Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-])=O.[CH2:11]([N:18]([C:42]1[CH:47]=[C:46](Cl)[N:45]=[CH:44][N:43]=1)[C:19]([N:21]([C:30]1[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=1[Cl:41])COCC[Si](C)(C)C)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([C:42]1[N:43]=[CH:44][N:45]=[C:46]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:34](=[O:37])[CH:33]=[CH2:32])[CH:47]=1)[C:19]([NH:21][C:30]1[C:31]([Cl:41])=[C:32]([O:39][CH3:40])[CH:33]=[C:34]([O:37][CH3:38])[C:35]=1[Cl:36])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(Cc2ccccc2)c2cc(Cl)ncn2)c1Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2ccccc2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Yield: 20 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2G (Example 123), substituting 2-nitro-phenylamine and 1-benzyl-1-(6-chloro-pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-urea (preparation shown below) in step (d) to afford the title compound (26 mg, yield: 20% over five steps). 1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.68 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 7.69 (d, 1H), 7.33-7.19 (m, 6H), 6.92 (s, 1H), 6.45 (dd, 1H), 6.24 (d, 1H), 6.18 (s, 1H), 5.74 (d, 1H), 5.07 (s, 2H), 3.95 (s, 6H); MS (ESI): 593 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:33][C:34](=[O:52])[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.C(N(C(C)C)CC)(C)C.C(O)=O>O1CCOCC1>[CH:34]([OH:52])=[O:33].[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O=CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)CC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
Intermediate 14c (120 mg, 0.31 mmol) was dissolved in 1,4-dioxane (2.0 mL) and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 124 mg, 0.31 mmol) and diisopropylethylamine (106 μL, 0.61 mmol) were added. The reaction was heated to 60° C. for 20 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, then further purified by HPLC (C18 X-select column, 20-70% MeCN in H2O, 0.1% formic acid) to give the title compound as the formic acid salt (103 mg, 0.16 mmol, 52%). LCMS (Method 5): Rt 3.63 min, m/z=648 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.90-1.99 (1H, m), 1.99-2.07 (1H, m), 2.10-2.19 (1H, m), 2.21-2.30 (1H, m), 2.37 (3H, s), 2.38 (3H, s), 2.52-2.67 (8H, br s), 4.05-4.09 (1H, d, J 14.3 Hz), 4.11-4.15 (1H, d, J 14.3 Hz), 4.88-4.93 (1H, dd, J 8.9, 5.6 Hz), 5.41-5.44 (1H, t, J 4.3 Hz), 6.33 (1H, s), 7.22-7.36 (11H, m), 7.63-7.67 (1H, d, J 10.0 Hz), 8.21-8.22 (1H, d, J 1.9 Hz), 8.44-8.45 (0.25H, s).
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:13])[CH2:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=O.C([O-])(O)=O.[Na+].C(OCC)C>CO.O>[CH2:16]([O:15][CH2:14][C:10]1([CH3:13])[CH2:11][N:12]2[C:8](=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:24]2)[CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC1(COCc2ccccc2)CN=C(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC1(COCc2ccccc2)Cc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cn2C1
Reaction time: 48 h

