Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CCN(C(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>C1COCC1>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(C#N)cc2[N+](=O)[O-])c(OC)c1
Reaction time: 24 h

Procedure:
A solution of 4-fluoro-3-nitrobenzonitrile (5.0 g) in THF (100 mL) was treated with DIEA (6.3 mL) and 2,4-dimethoxybenzylamine (5.0 mL), and then stirred for 24 h. The solvent was evaporated and the crude mixture was dissolved in EtOAc (100 mL). The solution was washed once with 1 M HCl and twice with saturated aqueous NaCl (100 mL each). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (20% EtOAc/DCM) provided 9.25 g of the title compound.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.S(C1C=CC(C)=CC=1)([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:17][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:13][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1cccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Temperature: 5 °C
Reaction time: 20.5 h
Yield: 16 %

Procedure:
Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed with hexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 5-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 1 hour affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol) in DMF (50 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 20.5 hours, quenched by the addition of saturated aqueous ammonium chloride (25 mL), poured onto water (750 mL), and extracted with ether (3×375 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×375 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (50%→60% acetone in hexanes) affording the desired product (1.11 g) as a tan solid. ESMS:MH+ 202.2.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:12]1[CH:11]=[C:10]([CH:6]2[O:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: CCCN1CCOC(c2ccc(O)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 55 h
Yield: 43.3 %

Procedure:
To the phenol from example 29 (200 mg, 0.9 mmol) in dichloromethane (5 ml) was added N-bromosuccinimide (161 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for 55 hours, before concentrating in vacuo. The crude product was purified by column chromatography on silica eluting with dichloromethane:methanol (95:5) to give the title compound as a white foam (117.5 mg, 0.39 mmol, 44%). 1H NMR (CDCl3, 400 MHz) δ: 0.96 (t, 3H), 1.59 (q, 2H), 2.03 (t, 1H), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 (d, 1H), 2.98 (d, 1H), 3.82 (t, 1H), 4.01 (d, 1H), 4.56 (d, 1H), 6.96 (d, 1H), 7.20 (d, 1H), 7.49 (s, 1H). LRMS: m/z 302 (M−H+, Br isotope).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[O:25][C:26]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=4[CH:28]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:34])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:33].[Cl:33][C:30]1[CH:31]=[CH:32][C:26]2[O:25][C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:16](=[O:34])[CH2:17]3)(=[O:23])=[O:22])=[CH:28][C:27]=2[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4o3)CC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 193.7 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(5-chlorobenzofuran-2-sulfonyl)-2-piperazinone (270 mg) were added 4N hydrochloric acid in ethyl acetate (8 ml) and methanol (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give 4-(5-chlorobenzofuran-2-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (229 mg).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.501 g (5.0 mmol) of 1-hexanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.77 g (87.7%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:37])[CH2:33][N:34]=[C:35]=[O:36])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:37])[CH2:33][NH:34][C:35]([N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:36])[CH3:30]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Product: CCOC(=O)CNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 87.3 %

Procedure:
In a manner similar to the method described in Example C3, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (80 mg, 0.189 mmol) was reacted with isocyanato-acetic acid ethyl ester (122 mg, 0.945 mmol) to give rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid ethyl ester (91.2 mg, 87%). HRMS (ES+) m/z Calcd for C27H29Cl2F2N3O3+H [(M+H)+]: 552.1627; Found: 552.1629.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:9][C@H:8]1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=3[S:20][CH:21]=2)[CH2:13][CH2:12]1)=[O:6]>O1CCOCC1.CO>[F:28][C:26]([F:27])([F:29])[C:23]1[CH:24]=[CH:25][C:18]2[C:17]([N:14]3[CH2:15][CH2:16][N:11]([CH2:10][C@@H:8]4[CH2:9][C@H:7]4[C:5]([OH:6])=[O:4])[CH2:12][CH2:13]3)=[CH:21][S:20][C:19]=2[CH:22]=1
Reactant: COC(=O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Yield: 81 %

Procedure:
Add 5N NaOH solution (425 mL, 226 mmol) to a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester, Example 6a, (18.0 g, 45.1 mmol) in dioxane/methanol (400 mL, 3:1) and heat the reaction at 60° C. for 6 h. Selectively remove most of the methanol and acidify the remaining dioxane solution to pH 5–6 with 2N acetic acid. Collect the desired compound, which precipitates from solution, to obtain 14.08 g (81%) of colorless crystals, m/z=385 (M+H)+
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)c1ccccc1
Yield: 68 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and benzaidehyde (0.01 mol) was subjected to the Procedure 1. The title compound was obtained in 68-72% yield.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 82464.7 %

