Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].CC(O)=O.[CH3:15][NH:16][CH3:17].[BH3-]C#N.[Na+]>CO>[CH3:15][N:16]([CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH3:17]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
To a solution of 3-cyanobenzaldehyde (2.50 g, 19 mmol) in MeOH:AcOH (25 ml, 99:1) was added dimethyl amine (2.5 ml, 50 mmol) at 0° C., followed by NaBH3CN (1.80 g, 29 mmol). The mixture was stirred at 0° C. for 18 hours, then evaporated, taken up in EtOAc, washed with 5% KHCO3, brine filtered (Whatman® 1 PS phase separator) and evaporated. The residue was purified by flash chromatography on silica gel (eluant EtOAc:MeOH 98:2 v/v) to give the title compound (1.15 g, 38 %).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:7](=[O:14])[C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[C:3]([O:5]C)=O.[OH-].[Na+].O.Cl>CS(C)=O>[CH3:15][C:2]1([CH3:1])[C:7](=[O:14])[C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH2:10][C:3]1=[O:5]
Reactant: COC(=O)C(C)(C)C(=O)C(C)(C)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
106 g (495 mmol) of methyl 2,2,4,4-tetramethyl-3,5-dioxohexanoate were added dropwise to a suspension of 19.8 g (495 mmol) of sodium hydroxide in 500 ml of dimethyl sulfoxide. The mixture was stirred at room temperature, treated with 500 ml of water and adjusted to pH 1 using hydrochloric acid, and the deposited precipitate was then filtered off with suction. After drying, 70 g (95%) of 2,2,4,4-tetramethyl-1,3,5-cyclohexanetrione were obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:20]>C(OCC)(=O)C.CO>[ClH:20].[ClH:20].[F:19][C:2]([F:1])([F:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(F)(F)F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: FC(F)(F)CCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(3,3,3-trifluoropropyl)-1-piperazinecarboxylate (5.77 g) in ethyl acetate (13 ml) and methanol (10 ml) was added dropwise 4N hydrogen chloride in ethyl acetate (29 ml) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to give the title compound (4.70 g) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH:13]12[CH2:21][CH:17]([CH2:18][NH:19][CH2:20]1)[CH2:16][N:15]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:14]2.[BH4-].[Na+]>CC#N>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH:7]([OH:10])[CH2:8][N:19]2[CH2:20][CH:13]3[CH2:21][CH:17]([CH2:16][N:15]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:14]3)[CH2:18]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CC(C)OC(=O)N1CC2CNCC(C2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(=O)N1CC2CC(CN(CC(O)c3ccc(C#N)cc3)C2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
4-Cyanophenacyl bromide (225 mg; 1 mmol) was added to a stirred solution of iso-propyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above; 212 mg; 1 mmol) in MeCN (2 mL). After stirring for 15 min at 0° C., NaBH4 (40 mg; 1 mmol) was added, and the reaction was allowed to warm to rt over 45 minutes. The reaction mixture was concentrated, dissolved in CH2Cl2 and washed with NaHCO3 (aq.) and brine. The organic layer was separated, dried and concentrated to give an oil which was purified using column chromatography (hexane:EtOAc:IPA; 50:49:1) to give the sub-title compound in 35% yield.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:14])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:14])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1ccn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccn2ncnc(Oc3ccc(N)cc3F)c12
Reaction time: 7 h
Yield: 92.1 %

Procedure:
To a heterogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine (3.04 g, 10.55 mmol) in anhydrous methanol (60 mL) and anhydrous tetrahydrofuran (40 mL), at ambient temperature under nitrogen atmosphere, was added zinc dust (6.90 g, 105 mmol) and ammonium chloride (5.64 g, 105 mmol). The mixture was stirred for 7 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to a pale yellow solid which was partitioned between chloroform and water. The aqueous layer was then extracted twice with chloroform. The combined chloroform layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (2.51 g, 92%) as a solid. 1H NMR (CDCl3) δ 7.86 (s, 1H), 7.64 (d, 1H, J=2.6 Hz); 7.08-7.03 (m, 1H), 6.61 (d, 1H, J=2.4 Hz), 6.55-6.45 (m, 2H), 3.78 (s, 2H), 2.60 (s, 3H); HRMS(ESI), 259.0995 (M+H)+ calc, 259.0997 (M+H)+ found.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[CH:8]([N:14]([CH:16]3[CH2:18][CH2:17]3)[CH3:15])[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([N:14]([CH3:15])[CH:8]2[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]3[C:3]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:2][CH:11]=[C:10]([O:12][CH3:13])[C:9]2=3)[CH2:18][CH2:17]1
