Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([I:3])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (20 g, 0.5 mol) in dimethylformamide (300 ml), a solution of m-iodophenol (100 g, 0.454 mol}in dimethylformamide was added dropwise and then stirring was continued for 30 min at 70°±5° C. To this reaction mixture, benzyl chloride (57.4 g, 0.454 mol) was added dropwise and the reaction was continued for 2 hours at 100°±5° C. The resultant mixture was taken up in H2O (1l) and extracted with ethyl acetate. The organic extract was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residual solid was recrystallized from ethanol to give the title compound as white crystals; yield: 119.7 g; mp. 51.0°-53.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:26])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(Nc2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CCOC(=O)c1ccc(N(C)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Yield: 76.8 %

Procedure:
Following general procedure F and using 4-[(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 16, 0.12 g, 0.35 mmol), potassium carbonate (0.49 g, 3.5 mmol) and iodomethane (0.50 g, 3.5 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.095 g, 80%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=9.1 Hz), 6.81 (d, 1H, J=2.3 Hz), 6.78 (d, 1H, J=2.3 Hz), 6.63 (d, 2H, J=9.1 Hz), 4.31 (q, 2H, J=7.1 Hz), 4.28 (s, 2H), 3.31 (s, 3H), 2.59 (q, 2H,J=7.6 Hz), 1.35 (t, 3H, J=7.1 Hz), 1.33 (s, 6H), 1.22 (t, 3H, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:26])[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CC(C)CCCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 4-methylpentylamino (Example 433, Part A) (0.278 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.470 g, 55%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1922, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.6 min, 100% purity.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (2.5 g, 14.56 mmol) and anhydrous potassium carbonate (7 g, 50.64 mmol) in dry DMF (25 mL) was stirred for 30 min at room temperature. Benzyl bromide (2 mL, 16.82 mmol) was added dropwise into the reaction mixture and heated at 65° C. for 14 h. The reaction mixture was cooled to room temperature, filtered and quenched with ice water (25 mL). The resulting mixture was extracted in ethyl acetate (2×20 mL) and the combined organic layers were washed with water (2×15 mL) followed by brine (20 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated. The crude product obtained was purified by crystallisation using 2% methanol in chloroform to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:19](O)=[O:20])[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])[CH:15]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)O)ccc2C1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1

Procedure:
According to method G, (S)-6-tert-butoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid was reacted with pyrrolidine. The product was thus obtained with the molecular weight of 344.46 (C20H28N2O3); MS (ESI): 345 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1>>[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:17]4[CH2:18][CH2:9][CH2:10][CH2:11][CH:16]4[CH3:15])=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5]
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Reactant: CC1CCCCN1
Product: CC1CCCCN1CCC(=O)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCCC4C)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (1.0 g, 2.5 mmol) was treated with 2-methylpiperidine (5 mL) according to the general aminolysis procedure to give the desired product JM-ACO-06 (916 mg, 69%) as a pale yellow/green solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]([C:18]2[C:19](=[O:28])[C:20]3[CH:27]=[CH:26][O:25][C:21]=3[N:22]([CH3:24])[CH:23]=2)=[O:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][C:26]1[O:25][C:21]2[N:22]([CH3:24])[CH:23]=[C:18]([C:16]([NH:15][CH2:14][C:13]3[CH:12]=[CH:11][C:10]([Cl:9])=[CH:30][CH:29]=3)=[O:17])[C:19](=[O:28])[C:20]=2[CH:27]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccoc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Temperature: 50 °C
Yield: 60.9 %

