Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([CH3:16])=[N:14][C:13]([OH:17])=[N:12]2)[CH:8]=[CH:9][CH:10]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([CH3:16])=[N:14][C:13]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nc(O)nn1-c1cccc(Cl)c1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1nc(C)n(-c2cccc(Cl)c2)n1
Yield: 68 %

Procedure:
The process was carried out as was Example 9 above, starting with 0.8 g of sodium, 20 ml of methanol, 75 ml of dimethylsulfoxide, 7.8 g of 1-(3-chlorophenyl)-3-hydroxy-5-methyl-1,2,4-1H-triazole and 6.7 g of ethyl 2-bromopropionate. The yield was 7.8 g of the desired product, an oil.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1.[CH3:23][C:24]1[NH:25][CH:26]=[C:27](I)[N:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCCC1>[CH3:23][C:24]1[NH:25][CH:26]=[C:27]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)[N:28]=1
Reactant: C[Sn](C)(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: Cc1nc(I)c[nH]1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)c[nH]1
Yield: 8.8 %

Procedure:
400 mg of 6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 4), 229 mg of 2-methyl-4-iodo-1H-imidazole, 8 mL of tetrahydrofuran, 9.1 mg of bis(dibenzylideneacetone)palladium and 4.6 mg of tris(2-furyl)phosphine are placed in a microwave tube. The reaction mixture is heated for 50 minutes in a microwave machine set at 130° C. and then concentrated to dryness. The residue is taken up in 3.5 mL of N,N-dimethylformamide and a further 150 mg of 2-methyl-4-iodo-1H-imidazole, 10 mg of bis(dibenzylideneacetone)palladium and 5 mg of tris(2-furyl)phosphine are added, followed by heating again for 40 minutes in a microwave machine set at 120° C. The reaction mixture is filtered, the insoluble matter is rinsed with methanol and dichloromethane and the combined filtrates are concentrated under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with dichloromethane and then with a 90/10 mixture of dichloromethane and methanol. The fractions containing the pure expected product are combined and evaporated to dryness under reduced pressure to give 28 mg of 6-(2-methyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:40]=[CH:41][C:42]2[O:46][C:45](=[O:47])[N:44]([CH2:48][CH2:49][O:50][CH3:51])[C:43]=2[CH:52]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][C:45](=[O:47])[N:44]([CH2:48][CH2:49][O:50][CH3:51])[C:43]=3[CH:52]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: COCCn1c(=O)oc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Yield: 23.5 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 250 mg) in acetonitrile (8 mL) with 5-bromo-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one (Example 24, step (i), 131 mg) was treated with an aqueous solution of sodium carbonate (2M, 0.483 mL). Nitrogen was bubbled through the solution and then 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The reaction mixture was heated at 85° C. for 18 h under nitrogen and allowed to cool to room temperature. Purification by chromatography on silica eluting with 50-100% ethyl acetate/isohexane as eluent afford the sub-titled compound (66 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:26][C:12]([F:11])([F:25])[C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
A mixture of 6-chloro-3-pyridinecarboxamide (0.11 mol), 1-[3-(trifluoromethyl)-phenyl]-piperazine (0.1 mol) and sodium carbonate (0.22 mol) in DMF (300 ml) was stirred at 120° C. overnight. The mixture was poured out into ice water (600ml) and stirred for 1 hour. The precipitate was filtered off and dried Part of this fraction (4 g) was taken up in DCM and an aqueous NaHCO3 solution. The mixture was separated into its layers. The aqueous layer was extracted three times with DCM. The combined organic layer was dried, filtered and the solvent was evaporated till a small volume. The precipitate was filtered off and dried, yielding 3.2 g of 6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-3-pyridinecarboxamide (intermediate 3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([OH:17])=O)[CH2:11][C@H:10]1[CH:12]([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C:25]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O>[F:14][CH:12]([F:13])[C@@H:10]1[CH2:11][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:15](=[O:17])[NH:31][S:28]([C:25]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:27][CH2:26]1)(=[O:29])=[O:30]
Reactant: C=CCCCCCC1(S(N)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1C(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCCC1(S(=O)(=O)NC(=O)[C@@]2(NC(=O)OC(C)(C)C)C[C@H]2C(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
To a solution of (1R,2R)-1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylic acid (100 mg, 0.398 mmol) in Tetrahydrofuran (4 mL) was added CDT (84 mg, 0.517 mmol) and the formed solution was stirred at r.t. for 3 h. 1-(hept-6-enyl)cyclopropane-1-sulfonamide (104 mg, 0.478 mmol) and DBU (0.120 mL, 0.796 mmol) were added and the reaction continued at r.t. overnight. The reaction was diluted with EtOAc. Washed with 5% citric acid, brine, dried over MgSO4, filtered and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜70% EtOAc-Hexane to afford the desire produce tert-butyl (1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamate (45 mg, 0.100 mmol, 25.09% yield). 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.95 (s, 2 H) 1.28-1.36 (m, 2 H) 1.36-1.47 (m, 6 H) 1.52 (s, 9 H) 1.58-1.67 (m, 2 H) 1.72 (d, J=10.54 Hz, 1 H) 1.78-1.95 (m, 2 H) 1.97-2.12 (m, 3 H) 4.88-5.05 (m, 2 H) 5.23 (b, NH) 5.65-5.92 (m, 2 H) 9.20 (b, NH).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:8]=2[CH:9]=1
Reactant: COc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(C)CC1)C2

