Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:51][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoate (360 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (2 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 217.9 mg (66%) of a white solid. 1H-NMR (300 MHz, DMSO-d6+DCl, ppm): δ 9.06˜9.04 (d, J=5.7 Hz, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.74˜8.47 (m, 1H), 8.44˜8.10 (m, 2H), 7.88 (s, 2H), 7.88˜7.84 (d, J=7.8 Hz, 2H), 7.75˜7.48 (m, 4H), 4.60 (s, 2H), 3.86 (s, 2H), 3.78 (s, 4H), 2.63˜2.58 (m, 2H), 2.31˜1.75 (m, 6H). MS (ES, m/z): 677 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[C:8]([C:15](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:16])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:31])[CH:3]=1.[NH3:32]>C1COCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[C:8]([C:15]([NH2:32])=[O:16])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:31])[CH:3]=1
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: N
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 100 %

Procedure:
2,3,4,5,6-Pentafluorophenyl 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate in THF was reacted with conc. NH3 solution as for example 37, step B. Recrystallisation (EtOAc/Hexane) yielded 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (100%); m.p. (EtOAc/Hexane) 282-284° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.39 (s, 1H), 8.35 (s, 1H), 7.89 (br s, 1H), 7.66 (dd, J=10.4, 1.7 Hz, 1H), 7.51-7.44 (br m, 2H), 7.42 (dd, J=8.5, 1.9 Hz, 1H), 5.55 (s, 1H), 3.38 (s, 3H). LCMS (ACPI−) 340 (100%), 338 (90%). Anal. Calcd for C13H11BrFN3O2: C, 45.9; H, 3.3; N, 12.4. Found C, 46.1; H, 3.2; N, 12.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)NCC2

Procedure:
A suspension of 21.9 gm (0.1 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one and 1.5 gm of 10% palladium-on-charcoal in 200 ml of glacial acetic acid was hydrogenated at 50° C. and at a hydrogen pressure of 5 bar. After the catalyst had been filtered off, the solvent was evaporated in vacuo, and the residue was taken up in methylene chloride. After the solution had been extracted with an aqueous sodium bicarbonate solution and washed with water, it was dried over magnesium sulfate, evaporated and purified over silica gel with methylene chloride and then with increasing amounts of methanol (up to 10%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:17]([CH2:29][CH3:30])[C:18]3[C:23]([C:24]=2[C:25]#[N:26])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=3)=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH2:29]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=2)[C:24]([C:25]#[N:26])=[C:16]1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCn1c(C#Cc2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C#Cc2ccc(N3CCNC3=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (55 mg, 0.13 mmol), prepared as in Example 1AC, is combined with K2CO3 (50 mg, 0.36 mmol) and DMF (550 μL). This mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted in EtOAc, and is washed with H2O, and then with brine. The organic layer is dried and concentrated. Purification by silica chromatography (10-50%, EtOAc/CH2Cl2) yields 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (47 mg, 94%) as a white solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH2:15]O)[CH:11]=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([N:21](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH2:15][C:19]#[N:21])[CH:11]=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1cc(CO)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CC#N)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-phenyl]-methanol (11.1 g, 41.67 mmol) in dichloromethane (80 ml) at 0° C. (ice bath), was added triethylamine (8.78 ml, 62.5 mmol) followed by methanesulfonyl chloride (3.87 ml, 50 mmol). After stirring for 2 hr, the reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The crude product was then dissolved in anhydrous DMF (80 ml) and sodium cyanide (6.28 g, 128 mmol) was added into the mixture. The mixture was stirred in an oil bath (60° C.) for 2 hr. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:20 to 1:10)) to afford 8.36 g (73%) of a white solid. m.p. 52-54° C.; 1H NMR (200 MHz, CDCl3) δ 0.12 (6H, s), 0.95 (9H, s), 4.2.35 (3H, s), 3.71 (2H, s), 4.71 (2H, s), 7.03 (1H, s), 7.08 (2H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=O.[CH:24]1([C:27]2[C:28]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:36]3[CH2:37][CH2:38][N:39]([C:9]([C:8]4[CH:13]=[CH:14][C:15]([N:17]5[CH2:21][CH2:20][O:19][C:18]5=[O:22])=[CH:16][C:7]=4[N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:23])=[O:11])[CH2:40][CH2:41]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:25][CH2:26]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Product: O=C(c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 22.2 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using methyl 2-(1,1-dioxoisothiazolidin-2-yl)-4-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 117 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (121 mg) described in Preparation Example 62, the title compound (61 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11]C)=[O:10])[N:8]=1>O1CCOCC1.O>[Cl:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=1
Reactant: COC(=O)c1csc(CCl)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1csc(CCl)n1
Yield: 90 %

