Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:31])[C:13]([N:15]([CH3:30])[N:16]=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:14])[CH3:2].CO.O.[OH-].[Li+].Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:30])[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:2].[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]([C:13]1[N:15]([CH3:30])[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])=[O:31])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(CS(C)(=O)=O)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(-c2ccc(F)cc2)nn(C)c1=O
Product: CCc1cc(C)cc(CC)c1C(=O)c1c(S(C)(=O)=O)c(-c2ccc(F)cc2)nn1C
Temperature: -5 °C

Procedure:
To a 10 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-1-methyl-2-oxoacetohydrazide ((4-64)-(1)-39) (0.66 g) and methanol (2.5 ml) were added under a nitrogen atmosphere. To the mixture, lithium hydroxide monohydrate (62 mg) was added under cooling on −5° C. bath, and stirred under ice-cooling for 4 hours. After cold dilute hydrochloric acid was added under ice-cooling, the mixture was added to cold water, and extracted with ethyl acetate 3 times. The organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=3:1) to give 0.31 g of 4-(2,6-diethyl-4-methylphenyl)-6-(4-fluorophenyl)-2-methyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-64)-(1)-39) and 0.12 mg of 5-[(2,6-diethyl-4-methylphenyl)carbonyl]-3-(4-fluorophenyl)-1-methyl-4-methylsulfonyl-1H-pyrazole (22-b).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: Oc1ccccc1Cl
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Oc2ccccc2Cl)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 36c, using 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide, and chlorophenol (commercially available) as starting materials to give the title compound as a white solid. mp.: 154-155° C., MS (ISP): 458.3, 460.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([O:27]CC4C=CC=CC=4)=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(OCc4ccccc4)cc3Cl)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(O)cc3Cl)cc2)cc1
Yield: 80 %

Procedure:
To 25 mL of dehydrated ethanol, 2.5 g (4.7 mmol) of 4-benzyloxy-2-chloro-benzoic acid 4-(4-pentyl-phenoxycarbonyl)-phenyl ester, 20 mL of cyclohexene, and 0.13 g of palladium hydroxide/carbon were added. Then, the mixture was refluxed for 12 hours under argon. The resulting reaction mixture was filtered, and the filtered liquid was concentrated. The residue was recrystallized from hexane/ethyl acetate. As a result, 1.65 g of a white solid was obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([CH3:40])[C:11]([O:13][C@@H:14]1[C@@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[O:17][C@@H:16]([N:26]2[C:30]3[N:31]=[C:32]([NH:37][CH:38]=[O:39])[N:33]=[C:34]([O:35][CH3:36])[C:29]=3[CH:28]=[CH:27]2)[CH2:15]1)=[O:12]>C(Cl)Cl>[Cl:1][C:28]1[C:29]2[C:34]([O:35][CH3:36])=[N:33][C:32]([NH:37][CH:38]=[O:39])=[N:31][C:30]=2[N:26]([C@@H:16]2[O:17][C@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[C@@H:14]([O:13][C:11](=[O:12])[CH:10]([CH3:40])[CH3:9])[CH2:15]2)[CH:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
N-chlorosuccinimide (87 mg, 0.67 mmol) is added to a solution of compound (18) (300 mg, 0.67 mmol in 5 ml of DMF). After it has been stirred (at room temperature for 20 h), the solution is added to a mixture of CH2Cl2 /5% aq. NaHCO3 (50 ml, 9:1). The organic layer is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2 /acetone, 95:5). The main zone is concentrated, and n-hexane is added to the residue. The precipitated colorless crystals (230 mg, 71%) are isolated. Melting point: 119-120° C. 1H-NMR ([D6 ] DMSO): δ=1.09 (d, J=7.0, CH3), 1.15 (d, J=6.9, CH3), 2.45, 2.60, 2.63, 2.89 (4m, CH and Hα,β --C(2')), 4.06 (s, OCH3), 4.18 (m, H--C(5')), 4.28 (m, H--C(4')), 5.35 (m, H--C(3')), 6.47 (m, H--C(1')), 7.58 (s, H--C(6)), 9.45 (d, J=8.9, NH), 10.84 (d, J=9.6, HCO). Anal. calculated for C21H27CIN4O7 (482.9): C, 52.23, H, 5.64, N, 11.60; found: C, 52.51, H, 5.69, N, 11.65.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[CH2:31]([C@@H:38]1[CH2:42][O:41][C:40](=[O:43])[NH:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(Cl)Cl>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([N:39]2[C@H:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][O:41][C:40]2=[O:43])=[O:10])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C(O)CCc1csc2ccccc12
