Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C@H:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:38][C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[C:22]3[CH:37]=[CH:36][C:25]([O:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH3:14])=[O:9])=[C:6]([CH3:44])[N:5]=[CH:4][N:3]=1.[Cl-].[NH4+:46]>>[C:31]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:25]2[CH:36]=[CH:37][C:22]([N:21]([CH2:38][C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[CH:18]3[CH2:19][CH2:20][N:15]([C@H:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:8]([C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=4[CH3:44])=[O:9])[CH2:16][CH2:17]3)=[CH:23][CH:24]=2)=[CH:35][CH:34]=1)(=[O:33])[NH2:46]
Reactant: [NH4+]
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1
Agent: [Cl-]
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(Oc3ccc(C(N)=O)cc3)cc2)CC1
Yield: 153.6 %

Procedure:
Using general procedure E, COMPOUND 302 (103 mg, 0.17 mmol) and ammonium chloride (23 mg, 0.42 mmol) afforded COMPOUND 303 as a white solid (160 mg, 100%). 1H NMR (CDCl3) δ 0.87-1.21 (m, 2H), 1.01 (d, 3H, J=6.0 Hz), 1.49-1.60 (m, 1H), 1.71-1.85 (m, 3H), 2.11-2.22 (m, 1H), 2.53 (s, 6H), 2.55-2.62 (m, 1H), 2.71-2.92 (m, 3H), 3.25-3.38 (m, 1H), 3.48-3.61 (m, 1H), 3.82-3.94 (m, 1H), 3.83 (s, 2H), 5.77 (br s, 2H), 6.62 (d, 1H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 6.92 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=3.3 Hz), 7.26-7.32 (m, 1H), 7.73 (d, 2H, J=7.8 Hz), 8.81 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.80, 22.33, 29.50, 30.86, 31.03, 40.62, 43.96, 46.17, 52.59, 56.51, 60.90, 114.86, 116.77, 121.09, 121.80, 126.32, 126.87, 129.62, 131.31, 141.91, 146.46, 158.01, 162.73, 163.46, 166.72, 169.17. ES-MS m/z 613 (M+H). Anal. Calcd. for C34H40N6O3S.0.3CH2Cl2: C, 64.55; H, 6.41; N, 13.17. Found: C, 64.29; H, 6.38; N, 12.96.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:29]=[C:30]([NH:34]N)[CH:31]=[CH:32][CH:33]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:36])[F:37])[CH:29]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(OC(F)(F)F)c3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 43. MS: M=477.2 (M+H)+
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.[C:40]1([N:46]=[C:47]=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:21][C:20]1[N:15]2[C:14](=[O:22])[N:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH:4]([NH:3][C:47]([NH:46][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH2:17][C:16]2=[CH:18][N:19]=1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccccc3)c3ccccc3)CC1)C2
Yield: 60.1 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) and DBU (0.15 g) were dissolved in acetonitrile (10 ml). Phenyl isocyanate (66 mg) was added thereto, and mixed at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) and solidified with ethyl acetate and diethyl ether to obtain the title compound (0.14 g, 59%) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:22][C:21](=[O:23])[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[N:5]=[C:4]([S:19][CH3:20])[N:3]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 51 %

Procedure:
A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (160° C.) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc/Hexane, 1:5) provided the title compound (109 mg, 51%): LC-MS m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.C(P)(C)(C)C.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc2c(c1[N+](=O)[O-])C1CCCCC1CC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P
Solvent: C1CCOC1
Product: COc1ccc(C2C(=O)c3ccc(OC)c([N+](=O)[O-])c3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 87.1 %

