Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(Cl)Cl>[OH2:6].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[C@H:8]([OH:12])[CH2:9][N:10]([C:17]([NH:16][CH3:15])=[O:18])[CH2:11]2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[C@H:8]([OH:12])[CH2:9][N:10]([C:17]([NH:16][CH3:15])=[O:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: OC1CNCC1Oc1ccc(Cl)cc1
Solvent: ClCCl
Product: CNC(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1
Product: O
Reaction time: 1 h

Procedure:
A solution of 0.9 g. of 4-(4-chlorophenoxy)-3-pyrrolidinol in 50 ml. of methylene chloride was cooled to 0° C. and 0.24 g. of methyl isocyanate in 5 ml. of methylene chloride was added dropwise over the period of 10 min. Cooling was discontinued and stirring was continued for 1 hr. Solvent was then removed and the residue was crystallized from dimethylsulfoxide-water; m.p. 95 0°-98.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].C([Li])CCC.[F:18][C:19]([F:31])([O:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:20](F)=[O:21].C(OCCOCC)(=O)C>C(OCC)C>[F:18][C:19]([C:20]([C:2]1[C:3]([Cl:12])=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([Cl:9])[C:7]=1[Cl:8])=[O:21])([F:31])[O:23][C:24]([F:29])([F:30])[C:25]([F:26])([F:28])[F:27]
Reactant: O=C(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: CCOCCOC(C)=O
Solvent: CCOCC
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(F)(F)OC(F)(F)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Hexachlorobenzene (35 g) was slurried in 160 ml of anhydrous ethyl ether at −40° C. A 2.5 M hexanes solution of n-butyllithium (54.1 mL) was added, and the reaction was stirred for 30 minutes at −40° C. Perfluoro-2-ethoxyacetylfluoride (40 g, 72 % pure, prepared from 2-ethoxyethyl acetate by the method described in Example 1 of U.S. Pat. No. 5,326,919, incorporated herein by reference) was added to the −40° C. reaction mixture which was then allowed to warm slowly to room temperature. The reaction mixture was quenched with 200 mL of cold 5% aqueous HCl. The aqueous mixture was extracted with ethyl ether and the extracts were dried over MgSO4 and rotary evaporated to give pentachlorophenyl perfluoroethoxymethyl ketone (49% crude yield). Vacuum distillation (105-109° C., 240 Pa) using a 15 cm Vigreux column gave 19.7 g of a colorless liquid which slowly crystallized on standing.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCCCCC(=O)O
Product: [N-]=[N+]=NCCCCC(=O)Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a one neck round bottom flask containing 5-azidopentanoic acid (0.88 g, 0.068 mol) was added thionyl chloride (7.35 ml, 0.102 mol). The reaction mixture was stirred at 60° C. for 2 h and the thionyl chloride was evaporated under reduced pressure to give crude 5-azidopentanoyl chloride. The distillation of crude acyl chloride gave a colorless liquid; 6.93 (62%), bp 111°-4° C. (1.2-1.4 mm); ir (neat) νmax : 2100 (N3) and 1800 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.37 (2H,δ --H), 3.00 (2H, α-H) and 2.1-1.2 ppm (4H, β--H and γ--H).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH2:26].Cl.[NH2:28]O>C(O)C.C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:28][OH:26])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=O)cc1
Reactant: NO
Reactant: O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C=NO)cc1

Procedure:
p-Hexadecylaminobenzaldehyde in ethanol-acetic acid is treated with a concentrated water solution of hydroxylamine hydrochloride. The solid is collected after a brief period, washed with alcohol, and dried to provide the product of the Example.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]#[CH:13])=[CH:8][C:7]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[CH:16]=[N:15]2)=[C:6]([F:23])[CH:5]=1.[Br:24]Br.O>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]#[C:13][Br:24])=[CH:8][C:7]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[CH:16]=[N:15]2)=[C:6]([F:23])[CH:5]=1
Reactant: C#CCOc1cc(-n2ncc(=O)n(C)c2=O)c(F)cc1Cl
Reactant: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)cnn(-c2cc(OCC#CBr)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a stirred mixture of 0.05 g (0.002 mole) of sodium hydride in 5 mL of tetrahydrofuran was added a solution of 0.55 g (0.0018 mole) of 2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 21, see Example III, Step J) in 5 mL of tetrahydrofuran. To this mixture was added a solution of 0.28 g (0.0018 mole) of bromine in 5 mL of tetrahydrofuran. After complete addition, the reaction mixture was stirred at room temperature for one hour. Water, 5 mL, was added to the mixture, and the total stirred at room temperature for two days. The mixture was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.45 g of 2-[4-chloro-2-fluoro-5-(3-bromo-2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid (mp 127°-129° C.), Compound 48 in the tables.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[CH2:2]1.C(OC(=O)C)(=O)C.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1.O.Cl>O.C1(C)C(C)=CC=CC=1>[N:32]1[CH:33]=[CH:34][N:35]=[CH:36][C:31]=1[N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[C:7](=[O:9])[CH:3]3[CH2:2][CH:1]([CH2:6][CH2:5][CH2:4]3)[C:10]2=[O:12])[CH2:30][CH2:29]1
