Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:11]=[C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:12]#[N:13])[C:3]=2[CH2:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2c(Br)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1CCC2=O
Temperature: 165 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (1.00 g, 4.74 mmol) in 5 mL of DMF was added Zn(CN)2 (556 mg, 4.74 mmol) and Pd(PPh3)4 (77 mg, 0.14 mmol), and the reaction mixture was stirred under microwave irradiation for 1 h at 165° C. The solvent was removed in vacuum to afford the crude compound, which was purified via column chromatography to afford 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12](F)[C:11]=3[F:21])[CH:5]=2)[CH2:3][CH2:2]1.[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:24][OH:25].CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:21])=[C:12]([NH:22][C@H:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:24][OH:25])[C:13]([F:19])=[CH:14][C:15]=3[N+:16]([O-:18])=[O:17])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 103, 0.300 g, 1.01 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.172 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) was heated in a sealed tube placed in an oil bath set at 135° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=1:1) to give the title compound as an orange solid (0.25 g, 57%). 1H NMR (400 MHz) 11.88 (s, 1H), 8.57 (s, 1H), 7.70 (d, J=13.2 Hz, 1H), 7.34 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 6.61 (b, 1H), 5.38 (s, 1H), 5.07 (t, J=5.6 Hz, 1H), 4.88 (m, 1H), 3.62-3.71 (m, 2H), 1.80 (m, 1H), 0.90 (m, 2H), 0.61 (m, 2H). MS: Calcd.: 433; Found: [M+H]+ 434.
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH:1]1([C:4](=[O:11])[C:5](=[CH:12][O:13][CH2:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C1CC1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C1CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Ethyl β-cyclopropyl-β-ketopropionate (247.0 g, 1.58 mole) [prepared according to the procedure described in J. Am. Chem. Soc., 70, 497 (1948)], triethyl orthoformate (468.3 g, 3.16 mole) and acetic anhydride (484.0 g, 4.74 mole) were combined and the solution was stirred at reflux for 4 h and at ambient temperature for 17 h. The excess reagents were distilled at water aspirator pressure (maximum head temperature permitted was 72° C.) and the oily pot residue was stirred at 10° C. with a mixture of ether and water. The ether layer was separated, washed once with cold water and dried over Na2SO4. Removal of the solvent gave 321.5 g (96%) of an orange-red liquid that was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C=O)CC1
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate (216 mg, 0.74 mmol, 1 eq.) and Dess Martin periodinane (377 mg, 1.2 eq., 0.89 mmol) were stirred in DCM (7 mL) for 1 h. HPLC and LCMS showed completion of the reaction. Sodium thiosulfate was then added and the biphasic mixture was stirred for 10 min, then the mixture was diluted with EtOAc (50 mL), the biphasic mixture was separated, the organics were dried (MgSO4), conc in vacuo and purified by ISCO chromatography (8 g SiO2, 0 to 15% EtOAc in Hexanes). Remaining DMP side product was observed so the residue was taken up in DCM, the insolubles filtered off, the filtrate concentrated and purified by ISCO chromatography (12 g SiO2, 0 to 10% EtOAc in Hexanes) to give, after concentration, 229 mg of tert-butyl 4-(2-formylphenyl)piperidine-1-carboxylate as a clear oil (still contains some DMP side product) which was used in the next step without further purification. LC/MS ES+1-Boc: 190.08.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[N:25]=1.[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][F:70])=[O:66])[CH:52]=[CH:53][C:54]=1B1OC(C)(C)C(C)(C)O1>>[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][F:70])=[O:66])[CH:52]=[CH:53][C:54]=1[C:24]1[N:25]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:29]=1
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NCCF)cc2F)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 14). Material was purified by using a TsOH cartridge (500 mg) followed by prep HPLC (low pH) to afford a white solid, (26 mg, 14%).
Reaction SMILES: ClCCl.[CH2:4]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C(Cl)=O.[C:32]([O:42][CH3:43])(=[O:41])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)O>N1C=CC=CC=1>[CH2:4]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH:33]([C:32]([O:42][CH3:43])=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:24])=[CH:18][CH:17]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Reactant: COC(=O)C(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCOc1ccc(CC(=O)OC(C(=O)OC)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a dichloromethane (20 ml) solution of 4-undecyloxyphenylacetic acid (2 g, 7 mmol.) was added dropwise oxalyl chloride (1 ml). The reaction solution was stirred at 50° C. for one hour, which was then cooled, followed by concentration under reduced pressure The concentrate was dissolved in dichloromethane (10 ml), and the solution was added dropwise to a dichloromethane (10 ml) solution of methyl mandelate (1.1 g, 6.5 mmol.). To the reaction solution was added pyridine (2 ml), and the mixture was stirred at room temperature for two hours, to which was then added water (50 ml), followed by extraction with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (developing solvent: IPE) to give methoxycarbonylphenylmethyl 4-undecyloxyphenylacetate (2-g, 1.4 g, 43%).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][C:16]=3[O:24][CH3:25])[O:10]C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2CC(C[Cl:45])OC2)C=CC=CC=1.COC1C=C(CCC)C=CC=1[O-].[Na+].Cl>>[ClH:45].[CH3:25][O:24][C:16]1[CH:17]=[C:18]([CH2:21][CH2:22][CH3:23])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCC1CN(C(c2ccccc2)c2ccccc2)CO1
Reactant: CCCc1ccc(OCC2CN(C(c3ccccc3)c3ccccc3)CO2)c(OC)c1
Agent: CCCc1ccc([O-])c(OC)c1
Agent: Cl
Agent: [Na+]
Product: CCCc1ccc(OCC(O)CNC(c2ccccc2)c2ccccc2)c(OC)c1

