Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[C:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:17])[C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[F:32])[CH2:12][CH2:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)C1CCN(CC2=Cc3ccccc32)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)C1CCN(CC2=Cc3ccccc32)CC1
Yield: 35 %

Procedure:
0.025 mole of 1-(benzocyclobuten-1-ylmethyl)-4-piperidinecarbonyl chloride (prepared by the action of oxalyl chloride on the acid described above), dissolved in 50 ml of dichloromethane, is introduced into a suspension of 0.025 mole of 1,3-difluorobenzene and 0.026 mole of aluminum trichloride in 10 ml of dichloromethane. When the gaseous evolution has ceased, the mixture is hydrolyzed with ice, settling is allowed to take place and the product is extracted with 1 N hydrochloric acid. The aqueous phase is then alkalinized and extracted with dichloromethane. After evaporation of the solvent, the expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].[C:23]([CH2:25]C(O)=O)#[N:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:25][C:23]#[N:24]
Reactant: COc1cccc(C=O)c1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cccc(C=CC#N)c1

Procedure:
3-Methoxybenzaldehyde (20.8 g, 0.15 mol) was treated with toluene (dry, 140 mL), pyridine (dry, 60 mL), ammonium acetate (0.59 g) and cyanoacetic acid (11.9 g, 0.14 mol) and then heated under reflux with a Dean-Stark trap for 71 h according to the procedure of Montgomery et. al (J. Med. Chem. 1993, 36, 55). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with 10% aq. HCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with 2-5% EtOAc in hexanes to give 3-methoxycinnamonitrile, 14.65 g (60%). This material was dissolved in EtOH (75 mL) and conc. HCl (15 mL) and hydrogenated with 10% Pd/C (2.0 g) at 70 psi on a Parr shaker for 67 h. The reaction mixture was filtered over Celite. The filtrate was extracted with EtOAc, and the EtOAc layer was concentrated under vacuum to give the hydrochloride salt of 3-(3-methoxyphenyl)propylamine as a waxy white solid, 17.3 g (93%). HPLC—(Method B)—tr=1.28 min. [M+H]+=166.30. 1H-NMR (300 MHz, CDCl3/CD3OD): δ=7.14-7.19 (m, 1H), 6.70-6.77 (m, 3H), 4.51-4.58 (m, 2H), 3.75 (s, 3H, OMe), 2.85-2.91 (m, 2H), 2.63-2.68 (m, 2H), 1.95-2.01 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+]>ClC1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[NH2:13][C:14]1[CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=[CH:22][C:23]=1[NH:24][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COC(=O)c1ccc(Cl)cc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of methyl 4-chloro-2-iodobenzoate (0.593 g, 2 mmol), methyl 3,4-diaminobenzoate (0.332 g, 2 mmol), copper (0.126 g, 2 mmol), and K2CO3 (0.276 g, 2 mmol) in chlorobenzene (40 mL) was heated to reflux for 20 hours, cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth (Celite®). The solution was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.453 g (68%) of the desired product. MS (DCI) m/e 334 (M+H)+, 352 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.47 (d, J=1.0 Hz, 1H), 7.21 (m, 2H), 6.80 (dd, J=8.5, 2.0 Hz, 1H), 6.65 (d, J=2.1 Hz, 1H), 5.30 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5](Br)[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]3[N:17]([CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:18](=[O:31])[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:20](=[O:23])[C:21]=3[N:22]=2)=[CH:10][CH:9]=1)Br)C.CC(C)([O-])C.[K+].C>C(O)(C)(C)C.O>[CH:25]1([CH2:24][N:19]2[C:20](=[O:23])[C:21]3[N:22]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([C:6]#[C:5][C:4]([OH:40])=[O:3])=[CH:13][CH:12]=4)[NH:15][C:16]=3[N:17]([CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:18]2=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C#Cc1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
2.8 g (4.1 mmol) 3-[4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]phenyl}2,3-dibromo-propionic acid ethyl ester (part a of this example) was added to 56 mL of 1M potassium t-butoxide in t-butanol (Aldrich) at room temperature. The mixture was stirred at room temperature for 2.5 hours, then 0.10 mL water was added. The solution was stirred for an additional hour then 1 g charcoal was added in 250 mL water. The mixture was stirred for 30 minutes then filtered. The filtrate was acidified with conc. hydrochloric acid (pH=1), then the resulting suspension was stirred for 15 minutes, filtered then washed with 3×50 mL water. The solid was dried under reduced pressure to give 1.63 g (81%) of title compound; 1H-NMR (DMSO-d6) δ: 8.15 (d, J=8.0 Hz, phenyl CH, 2H), 7.73 (d, J=8.0 Hz, phenyl CH, 2H), 3.87 (d, J=6.6 Hz, CH2N, 2H), 3.74 (d, J=6.8 Hz, CH2N, 2H), 1.88 (br s, c-hexyl CH, 1H), 1.4-1.8 (m, c-hexyl CH, CH2, 11H), 0.8-1.2 (m, c-hexyl CH2, 10 H); MS (ES—): 487 (M-1), 443 (M-1-CO2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([O:21][CH3:20])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: C[O-]
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Yield: 85.7 %

