=[CH:23]\[C@@H:24]2[NH:28][C:27](=[O:29])[CH2:26][CH2:25]2)=[CH:40][CH:39]=1)([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32]
Reactant: O=C1CC[C@H](CS(=O)(=O)c2nc3ccccc3s2)N1
Reactant: COc1nc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17 %

Procedure:
A 1 M solution of lithiumhexamethyldisilazide in tetrahydrofuran (35 mL) was added to a solution of (5R)-5-[(1,3-benzothiazol-2-ylsulfonyl)methyl]pyrrolidin-2-one obtained in Reference Example 3-12 (5.01 g) in tetrahydrofuran (150 mL) at −78° C. in a nitrogen gas stream, and the mixture was stirred at −78° C. for 40 minutes. A solution of (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(5-chloro-6-methoxypyridin-2-yl)methanone obtained in Reference Example 1-28 (3.2 g) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at −78° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=7:3→3:7) to give (5R)-5-[(E)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless oil (688 mg, 17%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:39])[CH2:33][C:34]1([CH2:37][OH:38])[CH2:36][CH2:35]1>>[OH:38][CH2:37][C:34]1([CH2:33][C:32]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(CC1(CO)CC1)=NO
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(CC4(CO)CC4)no3)C2)CC1

Procedure:
100 mg (0.24 mmol) of the compound from Example 100A and 61 mg (0.37 mmol) of the compound from Example 67A were reacted according to the General Method 2. Yield: 70 mg (56% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1.[Na].C(OCC)(=O)C>CO>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH2:25][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:7])=[O:6])=[CH:21][CH:20]=1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: O=CC=Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
2.01 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved in 30 ml of methanol, to the solution was added 1.60 g of p-chlorocinnamaldehyde, and the mixture was stirred for one hour at a room temperature. After an addition of 350 mg of sodium tetrahydrideborate in portions with ice cooling, the mixture was stirred for 30 minutes. After an addition of ethyl acetate, the reaction mixture was sequentially washed three times with water, and then twice with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The mixture was filtered and evaporated to remove the solvent under a reduced pressure. A residue was purified using a silica gel column (silica gel 80 g, eluant: 5% methanol in chloroform), and resulting crystals were washed with benzene/hexane (1:1), to obtain 2.30 g of the title compound as colorless crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH3:25])=[CH:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][C:20]([CH3:25])=[CH:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C)cc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.55 g (1.5 mmole) of [(2R)-8-methyl-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.50 g (2.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 6.0 mL of DMSO was heated at 65-7° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant to give 0.21 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 212-215° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][C:21]([F:22])=[C:16]([CH:17]=1)[NH2:15]
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: Nc1cc(B(O)O)ccc1F
Product: Nc1cc(-c2ccn3c(n2)nc2ccccc23)ccc1F

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (3-amino-4-fluorophenyl)boronic acid. 5-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoroaniline was obtained as a orange solid. 1H NMR (400 MHz, methanol-d4): δ 9.63 (d, J=7.2 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.88-7.80 (m, 2H), 7.73-7.68 (m, 2H), 7.19 (dd, J=10.8, 8.4 Hz, 1H); MS (ESI) m/z [M+H]+318.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:52]([N:51]([CH3:50])[C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57]
Reactant: C=CCCCCNC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cold solution of cis-N-Boc-4-hydroxy-L-proline (10 g. 1 eq.), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU 15.5 g, 1.12 eq.) and N-methylhex-5-en-1-amine tosylate salt 32a (13.6 g, 1.1 eq.), which was prepared according to Scheme 13 as described herein, in DMF (80 mL) containing DIPEA (29.4 mL, 3.9 eq.) was added dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, and then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 48 as a rose powder in 95% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.97-2.12 (m, 3H), 2.77-2.97 (m, 3H), 3.15-3.40 (m, 4H), 4.22 (br s, 1H), 4.50-4.62 (m, 1H), 4.90-5.04 (m, 3H), 5.71-5.83 (m, 1H); MS (ESI+): m/z=327 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].CCCCCC.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[C:14]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCCN1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCCN1C(=O)OCc1ccccc1
Yield: 86.9 %

Procedure:
To a solution of 2-pyrrolidinone (1.7 g, 21 mmol) in dry THF (25 mL), at −78° C., a 2.5 N solution of n-buthyllithium in n-hexane (8.4 mL, 21 mmol) is added. The mixture is stirred for 30′ and then a solution of benzyl chlorformate (3.03 mL, 21 mmol) in dry THF (30 mL) is added dropwise. The reaction mixture is stirred until the reaction is complete, quenched with saturated aqueous NH4Cl and ectracted with diethyl ether (3×). The combined organic phase is washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent gives 4 g (87%) of a colourless oil that is used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([F:19])[F:18])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:27][C:28]([NH2:30])=[O:29]>CC(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([F:18])[F:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH2:27][C:28]([NH2:30])=[O:29]
Reactant: Cn1c(C(F)F)nn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)F)nn(-c2cc(OCC(N)=O)c(Cl)cc2Cl)c1=O
Yield: 817.1 %

