Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>CCOCC.C(OCC)(=O)C>[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:29][CH3:30])[CH2:18][N:17]([C:15]([CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:16])[CH2:26][CH2:25]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 5 N hydrochloric acid in ether (5 ml) was added to a solution of 4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (3 g, 7.43 mmol) in ethyl acetate and the mixture was stirred for 2 hours at room temperature. The precipitate formed was collected by filtration and the white solid obtained was indetified as (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(piperidin-4-yl)-methanone (2.1 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCOCC1>[CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:34](=[O:35])[O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:25][CH:26]=2)[N:9]=1)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
(4-{4-[1-Methyl-1-(methylsulfonyl)ethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)amine (3.6 g, 8.77 mmol) was dissolved in dioxane (20 mL). Sodium bicarbonate (1.1 g, 13.15 mmol) was added, followed by phenyl chloroformate (1.1 mL, 8.77 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 20 mL DCM and 20 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[NH:5][CH:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH2:3]1.I[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([O:14][CH:15]([CH3:16])[CH3:17])[CH2:3]1
Reactant: C#Cc1ccc2c(c1)NC(OC(C)C)CC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N=C(OC(C)C)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.097 g (0.40 mmol) of 4,4-dimethyl-2-isopropoxy-1,2,3,4-tetrahydro-7-ethynylquinoline (Compound 27) and 1.16 g (0.75 ml, 4.2 mmol) of ethyl 4-iodobenzoate in 3.0 ml of diethylamine which was degassed under argon for 15 min, was added 0.043 g (0.23 mmol) of copper(I) iodide and then 0.064 g (0.09 mmol) of bis(triphenylphosphine)palladium(II) chloride. The reaction was stirred at room temperature for 16 h. The reaction mixture was then concentrated. Purification by flash chromatography (1.5% EtOAc in hexane) gave the title compound as an oil. PNMR (CDCl3) d 8.00 (2H, d, J=8.2 Hz), 7.54 (2H, d, J=8.1 Hz), 7.32 (1H, s), 7.23 (2H, s), 5.40 (1H, p, J=6.3 Hz), 4.37 (2H, q, J=7.1 Hz), 2.24 (2H, s), 1.39 (3H, t, J=7.1 Hz), 1.32 (6H, d, J=6.2 Hz), 1.24 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[N:7]1)=[O:5])[CH3:2].[CH2:17](OC(N1C2C(=C(Br)C=CC=2)C(OC)=N1)=O)C>>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:15])=[CH:12][CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(O)c2cc(Br)ccc21
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Product: CCOC(=O)n1nc(OC)c2cc(Br)ccc21

Procedure:
5-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CCIX was prepared from 5-bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester using the procedure described for preparation of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (Example 37).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[C:10]([F:19])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:21]([C:31]1([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][CH:38]=[CH:37]3)[CH2:33][CH2:32]1)[CH:22](N1C(=O)CCC1=O)O>C(O)C>[F:19][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:21]([C:31]4([C:34]5[CH:35]=[C:36]6[C:41](=[CH:42][CH:43]=5)[N:40]=[CH:39][CH:38]=[CH:37]6)[CH2:33][CH2:32]4)=[CH:22][N:1]=3)[CH:4]=2)[CH:13]=[CH:12][C:11]=1[S:14]([NH:17][CH3:18])(=[O:16])=[O:15]
Reactant: CNS(=O)(=O)c1ccc(-c2cnc(N)nc2)cc1F
Reactant: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzenesulfonamide (20 mg, 0.07 mmol) and 1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione (24 mg, 0.07 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=474.0.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: O=Cc1ccncc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccncc1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide in dry tetrahydrofuran (15 mL) at 0° C. was added n-butyl lithium (3.87 mL, 3.87 mmol) with constant stirring, yellow colour was observed. The yellow colour suspension was allowed to stir at room temperature for 40 min. After 40 min, the reaction mixture was cooled to 0° C. and 3-bromoisonicotinaldehyde (0.6 g, 3.23 mmol) in tetrahydrofuran (5 mL) was added drop wise, the yellow colour was disappeared. Reaction mass was allowed to stir at 0° C. to room temperature for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ether (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.69 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.41 (d, J=4.8 Hz, 1H), 7.02-6.95 (m, 1H), 5.95-5.91 (d, J=17.6 Hz, 1H), 5.60-5.57 (d, J=10.8 Hz, 1H). MS (M+2): 185.8.
Reaction SMILES: CO[C:3]([C:5]1[C:10]2[N:11]=[CH:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>CO>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:3]([C:5]1[C:10]2[N:11]=[CH:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCN
Solvent: CO
Product: CN(C)CCNC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 51 %

