Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[NH:15]([C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH3:14])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Solvent: ClCCl
Product: COC(=O)Cc1c(Cl)nc(C)nc1Nc1ccccc1
Temperature: 50 °C
Yield: 37.2 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine-5-acetic acid, methyl ester (8.5g, 36mM) and aniline (4.7g, 49mM) was heated at 50° C. for 13 hours. Methylene chloride (300ml) was added to the cooled mixture and the mixture filtered. The liltrate was washed with 2M hydrochloric acid (1×170ml, 1×85ml) and water. The organic layer was separated, stirred with 2M sodium hydroxide (110ml) and then separated. The aqueous layer was extracted with methylene chloride (2×85ml). The organic layers were combined, washed with water, over anhydrous magnesium sulphate and the solvent evaporated to afford a solid. This solid was purified by flash column chromatography on silica (Merck 9385), eluting with ethyl acetate/hexane (20:80 v/v) to give 4-anilino-6-chloro-2-methylpyrimidine-5-acetic acid, methyl ester (3.92g, 48.6%), m.p. 115°-116° C.; microanalysis, found; C,57.7; H, 4.5; N, 14.2%; C14H14N302. requires C, 57.6; H, 4.8; N, 14.4%; NMR: 2.53(3H,s,2-CH3), 3.79(3H,s, COOCH3), 3.80(2H,s,CH2), 7.05-7.65(5H, complex, aromatic), 7.9-8.0 (1H, broad,N--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:20]=3[N:19]=2)([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:13]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:20]=3[N:19]=2)([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: C=CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2c1CCN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-2-(2-(5-methoxy-7-methyl-1H-indol-4-yl)pent-4-en-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (Example 156-F) (150 mg, 0.405 mmol) in acetic acid (2.025 mL) was added sodium cyanoborohydride (38.2 mg, 0.607 mmol) and the reaction was stirred at room temperature for 1 hour. At this point the mixture was placed in an ice bath and quenched with NaOH (17.61 mL, 35.2 mmol) and then diluted with DCM. The layers were separated and the organic layer was dried over sodium sulfate, concentrated and absorbed onto silica and purified via FCC (0-100% EtOAc:heptanes) to give the title compound. MS (ESI+) m/z 373.3 (M+H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:16]=CC(O)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>N1C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Acetic anhydride (50 ml) is added to a solution of 4-nitrophenol (5.56 g, 40 mmol) in dry pyridine (50 ml). The solution is stirred at ambient temperature for 2 hr and then at 70° C. overnight with a reflux condenser under Ar. The mixture is poured onto ice, and a white precipitate is formed after standing for several hours. Water (400 ml) is added, and the white solid is collected by vacuum filtration and dried in vacuo to yield a white solid (5.1 g, 70%). ESI-MS (M+H)+: 182.2. 1H-NMR (CDCl3) δ 8.30 (2H, d, J=9.0 Hz, NO2CCH), 7.31 (2H, d, J=9.0 Hz, OCCH), 2.25 (3H, s, CH3).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:25]4[CH:26]=[C:21]([N:19]([CH3:20])[CH3:18])[CH:22]=[CH:23][CH:24]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
Reactant: CN(C)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1cccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)c1
Temperature: 140 °C
Yield: 10.2 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.13 g, 0.36 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol), 3-(N,N-dimethylamino)phenylboronic acid (68 mg, 0.41 mmol), cesium carbonate (235 mg, 0.72 mmol, 2.0 eq), and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8). The obtained residue was crystallized from methanol:1,2-dichloroethane (1:1, 1.5 mL) and filtered to give {3-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-dimethyl-amine as a white solid (13 mg, 10% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](O)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O.CC1N=C(O)N=C(C(OC)=O)C=1>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:18])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1cc(C(=O)OC)nc(O)n1
Agent: COC(=O)c1cc(C)nc(O)n1
Product: CCCCc1cc(C(=O)OC)nc(Cl)n1