Reactant: COc1cc(Br)cc2c1C(N(C)C1CC1)CCC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1ccc(C#C[Si](C)(C)C)c2c1C(N(C)C1CC1)CCC2(C)C
Yield: 76.5 %

Procedure:
Following General Procedure D and using 2-bromo-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 79, 1.08 g, 3.2 mmol), triethyl amine (5 mL), copper(I)iodide (0.061 g, 0.32 mmol), trimethylsilyl acetylene (3 mL, 21.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.225 g, 0.32 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-10% ethyl acetate in hexane as the eluent, the title compound (0.87 g, 80%) was obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])(=O)C.[NH4+].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20]>>[N+:19]([CH:22]([CH3:23])[CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)([O-:21])=[O:20]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(Cc1ccc(-n2cccn2)cc1)[N+](=O)[O-]

Procedure:
A mixture comprising 4-pyrazol-1-yl-benzaldehyde (7.0 g, 40.65 mmol), ammonium acetate (0.94 g, 12.19 mmol) and nitroethane (24 ml, 333.3 mmol) is stirred at reflux for 10 hours. The solvent is removed in vacuo and the resulting solid is dissolved in EtOAc and washed with water (3×50 ml). The organic portion is dried (MgSO4) and concentrated in vacuo to afford the title compound as an orange solid. [MH+ 230.1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[N:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)C1(c2cccnn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a mixture of 1-(pyridazin-3-yl)cyclopropanecarboxylic acid (160 mg, 0.97 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (445 mg, 1.17 mmol) and diisopropylethyl amine (330 mg, 2.4 mmol) in anhydrous dichloromethane (10 mL) was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (350 mg, 0.98 mmol) dissolved in anhydrous dichloromethane (10 mL) with diisopropylethyl amine (330 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with dichloromethane and washed with water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via column chromatography (100-200 silica gel mesh, 60-80% ethyl acetate in petroleum ether) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridazin-3-yl)cyclopropanecarboxamide (100 mg, 23%). MS (ES+APCI) (M+H) 436.2; LCMS retention time: 3.390 min (Method W1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:29]=[C:15]2[C:16]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:17][CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.Br[C:31]1C2=CN(C3C(Cl)=CC([N+]([O-])=O)=CC=3C#N)N=C2C(F)=C[N:32]=1>>[Cl:11][C:4]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[C:31]#[N:32]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4Cl)cc23)ncn1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4C#N)cc23)ncn1
Temperature: 80 °C
Yield: 20 %

Procedure:
Following the procedure described for [2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine, 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chloro-5-nitrobenzonitrile was heated at 80° C. overnight to afford the title compound as a pale yellow solid (43 mg, 20% yield). LCMS (Method C): RT=2.56 min, m/z: 425 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)N.[ClH:10].N([O-])=O.[Na+]>O.[Cu]Cl>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cl
Reactant: Cc1cc(C)cc(N)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)cc(Cl)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A total of 33.0 g of 3,5-dimethylaniline was added dropwise over 20 minutes to 200 ml of concentrated hydrochloric acid at such a rate that the temperature of the reaction was kept below 35° C. After several minutes of vigorous stirring, the reaction was cooled to -10° C. A solution of 19.7 g of sodium nitrite dissolved in 50 ml of water was added dropwise over 30 minutes at such a rate that the reaction temperature was kept between -12° C. to -16° C. Then, 3.0 g of copper (I) chloride was added and the reaction was warmed to 27° C. At this temperature foaming was noted and the reaction temperature was maintained below 35° C. with an ice