Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:8])=[O:7].CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:7])=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)Cc2ccc3c(c2)CCC(NS(=O)(=O)c2cccs2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccc2c(c1)CCC(NS(=O)(=O)c1cccs1)C2)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A mixture of 1.45 g of methyl 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoate, 10 ml of methanol, 9 ml of a 2N aqueous sodium hydroxide solution and 4 ml of tetrahydrofuran is stirred at room temperature overnight. Methanol and tetrahydrofuran are distilled off, and the residual mixture is washed and acidified. The precipitated crystals are collected by filtration, washed, dried and recrystallized from a mixture of tetrahydrofuran and isopropyl ether to give 1.33 g of 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoic acid as colorless crystals.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][C:21]1[C:22]([C:38](OC)=[O:39])=[N:23][N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:25](=[O:27])[CH:26]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:38]([C:22]1[C:21]([O:20][CH3:19])=[CH:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[N:23]=1)=[O:39]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c(=O)cc1OC
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (1.58 g, 16.2 mmol) and iPr2NEt (2.82 mL, 16.2 mmol) in CH2Cl2 (13 mL) was added AlMe3 (1.8 M solution in toluene, 9.0 mL, 16.2 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 4-methoxy-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridazine-3-carboxylate (1.77 g, 5.4 mmol) in CH2Cl2 (15 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (1.48 g, 83% yield) as a white solid: mp 127-129° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.37 (3H, s), 3.64 (3H, s), 3.91 (3H, s), 6.30 (1H, s), 7.55-7.60 (1H, m), 7.62-7.65 (1H, m), 7.82-7.86 (1H, m), 7.88 (1H, s). Anal. Calcd for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.47; H, 3.99; N, 11.83.
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:29])[CH2:5]1)[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+]>Cl>[CH2:1]([C:4]1([CH3:30])[C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:29])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C)CN(C)Cc2c1n(CC(C)(O)c1ccc(F)cc1)c1ccc(C)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCC1(C)CN(C)Cc2c1n(C=C(C)c1ccc(F)cc1)c1ccc(C)cc21

Procedure:
A solution of 1-(4-allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(4-fluoro-phenyl)-propan-2-ol (300 mg, 0.738 mmol) in 6N HCl (10 mL) was stirred at 80° C. for 2 h. The progress of reaction mass was monitored by TLC and LCMS. The reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (3×25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (1% MeOH-DCM) to yield 4-allyl-5-[2-(4-fluoro-phenyl)-propenyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The product is further purified by reverse phase HPLC followed by chiral HPLC separation to give enantiomers 274a and 274b. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.62 (m, 2H), 7.27 (s, 1H), 7.20 (m, 2H), 7.04 (m, 3H), 6.78-6.82 (m, 1H), 5.18 (d, 2H), 4.78 (d, 1H), 4.37 (d, 1H), 3.58 (m,2H), 3.18 (s, 3H), 2.40 (s, 3H), 2.38 (d, 2H), 1.82 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][C@H:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C=O)C>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][C@H:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:17]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:37][CH:36]=[CH2:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 0.33 h
Yield: 82 %