Procedure:
3-Diphenylmethyl-5-(2-methoxy-4-n-propyl-phenoxymethyl)oxazolidine from 3-diphenylmethyl-5-chloromethyl-oxazolidine and sodium 2-methoxy-4-n-propyl-phenolate; this product is hydrolysed with alcoholic-aqueous hydrochloric acid to give 1-(2-methoxy-4-n-propyl-phenoxy)-2-hydroxy-3-diphenylmethylamino-propane hydrochloride with a melting point of 108°-110°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1F)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>CS(C)=O>[CH2:18]([S:25][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(SCc2ccccc2)c(F)c1
Temperature: 75 °C
Yield: 95.6 %

Procedure:
3,4-Difluorobenzoic acid (964 mg, 6.1 mmol, 1 eq), cesium carbonate (3.97 g, 12.1 mmol, 2 eq) and benzyl mercaptan (763 mg, 6.14 mmol, 1 eq) were combined in dimethyl sulphoxide (5 ml) and the reaction mixture heated at 75° C. for 4 hours. The reaction mixture was poured into ethyl acetate (10 ml) then extracted into water (10 ml). The aqueous phase was acidified with 2M HCl, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated to yield the title compound as a white solid (1.53 g, 5.83 mmol, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH:10]([O:14]CC)OCC)=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:14][CH:10]=[CH:9][N:8]=2)=[CH:17][CH:18]=1
Reactant: CCOC(CNC(=O)c1ccc(Br)cc1)OCC
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: Brc1ccc(-c2ncco2)cc1
Temperature: 180 °C
Yield: 70 %

Procedure:
4-Bromo-N-(2,2-diethoxyethyl)benzamide was dissolved in concentrated sulfuric acid at 0° C. To phosphorus pentoxide (5.2 g, 18.3 mmol) was added the sulfuric acid solution, and the mixture was heated at 180° C. for 30 minutes. The reaction mixture was cooled down to room temperature, and poured into ice. The whole was made basic by addition of NaHCO3 and amnmonia aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (1.23 g, 70% yield).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=1)[CH:15]=[CH:16][C:17](OC)=[O:18])=[O:10].C[O-].[Na+].Cl>O.C(#N)C.CO>[C:1]1([N:7]2[CH:15]([C:14]3[CH:21]=[CH:22][CH:23]=[C:12]([NH:11][CH:9]=[O:10])[CH:13]=3)[CH2:16][C:17](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)C=Cc1cccc(NC=O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=CNc1cccc(C2CC(=O)NN2c2ccccc2)c1
Yield: 35.2 %