Procedure:
An aqueous solution of HCl (36%, 68 mL) was added to a solution of methyl 2-(chloromethyl)-1,3-thiazole-4-carboxylate (34 g, 177 mmol) in dioxane (680 mL), water (65 mL) and refluxed overnight. The dioxane was then removed in vacuo and the product was extracted from the aqueous layer with MTBE (4×473 mL), dried over MgSO4 and evaporated to give the title compound (28.3 g, 97%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[CH2:53][CH2:54][CH3:55].Cl>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52](=[O:56])[CH2:53][CH2:54][CH3:55])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCCC(=O)Cl
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (100 mg) and pyridine (19 μl) are dissolved in methylene chloride (1 ml) and thereto is added butyryl chloride (19 μl) at room temperature. The reaction solution is stirred at room temperature for 30 minutes, and thereto are added methylene chloride and 1N-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (84 mg). MS (m/z): 723 [M+H]+
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][C:9]=1[O:18][CH3:19].[C:20]([CH2:22][C:23]([N-:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:34])[CH:28]=1)=[O:24])#[N:21]>C(O)C>[OH:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[OH:33])[CH2:26][NH:25][C:23](/[C:22](=[CH:14]/[CH:13]=[CH:12]/[C:11]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([O:18][CH3:19])[CH:10]=1)/[C:20]#[N:21])=[O:24]
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Reactant: COc1cc(C=CC=O)ccc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccc(O)c(O)c2)ccc1O

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 4-hydroxy-3-methoxycinnamaldehyde (35 mg, 0.2 mmol) and N-(cyanoacetyl)3,4-dihydroxybenzylamide (40 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (53 mg, 72%). The product gave the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]([N:14]2[CH2:13][C@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:25])[CH3:11])[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15]2)=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-4-{(3S,4R)-3-(3,4-dichloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a yellow foam. MS m/e: 593.1 [M]+.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Product: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=423.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate AO).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=O)[CH2:2][CH3:3].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>CO.O>[CH2:11]([O:18][N:19]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(CC(=O)OC)=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 26.03 g (0.2 mol) of methyl propionylacetate in 300 ml of methanol, 100 ml of water and 35.12 g (0.22 mol) of benzyloxyamine hydrochloride, 19.69 g (0.24 mol) of potassium acetate were added and the mixture was stirred for 15 hours at room temperature. After distilling methanol off under reduced pressure, followed by adding 200 ml of water and extracting three times with 200 ml of ethyl acetate, the mixture was washed with water and a saturated aqueous sodium chloride and then dried over with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 47.06 g (yield: 100%) of a crude methyl 3-benzyloxyiminovalerate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].I[CH3:14].O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:14])[C:7]=12
Reactant: CI
Reactant: Clc1nccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccnc(Cl)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
To a solution of 7-chloro-1H-pyrrolo[2,3-c]pyridine (3.00 g, 19.7 mmol) in THF (30 mL) cooled to 0° C. was added 60% NaH in mineral oil (0.940 g, 23.6 mmol NaH). The reaction mixture was stirred at 0° C. for 20 minutes. Iodomethane (6.20 g, 43.7 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h and at 20° C. for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of 17-33% EtOAc/petroleum ether to give the title compound as a yellow solid (2.8 g, 85%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:22])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[C:23]([O:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:22])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 102 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 500 ml of pyridine is combined under ice cooling with 50.9 ml of benzoyl chloride and stirred for one hour under cooling. Then 9 ml of water is added dropwise and the mixture is stirred for another hour. The reaction solution is then stirred into ice water, the thus-formed precipitate is suctioned off, washed with water, and dried, thus obtaining 146 g of crude 15α-benzoyloxy-18-methyl-4-estrene-3,17-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:17]=3)[C:12]=2[NH:28][C:29]([C@H:31]2[CH2:36][CH2:35][C@H:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C:38]3=[O:43])[CH2:33][CH2:32]2)=[O:30])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[ClH:1].[NH2:20][C:15]1[N:14]=[C:13]2[C:12]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][C:38]4=[O:43])[CH2:33][CH2:32]3)=[O:30])=[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[O:19][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl [2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridin-5-yl]carbamate (5.55 g) obtained in Example 94 is suspended in methanol (20 ml), and thereto is added 4N hydrogen chloride-dioxane solution (50 ml) under ice-cooling. The mixture is stirred at room temperature for 8 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration to give the title compound (4.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][NH:7][S:8](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)C.[NH3:45]>C1COCC1>[NH2:45][CH:12]([CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)[CH2:11][S:8]([NH:7][CH2:6][C:5]1[CH:40]=[CH:41][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: N
Reactant: O=S(=O)(/C=C/CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NCc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: NC(CCCc1c[nH]cn1)CS(=O)(=O)NCc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (E)-N-(4-chlorobenzyl)-5-(1-(triphenylmethyl)imidazol-4-yl)-1-pent-1-enesulfonamide (Example 5, step e) (290 mg, 0.50 mmol), ethanol saturated with ammonia (10 ml) and THF (10 ml) was sealed in a Teflon-lined pressure vessel and heated at 120° C. overnight. The solution was allowed to cool and the solvent evaporated. The residue was purified by flash column chromatography (silica, 1:10:90 ammonia(880)/methanol/dichloromethane) to give the title compound was obtained as a white solid (123 mg, 79%): 1H NMR (300 MHz, d6-DMSO) 7.92(1H, br s), 7.61(1H, d), 7.41(4H, m), 6.58(1H, d), 4.54(1H, m), 4.21(2H, s), 3.65(1H, dd), 3.50(1H, dd), 3.29(2H, s), 2.67(2H, m), 2.65(2H, t), 2.10(1H, m), 1.95(1H, m), 1.81(1H, m), 1.66(1H, m). Found: C, 50.17; H, 5.99; N, 15.48%; C15H21ClN4O2S requires: C, 50.48; H, 5.93; N, 15.70%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C>[NH:3]1[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:6][N:5]=[N:4]1
Reactant: c1nnn[nH]1
Reactant: O=C(O)CCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCc1nnn[nH]1
Reaction time: 0.25 h
Yield: 59001.4 %

