Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[CH3:17])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[CH3:17])[CH2:6][CH2:7]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1N1CCN(C)CC1
Yield: 86 %

Procedure:
A heterogeneous mixture of 4-(4-methylpiperazinyl)-3-methylnitrobenzene 5 (20 g, 85 mmol), 10% Pd/C (1.3 g) in methanol (1.2 liter) was hydrogenated [H2] at 40 PSI for 3 hours. The palladium catalyst was filtered through a pad of celite, washed with methanol (3×50 mL) and the combined filtrate was concentrated to afford 4-(4 methylpiperazinyl)-3-methylaniline 7 (15 g, 86%). 1H NMR (CD3OD): δ 6.83 (d, 1H, J=8.7 Hz), 6.59 (d 1H, J=2.7 Hz), 6.54 (dd, 1H, J=8.4 and 2.7 Hz), 2.84 (t, 4H, J=4.8 Hz), 2.60 (bm, 4H), 2.34 (s, 3H), 2.20 (s, 3H); LCMS: purity: 99.9%, MS (m/e); 206 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[CH3:6][NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)O.Cl[Si](C)(C)C.O>C(O)C.C(OCC)(=O)C>[ClH:3].[CH3:6][NH:7][CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CNCC1CCCCC1(O)c1cccnc1
Reactant: O=S(Cl)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCC1=C(c2cccnc2)CCCC1
Temperature: 65 °C

Procedure:
26 ml thionyl chloride were added dropwise to 5.20 g 2-methylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride and the mixture was heated (bath temperature 65 ° C) for 90 minutes, while stirring, and then concentrated under a water pump. After cooling, dilute sodium hydroxide solution (2 mol/l) was added, the mixture was extracted repeatedly with a mixture of equal volumes of tetrahydrofuran and ethyl acetate, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (3.25 g) was dissolved in 25 ml absolute ethanol and 8 ml ethyl acetate, and 4.1 ml chlorotrimethylsilane and 0.58 ml water were added in succession. The solid which had precipitated out (1.84 g) was filtered off with suction (cf. Example 79), the mother liquor was rendered basic with dilute sodium hydroxide solution (2 mol/l) and extracted repeatedly with a mixture of equal volumes of tetrahydrofuran and ethyl acetate, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The residue obtained (1.45 g) was chromatographed on silica gel with methanol, to which 0.05 percent by volume of aqueous ammonia solution (25 percent strength by weight) had been added. The product fraction (0.52 g) was dissolved in 50 ml ethyl acetate, and 0.66 ml chlorotrimethylsilane, followed by 92 μl water, were added. 0.57 g methyl-(2-pyridin-3-yl-cyclohex-1-enylmethyl)amine hydrochloride was obtained as a precipitate.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH:13]=2)[NH:8][C:7]=1[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[O:5].[OH-].[Na+].CC(O)=O.C(O)(C)C>CO.C1COCC1.O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH:13]=2)[NH:8][C:7]=1[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[O:5]
Reactant: COC(=O)C(C)(C)Cc1[nH]c2ccc(OCc3ccc4ccccc4n3)cc2c1C(=O)CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)c1c(CC(C)(C)C(=O)O)[nH]c2ccc(OCc3ccc4ccccc4n3)cc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The crude ester from step D was dissolved in a mixture of MeOH (20 mL), THF (20 mL), and H2O (5 mL). To this was added 10M NaOH (2.3 mL, 23 mmol). After stirring for 3 hours, the solution was cooled to 0° C., and HOAc (1.5 mL) was added dropwise. The solution was partly concentrated to remove the THF and MeOH, and the product was then extracted into EtOAc. The organic layer was washed with H2O and brine. After drying (MgSO4), the solution was filtered and evaporated to give a pale orange solid. The product was stirred vigourously with a mixture of isopropanol (30 mL) and H2O (3 mL) to give the title compound as an off-white amourphous solid (2.6 g). mp=193°-196° C. (dec).
Reaction SMILES: C(S[C:6](=[O:19])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[F:27]>>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[F:27])=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(Br)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Br)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-(4-bromobenzyl)-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-fluoro-phenol.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]3[C:12]([CH2:16][CH2:17][NH:18][C:19](=[O:27])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1>C(O)(=O)C.[Pd]>[O:28]=[C:4]1[CH2:3][CH2:2][C:11]2[C:10]3[C:12]([CH2:16][CH2:17][NH:18][C:19](=[O:27])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: O=C(Cc1ccccc1)NCCc1cccc2ccc3c(c12)C(=O)CC(=O)N3
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)NCCc1cccc2ccc3c(c12)CCC(=O)N3

