Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:3]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)[CH3:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[N:3]=[C:2]([S:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:5]=2)=[CH:19][CH:20]=1
Reactant: CCc1ccc(S)cc1
Reactant: Clc1ccc(-c2nc(Cl)cc(NCCCN3CCOCC3)n2)cc1
Product: CCc1ccc(Sc2cc(NCCCN3CCOCC3)nc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
Similarly, 4-chloro-2-(4-chlorophenyl)-6-[3-(morpholino)propylamino]-pyrimidine is reacted with p-ethylthiophenol to produce 2-(4-chlorophenyl)-4-(4-ethylphenylthio)-6-[3-(morpholino)propylamino]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)=O.[CH3:19][NH:20][NH2:21]>C(O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[CH2:4][C:3]([C:2]([F:18])([F:17])[F:1])([OH:16])[N:20]([CH3:19])[N:21]=2)=[CH:8][C:9]=1[CH3:15].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:20]([CH3:19])[N:21]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)=[CH:8][C:9]=1[CH3:15]
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Reactant: CNN
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)nn2C)cc1C
Product: COc1ccc(C2=NN(C)C(O)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., to a mixture of 4,4,4-trifluoro-1-(4-methoxy-3-methyl-phenyl)-butane-1,3-dione (described in Reference Preparation example 76) 6.8 g and ethanol 100 ml was added methyl hydrazine 1.7 g. The resulting mixture was raised to room temperature and was stirred for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to a silica gel column chromatography to give 5-(4-methoxy-3-methyl-phenyl)-2-methyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-ol 3.2 g and 5-(4-methoxy-3-methyl-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole 2 g.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C[O-].[Na+]>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(O)c1cccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Yield: 88.5 %

Procedure:
In the same manner as in Example 1(a), 15.8 grams (0.1 mole) 2-chloronicotinic acid, 64.0 grams (0.5 mole) 3-chlorophenol, 45 grams (0.21 mole) 25% sodium methoxide solution and 100 milliliters methanol were combined to produce 22.1 grams (88.6% of theoretical yield) of 2-(3-chlorophenoxy) nicotinic acid, m.p. 161°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][OH:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([Cl:18])=[N:11][OH:12])=[CH:6][C:5]=1[C:13]([F:15])([F:14])[F:16]
Reactant: COC(=O)c1ccc(C=NO)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(Cl)=NO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
To a solution of 4-(hydroxyimino-methyl)-2-trifluoromethyl-benzoic acid methyl ester (Example I11) (3.90 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (“NCS”) (2.318 g). The reaction mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was poured into water (400 ml). The solids were isolated by filtration and dried to give 4-(chloro(hydroxyimino)methyl)-2-trifluoromethyl-benzoic acid methyl ester (4.21 g) as an off-white powder. 1H-NMR (CDCl3, 400 MHz): 9.00 (s, 1H), 8.24-8.04 (m, 3H), 3.96 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH3:16].C(OCC)(=O)C>C(O)(C)C>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:16])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(NC2CCOCC2)n1
Reactant: N
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)c(NC2CCOCC2)n1
Temperature: 130 °C
Yield: 77 %

Procedure:
To a suspension of compound 32 (6.60 g, 23 mmol) in isopropyl alcohol (40 ml) was added ammonia (aq. 28%, 80 ml). This reaction mixture was heated to 130° C. for 14 hours in a pressure vessel. The reaction mixture was cooled down to room temperature and to this mixture was added ethyl acetate. The reaction mixture was washed with water and brine. The ethyl acetate layer was dried with sodium sulfate and concentrated to give compound 33 (4.75 g, 77%). 1H NMR (500 MHz, CD3OD) δ ppm 7.79 (1 H, s), 4.24 (1 H, m), 3.99-4.02 (2 H, dd, J=11.0, 2.2 Hz), 3.52 (2 H, td, J=11.9, 2.0 Hz), 1.92-1.96 (2 H, m), 1.69 (2 H, m); LCMS-ESI (POS), M/Z, M+1: Found 273, Calculated 273.0
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[N:29]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline Rf value: 0.1 (silica gel, methylene chloride/ethanol=5:1) C29H29N3O3
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5](CC1C=CC=CC=1)[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[NH:20])[NH:18][CH3:19])[CH:15]=2)[NH:10][CH:9]=1)[CH3:4].[H][H]>C(O)C.[Pd]=O>[ClH:1].[ClH:1].[CH2:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[NH:20])[NH:18][CH3:19])[CH:15]=2)[NH:10][CH:9]=1)[CH3:4]
Reactant: [H][H]
Reactant: CCN(CCc1c[nH]c2ccc(C(=N)NC)cc12)Cc1ccccc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: CCNCCc1c[nH]c2ccc(C(=N)NC)cc12
Yield: 142.7 %