Procedure:
Methyl 6-n-butyl-2-hydroxypyrimidine-4-carboxylate (prepared as described by Z. Budesinsky and F. Roubinek in Collection Czechoslovak Chem Commun., 26, 2871-2885 (1991)) is refluxed with phosphorous oxychloride, as described by the same authors for the chlorination of methyl 6-methyl-2-hydroxypyrimidine-4-carboxylate, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl.N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13])[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:14][CH:15]=1
Reactant: COC(CNCc1ccc(Br)cc1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
60.5 g (4-Bromo-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 270 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 76.0 g (386.4 mmol) p-toluenesulfonylchloride in 100 ml of dichloromethane was added and the solution was stirred at room temperature. After 3 h, the reaction mixture was washed twice with 2 N HCl and saturated sodium hydrogen carbonate-solution. The organic layer was dried over magnesium sulfate and evaporated. Final silica gel chromatography (heptane/ethylacetate 4:1) gave 59.9 g of the title compound. Rt=1.82 min (Method C). Detected mass: 396.1/398.1 (M−OMe−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:20]Br>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[CH2:19][Br:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(-c2cccc([N+](=O)[O-])c2)cccc1[N+](=O)[O-]
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=[N+]([O-])c1cccc(-c2cccc([N+](=O)[O-])c2CBr)c1
Yield: 77.4 %

Procedure:
The procedure of Example 8 was used except that the starting material was 0.80 g of 2-(3-nitrophenyl)-6-nitrotoluene which was reacted with 0.49 g of bromine and 33 mg of benzoyl peroxide. In this way, 0.80 g (77% yield) of yellowish crystals were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[O:36][CH:35]=[N:34][C:33]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:33]6[N:34]=[CH:35][O:36][C:32]=6[CH3:31])[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1ocnc1C1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncoc5C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine (0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 25 mg (25%) 1HNMR (400 MHz, DMSO-d6): δ 1.11 (m, 2H), 1.20-1.22 (m, 2H), 2.28 (s, 3H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz, 3H), 7.38-7.42 (m, 4H), 7.57 (s, 1H), 7.74-7.81 (m, 3H), 8.04 (s, 1H), 7.97-8.01 (m, 2H), 8.45-8.46 (m, 1H), 9.16 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccc(Cl)cc1
Yield: 72 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.3 g, 0.83 mmol) prepared in example 4b was reacted with 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 7a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow solid (Yield 0.45 g, 72%).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Ag-]=O.C1(C)C=CC=CC=1>[CH2:12]([O:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: ClCc1ccccc1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
A mixture of 2-hydroxy-4,6-dimethylnicotinonitrile (5.3 g, 36 mmol), benzyl chloride (5.7 mL, 45 mmol), silver(I)oxide (9.2 g, 40 mmol) and toluene (50 mL) were heated at 110° C. in a sealed tube for 20 hours. The mixture was cooled to room temperature and the solids were filtered and rinsed with dichloromethane. The filtrate was concentrated under vacuum and purified by column chromatography (40% EtOAc/Heptane) to give 2-(benzyloxy)-4,6-dimethylnicotinonitrile (Cpd II, 8.1 g, 94% yield) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17](=[O:29])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][C:10]=1[O:39]CC1C=CC=CC=1)(C)(C)C.[H][H]>[OH-].[OH-].[Pd+2]>[C:31]([NH:30][CH:16]([C:17](=[O:29])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:47])=[O:5])=[C:10]([OH:39])[CH:11]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1ccc(C=C(NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: O=C(O)COc1ccc(CC(NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1O
Reaction time: 8 h

