Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CCCP(=O)=O.Cl.[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH2:52]>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH:52][C:29]([C:23]1[C:22]2[CH2:21][CH2:20][N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)=[O:12])[CH:14]=3)[CH2:28][C:27]=2[CH:26]=[N:25][CH:24]=1)=[O:30]
Reactant: COC(=O)CN
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)CNC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 64.2 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (40 mg, 0.096 mmol), N,N-diisopropylethylamine (0.067 mL, 0.39 mmol), and catalytic DMAP in 2.5 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.069 mL, 0.116 mmol). After 6 min at rt, glycine methyl ester hydrochloride (18.1 mg, 0.144 mmol) was added and the reaction stirred at rt for 4 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc plus 10% MeOH to give the title compound as a light yellow solid (30 mg, 64%). 1H NMR (CDCl3) δ: 8.55 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.53 (d, J=11.4 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 7.33-7.40 (m, 1H), 7.20-7.32 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.62 (t, J=5.1 Hz, 1H), 4.47 (s, 2H), 4.24 (d, J=5.3 Hz, 2H), 3.81 (s, 3H), 3.56-3.61 (m, 2H), 3.20 (t, J=5.6 Hz, 2H), 2.85-2.99 (m, 1H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[H-].[Na+].I[CH2:23][C:24]1[N:25]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[O:27][C:28]=1[CH2:29][CH3:30].C(OCC)(=O)C>CC(OC)(C)C>[CH2:29]([C:28]1[O:27][C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[N:25][C:24]=1[CH2:23][O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1)[CH3:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](O)C1
Reactant: CCc1oc(-c2cccc(OC)c2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CCc1oc(-c2cccc(OC)c2)nc1CO[C@H]1CCC[C@@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
200 mg of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpropionate are added dropwise as solution in MTBE to a suspension of 65 mg of sodium hydride (60% by weight in mineral oil) in 10 ml of MTBE. After gas evolution ceases, 503 mg of 4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole are added as solution in MTBE, and the suspension is heated under reflux overnight. Ethyl acetate (MTBE can also be used) is added to the reaction mixture, and the mixture is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate gradient), resulting in 323 mg of tert-butyl 2-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}-2-methylpropionate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)\[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)\[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Reaction time: 3 h
Yield: 68.5 %

Procedure:
In 50 ml of methanol, was dissolved 2.9 g (0.01 mole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (melting point 108°-109° C.) characterized by the NMR spectrum given below. To the solution was added 0.38 g (0.01 mole) of sodium borohydride, while keeping the temperature of the reaction system at 20° C. or below by cooling in ice. To the solution, after having been kept at 20° C. for 3 hours, was added 1 ml of acetic acid to effect decomposition. The organic layer was extracted with 100 ml of ethyl acetate and the extract was washed with 50 ml of a 5% aqueous hydrogencarbonate solution, and dried over anhydrous sodium sulfate. After the removal of the solvent by distillation under reduced pressure, the residue was recrystallized from n-hexane to obtain 2.0 g (69% yield) of the captioned compound having a melting point of 153°-155° C. The elementary analysis and NMR spectrum (determined on a solution in deuterochloroform and expressed in terms of δ value) of each compound were as shown below:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.C1O[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19]C1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.C(O)C>[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(=O)CC3)c2cc1OC
Yield: 98 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (30 g), 4-piperidone ethylene ketal hydrochloride (25 g), triethylamine (35 g) and ethanol (250 ml.) were refluxed together for 3 hours. Aqueous sodium carbonate was added followed by extraction with chloroform after which the chloroform extract was dried and evaporated in vacuo to give an oil. The oil was redissolved in aqueous hydrochloric acid (1.5N, 200 ml.) and refluxed for 2 hours followed by cooling, basification (Na2CO3 10% soln) and extraction into chlororform. Evaporation of the dried chloroform extract gave 4-(4-oxo-piperidino)-6,7-dimethoxyquinazoline (37.6 g) m.p. 176°-8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH3:13])=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH:29]1([NH:32][C:10](=[O:12])/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH3:13])[CH2:31][CH2:30]1
Reactant: C/C(=C\C(=O)O)c1cccc(F)c1
Reactant: NC1CC1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C/C(=C\C(=O)NC1CC1)c1cccc(F)c1