Procedure:
108 g of phenylhydrazine, 205 g of methyl 3-formamidocinnamate, 200 ml of a 28% methanol solution of sodium methoxide and 400 ml of acetonitrile were mixed and heated under reflux for 1 hour in a nitrogen stream. 2 of the reaction solution was poured into water and 100 ml of concentrated hydrochloric acid was added. Then, precipitate was produced. The precipitate was collected by filtration and recrystallized from acetonitrile to obtain 99 g of 1-phenyl-5-(3-formamidophenyl) pyrazolidin-3-one as white crystals.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21]C)=O)[O:14][CH:15]=1)C1C=CC=CC=1.C1CCCCC=1.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:69][C@@H:70]([CH2:84][C:85]1[CH:90]=[C:89]([F:91])[CH:88]=[C:87]([F:92])[CH:86]=1)[C@H:71]([OH:83])[CH2:72][NH:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([CH2:81][CH3:82])[CH:76]=1>C(O)C.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-]>[F:91][C:89]1[CH:90]=[C:85]([CH:86]=[C:87]([F:92])[CH:88]=1)[CH2:84][C@H:70]([NH:69][C:19](=[O:21])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([C:13]2[O:14][CH:15]=[C:11]([CH2:10][CH2:9][OH:8])[N:12]=2)[CH:17]=1)[C@H:71]([OH:83])[CH2:72][NH:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([CH2:81][CH3:82])[CH:76]=1
Reactant: COC(=O)c1cccc(-c2nc(CCOCc3ccccc3)co2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: [Pd+2]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: C1=CCCCC1
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3nc(CCO)co3)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 3-{4-[2-(benzyloxy)ethyl]-1,3-oxazol-2-yl}benzoate (300 mg, 0.9 mmol), 20% palladium(II) hydroxide on carbon (65 mg), and cyclohexene (3 mL) in absolute ethanol (3 mL) are refluxed 1 h. The reaction is cooled, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue is redissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL) is added lithium hydroxide (75 mg, 1.8 mmol). The reaction mixture is stirred at room temperature for 3 h, and concentrated under reduced pressure. The residue is dissolved in DMF (5 mL), and diisopropylethylamine (625 μL, 3.6 mmol), HATU (540 mg, 1.4 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in EXAMPLE SP-272 (407 mg, 1 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with chloroform, washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound. ESI MS m/z 550.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4](Cl)[N:3]=1.CCN(CCO[C:21]1[CH:22]=[CH:23][C:24]([CH2:27]C2C=CC=CC=2)=[CH:25][CH:26]=1)CC.Cl.C([Mg]Cl)C1C=CC=CC=1.[Cl-].[NH4+]>[Ni].O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([CH2:27][C:24]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Reactant: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: [Ni]
Agent: Cl
Agent: Cl[Mg]Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1c(Cl)nc(Cl)nc1Cc1ccccc1