Procedure:
To a solution of 1.018 g (2.95 mM) of 3-hexadecylthio-2-methoxypropylamine IVa2 in 15 ml of dichloromethane and 0.534 ml (3.83 mM) of triethylamine is added 0.563 mg (3.24 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at 0° C. for 3 hours. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 1.275 g (2.62 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane IIIa2 as a colorless powder in 89% yield.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][NH2:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][NH:15][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17]([CH3:16])(=[O:18])=[O:19])[CH:22]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Reactant: NC[C@@H]1CN(Cc2ccc(Cl)s2)CCO1
Product: CS(=O)(=O)Nc1cccc(CC(=O)NC[C@@H]2CN(Cc3ccc(Cl)s3)CCO2)c1
Yield: 45.8 %

Procedure:
Example 50 was prepared in an analogous manner to Example 44 using a mixture of Intermediate 14A (0.1 g) and Intermediate 18(0.1 g) to give the title compound (0.085 g).
Reaction SMILES: CO.[OH-].[Na+].C([O:8][C:9]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])=[O:12])(=O)C>C1(C)C=CC=CC=1>[C:34]([C:31]1[CH:32]=[CH:33][C:9]([OH:8])=[C:10]([CH:30]=1)[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])=[O:12])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C(C)(C)C)ccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.7 %

Procedure:
Methanol (2 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.26 mL) were added to the obtained methyl 2-(2-acetoxy-5-tert-butylbenzamido)-4-phenylbenzoate (0.023 g), followed by stirring at room temperature for 15 hours. Toluene was added to the reaction mixture. The aqueous layer was separated and adjusted to a pH of 3.0 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.010 g of 2-(5-tert-butyl-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:27]([CH3:29])[CH3:28])[CH:35]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(C)C)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.2 %