Procedure:
To a solution of 18.0 g of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutes. To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)[OH:22].N([O-])=O.[Na+].F[B-](F)(F)F.[Na+]>O>[OH:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Sc1ccccc1O
Reaction time: 0.33 h

Procedure:
Suspend 10.15 g (35 mmoles) of the amino acid of Step A in 75 ml of water and add 4 ml concentrated sulfuric acid (7.36 g, 75 mmoles, 140 meq.). Cool the mixture in an ice-bath and add 3.657 g (53 mmoles) of sodium nitrite in portions at 0°-5° C. Stir the suspension in the cold for 20 minutes. Add 10 g (91 mmoles) of sodium fluoroborate and stir for an additional 20 minutes. Separate the precipitated crude diazonium fluoroborate, suspend tne precipitate in 250 ml of 50% sulfuric acid and heat in an oil bath at 90°-100° C. for 45 minutes. Cool the mixture and separate the precipitate. (Yield: 7.76 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:13]=[N:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:16]([O:15][N:14]=[CH:13][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][C@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)C[C@H](C)C[C@H](C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](C)CC(C=NOCc2ccccc2)(C(=O)O)C1
Temperature: 90 °C

Procedure:
A mixture of (3S,5R)-1-(benzyloxyimino-methyl)-3,5-dimethyl-cyclohexanecarboxylic acid methyl ester (4.8 g, 15.8 mmol) and lithium hydroxide monohydrate (6.6 g, 158 mmol) in THF (170 mL) and water (85 mL) was heated at 90° C. for 48 h. The reaction mixture was acidified to pH 3 with 6N aqueous HCl and was extracted with dichloromethane (75 mL×6). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (1.8 g, 39%). MH+290.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]3([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:22][CH2:21][CH2:20][O:19]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1>>[CH:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:46]=[CH:47][C:38]=1[CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]3([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:22][CH2:21][CH2:20][O:19]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-bromomethyinaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy)-phenyl]-piperidine-1-carboxylate as white crystals; MS: 624 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[F:28])[CH:18]=2)[C:13]([CH3:31])([CH3:30])[C:12]1=[O:32])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[F:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([CH3:31])([CH3:30])[C:12](=[O:32])[N:11]2[CH2:10][CH2:9][OH:8])=[CH:15][CH:16]=1)=[O:29]
Reactant: CC1(C)C(=O)N(CCO[Si](C)(C)C(C)(C)C)c2cc(NC(=O)c3ccncc3F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(CCO)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (prepared in analogy to example 65c and 26 from 6-bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)-3,3-dimethylindolin-2-one and 3-fluoroisonicotinic acid; 195 mg, 426 μmol) in THF (10 ml) was added a solution of TBAF in THF (1M, 639 μl, 639 μmol). After 2 hours at room temperature the reaction mixture was treated with water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as light yellow solid (151 mg).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][C@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[C@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCN[C@H](C)C1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)[C@H](C)C1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 28 mg (R)-3-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:24])[C:10](O)=[C:9]2[C:26]([CH:28]2[CH2:30][CH2:29]2)=O)=[CH:4][CH:3]=1.[NH:31]([C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1)[NH2:32]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:26]([CH:28]4[CH2:29][CH2:30]4)=[N:32][N:31]([C:33]4[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=4)[C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cn1nccc1NN
Reactant: Cc1cc(N2C(=O)C(O)=C(C(=O)C3CC3)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Solvent: CCOCC
Product: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3-c3ccnn3C)C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 114.1 using 5-(4-chlorophenyl)-4-(cyclopropanecarbonyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 117.1) and 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2). The crude material was first purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) followed by preparative achiral SFC (column Silica, gradient 23-28% in 6 min_total 11 min). A third purification was performed by preparative HPLC (Gilson gx-281. Column: Sunfire C18, 30×100 mm, 5 mm. Flow: 30 mL/min. Gradient: 30% to 60% B in min; A=0.1% TFA in H2O, B=CH3CN. Detection: UV). The fractions were combined, basified with NaHCO3, the CH3CN was removed under reduced pressure and the resulting aqueous layer was extracted with CH2Cl2, the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford, after trituration in Et2O, a white solid. tR: 0.99 min (LC-MS 2); ESI-MS: 499 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.03-0.14 (m, 1H) 0.67-0.80 (m, 2H) 0.80-0.92 (m, 1H) 1.78-1.85 (m, 1H) 2.42 (s, 3H) 2.61 (s, 3H) 3.85 (s, 3H) 6.55 (s, 1H) 6.63 (d, J=2.0 Hz, 1H) 7.30 (s, 1H) 7.37 (d, J=8.6 Hz, 2H) 7.46 (d, J=8.6 Hz, 2H) 7.56 (d, J=1.6 Hz, 1H) 8.39 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.[Br:24]N1C(=O)CCC1=O>CN(C)C=O>[Br:24][C:12]1[CH:11]=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:4]([OH:3])=[O:23])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(OC)cc1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)CC(O)(C(=O)O)C(F)(F)F)cc1Br