Procedure:
12 G. of 10-chloro-8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin are treated with 16.3 g. of N-methylpiperazine and stirred for 10 minutes at 110°-120° C. (internal temperature). Thereafter, the mixture is cooled and treated with 2N sodium hydroxide. The mixture is then extracted with ether and the organic phase washed with water. The ether solution is extracted with dilute methanesulfonic acid and the acidic solution made alkaline with sodium hydroxide and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulfate and concentrated, and there is obtained 1-{8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine having a melting point of 141°-144° C. This base is converted by treatment with methanesulfonic acid into the methanesulfonate which has a melting point of 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:22]([CH3:24])[CH3:23].CO>[Ni].C1COCC1>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])([N:22]([CH3:23])[CH3:24])[C:6]2=[O:21])=[CH:17][CH:16]=1
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc(N)cc2)c2ccc(Cl)cc21
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 1.88 g of the compound obtained in EXAMPLE 245, 0.9 g of Raney® nickel, 40 ml of MeOH and 40 ml of THF is hydrogenated at atmospheric pressure for 2 hours at RT. The catalyst is filtered off on C elite® and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 1.58 g of the expected product, which is used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25](N)=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C@H:11]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCC(N)=O)CC[C@H]2c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@H](CCCO)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 96° C., [α]D20=−97.1° (c=1.0723 in chloroform) and MS: m/e=378.2 (M+H+)] was prepared in accordance with the general method of example 44 from (2S,5R)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester [see example 59: colorless oil, [α]D20=−96.4° (c=1.0992 in chloroform) and MS: m/e=406.1 (M+H+)].
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][N:11]2[C:14](=[O:16])[CH3:15])=[CH:7][CH:6]=1.CCOCC>CN1C(=O)CCC1>[C:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:1]#[N:2])[CH:13]=2)[C:9]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CC(C)(c2ccccc2)c2ccc(Br)cc21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CC(=O)N1CC(C)(c2ccccc2)c2ccc(C#N)cc21
Temperature: 175 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
CuCN (179 mg, 2 mmol) was added to a solution of 1-(6-bromo-3-methyl-3-phenyl-2,3-dihydro-indol-1-yl)-ethanone (330 mg, 1 mmol) in NMP (5 mL). The reaction was stirred at 175° C. for 16 h. Et2O was added to the mixture and the solid was filtered off. The filtrate was washed with 2 M aqueous HCl and saturated aqueous NaHCO3. The solvent was removed in vacuo to give the title compound (250 mg) as a brown solid. MS: [M+H]+=277.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH2:34]([N:37]([CH2:38][CH2:39][CH3:40])[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH2:35][CH3:36]
Reactant: CCCNCCC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 76.2 %

Procedure:
Operations are carried out as for Example 7, starting from 1.42 g of 1-(2-chlorophenyl) isoquinoline 3-carboxylic acid, 0.58 g of triethylamine, 0.62 g of ethyl chloroformate and 0.66 g of N-propyl propylamine in 50 ml of chloroform. 1.40 g of N,N-dipropyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 101° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].[CH3:11][C:12]([CH3:16])=[CH:13][CH2:14]O>O1CCOCC1>[CH3:1][C:2]1[C:8]([CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11])=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[OH:4]
Reactant: Cc1cc(O)c(C)cc1O
Reactant: CC(C)=CCO
Solvent: C1COCCO1
Product: Cc1cc(O)c(C)c(CCC(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
2,5-Dimethylbenzoquinone (5 g) in ethyl acetate was shaken with an aqueous solution of sodium hydrosulfite. The organic layer was separated, washed, dried and evaporated to yield 2,5-dimethylhydroquinone. To a solution of 2,5-dimethylhydroquinone (5 g), prepared as described above, and 3-methyl-2-buten-1-ol (3.1 g) in dioxane (20 mL) was added BF3-ether (4.5 mL) at room temperature under nitrogen. The solution was stirred at room temperature for one hour, extracted with ethyl acetate, washed with water and dried. The mixture containing starting material and alkylated product was hydrogenated in methanol (100 mL) with 5 drops of concentrated HCl in the presence of Pd/C (10%, 200 mg) at60 psi for 18 hours. Workup and chromatography (silica gel hexane-ethyl acetate 5% to 12%) gave 2 g of the desired product, 2,5-dimethyl-3-(3-methyl-butyl)-hydroquinone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].O>CN(C=O)C>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine (1.0 g, 9.16 mmol) in DMF (5 ml) at room temperature was added potassium carbonate (2.53 g, 18.32 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 15 min. Then, 4-chloro-3-nitropyridine (1.45 g, 9.16 mmol) was added and the resulting solution was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and evaporated. 4-(6-Methylpyridin-3-yloxy)-3-nitropyridine (2.1 g, 100%) was obtained as an orange oil, which precipitated on standing, mp 87-90° C., and was used in the next step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])[CH2:23][CH2:22]1>>[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([O:20][CH:21]2[CH2:22][CH2:23][CH:24]([CH2:27][CH2:28][CH:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])[CH2:25][CH2:26]2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)NC(C)CCC1CCC(O)CC1
Product: CC(=O)NC(C)CCC1CCC(Oc2ccc(OC(C)C)nc2)CC1