Procedure:
The product of Example 115 (3 mmol) is dissolved in acetic acid (70 ml). After several purges with argon, 10% palladium-on-carbon (600 mg) is added and the mixture is placed under a hydrogen atmosphere. Stirring is carried out at ambient temperature until the end of the reaction (monitored by TLC) and the palladium is filtered off over Celite. The acetic acid is evaporated off to dryness and the residue is chromatographed on silica gel to yield the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[CH:15]=[CH:14]2>>[O:17]1[C:18]2[C:13](=[CH:12][C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:12]=[C:13]5[C:18](=[CH:19][CH:20]=4)[O:17][C:16](=[O:21])[CH:15]=[CH:14]5)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]1=[O:21]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2oc(=O)ccc2c1
Product: O=c1ccc2cc(Nc3ncc(F)c(Nc4ccc5oc(=O)ccc5c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminocoumarin were reacted to yield N2,N4-bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.17 (d, 2H, J=3.6 Hz), 7.97-7.74 (m, 5H), 7.40 (1H, d, J=8.7 Hz), 7.30 (d, 1H, J=9 Hz), 6.50 (d, 1H, J=10.2 Hz), 6.40 (d, 1H, J=9.3 Hz); LCMS: ret. time: 19.05 min.; purity: 94%; MS (m/e): 417 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]1[C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[NH:21][S:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[N:14]([CH:31]([CH3:33])[CH3:32])[CH:13]=1)[N:8]([CH3:34])[CH2:7][CH2:6]2.[C:35](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]1[C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[NH:21][S:22]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][CH2:26]3)(=[O:24])=[O:23])[N:14]([CH:31]([CH3:32])[CH3:33])[CH:13]=1)[N:8]([CH3:34])[CH2:7][CH2:6]2
Reactant: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCNCC3)ccnc21
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCN(C)CC3)ccnc21
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a stirred solution of N-(3-(5-fluoro-1-methylindolin-6-yl)-1-isopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-4-sulfonamide, hydrochloride (D39) (248 mg, 0.488 mmol) in MeOH (8 mL) at RT was added acetic acid (0.279 mL, 4.88 mmol), formaldehyde (37% solution in water) (0.218 mL, 2.93 mmol) and sodium cyanoborohydride (307 mg, 4.88 mmol). The reaction mixture was stirred at RT for an hour. The reaction mixture was concentrated in vacuo. The residue was passed through SCX cartridge (eluted with MeOH followed by 2M NH3 in MeOH solution; 100 mL each). The basic fractions were concentrated in vacuo to afford a material which was purified using chromatography on silica, eluted with 0-10% MeOH in DCM to afford the title compound (84 mg). LCMS (A): m/z (M+H)+ 486, C25H32FN5O2S requires 485 (acidic).
Reaction SMILES: C1C([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=CC=C(N=C=O)C=1.[N-:20]=[C:21]=[O:22].[N-]=C=O.CC1C(C)=C(C)C(C)=C(C)C=1C.N(CCCCCCN=C=O)=C=O.[N-]=C=O.[N-]=C=O.COC1C=CC=CC=1C1C=CC=CC=1OC.C1(N=C=O)C(N=C=O)=CC=CC=1.[N-]=C=O.[N-]=C=O.C1C=CC(C2C=CC=CC=2)=CC=1.CC(C)(CC(C)CCN=C=O)CN=C=O.CC(CC(C)(C)CCN=C=O)CN=C=O>>[CH3:7][C:8]1[C:9](=[CH:10][C:11](=[CH:12][CH:13]=1)[N:14]=[C:15]=[O:16])[N:20]=[C:21]=[O:22]
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Reactant: [N-]=C=O
Agent: CC(CCN=C=O)CC(C)(C)CN=C=O
Agent: CC(CN=C=O)CC(C)(C)CCN=C=O
Agent: COc1ccccc1-c1ccccc1OC
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
diphenylmethane-4,4′-diisocyanate (MDI); hydrogenated diphenylmethane-4,4′-diisocyanate (H12MDI); tetra-methyl xylene diisocyanate (TMXDI); hexamethylene-1,6-diisocyanate (HDI), of the formula OCN—(CH2)6—NCO; naphthalene-1,5-diisocyanate; 3,3′-dimethoxy-4,4′-biphenyldiisocyanate; 3,3′-dimethyl-4,4′-bimethyl-4,4′-biphenyldiisocyanate; phenylene diisocyanate; 4,4′-biphenyidiisocyanate; 2,2,4-trimethylhexamethylene diisocyanate and 2,4,4-trimethylhexamethylene diisocyanate, of the formulae
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C>CS(C)=O>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred solution of N-Cbz-L-prolinol (5 g; 21.26 mmol, from steps 24b or 24c above) in 20 mL of anhydrous DMSO were added 8.89 mL (63.79 mmol) of triethylamine and 10.75 g (63.79 mmol) of SO3 -pyridine complex in 35 mL of DMSO. The reaction mixture was stirred at room temperature for 10 min; then poured into 200 mL of ice water. The mixture was extracted with ether, the extract was dried over Na2SO4 and concentrated to afford the title product, 3.058 g (70% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Reactant: N#CBr
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@]1(C)N=C(N)OCC1(F)F
Yield: 61 %