Procedure:
In 5 mL of methanol, 11 mg (0.037 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid methyl ester prepared in Step B was dissolved, and 100 μL of N,N-dimethylethylenediamine was added thereto and the solution was refluxed under heating with stirring for two hours. The solvent was distilled under reduced pressure, and the residue was separated by Megabond Elute Silica Gel (1 g, dichloromethane:methanol=30:1 to 4:1) to obtain 7.3 mg (51%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid (2-(dimethylamino)ethyl)amide as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:18].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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:18]=[C:7]1[N:6]([CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[CH:3]=2)[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1ccc2c(c1)N(Cc1cccc(I)c1)C(=O)CO2
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)N(Cc1cccc(-c3ccncc3)c1)C(=O)CO2

Procedure:
To a solution of 4-(3-iodo-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.100 g, 0.254 mmol) and Pd(PPh3)4 (0.015 g, 0.01 mmol) in DMF (20.0 mL) was added pyridine-4-boronic acid (0.034 g, 0.279 mmol) followed by the addition of Na2CO3 (2 mL, 2.0 M solution). The solution was heated to reflux overnight with good stirring. The heat was turned off, the solution was poured into H2O (30 mL), and the organic phase was extracted with CH2Cl2 (3×40 mL). The organic phase was than dried over MgSO4, filtered, and concentrated down under reduced pressure. The product was chromatographed with CH2Cl2/MeOH (9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:14][CH:13]=[CH2:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)c(OC)c1
Temperature: 130 °C

Procedure:
To a 50 mL flask containing a stir bar were added 2-methoxy-4-bromobenzonitrile (0.30 g, 1.4 mmol), palladium tetrakis (82 mg, 0.071 mmol), allyltri-n-butyltin (0.877 mL, 2.83 mmol), and lithium chloride (0.120 g, 2.83 mmol). The resulting mixture was then dissolved in anhydrous toluene (16 mL); the flask was placed in an oil bath and heated at 130° C.; LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction had gone to completion. The flask was taken out of the oil bath and cooled to room temperature. To the flask was poured EtOAc (40 mL) and the mixture was transferred into a separatory funnel and washed with aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then dissolved in DCM and absorbed into silica gel. The slica gel was then loaded onto a silica column for separation with the solvent systems of hexanes/EtOAc (1/0.3); this gave 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile. LC-MS (IE, m/z): 174 [M+1]+; tR=2.10 min.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][NH2:33])[CH:27]=1>>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:33]2)[CH:27]=1
Reactant: NNc1cccnc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccnc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and pyridine-3-yl-hydrazine according to the method described for example 43. MS: M=400.1 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C@H:28]([NH:32]C(=O)OC(C)(C)C)[C@H:29]2[CH2:31][O:30]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH:18][CH2:31][C@@H:29]([OH:30])[C@@H:28]([NH2:32])[CH2:27][C:22]2[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[CH:21]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OCCC)ccc21
Yield: 66 %