Procedure:
{4-[2-Benzoylamino-2-(4-phenyl-butylcarbamoyl)-vinyl]-2-benzyloxy-phenoxy}-acetic acid tert-butyl ester of Step C (80 mg, 0.13 mmol) is dissolved in ETOH (2 mL) and Pd(OH)2 (13 mg) on carbon is added. Hydrogen is applied and stirred overnight. The mixture is filtered through 0.45 μm Gelman Acrodisc and the filtrate is concentrated to oil. The oil is dissolved in TFA (2 mL). After 3 hours, the TFA is removed by evaporation. The crude material is purified by reverse phase chromatography (C18, CH3CN/H2O) to provide the title compound (compound 40), {4-[2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-hydroxy-phenoxy}-acetic acid; 1H NMR (400 MHz, DMSO-d6): δ8.40 (d, 2H), 7.95 (t, 1H), 7.78 (d, 2H), 7.49 (m, 1H), 7.41 (m, 2H), 7.23 (m, 2H), 7.15 (m, 3H), 6.75 (s, 1H), 6.68 (d, 1H), 6.62 (d, 1H), 4.54 (m, 1H), 4.48 (s, 2H), 3.08 (m, 2H), 2.85 (m, 2H), 2.54 (m, 2H), 1.52 (m, 2H), 1.40 (m, 2H); MS (ES+) m/z 491 (M+1).
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:4][CH2:3]1.C(OC(C)C)(=O)C.[CH3:60][S:61](O)(=[O:63])=[O:62]>O>[CH3:60][S:61]([O:18][C@H:16]1[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]2[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]([C@@H:40]([F:51])[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=3)=[C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:52])[CH2:7][CH2:6]3)[C:17]1=2)(=[O:63])=[O:62]
Reactant: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](O)CC(C)(C)C4)CC2)nc1
Reactant: CS(=O)(=O)O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OS(C)(=O)=O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To 40.7 mg (0.055 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 16, 0.28 ml of isopropyl acetate and 0.008 ml of ultrapure water were added, and the reaction mixture was stirred at room temperature to obtain a homogeneous solution. Then, 0.004 ml (0.062 mmol) of methanesulfonic acid was added thereto, and the reaction mixture was stirred at the same temperature for 90 minutes. The precipitated solid was obtained by filtration, washed with 0.04 ml of isopropyl acetate three times and then dried under reduced pressure at 40° C. to provide 38.7 mg of the title compound as a white powder (yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N12CCCN=C1CCCCC2>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:10]=[C:9]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12)C(F)(F)F
Temperature: 0 °C
Yield: 40 %

Procedure:
Crude N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide was suspended in dichloromethane (25 mL) and treated with trityl chloride (0.72 g, 2.58 mmol) under stirring. The suspension was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL, 2.78 mmol) was added, producing immediate solubilization. After stirring at 0° C. for 3 hours the reaction mixture was poured into 50 mL of ice containing 1N HCl (5 mL) and extracted with dichloromethane. The organic layer was washed with NaHCO3, brine, dried and concentrated to a crude material that was purified by flash chromatography (eluant: DCM). The desired product was obtained as a white solid (450 mg, yield 40% over two steps)
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:14][C:15]([C@H:17]1[CH2:19][C@@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:4]1C=N[C:7]([O:10][CH2:11][CH2:12]C)=[CH:8][CH:9]=1.[NH2:26][C@H:27](C1C=CC(OCC)=CN=1)CO.BrC1C=CC(OCC)=CN=1>>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C@@H:3]([NH:14][C:15]([C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:16])[CH2:2][OH:1])=[N:26][CH:27]=1)[CH3:12]
Reactant: CCCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: CCOc1ccc([C@@H](N)CO)nc1
Agent: CCOc1ccc(Br)nc1
Product: CCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1