Procedure:
Starting from (1S,2S)-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (intermediate J5.3) the cyclization with cyanogen bromide yielded the (1S,2S)-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (61% yield) as a white solid. MS (ISP): m/z=263.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH2:3]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Yield: 91.2 %

Procedure:
A solution of (S)-1-benzyl 2-tert butyl 5-oxopiperidine-1,2-dicarboxylate (14.55 g) in ethanol (437 mL) was ice-cooled, and sodium borohydride (1.65 g) was added, followed by allowing to react under ice cooling for 20 minutes. Saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture until effervescence was quenched, and the generated salt was dissolved with the addition of water. The organic solvent of the mixture was distilled off under reduced pressure, and the aqueous layer of the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1→2/1) to afford 13.35 g of the title compound as a colorless oil (yield 91%). Enantiomeric excess 98.8% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=4/1, flow rate 1 mL/min., retention time 9.1 min.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:30])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[C@@H:18]([CH3:29])[CH2:17]3)[CH:10]=2)[CH:8]=1.CC(OC([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=2)[C:47]([OH:49])=O)[CH2:40][CH2:39]1)=O)(C)C>>[F:30][C:6]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:29])[CH2:17]3)[CH:10]=2)=[CH:8][C:3]([CH2:2][NH:1][C:47](=[O:49])[C:46]2[CH:50]=[CH:51][CH:52]=[C:44]([CH:41]3[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]3)[CH:45]=2)=[CH:4][CH:5]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 18 %

Procedure:
Following the standard procedure outlined in Example 57, 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate, 50 mg, 0.121 mmol) was reacted with the commercially available 3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)benzoic acid (37 mg, 0.121 mmol) to give the title compound (11 mg, 18%). LC/MS: m/z, 501 (M+H), 1.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[O:10].[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:11](=[O:12])(=[O:13])[NH2:14])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH3:15])[CH2:18][CH2:19]1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: COC1CCNCC1
Solvent: C1CCOC1
Solvent: CO
Product: COC1CCN(C(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 392A in anhydrous tetrahydrofuran (6 mL) was added 4-methoxypiperidine (451 mg). The mixture was stirred at 60° C. for 3 hours. The mixture was cooled, mixed with methanol (20 mL) and silica gel (6 g) and concentrated. The material was purified on a silica gel column and was eluted with 10% methanol in dichloromethane to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:5][C:6](=[O:48])[C@@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].[CH3:54][O:55][C:56]1[CH:79]=[CH:78][C:59]([CH2:60][O:61][C:62]([NH:64][C@H:65]([C:75](O)=[O:76])[CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[O:63])=[CH:58][CH:57]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:5][C:6](=[O:48])[C@@H:7]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH:17][C:75](=[O:76])[C@H:65]([CH2:66][O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[NH:64][C:62]([O:61][CH2:60][C:59]1[CH:78]=[CH:79][C:56]([O:55][CH3:54])=[CH:57][CH:58]=1)=[O:63]
Reactant: COc1ccc(COC(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-Tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L-leucine methyl ester (example 1, h), 1.6 g., is dissolved in 30 ml. of dimethylformamide and treated with 0.789 g., of Nα -p-methoxybenzyloxycarbonyl-O-benzyl-L-serine and cooled in an ice bath. 1-Hydroxybenzotriazole, 326 mg., and finally 500 mg., of dicyclohexylcarbodiimide are added and the reaction mixture stirred to room temperature overnight and for twenty-four additional hours. The reaction mixture is filtered and the solvent removed under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.25 N hydrochloric acid, saturated sodium chloride solution, 5% sodium bicarbonate solution, and finally, saturated sodium chloride solution. The ethyl acetate solution is refrigerated for several days and a gelatinous precipitate separated. After triturating with ether for two hours, the above named product is separated and dried, 1.7 g.
Reaction SMILES: ClC1C=C(C2OC([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=3[CH3:24])=NC=2)C=CN=1.Cl[C:26]1[O:27][C:28]([C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=2[Cl:38])=[CH:29][N:30]=1.ClC1OC(C2C=CN=C(Cl)C=2)=CN=1>>[Cl:38][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C:28]1[O:27][C:26]([NH:13][C:14]2[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=2[CH3:24])=[N:30][CH:29]=1
Reactant: Clc1ncc(-c2c(Cl)cncc2Cl)o1
Reactant: CCOCc1ccc(C)c(Nc2ncc(-c3ccnc(Cl)c3)o2)c1
Agent: Clc1cc(-c2cnc(Cl)o2)ccn1
Product: CCOCc1ccc(C)c(Nc2ncc(-c3c(Cl)cncc3Cl)o2)c1
Yield: 81 %