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1csc2ccccc12)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-benzo[b]thiophen-3-yl-propionic acid (2.1 g, 0.010 mol), triethylamine (4.12 g, 0.040 mol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added pivaloyl chloride (1.38 mL, 0.011 mol). After stirring for 1.5 h at 0° C., lithium chloride (0.475 g, 0.011 mol) and (R)-4-benzyl-2-oxazolidinone (1.988 g, 0.011 mol) were added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. Then the mixture was washed with water (3×150 mL). The organic layer was separated, dried, and evaporated to give the crude product. The title product was obtained as a brown oil (90%) by flash chromatography on silica gel eluting with 100% methylene chloride. This compound was used immediately in the following procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
Prepared from commercially available 2-amino-5-bromopyridine (8.65 g, 50 mmol) and commercially available 4-chlorophenylboronic acid (12.08 g, 77 mmol) as described in example C.20 step 2. Obtained the crude 5-(4-chloro-phenyl)-pyridin-2-ylamine as an orange solid (89% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH2:11]CO)=[CH:4][CH:3]=1.ClC1C=C(CC2(C3C=CC([C:41]4[CH:42]=[N:43][NH:44][CH:45]=4)=CC=3)OCCNC2)SC=1.CN>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:41]3[CH:42]=[N:43][NH:44][CH:45]=3)=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1
Reactant: Clc1csc(CC2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)c1
Reactant: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: CN
Product: CNCC(O)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 79A, 79B and 79D but substituting ethanolamine for methylamine, the title compound was obtained. LCMS (PS-A3) Rt 5.28 min [M+H]+ 328, [M−H2O+H]+ 310. 1H NMR (Me-d3-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Cl[CH2:11][C:12]([OH:14])=O.[OH2:15]>O1CCOCC1>[O:3]1[CH2:8][CH2:7][CH:6]([O:9][C:12](=[O:14])[CH2:11][OH:15])[CH2:5][CH2:4]1
Reactant: O=C(O)CCl
Reactant: O
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(CO)OC1CCOCC1
Reaction time: 3 h

Procedure:
At 65°, 3.20 g (80 mmol) of 60% sodium hydride in oil (Fluka, pract.) are added to a solution of 2.042 g (1.902 ml, d=1.074; 20.0 mmol) of tetrahydro-2H-pyran-4-ol (Fluka, pract.) in 70 ml of absolute 1,4-dioxane. The resulting grey suspension is stirred for 3 hours under reflux, is allowed to cool to 65° again and then a solution of 1.89 g (20.0 mmol) of chloroacetic acid (Fluka, puriss.) in 40 ml of absolute 1,4-dioxane is added dropwise over a period of 20 minutes. The resulting grey-brown suspension is then heated to reflux again and stirred for 3 hours at that temperature. After stirring for a further 16 hours at room temperature, 10 ml of water are added dropwise over a period of 5 minutes and the resulting yellowish suspension is concentrated to dryness by evaporation under a high vacuum. The residue is taken up in 20 ml of water and the aqueous solution is extracted twice with 20 ml of ethyl acetate each time. The ethyl acetate extracts are then washed once with 10 ml of water. The aqueous phases are combined and then acidified with 4N hydrochloric acid (pH 1). The resulting solution is saturated with sodium chloride and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate phases are then washed twice with 20 ml of saturated sodium chloride solution each time. All the ethyl acetate extracts are subsequently combined, dried over magnesium sulfate, filtered and concentrated to dryness by evaporation under a high vacuum at 30°. The residue (yellow oil) is purified by bulb tube distillation (b.p. approximately 130° at 0.4 mm Hg) to give O-(tetrahydropyran-4-yl)-glycolic acid in the form of a colourless oil which, on being left to stand, solidifies to colourless crystals which melt at from 63.9° to 70.6° (sintering from 60.2°) and contain 0.08 mol (0.91%) of water.