Procedure:
Step BA (1): (1S,3R)-3-(allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-amine (940 mg, 3.8 mmol, from Step AY (1)) was reacted with tert-butyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate (1.0 g, 3.3 mmol) following a procedure analogous to Step AW (1) to afford, after purification, 1.2 g (66% yield) of (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol. LC-MS (M+H)+=547.20. 1H NMR (300 MHz, CDCl3) δ 0.9-1.1 (t, 3H) 1.3 (s, 9H) 1.7-1.9 (m, 2H) 1.9-2.0 (m, 1H) 2.5-3.1 (M, 5H) 3.4-3.5 (m, 1H) 3.7-3.8 (m, 1H) 3.8-4.0 (t, 2H) 4.0-4.1 (m, 2H) 4.5-4.6 (m 1H) 4.7-4.8 (m, 1H) 5.1-5.4 (m, 2H) 5.8-6.0 (m, 1H) 6.5-6.9 (m, 5H) 7.2-7.3 (d, 1H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH3:60])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH3:60])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 2 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (50 mg) and triethylamine (30 μL) are dissolved in dichloromethane (2 mL), treated with methyl chloroformate (11 μL) and stirred for 2 hours. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step. LC (method 4): tR=1.19 min; Mass spectrum (ESI+): m/z=773 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH3:11][S:12](Cl)(=[O:14])=[O:13].Cl>C(N(CC)CC)C>[CH3:11][S:12]([O:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])(=[O:14])=[O:13]
Reactant: CCOC(=O)NCC(C)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
29.4 g of ethyl 2-hydroxypropylcarbamate are dissolved in 27 g of triethylamine and 22.9 g of methanesulphonyl chloride are added dropwise thereto at 15°-20° C. over 1 hour while stirring. The thickening reaction mixture is stirred for 2.5 hours and then poured into ice-water. The mixture is acidified by means of 2 N hydrochloric acid and extracted three times with methylene chloride. The extracts are washed neutral with water and dried over sodium sulfate. After evaporating the solvent, there is obtained ethyl 2-(methylsulphonyloxy)propylcarbamate (nD20 =1.4577) which can be used without further purification.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:16](=[O:59])[NH:17][CH:18]([C:22](=[O:58])[N:23]([CH:25]([CH:54]([CH2:56][CH3:57])[CH3:55])[CH:26]([O:52][CH3:53])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH:35]([S:48]([CH3:51])(=[O:50])=[O:49])[CH2:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])[CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])C)C1C=CC=CC=1.O>CC(O)(C)C.[OH-].[OH-].[Pd+2]>[CH:54]([CH:25]([N:23]([CH3:24])[C:22]([CH:18]([NH:17][C:16](=[O:59])[CH:12]([NH:10][CH3:9])[CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])=[O:58])[CH:26]([O:52][CH3:53])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH:35]([S:48]([CH3:51])(=[O:50])=[O:49])[CH2:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])([CH2:56][CH3:57])[CH3:55]
Reactant: CCC(C)C(C(CC(=O)N1CCCC1C(CC(=O)NCCc1ccccc1)S(C)(=O)=O)OC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCC(C)C(C(CC(=O)N1CCCC1C(CC(=O)NCCc1ccccc1)S(C)(=O)=O)OC)N(C)C(=O)C(NC(=O)C(NC)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a stirred solution of the crude {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfonyl-2-phenethylcarbamoyl-ethyl)-pyrrolidin-1-yl]-4-oxo-butyl}-methyl-carbamoyl)-2-methyl-propylcarbamoyl]-2-methyl-propyl}-methyl-carbamic acid benzyl ester (311 mg) obtained above in tBuOH (9 ml) and H2O (1 ml) was added Pd(OH)2 on carbon(ca. 20 wt %, 1 g) at room temperature and then the mixture was set under H2 atmosphere. After being stirred at room temperature for 13.5 hr, the mixture was filtrated through a pad of celite and washed with MeOH. The filtrate and washings were combined and concentrated in vacuo to give the crude gum (285 mg), which was purified by preparative HPLC (column: ODS-80Ts, eluent: 40/30 H2O:CH3CN/0.05% TFA). The appropriate fractions were lyophilized to give the title compound as a white amorphous powder (160 mg, 58%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[K+].Br[CH2:16][C:17]1[CH2:18][O:19][C:20]2[C:25]([CH:26]=1)=[C:24]1[O:27][CH2:28][CH2:29][O:30][C:23]1=[CH:22][CH:21]=2>CN(C)C=O.O>[O:27]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[C:23]2[O:30][CH2:29][CH2:28]1)[O:19][CH2:18][C:17]([CH2:16][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])=[CH:26]3
Reactant: BrCC1=Cc2c(ccc3c2OCCO3)OC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1=Cc2c(ccc3c2OCCO3)OC1
Reaction time: 10 h

Procedure:
2.36 g (12.75 mmol) of potassium phthalimide and also 0.166 g (1 mmol) of potassium iodide are added to a solution of 2.54 g (8.5 mmol) of the brominated compound obtained in Step E in 20 ml of anhydrous N,N-dimethylformamide; the medium is then stirred under argon for 10 hours. The solvent is evaporated in vacuo; the residue obtained is then taken up in water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) yields the title phthalimide in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](O)(=[O:14])[C:12]#[CH:13].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:14])[C:12]#[CH:13]
Reactant: C#CC(=O)O
Reactant: Cc1cc(O)cc(C)c1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
To a stirred solution of 4-bromo-3,5-dimethylphenol (40.87 g, 203.3 mmol) and propiolic acid (20.91 g, 298.5 mmol) in CH2Cl2 (400 mL) was added DCC (50.78 g, 246.1 mmol) in CH2Cl2 (100 mL) and DMAP (0.82 g, 6.7 mmol) at 0° C. The mixture was stirred at room temperature for 3 h and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexanes:EtOAc:CH2Cl2=20:1:10). The fractions containing the desired compound were concentrated. To the concentrate added hexane and the precipitated solid was collected by filtration. The solid was washed with hexane and dried to give the title compound 6-1 (26.12 g, 51% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cccnc1)N1CCOCC1
Product: O=C(NCC(c1cccnc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21][CH3:22])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OC

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (1000 mg, 4.32 mmol) and methyl L-norvalinate hydrochloride (1090 mg, 6.49 mmol) are reacted by general procedure 6. The crude product is purified by workup method 1. The product is obtained in quantitative yield.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and phenylhydrazine according to the method described for example 1. MS: M=383.2 (M+H)+