Procedure:
The same procedure outlined above in the preparation of 5-(2-chloropyridin-4-yl)-N-(5-(ethoxymethyl)-2-methylphenyl) oxazol-2-amine was used. However 2-chloro-5-(3,5-dichloropyridin-4-yl)oxazole was used instead 2-chloro-5-(2-chloropyridin-4-yl)oxazole. Yield=81%.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5][C:4]=2[CH:3]=[C:2]1[C:15]([O:17]CC)=[O:16].[ClH:20]>[OH-].[K+]>[ClH:20].[S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OCC)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2c(s1)CCNC2
Temperature: 0 °C
Yield: 30 %

Procedure:
Diethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1.76 mmol) in 3.5 N KOH solution (3 ml) was refluxed for 3 h (monitored by TLC). The reaction mixture was cooled to 0° C. and acidified with conc. HCl. The solid was collected by filtration and dried to give the desired product. Yield: 30%.
Reaction SMILES: [H][H].[C:3]1([C:15]2[C:16](=[O:30])[NH:17][C:18](=[O:29])[C:19]=2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[CH:4]=1.CC(C)([O-])C.[K+]>[OH-].[Pd+2].[OH-].C1COCC1>[C:3]1([C@H:15]2[C@@H:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:18](=[O:29])[NH:17][C:16]2=[O:30])[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[CH:4]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Temperature: 50 °C

Procedure:
Palladium hydroxide (20 wt % Pd on carbon, 11.5 kg) was charged to a properly prepared reaction vessel. THF (340 kg) was added to produce a slurry, and the catalyst was prereduced with hydrogen (50-75 psi). Compound 6 (115 kg) was charged to an empty vessel followed by THF (353 kg). The resulting mixture was stirred until dissolution was complete. The solution of Compound 6 was then transferred to the slurry of the catalyst. A solution of potassium tert-butoxide (1.6 M in THF, 36 kg) was charged to an empty reactor followed by THF (21 kg). This resulting solution was also transferred to the reaction mixture followed by an additional rinse with THF (340 kg). The batch was then heated to 45-55° C. under 65-80 psi of hydrogen. It is not necessary to isolate the intermediate cis racemate (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (Compound 7 in Scheme I).
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[C:10]2[CH2:11][CH2:12][CH:13](C(O)=O)[CH2:14][C:9]=2[NH:8][CH:7]=1.S(Cl)(Cl)=O>ClCCCl>[N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[NH:8][CH:7]=1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: c1nc2c([nH]1)CCCC2
Temperature: 30 °C

Procedure:
4,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid sulfate (1.32 g) was refluxed in 10 ml of 1,2-dichloroethane together with 1.78 g of thionyl chloride for 30 minutes, and the excess of thionyl chloride and the solvent were removed by distillation under reduced pressure. To the residue was added 10 ml of 1,2-dichloroethane, and 1.6 ml of indoline was added dropwise thereto at 30° C. or lower while stirring followed by stirring at room temperature for 2 hours. The reaction mixture was successively extracted once with 30 ml of water and twice with 20 ml of water. The combined aqueous layer was adjusted to a pH of 9 to 10 with a 10% sodium hydroxide aqueous solution and then extracted with methylene chloride. The combined methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.1 g (82.7%) of 5-(2,3-dihydroindol-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[CH:18][N:17]([CH:27]([CH3:29])[CH3:28])[C:13]=2[N:14]=[CH:15][N:16]=1.C(N(CC)CC)C>ClCCl>[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:24][CH:25]=3)=[CH:18][N:17]([CH:27]([CH3:29])[CH3:28])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)n1cc(-c2ccc(N)cc2)c2c(N)ncnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(NC(=O)c3ccccc3)cc2)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Benzoyl chloride (101 mg) in dichloromethane (1.0 ml) was added to a mixture of 4-amino-5-(4-aminophenyl)-7-isopropylpyrrolo[2,3-d]pyrimidine (175 mg), in dichloromethane (7 ml) and triethylamine (73 mg) at 0° C. under nitrogen with stirring. The mixture was stirred at 0° C. for four hours and then allowed to warm up to ambient temperature over one hour. The reaction mixture was stirred at ambient temperature for 18 hours and then quenched by the addition of saturated sodium bicarbonate solution (10 ml) with ice-cooling. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water, dried and evaporated to give a pale yellow solid which was purified by preparative HPLC to give N-(4-{4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-benzamide, m.p. 192-195° C.