Procedure:
Combine 6-Methoxy-5-nitro-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (0.377 g, 1.37 mmol), 4-bromoanisole (0.258 g, 1.37 mmol), palladium acetate (15.5 mg, 0.07 mmol), t-butyl phosphine (0.042 g, 0.208 mmol), sodium t-butoxide (0.145 g, 1.51 mmol), tetrahydrofuran (12.0 mL), and stir under nitrogen atmosphere at 80° C. in a glass bomb. After 18 hours, quench reaction with acetic acid (5 mL) in a glove box and extract with ethyl acetate. Wash the ethyl acetate with sodium bicarbonate solution and then brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (0.455 g, 87%) as a yellow foam. TLC Rf=0.16 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 8.23 (d, 1H, J=8.8 Hz), 7.06 (m, 3H), 6.92 (m, 2H), 4.01 (m, 4H), 3.83 (s, 3H), 3.10 (dt, 1H, J=8.4, 4.3 Hz), 2.76 (m, 1H), 1.82 (m, 4H), 1.47 (m, 4H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[F:9][C:10]([F:15])([F:14])[C:11]([NH2:13])=[O:12].[I-].[Na+].P([O-])(O)(O)=O.[K+]>CN(C)C=O.O>[F:9][C:10]([F:15])([F:14])[C:11]([NH:13][CH2:4][CH2:5][CH2:6][C:7]#[CH:8])=[O:12]
Reactant: NC(=O)C(F)(F)F
Reactant: C#CCCCCl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCNC(=O)C(F)(F)F
Reaction time: 21 h
Yield: 45.2 %

Procedure:
Sodium hydride (60% dispersion in oil, Alfa) was rendered oil-free by thoroughly and rapidly washing with pentane and then vacuum-drying. Oil-free sodium hydride (4.40 g, 0.110 mole, 1.1 eq) was added in about 20 portions over 25 min to a solution of 5-chloropentyne (10.6 mL, 0.100 mole, 1.0 eq), trifluoroacetamide (14.13 g, 0.125 mole, 1.25 eq), and sodium iodide (14.99 g, 0.100 mole, 1.0 eq) in dry dimethylformamide (250 mL, Aldrich). The reaction mixture was stirred at 25° for 4.5 h and at 60° for 21 h. After cooling, the reaction mixture was added to a solution of potassium dihydrogen phosphate (43.5 g, 0.250 mole, 2.0 eq) in water (500 mL). This solution was extracted with pentane (2×500 mL) and ether (3×500 mL). The combined organic layers were washed with water (1×100 mL), dried over magnesium sulfate, and concentrated with a rotary evaporator. Fractional distillation twice through a 20 cm Vigreux column afforded 8.09 g (45%) of 5-trifluoroacetamido-1-pentyne (58) as a colorless, mobile liquid (bp 68-69° at 13 torr.)
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH:16]([OH:27])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH:16]([OH:27])[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: COc1ccccc1OCC(O)CCCl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1ccccc1OCC(O)CCN1CCN(c2ccccc2)CC1
Yield: 63.1 %

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 3.2 g (0.02 mole) of 1-phenylpiperazine, 4.8 g (0.02 mole) of 4-chloro-1-(2-methoxyphenoxy)-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 4.5 g (64%) of white powder, m.p. 101°-102° C. Recrystallizing solvent used was iropropyl alcohol.
Reaction SMILES: O[C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][O:14][CH3:15])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH3:26])=[CH:19][CH:18]=1)[CH3:16]>CO.[Pd]>[OH:33][C:29]1[CH:28]=[C:27]([CH:2]2[C:7]3[CH:8]=[CH:9][C:10]([O:12][CH2:13][O:14][CH3:15])=[CH:11][C:6]=3[O:5][CH2:4][C:3]2([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:22]=2)[CH3:16])[CH:32]=[CH:31][CH:30]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(O)c2)cc1
Reaction time: 12 h
Yield: 51.7 %

Procedure:
(3RS,4RS)-4-Hydroxy-4-(3-hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (1.19 g, 2.63 mmol) prepared in Example 35 was dissolved in methanol (50 ml), and 10% Pd/C (200 mg) was slowly added dropwise thereto. The reaction mixture was stirred under hydrogen atmosphere for 12 hours and then filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 594 mg (yield: 50%) of the title compound as a colorless foam.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][S:21][CH2:22][CH3:23])C(OCC)=O)=[O:5])C.Cl>[OH-].[Na+]>[C:4]([OH:5])(=[O:3])[CH2:6][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][S:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(CCCCCCOCCSCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCSCCOCCCCCCCC(=O)O
Yield: 97.2 %