Procedure:
The fine suspension obtained by mixing 40 g (0.177 mol) of the compound of Example 2, 200 ml of toluene and 2 g of nickel catalyst NiCl2.dppe is brought to 0° C. in a 0.5 liter reactor, rendered inert with nitrogen and equipped with an anchor stirrer, and treated by addition of 97.6 ml (0.195 mol) of a 2M solution of benzylmagnesium chloride in tetrahydrofuran without exceeding 10° C. At the end of the progression of the coupling, the reaction mixture is treated by addition of 120 ml of a 10% ammonium chloride solution and the upper organic phase is separated, washed with 10% aqueous ammonium chloride solution until decoloured and evaporated to dryness under vacuum. The oily residue obtained is purified by distillation under vacuum in order to remove, as distillation tops, the residual starting material and to result in 39.6 g of 2,4-dichloro-5-(1-methylethyl)-6-(phenylmethyl)pyrimidine (yellow oil, boiling temperature at 0.2 mbar=145-150° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:51])([CH3:50])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)[C:17]1=[O:49])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:52]>CO>[ClH:52].[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:51])([CH3:50])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:32][CH:33]=2)[C:17]1=[O:49])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 9.83 g (0.55 mmol) of 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(t-butoxycarbonylamino)methyl][1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide (Step H) in 170 mL of methanol was added 120 mL of 9 N aqueous hydrochloric acid. Periodically 10 mL portions of methanol were added to the reaction mixture to dissolve precipitates which form during the reaction (50 mL total). The reaction mixture was stirred overnight at room temperature then the solvent was removed under vacuum. The resulting oil was dissolved in methanol and the solvent was removed under vacuum to afford 8.57 g (96%) of the title compound as an off-white foam. 1H NMR (200 MHz, CD3OD): δ 1.40 (s, 6H), 1.90 (m, 1H), 2.20-2.65 (m, 3H), 4.02 (s, 2H), 4.32 (m, 1H), 4.96 (d, 16 Hz, 1H), 5.00 (s, 2H), 5.25(d, 16 Hz, 1H), 7.08-7.65 (m, 17H). FAB-MS: calculated for C36H38N4 O4 590; found 591(M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:11])(=[O:14])[CH3:13]
Reactant: OCCc1ccc(Br)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)ethanol (3.01 mmol) in dichloromethane (5 mL) and pyridine (10 mL) was treated with 4-(dimethylamino)pyridine (0.151 mmol) and acetic anhydride (9.04 mmol). The reaction was stirred overnight at room temperature. At this point the reaction was diluted with dichloromethane (100 mL). The organic layer was washed three times with 1N aq HCl, once with saturated aq sodium bicarbonate, and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale beige oil (710 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 1.96 (s, 3 H) 2.90 (t, J=6.44 Hz, 2 H) 4.20 (t, J=6.57 Hz, 2 H) 7.26-7.43 (m, 2 H) 7.51 (dd, J=9.73, 1.89 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccc(F)cc1C(=O)Cl

Procedure:
A mixture of 8.0 g of 5-fluoro-2-methylbenzoic acid and 52 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are removed under vacuum and two times 50 ml of toluene is added and the solvent removed under vacuum to give 8.5 g of product as a gum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
260 mg (90.0%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (187 mg, 0.625 mmol), 1-(2-fluorophenyl)piperazine (148 mL, 0.937 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH:1]1([C:9]([O:11]CC)=[O:10])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[OH-].[K+]>C(O)C.O>[CH:1]1([C:9]([OH:11])=[O:10])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: CCOC(=O)C1CC12CCOCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CC12CCOCC2
Temperature: 60 °C

Procedure:
A solution of 120.50 g of ethyl 6-oxaspiro[2.5]-octane-1-carboxylate in 700 ml of ethanol/water 3.5:1 is mixed with 55.20 g of potassium hydroxide. The reaction mixture is heated at 60° C. for 4 hours, the ethanol is distilled off and the aqueous residue is diluted with water and extracted with tert-butyl methyl ether. The aqueous phase is adjusted to pH 2 with 4M hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a yellowish oil and is employed without further purification for the next stage. Rt=2.13 (Gradient I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCN(C(C)C)C(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][N:13]2[C:38]([NH:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=C=Nc1cccnc1
Reactant: Fc1cc(C2NCCc3ccccc32)ccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)c(F)c1

Procedure:
1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.1500 g, 0.508 mmol, Example 71 Step 3) was dissolved in 3 mL CH2Cl2 and DIEA (0.0884 mL, 0.508 mmol) and 3-pyridyl isocyanate (0.0732 g, 0.610 mmol) were added at RT. The mixture was stirred over night and hydrolyzed with 2 mL water. The reaction was extracted 3 times with EtOAc (3×20 mL), dried over MgSO4 and evaporated. The crude product was purified via glass column chromatography providing 1-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI, positive ion) m/z: 416.0 (M+H). The majority of the material was submitted for chiral purification (SFC):