Procedure:
In a manner similar to Example 1, the reaction of 0.72 g (0.00023 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-3-difluromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one, 0.32 g (0.00023 mole) of potassium carbonate, and 0.47 g (0.00025 mole) of iodoacetamide in 5 mL of acetone produced 0.69 g of [2,4-dichloro-5-(3-difluoromethyl-4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]acetamide (mp 190°-193.5° C).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1.C[N+]1([O-])CCOCC1.C(#N)C>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH:27]=[O:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCCc1nc(N)c2c(n1)c(CCCCO)cn2COCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCCc1nc(N)c2c(n1)c(CCCC=O)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
A mixture of 4-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butan-1-ol (884 mg, 2.311 mmol), N-methylmorpholine N-Oxide (420 mg, 3.59 mmol), powdered 4 Å molecular sieves and tetrapropylammonium perruthenate (58 mg, 0.165 mmol) was placed under nitrogen and a mixture of anhydrous dichloromethane (27 mL) and anhydrous acetonitrile (3 mL) added. The reaction mixture was stirred at ambient temperature for 2 hours, Additional N-methylmorpholine N-Oxide (390 mg, 3.33 mmol) and tetrapropylammonium perruthenate (38 mg, 0.108 mmol) in anhydrous DCM (5 mL) was added and the reaction mixture stirred at ambient temperature for a further 2 hours. Additional N-methylmorpholine N-Oxide (130 mg, 1.11 mmol) and tetrapropylammonium perruthenate (100 mg, 0.284 mmol) were added and the reaction mixture stirred at ambient temperature for a further 30 mins, The reaction mixture was filtered through Celite and the cake washed with DCM three times. The reaction solvent was removed in vacuo and the residue dissolved in DCM and passed through Celite a second time. The cake was washed with DCM three times and the solvent removed in vacuo to give a black gum. The sample was dissolved in dichloromethane and purified by chromatography on on silica (100 g) using a gradient of 0-25% methanol-dichloromethane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give an orange gum with a black tinge. The sample was dissolved in dichloromethane and purified by chromatography on on silica (100 g) using a gradient of 0-25% methanol-dichloromethane over 80 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow gum (268 mg).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10](=[O:40])[C@H:11]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:12][C:13](=[O:32])[C@H:14]([CH2:28][C:29](=[O:31])[OH:30])[NH:15][C:16](=[O:27])[C@@H:17]([CH3:26])[NH:18]C(OC(C)(C)C)=O>C(OCC)C>[ClH:1].[CH3:8][O:9][C:10](=[O:40])[C@H:11]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:12][C:13](=[O:32])[C@H:14]([CH2:28][C:29](=[O:30])[OH:31])[NH:15][C:16](=[O:27])[C@@H:17]([CH3:26])[NH2:18]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Reaction time: 1 h

Procedure:
To 20 ml of 4N-HCl/dioxane was added 2.0 g of N-t-butoxycarbonyl-D-alanyl-α-L-aspartyl-L-phenylalanine methyl ester under ice cooling. The mixture was stirred for 1 hour. To the reaction mixture was added 150 ml of ethyl ether. Precipitated crystals were collected by filtration. Yield, 1.6 g; m.p., 205°-208° C. (decomposed).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:28]1[CH:27]=[N:26][N:25]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
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
Solvent: O
Product: Clc1ccc2c(cc(-c3cnn(C4CCCCO4)c3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.120 g, 0.373 mmol, from Example 62, Step 2), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g, 0.41 mmol, Aldrich) and Na2CO3 (0.20 g, 1.9 mmol) in 1,2-dimethoxyethane (4 mL) and water (0.7 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol) was added, and the reaction was heated to reflux for 1.5 hours. Upon cooling to room temperature, the mixture was partitioned between water and EtOAc, and the aqueous layer was extracted a total of three times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded product. Yield: (0.106 g, 72%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[C:23]([Cl:25])[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[C:12]([CH:21]=2)[C:13]([N:15]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[CH3:16])=[O:14])=[C:5]([Cl:26])[CH:4]=1.C[N+]1([O-])CC[O:31]CC1>C(#N)C>[CH:17]1([N:15]([CH3:16])[C:13](=[O:14])[C:12]2[CH:21]=[C:8]([O:7][C:6]3[C:23]([Cl:25])=[CH:24][C:3]([CH:2]=[O:31])=[CH:4][C:5]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[OH:22])[CH2:20][CH2:19][CH2:18]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CN(C(=O)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O)C1CCC1
Solvent: CC#N
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(C=O)cc2Cl)ccc1O)C1CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of the title compound of Step G (130 mg, 0.28 mmol) in dry acetonitrile (6 ml) at room temperature under nitrogen was added molecular seives (4 A°, 50 mg). After stirring for about 15 minutes at room temperature, N-methylmorpholine N-oxide (66 mg, 0.57 mmol) was added. The resulting mixture was stirred at room temperature for about 18 hours, then filtered through a short pad of silica gel with an acetonitrile wash. The filtrate was concentrated to afford the title compound (88 mg) as an off-white foam which was used in the next step without further purification. MS (APCl−) Calc: 393.1, found: 392.1 (M−1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.[C:13]1(N)[CH:18]=[CH:17][CH:16]=C[C:14]=1[NH2:19]>C(O)(=O)C.O>[CH:11]1[C:1]2[C:2](=[O:4])[N:19]=[C:14]3[CH:13]=[CH:18][CH:17]=[CH:16][C:5]3=[N:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CC(=O)O
Product: O=c1nc2ccccc2nc2ccccc12
Temperature: 75 °C
Yield: 96 %

Procedure:
A mixture of isatoic anhydride (1 mol) and 1,2 phenylenediamine (1.1 mol) in aglacial acetic acid (60%) was heated at 75° C. for 3 hrs. The resulting mixture was diluted with water and solid filtered to obtained dibenzo[b,e][1,4]-diazepine-11-one in 96% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[O:5])[CH3:2].[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(Cl)cccc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(Cl)cccc2c1NC1CCCC1

Procedure:
4,8-Dichloro-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.93 mmol) was treated with cyclopentylamine following general procedure B to afford 8-chloro-4-cyclopentylamino-quinoline-3-carboxylic acid ethyl ester (220 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (165 mg) following general procedure E.