Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:43][O:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.C(N(CC)CC)C>[C:50]([O:49][C:48](=[O:54])[NH:47][CH2:46][CH2:45][O:44][NH:43][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of the carboxylic acid (6b, 1.34 g, 4.87 mmol) of Example 9 or 16 in methylene chloride (35 mL) were added triethylamine (2.71 mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole.monohydrate (1.15 g), and tert-butyl 2-(aminooxy)ethylcarbamate (1.12 g) described in Reference Example 9, followed by agitating at room temperature overnight. To the residue resulting from concentrating the reaction solution under reduced pressure was added water, followed by extracting with ethyl acetate. The resulting organic layer was washed with 0.1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtrated, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/2-0/10) to afford 1.77 g of the title compound (yield 84%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[F:21][C:3]1[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([F:22])[CH:24]=1
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a solution of (3-amino-2,6-difluorophenyl)(quinoxalin-6-yl)methanone (40 mg, 0.14 mmol, 1.0 eq.) in DCM (5 mL) were added TEA (31 mg, 0.28 mmol, 2.0 eq.) and 3-fluorobenzoyl chloride (22 mg, 0.14 mmol, 1.0 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The residue was purified via flash column chromatography (PE/EA=2/1, v/v) to afford N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-fluorobenzamide (26 mg, 45%). LRMS (M−H+) m/z calculated 406.1. found 406.1. 1H NMR (CDCl3, 400 MHz) δ 8.88-8.90 (dd, 2H), 8.55-8.60 (m, 1H), 8.43 (s, 1H), 8.33-8.35 (m, 1H), 8.19-8.21 (m, 1H), 7.88 (s, 1H), 7.54-7.57 (m, 2H), 7.40-7.45 (m, 1H), 7.22-7.24 (m, 1H), 7.04-7.09 (t, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[C@H:12]2[CH2:23][C@@H:9]1[C@H:10]([O:24][CH2:25][C:26](O)=[O:27])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].N12CCCN=C1CCCCC2>CN(C)C=O>[C:21]([C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14]([C@@H:13]1[C@H:12]2[CH2:23][C@H:9]([C@H:10]([O:24][CH2:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:27])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15])#[N:22]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)NS(C)(=O)=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [((1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]acetic acid obtained in Example 15-2 (195 mg) in dimethylformamide (2.5 mL), was added 1,1′-carbonyldiimodazole (165 mg). The mixture was stirred at room temperature. After 30 minutes, methanesulfonamide (66 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (106 mg) were added, and the resulting mixture was stirred at room temperature for 12 hrs.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH3:20])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH3:20])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1)c1ccc([N+](=O)[O-])cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3)cc2)c1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A high-pressure vial was filled with the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide (50 mg, 0.1 mmol, 1 equiv), the phenylboronic acid (19 mg, 0.15 mmol, 1.5 equiv), K2CO3 (29 mg, 0.2 mmol, 2 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.1 equiv), dioxane (1.5 mL) and water (0.3 mL). The mixture was degassed for 5 min under argon atmosphere and the vial was sealed. The reaction mixture was heated at 100° C. for 30 min under microwaves. The solution was then concentrated in vacuo, filtered and purified by preparative HPLC to afford a beige powder (50 mg, 0.1 mmol, 100%). ESI-MS (m/z): 476 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>CC#N>[CH:24]1([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:26][CH2:25]1
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 103.4 %

Procedure:
To a solution of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (1.0 g, 4.74 mmol) in CH3CN (10 ml), K2CO3 (0.327 g, 2.37 mmol) and (bromomethyl)cyclopropane (0.460 ml, 4.74 mmol) were added and the mixture was heated under MW irradiation at 100° C. for 1 hour. The insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness to give crude methyl 2-(4-(cyclopropylmethoxy)-3-nitrophenyl)acetate (1.3 g, yield considered to be quantitative, MS/ESI+265.9 [MH]+). This crude was used without any additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.C([O-])=O.[NH4+].[C:27](#N)[CH3:28]>[Pd]>[CH2:15]([C:11]1[C:12](=[O:14])[NH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:1][CH2:27][CH3:28])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])=[N:9][C:10]=1[CH2:17][CH3:18])[CH3:16]
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CC#N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCCOc1ccc(NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
The compound (2.2 g, 7.3 mmol) of example 42 was dissolved in 50 ml of 80% acetonitrile aqueous solution, and added with 0.14 g of 5% Pd/C and 5 g of ammonium formate, followed by stirring at room temperature for 20 h under nitrogen atmosphere. The reaction mixture was filtered off Pd/C and distilled off the solvent. The residue was dissolved in CH2Cl2 (50 ml), washed with water (50 ml) and saturated saline (50 ml), dried with anhydrous Na2SO4, and concentrated to dryness to give a white solid crude, which was passed through a silica gel column (eluant: 10% petroleumether-ethyl acetate) to afford the title compound (1.9 g, yield: 79%). 1H NMR (CDCl3) δ: 8.38 (1H, d), 7.33 (1H, dd), 7.04 (1H, d), 4.19 (2H, t), 4.04 (2H, q), 2.66 (2H, q), 2.59 (2H, q), 2.01 (2H, m), 1.28 (3H, t), 1.19 (3H, t), 1.15 (3H, t), 1.06 (3H, t).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([C:11]#[C:12][CH2:13]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.N1C=CC=CC=1>[C:5]1([C:11]#[C:12][CH2:13][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCC#Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrCC#Cc1ccccc1
Temperature: 40 °C
Yield: 248.9 %