Reactant: NCCCCN1CCN(c2cnccn2)CC1
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1C2CCCC(C2)C(=O)N1CCCCN1CCN(c2cnccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Cyclohexane dicarboxylic acid (1.65 g., 9.6 mmole) was dissolved in 75 ml. of acetic anhydride and refluxed for 3 hours under N2. The solvent was removed in vacuum and replaced with 250 ml. of methylene chloride. 1-(4-Aminobutyl)-4-(2-pyrazinyl)piperazine (2.35 g., 10 mmole) was added and the mixture was stirred for 30 minutes at room temperature. The solvent was then replaced with 200 ml. xylene and the mixture was refluxed for 24 hours with water removal via a Dean-Stark trap. The product was concentrated to an oil in vacuum and column chromatographed in 100 g. silica gel with a gradient elution proceeding from methylene chloride to 5% isopropanol/methylene chloride. Evaporation of the relevant fractions gave 1.4 g. of the title compound, which was recrystallized from isopropanol with the addition of 4N isopropanolic HCl to give 900 mg. of monohydrochloride monohydrate; m.p. 226°-229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([CH3:16])[C:22](=[O:23])[C:21]1[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccncc1OC
Product: COc1cnccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 55, from (3′-methoxy-[4,4′]bipyridinyl-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (24%). MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7](/[C:12](/[C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[CH:13]/[C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH2:13][C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc3c(c2)CCO3)ccc1C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc3c(c2)CCO3)ccc1C1CC1

Procedure:
10% palladium-activated carbon (50 mg) was added to a solution of (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethenyl]pyrrolidin-2-one (240 mg) in methanol (3 mL), and the mixture was stirred at room temperature for four hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-2-one as an amorphous (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1.[N:24]1([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([NH2:40])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:40][C:33]3[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:31][CH:32]=3)=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: Nc1ccc(N2CCOCC2)c2ccccc12
Reactant: CN1C(=O)C(N=C=S)N=C(c2cccnc2)c2cc(Cl)ccc21
Product: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2cccnc2)c2cc(Cl)ccc21
Yield: 56 %

Procedure:
A solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3-pyridinyl)-2H-1,4-benzodiazepin-2-one (0.0282 g, 0.0823 mmol) and 4-(4-morpholinyl)-1-naphthalenamine (0.0188 g, 0.0823 mmol) in (CH2Cl)2 (2.5 mL) was heated at 70° C. for 24 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (1:2 CH2Cl2:EtOAc) to provide the title compound (0.0263 g, 56%). 1H-NMR (CDCl3): δ 8.72-8.68 (m, 2H), 8.29-8.25 (m, 1H), 8.11-8.07 (m, 1H), 8.05-8.00 (m, 2H), 7.64-7.55 (m, 5H), 7.38-7.33 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 4.03-3.96 (br m, 4H), 3.39 (s, 3H), 3.15 (br s, 4H). HRMS calculated for (C30H27ClN6O2S+H) (M+H)+: 571.1683. Found (ESI): 571.1699. Anal. Calcd for C30H27ClN6O2S+0.7 H2O: C, 61.73; H, 4.90; N, 14.40. Found: C, 61.93;H, 4.79; N, 13.87.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:20][P:21]([OH:32])([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C>C(OC(=O)C)C>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:20][P:21]([OH:32])([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(CP(=O)(O)CCCc2ccccc2)C(=O)O)cn1
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(CP(=O)(O)CCCc2ccccc2)C(=O)O)cn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
To a mixture of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid (0.170 g, 0.367 mmol) in ethylacetate (3 mL) at 4° C. was slowly added ethylacetate (4 mL. saturated with HCl(g)). The mixture was then stirred for 22 h. Concentration under reduced pressure gave the title compound (0.124 g, 93%) as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C(C(=O)O)C1(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)C(C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g, 3.5 mmol) in 18 mL of methylene chloride at 0° C. was added oxalyl chloride (0.61 mL, 7.0 mmol) and a catalytic amount of dimethylformamide (2 drops). The solution was stirred at ambient temperature for 1 hour, and then concentrated under reduced pressure to provide 0.56 g of the title compound.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:32])=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH3:9].[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][C:24]([CH3:32])=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)N(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NO)nc1C(=O)N(C)C
Product: N