Procedure:
Prepared analogously to Compound 21 using IM46 and (R)-2-Amino-2-(5-ethoxy-pyridin-2-yl)-ethanol (prepared from commercially available 2-Bromo-5-ethoxy-pyridine CAS 42834-01-5 analogously to IM36). Compound 52 was further purified by SFC (Column: Chiralpack OJ250×30 mm, Mobile phase: Supercrital CO2/MeOH+NH4OH=55/45 at 50 mL/min, column temperature: 38° C., Nozzle Pressure: 100 Bar, Nozzle Temp=60° C., Evaporator temp=20 C, Trimmer temp=25° C., Detector: 220 nm). Yield=163 mg. 1H NMR (CDCl3 400 MHz, TMS): δ 8.15 (d, J=2.8 Hz, 1H), 7.08-7.31 (m, 6H), 7.06 (d, J=7.2 Hz, 2H), 5.11-5.15 (m, 1H), 4.00-4.08 (m, 3H), 3.87-3.90 (m, 1H), 2.47-2.52 (m, 1H), 1.63-1.76 (m, 3H), 1.43 (t, J=7.2 Hz, 3H), 1.27-1.31 (m, 1H); [α]20, D=182.0 (c=0.234 g/100 mL, EtOH)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)=[O:19])[CH2:9][N:8](C(OCCCC)=O)[CH2:7]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[NH:17][C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:35])[CH2:9][NH:8][CH2:7]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CN(C(=O)OCCCC)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CNC2)cc1
Yield: 25.2 %

Procedure:
A solution of tent-butyl 3-(2-ethoxy-2-oxoethyl)-3-(3-(4-octylphenyl)ureido)azetidine-1-carboxylate (0.5 mmol) in CH2Cl2 (5 mL) was cooled with an ice/water bath and treated with trifluoroacetic acid (0.5 mL). The reaction was monitored (TLC) to completion (3-4 hrs) at which point the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was purified by column chromatography to obtained the title compound (49 mg, 65%). 1H NMR (400 MHz, CD3OD) δ 7.21 (d, 2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 4.14 (q, 2H, J=6.8 Hz), 3.80 (d, 2H, J=9.6 Hz), 3.69 (d, 2H, J=9.6 Hz), 3.11 (s, 2H), 2.55 (t, 2H, J=7.6 Hz), 1.60-1.55 (m, 2H), 1.33-1.21 (m, 13H), 0.90 (t, 3H, J=6.4 Hz); MS ESI 390.3 [M+H]+, calcd for [C22H35N3O3+H]+ 390.54.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl>CC#N.CN(C1C=CN=CC=1)C.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(I)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1cc(I)ccc1F)N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-iodobenzoic acid (2 g, 0.0088 mol) was dissolved in MeCN (44 ml) and the mixture cooled to 0° C. Morpholine (0.929 ml, 1.2 eq) followed by EDCI.HCl (2.03 g, 1.2 eq) and DMAP (108 mg, 0.1 eq) were added and the mixture stirred overnight. The mixture was diluted with EtOAc, washed with NH4Cl(sat), dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-30% EtOAc in hexane) gave 2 g of M1-5. LCMS MH+=336.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>O.C(O)C>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:25]([C:24]4[CH:23]=[CH:22][C:21]([N:16]5[CH:20]=[CH:19][N:18]=[CH:17]5)=[CH:28][CH:27]=4)=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5ccnc5)cc4)[nH]c3cc21

Procedure:
2 g. (9.7 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)), 1.67 g. (9.7 mmole) 4-(1H-imidazol-1-yl)-benzaldehyde, 0.17 g. p-toluenesulphonic acid and 120 ml. ethanol were mixed together and heated under reflux for 3 hours while passing through air. The evaporation residue was suspended in water, neutralized with 2N aqueous ammonia and recrystallized from methanol to give 1.7 g. (49% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].N1C=CC=CC=1>ClCCl>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)(=[O:34])=[O:35])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.366 mmol, 810 mg), 3-nitrobenzene-1-sulfonyl chloride (2.366 mmol, 524 mg) and pyridine (4.73 mmol, 0.383 mL, 374 mg) were combined in dichloromethane (20 mL) and stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was separated, dried and concentrated under vacuum. The residue was purified by SCX chromatography to afford the title compound (875.3 mg). MS (ESI) m/z 528.0 [M+H]+