Procedure:
N-Bromosuccinimide (2.77 g) was added to a solution of N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 78, 2.46 g) in CHCl3 (100 mL). The reaction mixture was heated to 50° C. for 18 h. The mixture was allowed to cool to room temperature and was washed with water (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol, 99/1) followed by recrystallization from ethyl acetate to yield 1.87 g (61%) of the title compound as a white solid. Physical characteristics. M.p. 232-233° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.50, 8.57, 7.41-7.32, 7.23, 4.55, 3.92; MS (EI) m/z 394 (M+), 396 (M++2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[CH:24]([NH:23][C:18]([C:17]1[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=3[CH:14]=[CH:15][CH:16]=1)=[O:20])[CH2:25]2
Reactant: COc1ccc(-c2nc3cccc(C(=O)O)c3o2)cc1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: COc1ccc(-c2nc3cccc(C(=O)NC4CN5CCC4CC5)c3o2)cc1
Yield: 24 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 24% yield as a white solid: mp 166-167° C.; 1H NMR (500 MHz, CD3OD) δ 8.20 (dd, J=7.0, 2.0 Hz, 2H), 7.86 (d, J=7.9 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.14 (dd, J=1.9, 7.0 Hz, 2H), 4.26 (m, 1H), 3.91 (s, 3H), 3.42 (m, 1H), 3.02 (m, 1H), 2.92 (m, 3H), 2.83 (m, 1H), 2.16 (d, J=3.1 Hz, 1H), 2.07 (m, 1H), 1.84 (m, 2H), 1.68 (m, 1H); MS (ESI) m/z 378 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:27])[C@@H:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:5][C@H:6]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]([CH3:9])[CH3:8].[CH3:28][C:29]([CH3:37])([CH2:33][CH2:34][CH2:35][CH3:36])[C:30](O)=[O:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([O:11][CH2:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[CH2:5][C@H:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:3]([OH:27])[CH2:2][NH:1][C:30](=[O:31])[C:29]([CH3:37])([CH3:28])[CH2:33][CH2:34][CH2:35][CH3:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: CCCCC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
To a solution of tert-butyl (2S,3S,5S)-1-amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptan-3-ylcarbamate (500 mg, 1.32 mmol) in CH2Cl2 (15 mL), were added 2,2-dimethylhexanoic acid (220 mg, 1.45 mmol), HOBt (360 mg, 2.65 mmol) and EDCl (500 mg, 2.65 mmol). The mixture was cooled to 0° C. and DIEA (850 mg, 6.6 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel to produce tert-butyl (2S,3S,5S)-5-(benzyloxymethyl)-1-(2,2-dimethylhexanamido)-2-hydroxy-6-methylheptan-3-ylcarbamate (310 mg, 46%); MS: 507 (M++1)
Reaction SMILES: CN.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([S:16]C)=S)[CH2:13][CH2:12][CH2:11][S:10]2)=[CH:5][CH:4]=1.C.[C:19](#[N:21])C>C(O)C>[CH3:19][NH:21][C:14]([C:9]1([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH2:11][S:10]1)=[S:16]
Reactant: CC#N
Reactant: CSC(=S)C1(c2ccncc2)CCCS1
Agent: CN
Solvent: CCO
Product: CNC(=S)C1(c2ccncc2)CCCS1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (12 cc) is added dropwise, in the course of 15 minutes, to a solution of methyl 2-(pyrid-4-yl)-tetrahydrothiophen-2-carbodithioate (16 g) in ethanol (35 cc), kept at 20° C. The solution is subsequently stirred for 1 hour at a temperature of about 20° C. and is then cooled to 0° C. The resulting crystals are filtered off, washed twice with ethanol (30 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. A crystalline crude product (11 g) is thus obtained, which is redissolved in boiling ethanol (100 cc); decolourising charcoal (0.3 g) is added to the solution obtained, which is filtered hot, and the filtrate is then cooled for one hour at 0° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product thus obtained (9 g) is chromatographed on neutral silica gel (20 g) contained in a column of diameter 1.7 cm. Elution is carried out with methylene chloride (1000 cc) and then with a methylene chloride/ethanol mixture (90/10 by volume; 250 cc), 250 cc fractions being collected. Fractions 1 to 5 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product thus obtained (8 g) is dissolved in boiling ethanol (94 cc); decolourising charcoal (0.4 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 15 hours at a temperature of about 5° C. The resulting crystals are filtered off, washed twice with ethanol (14 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product thus obtained (6.9 g) is dissolved in boiling acetonitrile (75 cc) and the solution, to which decolourising charcoal (0.2 g) is added, is filtered hot and the filtrate is then cooled for 1 hour at 0° C. The resulting crystals are filtered off, washed with acetonitrile (7 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. N-Methyl-2-(pyrid-4-yl)-tetrahydrothiophen-2-carbothioamide (5.9 g), melting at 178° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C@@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: C[C@H](O)CN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (305 mg, 0.685 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(+)-1-amino-2-propanol (110 μmL, 1.40 mmol), WSCI.HCl (200 mg, 1.04 mmol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) were added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (285 mg, yield 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH2:18][C@@H:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C@@H:12]2[NH2:29].C([BH3-])#N.[Na+].O1CCCC1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:29][C@H:12]2[CH2:13][CH2:14][C@H:15]3[C@H:16]4[C@H:26]([CH2:27][CH2:28][C@:11]23[CH3:10])[C@:24]2([CH3:25])[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17]4)=[CH:4][CH:3]=1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)CC[C@@H]12
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccc(Cl)cc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzaldehyde (0.464 g), 5α-androstan-17β-amine(4.40g) glacial acetic acid (0.99 g), sodium cyanoborohydride (0.21 g) and tetrahydrofuran (5 ml) were added to methanol (11 ml). The resulting mixture was warmed to dissolve the solid in solution and allowed to stir overnight at room temperature. Excess solvent was removed under reduced pressure. Water was added and made basic (pH 9) with 50% aqueous NAOH. The mixture was extracted with ether and the organic layer became cloudy. Celite was used to filter the organic layer. The aqueous layer was washed with ether and the combined organic layers were dried (NaSO4), filtered and concentrated. The crude solid was mixed with 10 g of flash silica gel and dissolved in ethyl acetate. The solvent was removed and the silica was poured on top of the chromatographic column. The compound was eluted with 50% ethyl acetate-hexane. The title compound was obtained as a solid which was recrystallized from acetone (0.364 g) mp 101°-102° C. (PLA2, diabetes)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.Cl[C:28]([O:30][CH3:31])=[O:29]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:28](=[O:29])[O:30][CH3:31])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: COC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield according to the general procedure for the preparation of carbamates (Method D) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and methyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:7].[BH4-].[Na+]>CO.O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[OH:7])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a solution of 3,3′-bis(trifluoromethyl)benzophenone (11.4 g, 36 mmol) in MeOH (50 mL) was added sodium borohydride (1.9 ml, 53 mmol) portionwise at rt. The suspension was stirred at rt for 24 h. The reaction was diluted slowly with water and extracted with CH2Cl2. The organic was washed successively with water, brine, dried over Na2SO4, and concentrated to give bis(3-(trifluoromethyl)phenyl)methanol (10.8 g, 94% yield). The crude oil was used in the next reaction without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].O.[OH-].[Na+].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH3:12])[C:14]=1[NH:20][C:21]([N:8]=[C:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])=[O:22]
Reactant: CN1CCCC1=N
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C)c1NC(=O)N=C1CCCN1C