Procedure:
The product of Stage (i) (0.18 g) dissolved in absolute ethanol (25 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on charcoal. After the uptake of hydrogen had ceased the catalyst was removed by filtration and the filtrate reduced to dryness. The residue was recrystallised from a mixture of ethanol and ethyl acetate to give the title compound as a powder (0.1 g), m.p. 244°-246°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=C(C=CC=2)C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:27][CH2:28][S:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CCCCCCCCC1C=CC=CC=1)[CH:31]([OH:36])[C:32]([O:34]C)=[O:33])([O:25]C)=[O:24]>>[C:23]([CH2:27][CH2:28][S:29][CH:30]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:42]=1)[CH:31]([OH:36])[C:32]([OH:34])=[O:33])([OH:25])=[O:24]
Reactant: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)OC
Reactant: O=Cc1cccc(CCCCCCCCc2ccccc2)c1
Product: O=C(O)CCSC(c1cccc(CCCCCCCCc2ccccc2)c1)C(O)C(=O)O

Procedure:
Similarly, following the procedure of Example (b), 3-bromobenzaldehyde was reacted with 1-phenylocta-1,7-diyne to yield 3-(8-phenyl-1,7-octadiynyl)benzaldehyde which was reduced to 3-(8-phenyloctyl)benzaldehyde and the latter was reacted as described in Example 35(a), (b) and (c) to give 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)phenyl]-2-hydroxypropanoic acid, dipotassium salt, hydrate as a mixture of isomers, -log KB value 6.2.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:30](=[O:32])[CH3:31])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a stirred solution containing 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (WO 2009/102736) (0.272 g, 0.849 mmol) and pyridine (0.137 mL, 1.90 mmol) dissolved in dichloromethane (2.1 mL) at 0° C. was added acetyl chloride (0.079 mL, 1.10 mmol) dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The solution was diluted with dichloromethane (20 mL) and washed successively with hydrogen chloride (1 N, 1×15 mL), saturated aqueous sodium bicarbonate (1×15 mL) and saturated sodium chloride solution (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (0.291 g, 95%): mp 169-171° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.28 (s, 1H), 2.22 (s, 3H). ESIMS m/z 362 ([M+H]+).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[CH:37][C:38](OC)=[C:39]([OH:41])[CH:40]=1.[CH2:44]1COCC1>>[OH:41][C:39]1[CH:40]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:36]=[CH:37][C:38]=1[CH3:44]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Reactant: C1CCOC1
Reactant: COc1ccc(N)cc1O
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)cc2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 65, 100 mg, 0.225 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (34 mg, 0.25 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 32% (38 mg, 0.071 mmol) of the title compound.
Reaction SMILES: [C:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.OC[CH:40]=[CH:41][C:42]1[CH:64]=[CH:63][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:47])=[CH:44][CH:43]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH2:1][CH:40]=[CH:41][C:42]2[CH:64]=[CH:63][C:45]([C:46]([NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[NH:55][C:56](=[O:62])[O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:47])=[CH:44][CH:43]=2)(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCC=Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-Boc-4-tolylsulfonamide (221 mg, 0.81 mmol) and PPh3 (427 mg, 1.63 mmol) in anhydrous THF (4 ml) under nitrogen was successively added a solution of compound XVIII (200 mg, 0.54 mmol) in anhydrous THF (1 ml) and diethyl azodicarboxylate (DEAD) (214 μl, 1.36 mmol). After 16 h, the reaction mixture was quenched with water and diluted with AcOEt. After separation the organic layer was successively washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane:40/60) to afford the title compound XVIIg (337 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][C:10]([N:26]1[CH2:25][CH:24]2[CH:28]([C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23]2=[O:29])[CH2:27]1)=[O:12]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c(Cl)cccc3Cl)CC12
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2,6-dichlorophenyl)acetic acid (1.43 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 20 hours, then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 23.5 cm), eluting with dichloromethane and collecting 15 cc fractions. Fractions 1 and 2 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (4 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-dichlorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (0.62 g) melting at 201° C. is obtained.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Na].[CH3:12][O:13][C:14](=[O:23])[C:15]([CH:18](OC)OC)=[CH:16]O.O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]1[CH:16]=[N:9][C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:10][CH:18]=1)=[O:23]
Reactant: N=C(N)c1cccnc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(-c2cccnc2)nc1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
To a solution of nicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylic acid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100° C. under N2 for 3 hours. After this time the reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.7 g, 51%). MS: 216 (M+H).
Reaction SMILES: [ClH:1].Cl[CH2:3][C:4](=N)OCC.[CH2:9]([NH:11][C:12]1[CH:13]=[N:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:17]=1[NH2:18])[CH3:10]>CCO>[Cl:1][CH2:10][C:9]1[N:18]([CH2:3][CH3:4])[C:17]2[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOC(=N)CCl
Reactant: CCNc1cnc(C(F)(F)F)cc1N
Reactant: Cl
Solvent: CCO
Product: CCn1c(CCl)nc2cnc(C(F)(F)F)cc21
Temperature: 25 °C