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.26 g, 0.81 mmol) and sodium methoxide (prepared from 75 mg of sodium, 3.26 mmol) in dry MeOH (15 mL) is heated at 90° C. in a pressure vessel for 18 h. The mixture is poured into water and extracted with EtOAc to give 4-(3-bromoanilino)-7-methoxypyrido[2,3-d]pyrimidine (0.23 g, 86%). 1H NMR (DMSO) δ 9.88 (1H, brs), 8.82 (1H, d, J=8.9 Hz), 8.71 (1H, s), 8.18 (1H, dd, J=8.0, 1,9 Hz), 7.36 (1H, dd, J=8.1, 8.0 Hz), 7.29 (1H, ddd, J=8.1, 1.9, 1,9 Hz) 7.15 (1H, d, J=8.9 Hz), 4.01 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(/C=C/C(=O)O)c(-c3ccccc3)c2)cc1
Yield: 91.8 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoate (600 mg), a 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 60° C. for 3 hours and 1N hydrochloric acid (7 ml) was added, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoic acid (521 mg, yield: 92%). This was recrystallized from ethyl acetate-hexane. Melting point: 154–155° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[S:17][CH:18]=[C:19]([Cl:21])[N:20]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[S:17][CH:18]=[C:19]([Cl:21])[N:20]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Reactant: Clc1csc(Cl)n1
Product: COC(=O)[C@H](Cc1nc(Cl)cs1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2,4-dichlorothiazole (prepared according to Reynaud, Pierre; Robba, Max; Moreau, Robert C; New synthesis of the thiazole ring; Bulletin de la Societe Chimique de France (1962), 1735-8). MS m/z: 321 (23%, M+1), 265.0 (100%, M−55.1).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:17])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([C:31]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH:4]=2.[N+](=[CH:48][CH3:49])=[N-].CCOCC>CO>[CH2:23]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][CH2:19][O:18][C:16]([C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[C:3](=[CH:4][C:5]([C:31]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])=[CH:6][CH:7]=3)[C:2]([O:1][CH2:48][CH3:49])=[CH:15][C:14]=2[CH:13]=1)=[O:17])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)cc(O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Reactant: CC=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)cc(OCC)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Reaction time: 8 h

Procedure:
The corresponding 9-ethoxy derivative is prepared by reacting a solution of bis[3-(dibutylamino)propyl] 9-hydroxyphenanthrene-2,7-dicarboxylate in methanol with diazoethane by co-distillation with ether into the reaction mixture at -10° to 30°C. After standing overnight, the crude bis[3-(dibutylamino)propyl]9-ethoxyphenanthrene-2,7-dicarboxylate so obtained is converted to its dihydrochloride salt by the addition of ethereal hydrogen chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:29]=[C:30]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)[CH:31]=[CH:32][CH:33]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:42]1([C@@H:48]2[CH2:52][CH2:51][NH:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:50]4[CH2:51][CH2:52][C@@H:48]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:49]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:29]=[C:30]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)[CH:31]=[CH:32][CH:33]=2)[CH:17]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)c2)S(=O)(=O)N1
Reactant: c1ccc([C@@H]2CCNC2)cc1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CC[C@@H](c6ccccc6)C5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (134 mg, 0.2 mmol) was treated as described in general procedure R using excess (S)-3-phenyl-pyrrolidine (147 mg, 1 mmol) to give the desired compound 5-(3-{4-(2,4-dichloro-phenyl)-2-{4′-[(3S)-3-phenyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl}-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1, 1-dioxide.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH2:6].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][N:20]=1>>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][S:29]([C:25]1[CH:24]=[C:23]2[C:28]([C:19]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]=3[O:8][CH3:7])=[N:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1)(=[O:31])=[O:30]
Reactant: NC1=NCCS1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)NC3=NCCS3)ccc12