Procedure:
A solution of the above ethyl 2-ethoxycarbonyl-9-oxa-12-thiatetradecanoate (2 g, 5.8 mmol) in 20% NaOH (10 mL) was refluxed for 6 h. The solution was acidified with HCl (pH 2), and extracted with ethyl acetate (120 mL). The organic phase was washed with water (2×30 mL), brine (30 mL) and dried (Na2SO4). After evaporation of the solvent, the resulting product was heated on an oil bath at 180° C. to 200° C. for 15 min. The crude product was purified by Kugelrohr distillation to afford the title compound, 9-oxa-12-thiatetradecanoic acid (1.4 g, 98%); bp 121° C.-125° C./0.005 torr; IR(neat):3020 (broad) and 1730 cm-1 ; 1NMR: 1.27 (3H, t, J=7.7 Hz), 1.34 (6H, m), 1.53-1.68 (4H, m), 2.36 (2H, t, J=7.1 Hz), 2.58 (2H, q, J=7.7 Hz), 2.71 (2H, t, J=7 Hz), 3.45 (2H, t, J=6.8 Hz), 3.59 (2H, t, J=7 Hz), and 10.6 ppm (lH, br s); Found: C, 58.11, H, 9.8%. Calcd for C12H24SO3 : C, 58.03, H, 9.74%.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[S:24][C:23]([C:25](Cl)=[O:26])=[CH:22][CH:21]=2)[C:16]=1[CH3:28]>>[CH3:3][N:4]([CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:25]([C:23]2[S:24][C:20]([C:17]3[C:16]([CH3:28])=[C:15]([C:14]([F:29])([F:30])[F:13])[O:19][N:18]=3)=[CH:21][CH:22]=2)=[O:26])[CH2:7]1)[CH3:12]
Reactant: CN(C)C[C@@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](CN(C)C)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from dimethyl-(R)-1-piperidin-3-ylmethyl-amine, dihydrochloride (Preparative Example 28, 108 mg, 0.5 mmol) and 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) as described for the R isomer (Example 70). Colorless solid (41 mg, 41%). LC/MS 5.28 min, [M+1]+ 402.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](=O)[CH2:19]Br.CN(C)C=O.C(O)C>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[O:3][CH:19]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3C(F)(F)F)co2)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-carbamoylbenzoate (896 mg), 2-trifluoromethylphenacyl bromide (2.22 g) and N,N-dimethylformamide (5 ml) was stirred at 130° C. for 2 hours. Hot ethanol was added to the reaction mixture, which was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was subjected to a silica gel column chromatography to obtain methyl 4-[4-(2-trifluoromethylphenyl)-2-oxazolyl]benzoate as an oil from a fraction eluted with ethyl acetate-hexane. This oil was dissolved in a mixture of tetrahydrofuran (10 ml) and ethanol (10 ml), and hydrolyzed by adding a 1N aqueous solution of sodium hydroxide (10 ml). The reaction mixture was neutralized with 1N hydrochloric acid, and precipitated crystals were collected by filtration. The product was recrystallized from acetone-hexane to obtain 4-[4-(2-trifluoromethylphenyl)-2-oxazolyl]benzoic acid (203 mg, yield: 12%). Colorless prisms. Melting Point: 264 to 265° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:36])[C:19](=[O:35])[NH:20][N:21]=2)[C@@H:10]([CH3:37])[CH2:9]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:35])[C@H:18]3[CH3:36])=[CH:15][C:14]=1[C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:37]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCNC[C@@H]4C)cc3N21
Temperature: 20 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of (3R,4R)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.076 g, 0.149 mmol) in HCl (4M in EtOAc, 15 mL) was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.065 g, 98%). 1H NMR (MeOD, 400 MHz) δ 7.50-7.41 (m, 1H), 7.32-7.19 (m, 3H), 6.91 (brs, 1H), 6.86 (s, 1H), 4.80 (m, 1H), 4.70-4.59 (m, 2H), 3.48 (m, 1H), 3.15-2.98 (m, 2H), 2.82 (m, 1H), 2.43 (m, 1H), 1.88 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 0.91 (brs, 3H). LC/MS (Table 1, Method 4) Rt=1.534 min.; MS m/z: 409 [M+H]+. SFC (Table 1, Method 43), Rt=1.341 min.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[CH:8][N:7]=1.O>C(O)C>[Cl:5][C:6]1[CH:11]=[C:10]([O:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=1
Reactant: CC[O-]
Reactant: Clc1cc(I)ccn1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccnc(Cl)c1