Procedure:
(S)-2-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-phenyl-1-(N-t-butoxycarbonylamino)ethane (1.1g, Example 2b) was dissolved in 20ml anhydrous DMF and sodium hydride (0.085g) was added. The reaction mixture was stirred for 20 min and allyl bromide (0.300g) added and stirred for a further 16h. The reaction was quenched by the addition of water (30ml) and poured into 100ml ethyl acetate. The organic layer was washed with water (3×20ml), brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica eluting with 10% Ethyl acetate/hexane to give (S)-2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1-phenyl-1-(N-t-butoxycarbonyl-N-allylamino)ethane as a colourless oil 0.980g. m/z=504 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[N:12][C:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[C:45]#[C:46][C:47](OCC)=[O:48]>C1COCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[N:12]=1)[C:47](=[O:48])[C:46]#[CH:45]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1-c1ccc(F)cc1F
Reactant: CCOC(=O)C#C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CC(=O)C(c1ccc(CO)c(-c2ccc(F)cc2F)n1)c1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(2,6-difluorobenzyl)-2-(2,4-difluorophenyl)pyridine (from Step D above, 4.63 g) in THF was added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0 M in THF) at −78° C. After stirring ½ h at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (2.2 mL) was added. The mixture was warmed to 0° C. and stirred for a couple of hours until reaction complete. The reaction was quenched with 0.1 N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue in THF was added TBAF (25 mL, 1N in THF) at 0° C. and stirred for 1 h. The solution was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% methylene chloride) to give title compound (1.08 g).
Reaction SMILES: [F:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.CO.[H][H]>C1C=CC=CC=1>[F:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)=Cc1ccccc1
Reactant: [H][H]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: c1ccccc1
Product: OCC(F)=Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of the above ester (1.80 g, 9.27 mmol) in 50 ml benzene is added dripwise at RT a 1.78 M solution of diisobutyl aluminum hydride; stir 20 minutes. Add 3 ml more diisobutyl aluminum hydride. Reaction is worked up by adding MeOH until hydrogen evolution ceases, then extracting in ether/dilute HCl solution. The aqueous layer is extracted 2× with ether. The ether layers are washed with dil. HCl, water and brine, dried (Na2SO4) and evaporated under vacuum to yield 2-fluoro-3-phenyl-2-propen-1-ol.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]([OH:31])[CH2:19][NH:20][CH2:21][CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1>C(O)C>[NH:7]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]([OH:31])[CH2:19][NH:20][CH2:21][CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: OC(CNCCNc1ccccc1Cl)COc1cccc2c1cnn2C1CCCCO1
Solvent: CCO
Product: OC(CNCCNc1ccccc1Cl)COc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.8 g. (175 mmol) 1-[1-(Tetrahydropyran-2-yl)-indazol-4-yloxy]-3-[2-(2-chlorophenylamino)-ethylamino]-propan-2-ol in 250 ml. ethanol are mixed with the ion exchanger "Amberlite" CG 120 II (H+ form) and then stirred for 24 hours at 25° C. The ion exchanger is separated off and thoroughly washed with 2% ammonia in methanol. The combined solutions are evaporated and the residue obtained is recrystallized from ethyl acetate. There are obtained 3.6 g. (57% of theory) of the desired compound; m.p. 129°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[C:37]([CH3:39])[CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].CCN=C=NCCCN(C)C.Cl>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:36]=[C:37]([CH3:39])[CH:38]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:21])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1cc(C)cc(CN)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C)cc(C(=O)OC)c3)cn2)C1

Procedure:
Methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methylbenzoate was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-5-methylbenzoate hydrochloride using Amidation Method 2 (EDCl).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][N:12]([CH:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1)[C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h

Procedure:
4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension of N-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured into water, and the resultant precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This results in the product with the molecular weight of 263.30 (C13H17N3O3): MS (ESI): 264 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:16]([CH3:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18])[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[NH:24][C:25]([C@@H:27]([NH2:31])[CH2:28][O:29][CH3:30])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:16]([CH3:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18])[C:5]([NH:31][C@H:27]([C:25]1[NH:24][C:23]2[CH:32]=[CH:33][C:20]([Cl:19])=[CH:21][C:22]=2[N:26]=1)[CH2:28][O:29][CH3:30])=[O:7]
Reactant: CC1COCC(=O)N1c1ccc(C(=O)O)cc1Cl
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)c1ccc(N2C(=O)COCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoic acid and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TBTU and TEA in DMF.
Reaction SMILES: [C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([OH:16])=O)(=[O:3])[CH3:2].CC(C)[C@H](NC(OC)=O)C(N1C(C([NH:39][CH2:40][C:41]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]4[N:56]=[C:57]([C@@H:60]5[CH2:64][CH2:63][CH2:62][N:61]5[C:65](=[O:75])[C@@H:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[CH:67]([CH3:69])[CH3:68])[NH:58][CH:59]=4)=[CH:51][CH:50]=3)=[CH:45][CH:44]=2)=[O:42])=O)CC2(CN(C(OC(C)(C)C)=O)C2)C1)=O>>[C:1]([N:4]1[C:8]2([CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH2:7][CH2:6][CH:5]1[C:14]([NH:39][CH2:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[CH:51][C:52]([C:55]3[N:56]=[C:57]([C@@H:60]4[CH2:64][CH2:63][CH2:62][N:61]4[C:65]([C@@H:66]([NH:70][C:71](=[O:72])[O:73][CH3:74])[CH:67]([CH3:69])[CH3:68])=[O:75])[NH:58][CH:59]=3)=[CH:53][CH:54]=2)=[CH:45][CH:44]=1)=[O:42])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(C(=O)O)CCC12CCOCC2
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC1C(=O)NCC(=O)c1ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc1)CN(C(=O)OC(C)(C)C)C2)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(C)=O)cc3)cc2)c[nH]1)C(C)C
Yield: 66.2 %