Temperature: 45 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A solution of 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-N,N,5-trimethyl-1,3-oxazole-4-carboxamide (Preparation 73) (105 mg, 0.23 mmol) in ethanol (5 ml) was treated with 5% palladium on barium sulphate (45 mg) and ammonium formate (73 mg, 1.15 mmol) and the mixture was heated at 45° C. for 17 hours. Further palladium on barium sulphate (30 mg) and ammonium formate (60 mg, mmol) were added and the heating was continued for 2 hours. The solution was filtered through Arbocel® and the solvent removed from the filtrate under reduced pressure. The residue was azeotroped from dichloromethane (×3) then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0.2 to 90:10:1) to afford the title compound as a foam (25 mg).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCCCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 mmol) was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 mmol) and sodium triacetoxyborohydride (13.8 g, 65 mmol). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 mmol) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) and the layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-amino octane (14.6 g, 88%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1.C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
N-[1-(4-Amino-benzenesulfonyl)-piperidin-4-yl]-acrylamide (0.09 g, 0.3 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.1 ml, 0.6 mmol) in one portion followed by the drop wise addition of benzyl chloroformate (0.05 ml, 0.33 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% EtOAc) to give the title compound (0.04 g, 34% yield) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:17][NH:18][O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:17][N:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: Clc1ccc(CNOCCCN2CCOCC2)cc1Cl
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(Cl)c(Cl)c2)OCCCN2CCOCC2)O1
Yield: 64.7 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.49 mmol) with N-(3,4-dichlorobenzyl)-O-(3-morpholin-4-yl-propyl)-hydroxylamine (0.150 g, 0.49 mmol) as described in the preparation of compound 44-C gave 0.150 g (65% yield) of the title amide as white crystals after chromatography on silica gel: mp 77–78° C. (ether-hexane). 1HNMR 400 MHz (C6D6) δ (ppm): 1.09 (6H, s, CH3), 1.47 (2H, m, CH2), 2.17 (2H, t, J=6.5 Hz, NCH2), 2.22 (4H, m, NCH2), 3.66 (2H, t, J=6.0 Hz, OCH2), 3.73 (4H, m, OCH2), 4.56 (2H, s, NCH2), 6.82 (1H, s, CH), 6.98 (1H, dd, J=2.0 Hz and J=8.0 Hz, aromatic), 7.06 (1H, d, J=8.0 Hz, aromatic), 7.40 (1H, d, J=2.0 Hz, aromatic). Anal. Calcd for C21H26Cl2N2O6: C, 53.28; H, 5.53; N, 5.91. Found: C, 53.31; H, 5.67; N, 5.77.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=1.P(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:36][C:37]1[N:42]=[CH:41][C:40]([N:43]([CH:44]([CH3:46])[CH3:45])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:39][CH:38]=1
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: CC(C)Nc1ccc(Cl)nc1
Solvent: ClP(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a solution of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (30 mg, 0.06 mmol) and (6-chloro-pyridin-3-yl)-isopropyl-amine (Preparation 2(A)) (10.1 mg, 0.06 mmol) in benzene (2 mL) was added PCl3 (2.0 M in CH2Cl2, 0.1 mL, 0.198 mmol) and the reaction was heated at reflux for 24 hours. The reaction was cooled to room temperature and was diluted with CH2CO2. The organic solution was washed consecutively with aqueous NaHCO3 (1×), water (1×), 1N HCl (1×), and water (1×). The organic solution was dried (MgSO4) and the volatiles were concentrated in vacuo. The residue was purified by medium pressure chromatography eluting with 10% EtOH in CH2Cl2 to yield 5 mg of N-(6-chloro-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.26 (s, 1H), 8.17 (s, 1H), 7.76-7.29 (m, 11H), 7.06 (m, 3H), 6.83 (d, 1H), 5.04-4.87 (m, 1H), 4.45-4.15 (m, 1H), 3.94-3.82 (m, 3H), 3.72 (m, 1H), 0.06 (s, 6H); MS 616.6 (M+1), 614.5 (M−1).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(N(CC)CC)C.O>O1CCCC1>[CH3:30][N:31]([CH3:35])[C:32]([N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)=[O:33]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCC2(CC1)CN=C(c1cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (82 mg) and dimethylcarbamoyl chloride (100 μL) in tetrahydrofuran (3 ml) was added triethylamine (100 μL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (43 mg, yield 46%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 245° C.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:86])[C@@H:76]([NH2:85])[CH2:77][CH:78]2[CH2:82][O:81][C:80]([CH3:84])([CH3:83])[O:79]2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]>CN(C=O)C.C(OCC)(=O)C>[CH2:64]([O:66][C:67]([N:69]1[CH2:70][CH2:71][N:72]([C:75](=[O:86])[C@@H:76]([NH:85][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:77][CH:78]2[CH2:82][O:81][C:80]([CH3:83])([CH3:84])[O:79]2)[CH2:73][CH2:74]1)=[O:68])[CH3:65]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC2COC(C)(C)O2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC2COC(C)(C)O2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 120 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 3 ml DMF were added 50 μl DIPEA, 111 mg HATU and 96 mg 4-[(S)-2-Amino-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propionyl]-piperazine-1-carboxylic acid ethyl ester. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent deprotection reaction. Yield: 238 mg.