Procedure:
33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl-methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/1) to yield 5 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C.O>[NH2:12][C:10]([C:3]1[C:2]([F:1])=[C:7]([CH:6]=[CH:5][C:4]=1[F:9])[O:8][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,6-difluoro-3-hydroxybenzenecarboxamide (1.2 g, 7 mmol, 1 equiv.), K2CO3 (2.87 g, 21 mmol, 3 equiv.) and methyl bromoacetate (0.69 ml, 7.35 mmol, 1.05 equiv.) in DMF (30 ml) was stirred at r.t. for 18 h. The mixture was diluted with water and extracted with EtOAc (4×80 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure. The product was used crude on the next step. HPLC-MS (method 1): m/z 246 [M+H]+, Rt=2.08 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:19][CH3:20])[CH2:17][OH:18].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([NH:15][C@H:16]([CH2:19][CH3:20])[CH2:17][OH:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CC[C@@H](N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Sodium triacetoxyborohydride (4.63 g) was added portionwisely to a mixture of (R)-(-)-2-amino-1-butanol (1.5 g) and benzaldehyde (1.79 g) in dichloromethane (50 ml) at 0° C. and the whole was stirred at room temperature overnight. The mixture was washed with sodium carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give (R)-2-benzylamino-1-butanol (2.69 g) [IR (Neat): 3292, 1460, 1350, 1136, 1061 cm−1]. A solution of chloroacetyl chloride (2.1 g) in tetrahydrofuran (4 ml) was added to a mixture of the obtained oil (2.69 g) and potassium carbonate (4.6 g) in a mixture of acetone (20 ml) and water (20 ml) at 0° C. After 1 hour of stirring, the solvent was replaced with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give N-benzyl-N-[(2R)-2-(1-hydroxybutyl)]-2-chloroacet amide (2.73 g) [IR (Neat): 3430, 1640, 1450, 1420, 1355, 1045 cm−1, MASS (APCI): 256 (M+H)+, 220] as an oil. Potassium tert-butoxide (1.22 g) was added to a solution of the above obtained oil (2.7 g) in tert-butanol (20 ml) portionwisely at room temperature and the whole was stirred overnight. The mixture was evaporated in vacuo, and ethyl acetate and water were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo to give (5R)-4-benzyl-5ethyl-3-morpholinone (2.33 g) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(-c2cccs2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccs2)cc1
Yield: 35.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), 4-(thiophen-2-yl)benzoyl chloride (0.102 g; 0.445 mmol), and triethylamine (0.149 mL; 1.06 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.058 g (36%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.[H-].[Na+]>>[CH:13]1([CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: O=Cc1c(Cl)n(CC2CC2)c2ccccc12
Yield: 98.2 %

Procedure:
Prepared from (1) (18 g), cyclopropylmethyl bromide (16.2 g) and NaH (2.8 g) yielding (4) (23 g), m.p. 108°-109° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30].[Cl-].[Na+]>C(OCC)C>[CH3:2][O:3][CH:4]=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=1
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COC=Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
27.7 g of methoxymethyltriphenylphosphonium chloride is introduced into 350 ml of diethyl ether under nitrogen. At 0° C., 38.8 ml of n-butyllithium solution (1.6 M in hexane) is added in drops, and it is stirred for one hour at room temperature. 12 g of 4-isopropylbenzaldehyde in 50 ml of diethyl ether is now added, and it is stirred for one more hour. Sodium chloride solution is added to the reaction mixture, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 8.1 g of 1-methoxy-2-[4-(1-methylethyl)phenyl]-ethene 42 (E,Z-mixture) is obtained as a colorless oil, which is dissolved in 200 ml of acetone and stirred under nitrogen with 10 ml of 2N hydrochloric acid overnight. Sodium chloride solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. Chromatographic purification on silica gel with ethyl acetate/hexane yields 5.1 g of title compound 43 as a colorless oil.