Reaction SMILES: C([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:20]3=[CH:21][N:22]([C:24]4[C:29]([C:30]#[N:31])=[CH:28][C:27]([NH2:32])=[CH:26][C:25]=4[Cl:33])[N:23]=[C:19]3[C:18]([F:34])=[CH:17][N:16]=2)[N:11]=[CH:10][N:9]=1)(C)(C)C.Cl>>[CH:6]([OH:35])=[O:5].[NH2:32][C:27]1[CH:26]=[C:25]([Cl:33])[C:24]([N:22]2[CH:21]=[C:20]3[C:15]([NH:14][C:12]4[CH:13]=[C:8]([NH2:7])[N:9]=[CH:10][N:11]=4)=[N:16][CH:17]=[C:18]([F:34])[C:19]3=[N:23]2)=[C:29]([CH:28]=1)[C:30]#[N:31]
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(N)cc4C#N)cc23)ncn1
Agent: Cl
Product: N#Cc1cc(N)cc(Cl)c1-n1cc2c(Nc3cc(N)ncn3)ncc(F)c2n1
Product: O=CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of {6-[2-(4-amino-2-chloro-6-cyanophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamic acid tert-butyl ester and {6-[2-(4-amino-2-chloro-6-cyanophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (66 mg, ˜0.12 mmol) in HCl (4 N in dioxane, 5.0 mL, 20 mmol) was stirred at room temperature overnight. Additional HCl (4 N in dioxane, 1.0 mL, 10 mmol) was added and the reaction mixture was heated at 40° C. for 7 hours. The resultant suspension was concentrated under reduced pressure and the residue was triturated with diethyl ether. The solid obtained was dried under vacuum and was purified by HPLC [gradient: 5 to 60% acetonitrile (0.1% formic acid) in water (0.1% formic acid)], to afford the title compound as a white solid (30 mg, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.04 (d, J=2.4 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 8.06 (d, J=3.0 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 7.06 (d, J=2.5 Hz, 1H), 6.69 (s, 2H); 6.44 (s, 2H). LCMS (Method B): RT=2.70 min, m/z: 396 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24][N:29]2[C@@H:28]([CH3:27])[C@@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: C([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(OCC1C=CC=CC=1)=O.Cl.[H][H]>[Pd].C(O)C>[CH2:24]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12][NH:11][CH2:25]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCNCC12

Procedure:
A mixture of 3.0 g. of 3carbobenzoxy-2,3,4,4 a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 2 g. of hydrogen chloride, 3 g. of 10% palladium on carbon and 200 ml. of ethanol is hydrogenated on a Parr apparatus for 18 hours at 46 p.s.i. hydrogen pressure. The catalyst is filtered and the filtrate is concentrated. The residue is recrystallized from ethanol to give 0.55 g. of the product as the hydrogen chloride salt, m.p. 288°-290° .
Reaction SMILES: [CH:1](=[N:8][CH:9](C)C)C1C=CC=CC=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[CH:21]1C=CC=CC=1>>[CH3:1][N:8]([CH2:9][C:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[NH:12][CH:13]=1)[CH3:21]
Reactant: c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)N=Cc1ccccc1
Product: CN(C)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of N-benzylideneisopropylamine (7.5 g, 51 mmol) in benzene (10 mL) at 0° C. under a nitrogen blanket was added a solution of indole (5.0 g, 43 mmol) AcOH (30 mL) over a 3-hour period, after which the stirring was continued at 0° C. for an additional 3 hours. The bulk of the solvent was removed under reduced pressure and the remaining reaction mixture was poured into 400 mL of ice water. The mixture was extracted with Et2O (3×75 mL), and the aqueous layer was cooled to 0° C. and made basic with 30% aqueous NaOH to a pH 11–12 range. The precipitate was extracted with CH2Cl2 (2×75 mL) and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to provide gramine Intermediate 6 as a yellow semisolid (3.06 g, 27%): TLC Rf (1:1 CH2Cl2/EtOAC)=0.45.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:14][OH:15])[CH:10]([OH:11])[CH:9]([OH:12])[CH:8]([OH:13])[CH2:7][NH:6]1.CO.[C:18]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>O.C(O)(=O)C>[CH:18]1([NH:3][CH2:4][C:5]2([CH2:14][OH:15])[CH:10]([OH:11])[CH:9]([OH:12])[CH:8]([OH:13])[CH2:7][NH:6]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1(CO)NCC(O)C(O)C1O
Reactant: O=C1CCCCCCCCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: OCC1(CNC2CCCCCCCCCCC2)NCC(O)C(O)C1O
Reaction time: 18 h
Yield: 67 %

Procedure:
2.65 g of 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine dihydrochloride (Preparation example 11) are dissolved in 21 ml of water, and 60 ml of methanol 1.5 ml of acetic acid and 6 g of cyclododecanone are then added. When a solution is obtained, 1.35 g of sodium cyanoborohydride are added. The mixture is stirred for 18 hours and the product which has precipitated is filtered off and washed with water. 2.4 g of a colourless complex are obtained, and the complex is discharged onto an Amberlite IR 120 H+ exchange column to liberate the base. The column is washed with about 3 l of water and the desired compound is liberated with 2% strength aqueous ammonia. The product fractions, determined by thin layer chromatography, are collected and concentrated. The evaporation residue crystallises on trituration with isopropanol. 1.8 g of a colourless product of melting point 171°-172° C. are obtained.