water bath. After one hour, the reaction was poured onto 350 g of ice. Once the ice melted the crude product was extracted with 400 ml of hexanes, the organic phase was dried with magnesium sulfate, filtered, and concentrated to yield 20.2 g of a liquid. This material was diluted with 5 ml of hexanes and chromatographed on neutral alumina (Brockman 1, 150 mesh), eluting with 1200 ml of hexanes and collecting 200 ml fractions. The desired 95% pure intermediate, 10.1 g, was isolated cleanly in fractions 1 and 2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[CH2:10][C@@H:11]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:12]([NH:14][C@@H:15](CC1C=CC=CC=1)[CH2:16][O:17]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:36](CO)[C:37](C)([CH3:39])[CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:8][C:9](=[O:34])[CH2:10][C@@H:11]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:12]([NH:14][C@H:15]([CH2:16][OH:17])[C:37]([CH3:39])([CH3:38])[CH3:36])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: COC[C@H](Cc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)C(C)(C)C
Yield: 90 %

Procedure:
As described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxyethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartic acid β-benzyl ester (1.00 g, 3.10 mmol) and L-t-leucinol (400 mg, 3.40 mmol) were coupled with BOP to afford 1.20 g (90%) of 3(R)-(t-butoxycarbonylamino)-N-(1(S)-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid benzyl ester as a white powder, mp 186-7° C. 1H NMR (CDCl3): δ 7.22 (s, 5H), 6.52 (d, 1H, J=9.3 Hz), 5.62-5.52 (m, 1H), 5.25 (dd, 2H, J=12.1, 18.7 Hz), 4.58-4.48 (m, 1H), 3.90-3.78 (m, 2H), 3.58-3.50 (m, 1H), 3.22-3.10 (m, 1H), 2.78 (dd, 1H, J=5.9, 17.7 Hz), 2.52-2.45 (m, 1H), 1.22 (s, 9H), 0.98 (s, 9H). IR: 3322, 2690, 1730, 1664 1528, 1367, 1249, 1165, 1050 cm−1. Anal. Calculated for C22H34N2O6: C, 62.52; H, 8.12; N, 6.63. Found: C, 62.20; H, 8.13; N, 6.62.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([N:21]([CH3:22])[CH3:19])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C(=O)N(C)C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
44 g 5-tert-butyl-2-methoxy-3-nitro-benzoic acid are dissolved in 400 ml of tetrahydrofuran, combined with 31 g carbonyldiimidazole and stirred for 2 hours at 50° C. The mixture is cooled to ambient temperature, combined with 173 ml of a 2 M solution of dimethylamine in tetrahydrofuran and stirred for a further 16 hours at 50° C. Then it is diluted with ethyl acetate and washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel with chloroform.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[C:17]1([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[OH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH:23]([O:24][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1C(O)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: Cc1ccccc1C(OC(=O)O[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with phenyl-o-tolyl-methanol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:15]1[C:14]([C@H:11]2[C@H:10]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=[C:17]([F:20])[CH:16]=1
Reactant: [H][H]
Reactant: Fc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2COc2ccc3c(c2)OCO3)cc1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Yield: 98.7 %

Procedure:
A solution containing 8.4 g (0.02 mol) of (−)trans-1-benzyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine in 120 ml of ethanol is hydrogenated in an autoclave in the presence of 0.6 g of 10% palladium-on-carbon catalyst at 30 to 40° C. under 2×105 Pa pressure for 2 to 3 hours. After taking up the hydrogen, the catalyst is filtered under nitrogen gas and the filtrate is evaporated to solvent-free to give 6.5 g of paroxetine base as evaporation residue in the form of a colourless oil. The product is suspended in 80 ml of water and after adding 2 ml of glacial acetic acid, it is stirred until dissolution. Then, the solution of 2 g of ammonium chloride in 10 ml of water is added to the mixture. After stirring for 4 hours, the precipitated crystalline title product is filtered at 10° C., twice washed with 10 ml of cold water each and dried on air to obtain 6,5 g (89%) of title compound, m.p.: 136-138° C.; [α]D20−86.6° (c=1, methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH2:30])[CH:25]=[CH:24]2)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[CH3:17][S:18]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH:30][C:14]([C:11]1[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=1)=[O:15])[CH:25]=[CH:24]2)(=[O:20])=[O:19]