Procedure:
The title compound was prepared in a manner analogous to example 512 except 4,5-dihydrothiazol-2-amine (Pfaltz & Bauer) was used instead of 2-aminothiazole and 4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline-7-sulfonyl chloride was used instead of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride. (M+H)+=469.0.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:12])[C:9]=1[CH:10]=[O:11].O>CO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of sodium borohydride (322 mg, 8.5 mmol) in anhydrous methanol (10 mL) was added a solution of 3,5-dichloropyridine-4-carbaldehyde (1.0 g, 5.7 mmol) in anhydrous methanol (5 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3,5-dichloropyridin-4-yl)methanol was obtained (940 mg, 93% yield) and used for the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 2.23 (t, J=7.1 Hz, 1H), 4.94 (d, J=7.1 Hz, 2H), 8.52 (s, 2H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CN2CCCCC2)nc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide (0.11 mmol) was used in general procedure 5 with piperidine (0.12 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(piperidin-1-ylmethyl)nicotinamide. MS (Q1) 448.1 (M)+
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][NH2:17].[O-]CC.[Na+].C(O)C>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:3][CH2:2][C:1](=[O:5])[NH:17]1
Reactant: C=CC(=O)OCC
Reactant: NNc1ccc(Cl)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCN(c2ccc(Cl)cc2Cl)N1
Reaction time: 1 h

Procedure:
105.0 g (1.05 mol) of ethyl acrylate is added dropwise to a mixture of 37.3 g (211 mmol) of 2,4-dichlorophenylhydrazine, 18.6 g (273 mmol) of sodium ethoxide, 150 ml of ethanol and 150 ml of toluene and the mixture is subsequently stirred for 1 hour. The reaction mixture is evaporated to 100 ml and the residue is taken up in water. The organic phase is separated off and extracted with 5% strength NaOH. The combined aqueous phases are adjusted to a pH of 6.5 and the solid formed is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[C:4]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate (1.20 g, 2.68 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (0.730 g, 5.37 mmol, 2.00 equiv), Pd(PPh3)4 (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (12 mL), and water (2 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to provide 1.00 g (81% yield) of tert-butyl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 459 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:19]([O-])=[O:20])([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:12]([CH3:18])([CH3:11])[CH2:13][O:14][CH2:15][O:16][CH3:17])[O-:20]
Reactant: COCOCC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COCOCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.3 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (293.3 mg, 2.06 mmol), 2-methyl-2-nitro-1-(methoxymethoxy)propane (382.7 mg, 2.35 mmol) and zinc (266 mg, 4.07 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.46 ml, 8.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 19 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (361.9 mg; 56%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.25 g, 0.67 mmol) was dissolved in THF (10 ml). To this was added diisopropylethylamine (0.33 ml, 1.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.06 ml, 0.74 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 20% heptane, 80% ethyl acetate) to give the title compound (57 mg, 20% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.Cl.O>CC(O)=O>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 14 (45.06 g, 62.6 mmol, 1 eq.), in AcOH (338 mL) was added 1N HCl (188 mL) over 1 min. The reaction mixture was heated at 40° C. for 2 h. After cooling down to r.t., water (676 mL) was added. The reaction mixture turned into a suspension and was stirred at r.t. for 15 min. The solid was collected by filtration and the product cake was washed with water (2×100 mL) then dried in vacuum for 30 min to afford a crude hydrochloride salt of 15 as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[OH:26][N:25]=[C:12]([C@@H:11]1[C@:15]2([CH3:23])[C@H:8]([C:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]2)=[CH:5][CH:6]=3)[CH2:9][CH2:10]1)[CH3:13]
Reactant: NO
Reactant: CC(=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
The crude 3β-hydroxy-5,7-pregnadien-20-one (1.3 g) prepared in (a) was dissolved in 30 ml of pyridine, and after addition of hydroxylamine hydrochloride (863.2 mg), the solution was stirred for 5 hours at room temperature. After distilling off the pyridine under vacuum, methanol was added to the residue and the precipitating crystal was collected by filtration to obtain 1.04 g of the desired oxime compound.