Procedure:
Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: ON=C1CCN(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 102.2 %

Procedure:
To a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.71 mmol) in pyridine (5 mL) is added hydroxylamine hydrochloride (0.59 g, 8.57 mmol). After stirring at 90° C. for 5 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and brine. The organic layer is dried over MgSO4, filtered, and filtrate concentrated to afford 1-benzylpyrrolidin-3-one oxime (1.11 g) as an oil. MS CI: m/z 191 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.Cl.[O:28]([NH2:30])[CH3:29]>CCO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=[N:30][O:28][CH3:29])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10]
Reactant: CON
Reactant: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCCc2[nH]cc(C(=O)Nc3ccccc3F)c21
Temperature: 120 °C
Yield: 72.7 %

Procedure:
4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide (0.73 mmol), pyridine (2.2 mmol), EtOH (10 ml) and methoxylamine hydrochloride (2.2 mmol) are combined in a sealed tube and heated at 120° C. for 16 hours. The reaction mixture is cooled to room temperature, the solvent is removed in vacuo and the residue is treated with 10 ml of H2O for 5 minutes. The resulting solid is collected by vacuum filtration to yield 160 mg (72%) of 4-methoxyimino-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide as a white solid. 1H NMR (DMSO-d6) δ1.80-1.86 (m, 2H), 2.62-2.73 (m, 4H), 3.81 (s, 3H), 7.10-7.29 (m, 3H), 7.48 (d, 1H), 8.01 (t, 1H), 11.70 (s, 1H), 11.81 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33])[CH2:12][CH2:11][CH:10]=[C:9]3B1OC(C)(C)C(C)(C)O1.I[C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1.[OH-].[Ba+2].[OH-]>C(#N)C.O.Cl>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33])[CH2:12][CH2:11][CH:10]=[C:9]3[C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1csc(I)n1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(C)cs2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,3-dimethyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-m-tolyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (step 5) (295 mg, 0.66 mmol), 2-iodo-4-methylthiazole (Intermediate O) (135 mg, 0.60 mmol), Pd-118 (19.6 mg, 0.03 mmol) and barium hydroxide (206 mg, 1.20 mmol) in acetonitrile/water (1:1, 3 mL) was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with 1M HCl (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were filtered through a hydrophobic frit and the solvent was removed under vacuum. The residue was purified by chromatography on silica, eluting with 1-2% MeOH/DCM to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:3][C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: CCn1nc(C)cc1N
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of 5-amino-1-ethyl-3-methylpyrazole (7.5 g, 0.06 mol), 2-iodobenzoic acid (14.88 g, 0.06 mol), DMF (50 ml) Cu(OAc)2 ·H2O (0.5 g) and K2CO3 (8.3 g, 0.06 mol) was refluxed under a nitrogen atmosphere for 20 hours. The reaction mixture was cooled to room temperature and then was poured into ice-water. The mixture was neutralized with acetic acid and the resulting solid was collected by filtration, washed with water and dried to afford 7.1 g (48%) of N-(1-ethyl-3-methylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C=O)[CH2:7]2.B(Br)(Br)Br.CO>ClCCl>[CH3:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: COc1ccc2c(c1C)CCN(C=O)C2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1c(O)ccc2c1CCNC2
Reaction time: 1.42 h