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc2c(ccn2NC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.62 mmol) in EtOAc (10 mL) is added to a stirred solution of 5-methanesulfonyl-indole-1-ylamine (0.62 mmol) and K2CO3 (3.08 mmol) in EtOAc (10 mL) and H2O (10 mL) at 0° C., and the reaction mixture is warmed to rt and stirred overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is triturated with DCM to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (85 mg, 34%) as a solid. MS: 411 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.13 (s, 3H), 6.81 (m, H) 7.25-7.39 (m, H), 7.49-7.67 (m, 3H), 7.72-7.84 (m, H), 8.21-8.32 (m, 2H), 8.39 (d, H), 9.41 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([Mg]Br)=[CH:36][CH:35]=1>O1CCCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[N:9]=[C:10]([N:11]3[CH2:12][CH2:13][C:14]([OH:17])([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: O=C1CCN(C2=NC(Cc3ccc4ccccc4c3)C(=O)Nc3ccc(Cl)cc32)CC1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(C3=NC(Cc4ccc5ccccc5c4)C(=O)Nc4ccc(Cl)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
7-Chloro-3-(naphthalen-2-ylmethyl)-5-(4-oxopiperidin-1-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (18 mg, 0.04 mmol) was dissolved in anhydrous tetrahydrofuran (0.2 mL) under nitrogen, 4-methoxyphenylmagnesium bromide (0.5M solution in tetrahydrofuran, 0.5 mL, 0.25 mmol) was added dropwise. After stirring at ambient temperature for 1 hour the reaction was quenched with water (1 mL), diluted with ethyl acetate, separated, washed with water, dried with sodium sulfate, decanted, and concentrated. The residue was redissolved in ethyl acetate (0.5 mL) and hexanes added slowly (total of 6 mL). A solid precipitated and was collected by filtration. Washing with hexanes provided 7-chloro-5-(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (10 mg, 43% yield). ESI m/z measured 540.2062 [M+H]+. calculated 540.2054.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=2)=[CH:12][CH:11]=1.C(O)(=O)C>ClCCl>[Br:8][C:18]1[O:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:20][C:19]=1[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nc(-c3ncccn3)co2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc(-c3ncccn3)c(Br)o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NBS (2.03 g, 11.4 mmol) and 2-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrimidine (1.4) (2.5 g, 10.36 mmol) in a solvent mixture of 1:1 acetic acid and dichloromethane were stirred at room temperature for 3 hr. Then the solvents were removed in vacuo, and the resulting residue was dissolved in EtOAc. The solution was washed with aqueous Na2S2O3 and brine, and dried over MgSO4. The drying agent was filtered off and the filtrate was concentrated to give the title compound. LC-MS m/z 321.96 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19](I)[CH:18]=[N:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH2:30]([OH:33])[C:31]#[CH:32]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19]([C:32]#[C:31][CH2:30][OH:33])[CH:18]=[N:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Under an argon atmosphere, a mixture of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide (Preparation 23, 0.053 g), dichlorobis(triphenylphosphine)palladium (II) (4.1 mg), copper(I) iodide (18.3 mg), and diethylamine (1.5 mL) is treated with a solution of propargyl alcohol (11 μL). The reaction mixture is stirred at room temperature overnight. The mixture is diluted with EtOAc and then filtered through a Celite-packed, sintered-glass funnel. The cake is washed with CHCl3 until the washings are colorless. The organic filtrate is washed with aqueous saturated ammonium chloride and water, dried (Na2SO4) and concentrated in vacuo. The crude solid is triturated with ether, filtered and washed with ether to give 0.032 g (71%) of the title compound as a light brown solid. Physical characteristics: mp 201-206° C.; 1H NMR (400 MHz, DMSO-d6) δ4.21, 4.39, 4.54, 5.51, 7.40, 8.52, 9.0, 9.7; IR (drift) 3368, 1660, 1612, 1597, 1551, 1479, 1410, 1397, 1377, 1353, 1256, 1036, 812, 674, 650 cm−1; MS (EI) m/z 382 (M+, 6); HRMS (FAB) m/z 383.0917 (C19H15ClN4O3+H).