Procedure:
5-Benzyl-3-(benzyloxymethyl)-3-methyl-3,4-dihydro-2H-pyrrole (108 g, 0.368 mol), 2-bromo-1-(4-chlorophenyl)-1-ethanone (100 g, 0.428 mol) and NaHCO3 (34.6 g, 0.42 mol) are dissolved in methanol abs. (950 ml) in a 2 l flask and, adjusted to a temperature of 40° C., stirred for a total of 2 d with exclusion of light. The supernatant methanol phase is poured off from the viscous, green-brown substance at the bottom of the solution formed during the reaction, and the material is taken up with diethyl ether (1 l) and water (800 ml) and partitioned. The water phase is extracted 2 times with ether (600 ml). The collected ether solution is dried over Na2SO4 sicc. and concentrated. Solvent residues are removed in a high vacuum. 124 g of a viscous, swelling residue remain, which consists of the compound sought and which can be employed for. further reactions without further purification. For characterization, the substance is purified by means of column chromatography (Al2O3/hexane-diethyl ether 4:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13](I)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]#[C:25][C:13]2[N:12]=[C:11]([CH3:16])[N:10]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]=3)[CH:14]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCn1ncc(-n2cc(I)nc2C)cc1=O
Reactant: C#Cc1cccc(Cl)c1
Product: CCn1ncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, light yellow crystalline solid, MS: m/e=339.1, 340.6 (M+H+), was prepared in accordance with the general method of example 21a from 2-ethyl-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])=[CH:8][N:7]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccc(Cl)nc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Sulfurous dichloride (6.8 g, 57 mmol) was added to a solution of 6-chloronicotinic acid (4.5 g, 28.5 mmol) in toluene (40 mL) at 0° C. The mixture was stirred at 110° C. for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Benzyl alcohol (4.65 g, 43.1 mmol), pyridine (6.9 mL) and toluene (50 mL) were added to the residue. The mixture was stirred at 25° C. for 3 hours. HCl (20 mL, 4 N) was added and the mixture was extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl 6-chloronicotinate. MS ESI calc'd. for C13H11ClNO2 [M+H]+ 248. found 248. 1HNMR (400 MHz, DMSO-d6) δ 8.94 (d, J=2.0 Hz, 1H), 8.34-8.31 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.50-7.17 (m, 5H), 5.38 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[O:10][CH:9]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:16]2[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=2[OH:10])=[N:22][NH:23][CH:9]=1
Reactant: NN
Reactant: O=c1c(-c2ccccc2Br)coc2cc(O)c(Cl)cc12
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2Br)cc1Cl
Yield: 70 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2-Bromo-phenyl)-6-chloro-7-hydroxychromen-4-one (0.4 g, 1.1 mmol), hydrazine hydrate (10 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(2-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol as a white solid (0.28 g, 70%); Rf 0.6 ethyl acetate/hexane (80/20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])C(C#N)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:30]([OH:33])(=[O:32])[CH3:31]>Cl.O>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:31]([C:30]([OH:33])=[O:32])=[N:21]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(=O)O
Reactant: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: Cl
Solvent: O
Product: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (87) (1.35 g, 2.99 mmol) in glacial acetic acid (30 mL) and concentrated hydrochloric acid (6.7 mL) was heated to 120° C. for 3 d. At this time, the reaction was cooled to 0° C., diluted with water (50 mL) and stirred at 0° C. for 15 min. The product that precipitated was collected by filtration, washed with water and petroleum ether, air-dried under house vacuum for 15 min, and then dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (89) (1.17 g, 83%) as a light brown solid; ES(+)-HRMS m/e calcd for C17H13Cl2N5O5S (M+H)+ 470.0087, found 470.0088. Exact Mass=469.0014; Molecular weight=470.29
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].C1COCC1>CO.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(Cc1ccc(N)cc1)C(=O)O
Reaction time: 0.72 h
Yield: 87.1 %

Procedure:
2-Methoxy-3-(4-nitrophenyl)acrylic acid (6.7 g, 30 mmol) was taken up in methanol (700 ml) and THF (300 ml) and 10% Pd on C (wet basis) (0.67 g) was added. The mixture was hydrogenated at 45 psi for 43 mins, followed by repeated refills to 45-48 psi every hour for 3 hr and finally 48 psi for 18 hr. The resulting suspension was filtered through GF/F filter paper and the filter residue washed with MeOH (200 ml). The filtrates were concentrated to an off-white solid. The solid was slurried in IMS (75 ml) at 20° C. for 1.5 hr, filtered, and washed with IMS/heptane (1:2) (20 ml) and dried on the filter for 1 hr to afford (±)-2-methoxy-3-(4′-aminophenyl)-propionic acid as an off-white solid (5.1 g, 88% yield)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>>[F:29][C:11]([F:10])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([O:27][C:2]4[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Product: N#Cc1cc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)ccn1
Yield: 62 %

Procedure:
Obtained in 62% yield by an analogous procedure to Example 448, starting from 4-chloro-2-cyanopyridine and 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:24][CH2:25][CH3:26])=O.[CH3:32][C:33]([CH3:41])([CH2:39]O)[CH2:34][C:35]([O:37][CH3:38])=[O:36].[S:42]1C=CC=C1CC(O)=O>C1COCC1>[C:25]([S:42][CH2:39][C:33]([CH3:41])([CH3:32])[CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:24])[CH3:26]
Reactant: COC(=O)CC(C)(C)CO
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)CSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (107.8 g, 0.411 mol) in THF (700 mL) maintained at 0° C. was added dropwise DEAD (diethyl azodicarboxylate) (64.7 mL, 0.411 mol) and the mixture was stirred at 0° C. for 30 min until the complex was precipitated. A solution of the alcohol of Step 8 (30 g, 0.205 mol) and thiolacetic acid (29.4 mL, 0.411 mol) in THF (300 mL) was then added dropwise (mechanical stirring). After 4 days at 4° C. the reaction mixture was evaporated to dryness, the white precipitate was suspended in 30:1 hexane:EtOAc and filtered. The residual oil was then purified by a flash chromatography using toluene then 100:1 toluene:EtOAc to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:6]=1.[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:6]=1
Reactant: Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(SCc2csc(N)n2)cc1
Yield: 78.8 %