Procedure:
A suspension of NaH (0.045 g, 80% suspension in oil) in DMF (1 ml) was added to a solution of tetrazole 44 (0.095 g, 1.35 mmmol) in DMF (1 ml). After stirring the reactants for 15 min, a solution of 12-iodo-dodecanoic acid 45 (0.2 g, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 1 h and at 55° C. for 1.5 h and then concentrated in vacuo. The residue was treated with 1N HCl(5 ml) and extracted with EtOAc (2×10 ml). The organic layer was washed with water, dried (Na2SO4), concentrated under reduced pressure and the residue was crystallized from EtOAc/Hexane to give the title compound 46 (0,095 g, 26%) as a 1:3 mixture of N-3 and N-1 isomers, respectively. This mixture was tested directly as a substrate for NMT. 1H NMR (CDCl3) δ: 8.59 and 8.5 (2s, 1H); 4.65 and 4.43 (2t, 2H, J=7.2 Hz); 2.35 (t, 2H, J=7.5 Hz); 1.95 (m, 2H); 1.63 (m, 2H); 1.26 (m, 14H). FABMS: m/z 269 (M+H); 251 and 241. HRMS: m/z=C13H24N4O2Li, calc: 275.2059, found: 275.2004 (M+Li).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:75]=[CH:74][C:67]2[B:68]([OH:73])[O:69][C:70]([CH3:72])([CH3:71])[C:66]=2[CH:65]=1.Cl>C(#N)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:62][CH2:63][C:64]5[CH:75]=[CH:74][C:67]6[B:68]([OH:73])[O:69][C:70]([CH3:72])([CH3:71])[C:66]=6[CH:65]=5)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.72 mmol) in acetonitrile (5 ml) at 0° C. can be added Et3N (291.1 mg, 2.88 mmol), HATU (546.76 mg, 1.44 mmol) and 5-(aminomethyl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (194.2 mg, 0.86 mmol). The reaction mixture can be stirred overnight at rt. The mixture can be poured into 1N HCl solution and extracted with EA (20 ml×3). The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-TLC and prep-HPLC to give the final title compound.