Procedure:
A mixture of 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (50 mg, 0.14 mmol), 3-isopropylphenyl boronic acid (45 mg, 0.27 mmol), copper acetate (26 mg, 0.14 mmol), triethylamine (57 μL, 0.4 mmol) and powdered 4 Å molecular sieves in DCM (1 mL) were stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (EtOAc:petroleum ether) give the title compound (32 mg, 48%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](F)[N:29]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1.[CH3:36][O-:37].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:37][CH3:36])[N:29]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CCNCC4)c3)c2Oc2cccc(F)n2)N1C(=O)C1CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(Oc2c(-c3cnn(C4CCNCC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-cyclopropyl(5-(6-fluoropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.024 g, 0.05 mmol), and sodium methoxide (0.015 g, 0.28 mmol) in N,N-dimethylformamide (1 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (16% to 34% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.0033 g, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.79-0.87 (m, 1H), 0.91-1.00 (m, 2H), 1.10-1.18 (m, 4H), 1.39-1.49 (m, 1H), 1.79-1.84 (m, 2H), 1.97-2.09 (m, 3H), 2.18-2.41 (m, 2H), 2.62-2.79 (m, 3H), 3.12-3.19 (m, 2H), 3.62 (s, 3H), 4.15-4.27 (m, 1H), 4.72-4.89 (m, 1H), 6.41 (t, J=8.00 Hz, 2H), 7.36 (d, J=8.40 Hz, 1H), 7.55-7.65 (m, 2H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 488 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)[CH3:2].[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:36])([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Method 2, product from alkylation step before hydrolysis) (50 mg, 0.10 mmol) in THF (1.0 mL) at 0° C. was added a 1.0 M solution of NaHMDS (0.15 mL, 0.15 mmol). The solution was stirred at 0° C. for 2 h, then iodomethane (41 mg, 0.29 mmol) was added neat. After stirring for 1 h the reaction was quenched with saturated ammonium chloride (50 mL), and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried with Na2SO4, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (EtOAc/hexanes) giving 31 mg (60%) of 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic acid ethyl ester. HPLC: Rt=3.79 (Method B). MS (ES+): mass calculated for C29H28Cl2N2O3, 522.15; m/z found 523.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.58 (d, J=8.4 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 77.17-7.14 (m, 4H), 7.08 (d, J=7.4 Hz, 1H), 7.05 (dd, J=2.0 Hz, 8.3 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 6.22 (s, 1H), 4.10 (m, 2H), 3.77 (s, 3H), 3.40 (d, J=13.9 Hz, 1H), 3.17 (d, J=13.9 Hz, 1H), 2.13 (s, 3H), 1.49 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 86.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), pyrrolidine (0.084 mL, 0.998 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (172 mg, 0.433 mmol, 87% yield). 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H); 7.89 (dd, J=8.33, 2.34 Hz, 1H); 6.74 (d, J=8.92 Hz, 1H); 6.67 (s, 1H); 3.94 (s, 3H); 3.50 (s, 4H); 1.95 (s, 4H). m/z (ESI, +ve ion) 398.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[BH3-]C#N.[Na+].[OH-].[Na+].O>C(O)(C(F)(F)F)=O>[CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
5,6,8,9,10,11-Hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (2.84 g, 11.4 mmol) was dissolved in TFA (35 mL). The reaction was cooled to 0° C. NaCNBH3(2.15 g, 34.27 mmol) was added in small portions over 30 min, keeping the temperature less than 5° C. The reaction was stirred at 0° C. for 2 h. Ice was added to the reaction flask, and the reaction was basified with 50% NaOH until pH=14. Water (20 mL) was added to dissolve the precipitate. The reaction was extracted with CHCl3(3×20 mL). The combined organic layers were washed with brine, dried, and concentrated to afford the title compound (1.67 g, 68%) as a pale-brown, amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 6.80–7.00 (m, 2H), 6.55–6.6.70 (m, 1H), 3.20–3.40 (m, 2H), 2.95–3.20 (m, 2H), 2.75–2.95 (m, 2H), 2.50–2.75 (m, 4H), 2.00–2.20 (m, 2H), 1.85–2.00 (m, 1H), 1.70–1.85 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:10][CH2:11][CH3:12])([CH3:9])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[CH:13]([N:16]=[C:17]=[N:18][CH:19]([CH3:21])[CH3:20])([CH3:15])[CH3:14].N=C=N>>[CH2:11]([O:10][Si:4]([O:3][CH2:1][CH3:2])([CH3:9])[CH2:5][CH2:6][CH2:7][NH:8][C:17]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:16][CH:13]([CH3:15])[CH3:14])[CH3:12]
Reactant: CCO[Si](C)(CCCN)OCC
Reactant: CC(C)N=C=NC(C)C
Agent: N=C=N
Product: CCO[Si](C)(CCCNC(=NC(C)C)NC(C)C)OCC

Procedure:
A mixture of 28.94 g of 3-(diethoxy(methyl)silyl)propylamine (0.151 mol, 20% excess) and of 15.9 g of diisopropylcarbodiimide (0.126 mol) was heated for 9 h at 80° C. (carbodiimide conversion of 97.3%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[CH2:17]([C:24]1[NH:25][CH2:26][CH2:27][CH:28]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:24]3[N:25]([CH2:26][CH2:27][CH2:28]3)[CH:2]=2)=[CH:6][CH:7]=1
Reactant: C1=C(Cc2ccccc2)NCC1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Reaction time: 42 h

Procedure:
According to the procedure of Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897), first 2-bromo-1-(4-fluorophenyl)ethanone (10.8 g, 0.05 mol) in portions and then NaHCO3 (5.0 g, 0.06 mol) are added to a solution of 2-benzylpyrroline (Example 1a, 15 g, 80%, 0.075 mol) in ethanol (150 ml) in a round-bottomed flask. The reaction mixture is stirred for 24-60 h with exclusion of light; during this time the temperature of the solution is kept between 30-40° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[O:7][N:6]=1>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[O:7][N:6]=[C:5]([CH2:4][NH:2][CH3:1])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Solvent: CCO
Product: CNCc1noc(-c2cccc(Cl)c2)n1
Yield: 100 %

Procedure:
MeNH2 in EtOH (6 mL, 8 M, 48 mmol) was added to 3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.5 g, 6.5 mmol) in EtOH (20 mL). After 20 h the solvent was evaporated and the residue was dried in vacuum to give 1.47 g (100%) of the title compound. LC-MS (M++1): 224