Procedure:
The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 4.87 (s, 2H), 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH2:6][CH2:5]2>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2
Reactant: Fc1cc2c(c(F)c1Br)CCN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Fc1cc2[nH]ccc2c(F)c1Br
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a solution of 5-bromo-4,6-difluoroindoline (3.6 g, 15.4 mmol) in chloroform (150 mL) was added manganese dioxide (5.3 g, 61 mmol) at room temperature/. The mixture was heated to reflux temperature for 2 hours then cooled to room temperature. The reaction was filtered and the filtrate was concentrated in vacuo. Flash column chromatography was then used to provide the title compound (3.6 g, yield 100%) as brown solid. MS (ES+): 232.0 (M+H). 1H NMR (CDCl3, 400 MHz): δ 8.27 (br. s, 1H), 7.19 (m, 1H), 7.02 (d, 1H), 6.61 (m, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Mg+2:11]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O:9][OH:10])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Mg+2:11].[Mg+2:11].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [O-2]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
An aqueous solution of malic acid is prepared by mixing 5.859 kg of malic acid with 18.18 L of water until the solution is clear. An aqueous solution of magnesium oxide is also prepared in a separate container by thoroughly mixing 3.515 kg of magnesium oxide in 18.18 L of water. The magnesium oxide solution is then slowly added to the malic acid solution. The resulting solution is cooled, and then spray dried to produce a powdered dimagnesiumhydroxy malate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[Cl:33])[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccccc2Cl)CC1
Yield: 12 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-chloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (8.2 mg, 12%) as light yellow oil. MS m/e=525.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1C=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[C:5]([CH3:15])[CH:4]=1)#[CH:2].[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24]C(I)=[CH:22][CH:21]=1.CO.[CH3:30][CH2:31]OC(C)=O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:8]1([C:7]2[CH:31]=[CH:30][C:4]([C:3]#[C:1][C:2]3[CH:22]=[CH:21][C:20]([CH2:19][C:18]([O:17][CH3:16])=[O:27])=[CH:25][CH:24]=3)=[C:5]([CH3:15])[C:6]=2[CH3:13])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(Cn2ccnc2)c(C)c1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(-n3ccnc3)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Using General Procedure F; 1-(4-ethynyl-2-methyl-benzyl)-1H-imidazole (Intermediate 141, 101.0 mg, 0.53 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 145.0 mg, 0.53 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (34.0 mg, 0.18 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (124 mg, 0.18 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5% MeOH-EtOAc) afforded 45.0 mg (25%) of the title compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH2:25][CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([N:10]3[CH2:9][CH2:8][CH:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:35][CH:34]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of tert-butyl (2-(5-(4-(4-chlorophenoxy)piperidine-1-carbonyl)-1H-indol-1-yl)ethyl)carbamate (112 mg, 0.23 mmol, Step-1), trifluoroacetic acid (1.5 mL), and dichloromethane (1.5 mL) was stirred at room temperature for 1 hour. After concentration in vacuo, the residue was purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX) to give 83 mg (83% yield) of the title compound as yellow oil. 13 mg of this material was further purified by preparative LC-MS to give 6.6 mg (51% yield) of the title compound.
Reaction SMILES: FC1C=C(F)C=CC=1CN1C2C=CC=C(N)C=2C=N1.[N:20]1[CH:21]=[C:22]([C:29]([OH:31])=O)[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][N:39]1[C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=2[CH:41]=[N:40]1>>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][N:39]1[C:47]2[C:42](=[C:43]([NH:48][C:29]([C:22]3[N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[N:20][CH:21]=3)=[O:31])[CH:44]=[CH:45][CH:46]=2)[CH:41]=[N:40]1
Reactant: Nc1cccc2c1cnn2Cc1ccccn1
Reactant: O=C(O)c1cnc2ccccn12
Agent: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Product: O=C(Nc1cccc2c1cnn2Cc1ccccn1)c1cnc2ccccn12

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(pyridin-2-ylmethyl)-1H-indazol-4-amine, respectively. MS (APCI) m/z=369 (M+H).