Procedure:
To a solution of 5-methyl-6-(methyloxy)-3,4-dihydro-2(1H)-isoquinolinecarbaldehyde (Preparation 12; 1.49 g; 7.26 mmol) in dichloromethane (25 ml) at 0° C. under nitrogen was slowly added boron tribromide (9.09 g; 36.3 mmol). After 85 min at 0° C., methanol (25 ml) was added slowly, and the resulting mixture was left standing at room temperature for three days. Removal of the solvent and trituration with methanol/dichloromethane gave a white solid residue; the mother liquors were concentrated and the residue applied to an SCX solid phase extraction cartridge (20 g) and eluted with methanol followed by 2N ammonia in methanol to elute the product. After evaporation of the solvent the title compound (780 mg) was obtained as a pale yellow solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:25]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[O:26])[CH2:12]2)[O:8][N:7]=1.[ClH:34]>O>[Cl:34][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:25]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[O:26])[CH2:12]2)[O:8][N:7]=1
Reactant: CCc1ccc(C2CC(c3nc(N)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 332 mg (4.81 mmol) of sodium nitrite in 1.25 ml of water was added dropwise at 0° C. to a solution of 1.60 g (2.40 mmol) of the amine from Example 24A in 60% purity in 25 ml of concentrated hydrogen chloride solution. After the addition had ended, the mixture was stirred at 0° C. for 1 h and then at RT for 45 min. The reaction mixture was diluted with 1 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 220 mg (22% of theory)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
First step: To a stirred solution of commercially available (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (8.78 g, 44 mmol) in CH2Cl2 (80 mL) at 0° C. were added Et3N (12.15 mL, 88 mmol) and methanesulfonyl chloride (5.09 mL, 66 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (50 mL) and TFA (15 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 2.63 g (34%) of (R)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.[Br:75][CH2:76][C:77](Cl)=[O:78]>C1COCC1>[Br:75][CH2:76][C:77]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:78]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCNC(=O)CBr)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
22 mg (0.023 mmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 101) were dissolved in 9.5 ml of THF and admixed at 0° C. with 4.2 μl of triethylamine. A solution of bromoacetyl chloride in THF was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated and the residue was purified by preparative HPLC. Thus, 6.9 mg (26% of theory) of the title compound were obtained as a foam.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[C@H:13]([CH3:28])[CH2:12][C:11]=2[CH:10]=1>CS(C)=O>[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[C@H:17]3[CH2:2][C@@H:16]43)[C@H:13]([CH3:28])[CH2:12][C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@H]12
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C[C@@H](C)[C@H]1[C@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@H]21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 131.8 %

Procedure:
—Sodium hydride (60% suspension in mineral oil, 1.15 g) was added to a suspension of trimethylsulfoxonium iodide (5.57 g) in dry dimethyl sulfoxide (115 ml) and the mixture was stirred at room temperature for 20 min. (7α,14β)-3-Methoxy-7-methylestra-1,3,5(10),15-tetraen-17-one (Example 7, step iv; 1.92 g) was added and stirring was continued for 1.5 h. The reaction mixture was poured into ice-water and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,14β,15β,16β)-3-methoxy-7-methyl-15,16-methyleneestra-1,3,5(10)-trien-17-one (2.65 g). The product was used in the following step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1.CCOCC>[ClH:24].[F:22][C:20]([F:21])([F:23])[CH2:19][C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
To a solution of 0.91 mmol 4-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in 30 ml dioxane was added dropwise 18.2 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 90 min. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a light brown crystalline solid (yield 73%). MS (m/e): 252.3 (M+H+, 100%).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:17][OH:18]>>[OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:18][CH3:17]
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Reactant: CO
Agent: Cl
Product: COC(=N)c1cccc(Cc2c[nH]cn2)c1O
Reaction time: 20 h

Procedure:
A suspension of 14.1 g (0.071 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzonitrile (prepared in example 1.1 above) in 420 ml of methanol is cooled to -40° C. and saturated with gaseous hydrochloric acid. The suspension is allowed to return to 10° C. and is saturated once again with gaseous hydrochloric acid. The reaction mixture is kept at that temperature for 20 hours. The solution is concentrated to 200 ml, 300 ml of ice-cold water and 300 ml of ethyl acetate are added to the concentrated solution and the solution is then neutralized using an aqueous sodium bicarbonate solution. The solution is filtered, and the aqueous phase is separated from the organic phase, then the aqueous phase is extracted twice with 300 ml of ethyl acetate and the organic phases are combined. The organic phase is washed with a saturated aqueous sodium chloride solution, is then dried over magnesium sulfate, filtered and evaporated under reduced pressure. 15.4 g of methyl 2-hydroxy-3-(1H-imidazol- 4-ylmethyl)-benzenecarboximidate are obtained as a beige solid product which is taken up in 210 ml of absolute ethanol.