Procedure:
To a mixture of 2-amino-4-(4-nitrophenylthiomethyl)thiazole (15 g) and ammonium chloride (2 g) in a mixture of tetrahydrofuran (100 ml), ethanol (150 ml) and water was added portionwise added the iron powder (15 g) at 80° C. with stirring. The mixture was refluxed for 2 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with chloroform. The precipitates were collected by filtration, washed with ether and dried in vacuo to give 2-amino-4-(4-aminophenylthiomethyl)thiazole (10.50 g, yield: 73.0%). mp: 130°-132° C.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15]3)[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CC(=O)C=Cc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C=C(O)CC(c2ccc3c(c2)CCC3)C1

Procedure:
Diethyl malonate (17.5 g; 110 mmole) was added to a solution of sodium metal (1.91 g; 83 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(5-indanyl)but-1-en-3-one (19.25 g; 103 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of two minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (30% solution, 50 ml) was added and the mixture was heated under reflux for a further 11/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulphate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-(5-indanyl)cyclohex-2-en-1-one, was obtained as a white solid (18.70 g; 79.6%), mp 198° C.
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.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]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:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]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: CN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CC1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide (0.11 mmol) was used in general procedure 5 with 1-methylpiperazin (0.12 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(4-methylpiperazin-1-ylmethyl)nicotinamide. MS (Q1) 464.0 (M)+
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([O:41][Si](C(C)(C)C)(C)C)[CH2:35]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([OH:41])[CH2:35]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 38.8 %

Procedure:
A procedure similar to that described in Example above, was followed, but using 1.10 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-phenoxybutyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 37, above] and 37.7 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.29 g of the title compound as whitecrystals, melting at between 120° and 122° C.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22](=[O:25])[NH:23][CH3:24])[C:10]=2[CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:24][NH:23][C:22]([CH2:21][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][NH:8][CH2:9][C:10]1=2)=[O:25]
Reactant: CNC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cn1c2c(c3ccccc31)CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 121 %

Procedure:
A 10 ml portion of dichloromethane solution containing 541 mg (1.58 mmol) of 2-t-butoxycarbonyl-9-methylcarbamoylmethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was mixed with 1 ml of anisole and 1 ml of trifluoroacetic acid and stirred overnight at room temperature. The solvent was removed by evaporation under a reduced pressure, and the resulting residue was precipitated by adding acetone and diisopropyl ether, thereby obtaining 465 mg (89% in yield) of 9-methylcarbamoylmethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[OH:27][CH:28]([CH3:32])[CH2:29][CH:30]=O>CO>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:30][CH2:29][CH:28]([OH:27])[CH3:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: CC(O)CC=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: CO
Product: Cc1ccc(NCCC(C)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.033 g, 0.09 mmol) was suspended in MeOH (1 mL). 3-Hydroxy-butyraldehyde (0.023 g, 0.27 mmol) and NaCN(BH3) (0.055 g, 0.88 mmol) were added. The suspension was stirred at room temperature for 18 h. 3-Hydroxy-butyraldehyde (0.023 g, 0.27 mmol) and NaCN(BH3) (0.055 g, 0.88 mmol) were added again and the suspension was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with brine. The water phase was extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using MeOH/CH2Cl2 1:50 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.7, 159.0 (dd), 155.4 (dd), 147.3, 146.0, 139.6, 135.0, 133.5, 132.0, 129.9, 126.7, 124.6 (dd), 124.0 (dd), 116.3, 115.9, 114.6, 112.8, 111.6 (dd), 104.9 (dd), 67.5, 42.1, 38.0, 24.0, 19.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36](N)=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11](C(=O)C3C=C(OC)C(OC)=C(OC)C=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:45]1CCOCC1.Cl>O>[C:39]1([C:33]2([C:36]([OH:45])=[O:37])[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][C@:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][NH:11][CH2:10]3)[CH2:31][CH2:32]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C1COCCO1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCN(CC[C@]2(c3ccc(Cl)c(Cl)c3)CCNC2)CC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Combine (+)-1-(2-(3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl)-ethyl)-4-phenylpiperidine-4-carboxylic acid amide prepared by the method of U.S. Pat. No. 5,635,510, issued Jun. 3, 1997 (200 g, 300 mmol), dioxane (400 mL), concentrated aqueous hydrochloric acid (400 mL), and water (400 mL). Heat to reflux. After 26 hours, cool to ambient temperature and concentrate the reaction mixture in vacuo at about 60° C. to a volume of about 700 mL. Add water (400 mL) and extract with 9/1 ethyl acetate/hexaneo Separate the layers and extract the aqueous layer twice with 1/1 ethyl acetate/hexane. Adjust the pH of the aqueous layer to about 7 using sodium hydroxide to form a solid. Filter and dry to give (S)-3-(2-(4-phenyl-4-carboxypiperidin-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.Br[CH2:14][CH:15]=[CH2:16]>>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: C=CCBr
Product: C=CCCc1ccc(C(C)(C)C)cc1

Procedure:
Compound I-2 can also be prepared by reacting 1-bromomethyl-4-(1,1-dimethylethyl)benzene with the Grignard reagent prepared from from 3-bromo-1-propene.