Procedure:
2-Isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (913 mg, 3.47 mmol) and N-[3-(4-hydroxycyclohexyl)-1-methylpropyl]acetamide (740 mg, 3.47 mmol) were reacted in analogy to example 50a. Yield: 95 mg (8%), M+H+: 349.3.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)=[CH:7][C:6]([NH:21][C@H:22]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:23]([NH2:25])=[O:24])=[C:5]([F:30])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[C:5]([F:30])=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:7]=1)[CH2:26][CH:27]1[CH2:28][CH2:29]1
Reactant: CC(=O)O
Reactant: N#Cc1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-phenylisoxazol-5-ylamino)phenylamino)-3-cyclopropylpropanamide (75 mg) in EtOH (1 mL) and DMSO (0.5 mL) at room temperature, aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.5 mL) was added. After being concentrated in vacuo, the residue was purified by HPLC to give the titled compound (13 mg). MS 424.4 (M+H); UV 201.0, 244.9, 289.1 nm; t 0.668 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[NH:48][C:47]=1[C:55](O)=[O:56].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(#N)C>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:55]([C:47]2[NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[N:46]=2)=[O:56])[CH2:21][C:22]2[N:23]=[CH:24][N:25]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A mixture of 355 mg (0.58 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-tritylimidazole-4-propionamide, 95 mg (0.58 mmol) of benzimidazole-2-carboxylic acid [Chem. Ber. 45, 3489 (1912)], 256 mg (0.58 mmol) of BOP and 0.12 ml (0.58 mmol) of Hunig base in 50 ml of acetonitrile is stirred at room temperature for 20 hours. Thereafter, the reaction mixture is evaporated under reduced pressure, the residue is taken up in 60 ml of ethyl acetate and washed twice with 20 ml of saturated potassium hydrogen carbonate solution. After drying the organic phase over sodium sulphate the solvent is evaporated under reduced pressure. For purification, the residue is chromatographed on 30 g of silica gel using a 15:1 mixture of methylene chloride and methanol as the eluent. There are obtained 379 mg of N-[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(1-tritylimidazol-4-yl)ethyl]-2-benzimidazolecarboxamide as a colourless foam; MS: 751 (M+H)+.
Reaction SMILES: [CH2:1]1[O:24][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[O:3][CH2:2]1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.O>[CH2:1]1[O:24][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12][N:25]=[N+:26]=[N-:27])[O:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2C2OCCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCc1ccccc1C1OCCO1
Yield: 95.7 %

Procedure:
A solution of 2-(2-(4-methylphenylsulphonyloxy)ethyl)benzaldehyde ethylene acetal (1.43 g, 4.10 mmol) and sodium azide (0.53 g, 8.2 mmol) in DMSO (20 ml) was stirred for 16 h, diluted with water, extracted three times with ether, washed with brine, dried over sodium sulphate and evaporated to afford the product as a yellow oil (0.86 g), MS (+EI) 190 [(M-NH2)+], 1H NMR (d6 -DMSO) 7.53-7.25 (4H, m), 5.92 (1H, s), 4.19-3.95 (4H, m), 3.53 (2H, t, J7.2 Hz), 2.98 (2H, t, J7.2 Hz).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][CH3:9])=[CH:4][F:5].S(=O)(=O)(O)[OH:17]>O>[F:5][CH2:4][C:3]([OH:17])([C:6]([F:12])([F:13])[C:7]([F:11])([F:10])[CH2:8][CH3:9])[C:2]([F:14])([F:15])[F:1]
Reactant: CCC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCC(F)(F)C(F)(F)C(O)(CF)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol may be prepared by fluorinating commercially available 3,4-hexanedione to form 3,3,4,4-tetrafluorohexane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-hexene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-hexene to form 2-trifluoromethyl-1,3,3,4,4-pentafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])c1cccc(F)c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(F)c4)ccc31)C1CCC(C2)N1
Yield: 46 %

Procedure:
Intermediate 2 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, hexanes/ethyl acetate) to give tert-butyl 2-(3-fluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (110 mg, 46%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.13-8.23 (m, 1H), 7.71-7.76 (m, 1H), 7.58-7.70 (m, 2H), 7.38-7.49 (m, 1H), 7.28-7.35 (m, 1H), 7.12-7.23 (m, 1H), 5.16-5.38 (m, 1H), 4.32-4.51 (m, 1H), 3.60 (s, 3H), 3.20-3.50 (m, 1H), 2.50 (d, J=16.2 Hz, 1H), 2.10-2.40 (m, 2H), 1.85-1.98 (m, 1H), 1.56-1.68 (m, 1H), 1.37 (br s, 9H).