Procedure:
From 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid ethyl ester by bromation with N-bromosuccinimide in dimethylformamide at 0° C. and subsequent saponification. Melting point 94-96° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([NH2:32])=[O:31]>CC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)CN1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 50.3 %

Procedure:
A solution of 70 mg (0.23 mmol) of 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] in 1 ml of acetone was successively treated with 69 mg (0.5 mmol) of potassium carbonate and 24 mg (0.25 mmol) of 2-chloroacetamide. The reaction mixture was heated to reflux during 18 h. For the working-up, 1 g of silica gel was added to the cooled reaction mixture, which was then evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 95:5:0.1-mixture of dichloromethane, methanol and ammonium hydroxide as the eluent. There were obtained 38 mg (51% of theory) of 2-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-acetamide as a white solid; MS: m/e 329 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:31]([O:30][C:28](=[O:29])[CH2:27][C:18]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=2[CH3:35])[CH2:19]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(OCc2ccccc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Yield: 71.7 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-methylphenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (3.93 g), 10% Pd/C (containing about 55% water, 400 mg), and methanol (40 mL) was stirred at room temperature for 75 minutes in a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.29 g).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([O:11]N2C(=O)CCC2=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:20]1.C(N(CC)CC)C>ClCCl>[OH:28][CH2:27][CH2:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])[CH2:20]1
Reactant: OCCCC1CCCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC(CCCO)C1
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1-({[(Phenylmethyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (8.70 g), 34.9 mmol) was added portionwise to a stirred mixture of 3-(3-piperidinyl)-1-propanol (5.02 g, 35 mmol) and triethylamine (5 ml, 3.63 g, 35.9 mmol) in dichloromethane (100 ml) at room temperature. The resultant mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (100 ml). The organic phase was dried (MgSO4), filtered and evaporated. The sample was purified by chromatography on silica (100 g cartridge loaded in dichloromethane) using a gradient of 0-100% ethyl acetate-cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless liquid (8.45 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:29][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:39][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Reactant: NCCc1cccc(F)c1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 141 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.75 (s, 1H) 8.36 (d, 2H) 7.96 (d, 1H) 7.65 (m, 2H) 7.27 (m, 1H) 7.18 (m, 2H)) 6.92 (m, 1H) 4.54 (s, 2H) 3.96 (t, 2H) 3.72 (s, 2H) 3.59 (t, 2H) 3.35 (t, 2H) 3.08 (t, 2H) 1.74 (s, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9]([C:11]1[C:20]2[O:21][C:22]3([C:32]([CH3:34])([CH3:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]3[CH3:35])[CH:23]=[N:24][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=O>N1CCCCC1.C(O)C>[C:1]([C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:11]1[C:20]2[O:21][C:22]3([C:32]([CH3:33])([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]3[CH3:35])[CH:23]=[N:24][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)#[N:2]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccccc2C1(C)C
Temperature: 60 °C

Procedure:
To a solution of 0.18 g (1.5 mmol) of ethyl cyanoacetate in a minimum quantity of ethanol are added 0.36 g (1 mmol) of the product of Example 1 and then two drops of piperidine. The mixture is heated at 60° C. until a precipitate appears. The precipitate obtained is filtered off, washed with ethanol and dried.