Reaction SMILES: [C:1]1([S:7]([NH:10][N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([C:30]([F:33])([F:32])[F:31])=[C:17]([N:22]4[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[N:24]=[CH:23]4)[CH:18]=3)[NH:13][C:12]2=[O:34])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:36]O>>[CH3:36][O:28][C:27]([C:25]1[N:24]=[CH:23][N:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[C:30]([F:33])([F:32])[F:31])[NH:13][C:12](=[O:34])[N:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:20]3=[O:21])[CH:26]=1)=[O:29]
Reactant: O=C(O)c1cn(-c2cc3c(=O)n(NS(=O)(=O)c4ccccc4)c(=O)[nH]c3cc2C(F)(F)F)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cn(-c2cc3c(=O)n(NS(=O)(=O)c4ccccc4)c(=O)[nH]c3cc2C(F)(F)F)cn1

Procedure:
A solution of 20 mg (0.04 mmol) of 1-(3-benzenesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid in 50 ml of a 6 M solution of hydrochloric acid in methanol is stirred at 70° C. for two days. Every half day another 50 ml of a 6 M solution of hydrochloric acid in methanol is added. Subsequently the solvent and hydrochloric acid are evaporated to yield 1-(3-benzenesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methyl ester: 1H-NMR; DMSO-d6 (400 MHz, ppm): 8.16 (s, 1H, imidazole); 8.10 (s, 1H, aromatic); 7.98 (s, 1H, imidazole); 7.70 (s, 1H, aromatic); 3.79 (s, 3H, COOCH3). LC-MS: 510 [M+H]+; Agilent LC/MSD 1100 Series, LC-MS method: Column: SunFireC8, 4.6*50 mm, 3.5 μm; positive MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)#[N:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:34]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1)#[N:35]
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccc(C#N)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (80 mg, 0.17 mmol), 3-cyano benzyl bromide (35.0 mg, 0.18 mmol, 1.05 equiv), and potassium carbonate (47.0 mg, 0.34 mmol) were combined in dimethylformamide (1.5 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 85.0 mg (85%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[CH:38]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C1C=CN=CC=1)C.ClCCl>[O:35]1[C:31]2([CH2:30][CH2:29][N:28]([C:26]([N:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)[CH2:15][CH:10]([NH:9][C:43]([CH:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:44])[CH2:11]3)=[O:27])[CH2:37][CH2:36]2)[O:32][CH2:33][CH2:34]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
177 μl of triethylamine (1.27 mmol) and 15.5 mg of DMAP (0.127 mmol) were added to a solution of the amine hydrochloride from Example 62A (200 mg, 0.422 mmol) in dichloromethane (10 ml), and 84 mg of cyclopentanecarbonyl chloride (0.633 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrogen chloride solution and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 112 mg (52% of theory)
Reaction SMILES: CN1CCOCC1.Cl.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[NH2:15].[C:20]1(=[O:41])[N:24]([NH:25][C@H:26]([C:33](O)=[O:34])[CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:23](=[O:36])[C:22]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:21]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O>[C:23]1(=[O:36])[N:24]([NH:25][C@H:26]([C:33]([NH:15][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][OH:9])=[O:34])[CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:20](=[O:41])[C:21]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:22]12
Reactant: O=C(O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Methylmorpholine (1.89 ml., 18.12 mmol.) was added to a solution of 6-hydroxy-L-norleucine, methyl ester, hydrochloride (10.66 mmol.) in methylene chloride (41 ml.)/dimethylformamide (11 ml.) at room temperature under argon. The resulting mixture was cooled to 0° C. and N-phthalimido-3-(3-thienyl)-L-alanine (3.21 g., 10.66 mmol.), hydroxy-benzotriazole (1.48 g., 10.98 mmol.), and 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (2.25 g., 11.73 mmol.) were added sequentially. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with 0.5 N hydrochloric acid, water, saturated sodium bicarbonate, and brine, and the organic layer was dried (sodium sulfate), filtered, and concentrated. The residue was flash chromatographed (Merck silica gel) eluting with 4:1 ethyl acetate/hexane to give 3.8 g. of title compound as a white foam. TLC (ethyl acetate) Rf =0.56.