Procedure:
This compound was prepared in an analogous fashion to 169 from 1-acetyl-8-oxa-1-azaspiro[4.5]decane-2-carboxylic acid (171) (56 mg, 0.25 mmol) and methyl {(1S)-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (142 mg, 0.25 mmol) to afford the title compound as an off-white solid (118 mg, 67% yield).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:41][CH2:42][N:43]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:29]=[CH:30][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:44][CH2:45]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2nc(Oc3ccc(OC(F)(F)F)cc3)ccc2C(=O)O)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 69.8 %

Procedure:
2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy)nicotinic acid (0.2 g, 0.48 mmol) and (2-Piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.11 g, 0.48 mmol) were coupled using the procedure of Example 5(c) to afford 0.21 g of the required product. Percentage purity (LCMS): 68.11%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(OCC)(=O)C>[CH3:15][CH2:14][O:13][P:9]([O:10][CH2:11][CH3:12])([CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N+:1]([O-:25])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(CCc1ccncc1)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCc1cc[n+]([O-])cc1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
Diethyl 2-(4-pyridyl)ethylphosphonate (10.3 g, 42 mmol) and 3-chloroperbenzoic acid (77%, 12.3 g, 54 mmol) were dissolved in ethyl acetate (200 ml), and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethanol-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (9.9 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH:22]([CH2:28][CH3:29])[C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH:22]([CH2:28][CH3:29])[CH2:23][OH:24])[C:6]=2[C:5]([CH:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC)n1c(Nc2c(C)cc(Cl)cc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C(CC)CO)c12
Temperature: 25 °C
Reaction time: 84 h
Yield: 67 %

Procedure:
To a solution of ethyl {4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butanoate (100 mg, 0.197 mmol) in tetrahydrofuran (1.5 mL) was added lithium tetrahydroborate (13 mg, 0.597 mmol), and the mixture was stirred at room temperature for 84 hr. An additional lithium tetrahydroborate (26 mg, 1.19 mmol) was added, followed by stirring at 50° C. for 24 hr. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound (61 mg, 0.132 mmol, 20%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:7]1=[O:16])C.O.[NH2:19][NH2:20]>C(O)C>[O:16]=[C:7]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=[CH:11][N:6]1[CH2:5][C:4]([NH:19][NH2:20])=[O:3]
Reactant: NN
Reactant: CCOC(=O)Cn1cccc(C(F)(F)F)c1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)Cn1cccc(C(F)(F)F)c1=O
Yield: 95 %

Procedure:
As described for example 112a, (2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 95%). MS: m/e=236.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C@@H:9]([OH:25])[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:37]I>C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C@@H:9]([O:25][CH3:37])[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)cc1C[C@H](O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](Cc1cc(Cl)ccc1C(=O)NC(C)(C)C)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of [(1R,2S)-3-(2-tert-Butylcarbamoyl-5-chloro-phenyl)-1-(2-fluoro-benzyl)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.40 g, 0.81 mmol) in 5 mL of THF is added a 60% dispersion of sodium hydride in mineral oil (64 mg, 1.6 mmol) and the reaction is allowed to stir for 20 minutes at room temperature. Methyl iodide (0.05 mL, 0.81 mmol) is added and stirring is continued for an additional hour. The reaction is quenched by addition of water and the product is extracted into dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant crude residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C1COCC1>[Br:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 31 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (1.0 g, 3.8 mmol) in THF (50 mL) was added N-bromosuccinimide (0.75 g, 4.2 mol). The mixture was heated at 70° C. for 1 h and concentrated in vacuum. The residue was taken up in water and EtOAc. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuum. The residue was purified by preparative LCMS to provide the desired product as a white powder (0.4 g, 30% yield). 1HNMR (400 MHz, d6-DMSO): δ 4.18 (t, J=7.5 Hz, 2H), 2.71 (s, 3H), 1.79 (m, 2H), 1.29 (m, 4H), 0.84 (m, 3H). LCMS calculated for C12H16BrN6O(M+H): 339.1, 341.1; found: 339.1, 341.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH3:18])[C:11](=[O:19])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>ClCCl>[CH2:30]([O:29][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH3:18])[C:11](=[O:19])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCCN1CCN(c2ccc(N)cc2F)CC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.5 g) was dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.33 ml) was added, and the mixture cooled to -20° C. Benzyl chloroformate (2.06 ml) was added, and the mixture stirred for 10 minutes at -20° C., before allowing the temperature to rise to ambient over 1.5 hours. Solvents were evaporated, the residue dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.28 g).