Procedure:
To a stirring solution of 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine hydrochloride in about 2 ml. of water is added about 50 ml. of benzene followed by 10 ml. of 50% NaOH. After stirring 1 min. the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice. The combined benzene extracts are filtered from a drying agent (dicalite pad) and rinsed well with dry benzene. To the filtrate is added in one portion with stirring 7.36 g. (0.05 mole) of 2,6-dimethylphenylisocyanate. The reaction mixture is stirred overnight. Solvent removel and recrystallization from ethyl acetate-ether gives the product, 1-(2,6-dimethylphenyl)-3-(1-methyl-2-pyrrolidylidene)urea, as white crystals, m.p. = 119°-120° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:34]=[C:32]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:30][CH:29]=3)[N:33]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)s1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate. Pale solid. 1H-NMR (CDCl3) δ: 2.69 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.14 (t, 4H, J=4.8 Hz, CH2), 3.72 (t, 4H, J=4.9 Hz, CH2), 6.89 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.95 (d, 2H, J=8.8 Hz, Ph-H), 6.98 (br. s, 1H, NH), 7.53 (d, 2H, J=9.1 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 368 [M+H]+ (C19H21N5OS requires 367.5).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Si:25]([O:32][C:33]1[CH:34]=[C:35](/[C:39](/[CH2:43][CH3:44])=[CH:40]/[CH:41]=O)[CH:36]=[CH:37][CH:38]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl.[Zn]>[C:28]([Si:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](/[C:39](/[CH2:43][CH3:44])=[CH:40]/[CH:41]=[C:20]([Br:24])[Br:21])[CH:34]=1)([CH3:27])[CH3:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: BrC(Br)(Br)Br
Reactant: CC/C(=C\C=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C(=C\C=C(Br)Br)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 1 h

Procedure:
1.17 g (18 mmol) of zinc powder, 4.7 g (18 mmol) of triphenylphosphine and 5.9 g (18 mmol) of carbon tetrabromide are stirred for 45 minutes in 150 ml of dichloromethane. A solution of 2.6 g (9 mmol) of (E)-3-[3-(tert-butyldimethylsilanyloxy)phenyl]pent-2-en-1-al in 10 ml of dichloromethane is added drop by drop. The reaction medium is stirred for 1 hour, then extracted with a mixture of water and of dichloro-methane. The residue is filtered on a silica column (eluent dichloromethane). A yellow oil is obtained (m=3.3 g; Y=83%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1.C[CH2:21][N:22](C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(F)c(F)c1
Yield: 37.3 %

Procedure:
A solution of 2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (421 mg, 1.398 mmol), methanamine, HCl (283 mg, 4.19 mmol) and DIPEA (1.465 mL, 8.39 mmol) in methanol (10 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(3,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (154 mg, 0.521 mmol, 37.2% yield). LC-MS (M+H)+=296.2.