Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27][CH3:28]>C1COCC1.ClCCl>[CH3:28][CH2:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([F:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: CCCNc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCNc1cccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.48) is added to a 20°-25° solution of 5-fluoroindole-2-carboxylic acid (I, 0.53 g) in THF (6 ml). After 1 hour of stirring the above reaction is added dropwise via cannula to a solution of [3-(propylamino)-2-pyridinyl]piperazine (II, PREPARATION 7, 0.72 g) in THF (6 ml) at -10° (ice/acetone bath). The reaction is stirred for 30 minutes at -10°, slowly warming to 20°-25°, and stirred 4 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), saline (40 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (40 g silica gel) eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 196°-198°; IR (mineral oil) 3200, 2920-3000, 1630 and 1424 cm-1 ; NMR (300 MHz, CDCl3) 9.82, 7.72, 7.35, 7.27, 7.03, 6.95, 6.86, 6.78, 4.32, 4.09, 3.21, 3.08, 1.71 and 1.05 δ; CMR (300 MHz, CDCl3) 162.3, 159.5, 149.7, 137.4, 135.1, 132.3, 130.7, 127.5, 127.4, 120.4, 116.3, 113.4, 112.9, 112.7, 112.5, 106.1, 105.8, 105.1, 105.0, 49.0, 45.2, 22.5 and 11.6 δ; MS (m/e) 382, 381, 190, 176, 164, 162, 134 and 120.
Reaction SMILES: O=[C:2]([CH3:20])[CH2:3][NH:4][C:5](=[O:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:7]>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:20][C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:6](=[O:7])[C:5](=[O:19])[NH:4][CH:3]=1
Reactant: CC(=O)CNC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
N-(2-Oxopropyl)-N′-[3-(trifluoromethyl)phenyl]ethanediamide (1.6 g, 5.5 mmol) and glacial acetic acid (15 ml) were placed in a vial (20 ml). To this solution was added concentrated sulfuric acid (40 drops), and the flask was sealed, and heated with stirring to 100° C. for 90 minutes. Another 40 drops of sulfuric acid was added, and the reaction was allowed to proceed for another 90 minutes. The reaction mixture was allowed to cool, and acetic acid was removed in vacuo. The residue was partitioned between EtOAc (60 ml) and water (40 ml). The aqueous phase was neutralized by addition of NaOH solution to pH 6 to 7. The organic phase was dried, and upon filtration and evaporation a crude product was obtained, which was purified on silica giving 6-methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (1.1 g, 74%) as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=O)[CH3:17].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([NH2:25])[CH3:17]
Reactant: CC(=O)c1ccc(F)cc1-c1ccc(F)cc1F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(F)cc1-c1ccc(F)cc1F

Procedure:
The title compound was prepared from 1-(2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethanone (720 mg, 2.9 mmol), anhydrous methanol (10 mL), ammonium acetate (4.44 g, 58 mmol), and sodium cyanoborohydride (362 g, 5.8 mmol) according to the procedure and in the same manner as described in Example 105, step b. The crude amine was immediately used without further purification in Example 114, step c;
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][C@@H:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(Cl)Cl.N1C=CN=C1>O>[Si:18]([O:8][C@H:7]1[CH2:6][CH2:5][C@@H:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C@@H:2]1[F:1])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@@H]1CC[C@H](O)[C@@H](F)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a 500 mL flask was added (1R,3S,4S)-ethyl 3-fluoro-4-hydroxycyclohexane-carboxylate (17 g, 89.3 mmol, 97.9% ee), TBSCl (17.5 g, 116.1 mmol) and DCM (200 mL). Imidazole (12.1 g, 178 mmol) was added to the resultant clear solution and the reaction mixture was stirred for 16 hours. Water (100 mL) was added and the mixture was stirred for a further 10 minutes. The phases were separated and the organic layer was washed with water (100 mL) and concentrated under reduced pressure (40±5° C., 50˜250 mbar). Purification by flash chromatography on silica eluting with a mixture of heptane and ethyl acetate (100:1) gave (1R,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexanecarboxylate as a colorless oil (20.6 g, yield 75.7%). 1H NMR (400 MHz, DMSO-d6): 4.38˜4.52 (m, 1H), 4.03˜4.08 (dd, J=12 Hz, J=8 Hz, 2H), 3.77˜3.81 (m, 1H), 2.54˜2.60 (m, 1H), 1.93˜2.06 (m, 1H), 1.58˜1.86 (m, 4H), 1.46˜1.50 (m, 1H), 1.17˜1.20 (t, J=12 Hz, J=6 Hz, 3H), 0.85 (s, 9H), 0.03˜0.04 (d, J=4 Hz, 8H), [M+H]+=305.1 via GC-MS (Instrument: Agilent Technologies, GC 6890N, MS 5975C. GC conditions: Column: HP—5 MS, Capillary: 30.0 m×250 μm×0.25 μm, Detecor parameters: Temperature: 350° C., Flow H2: 40 mL/min, Air flow: 400 mL/min, Makeup (He): 40 mL/min. Injector parameters: temperature: 200° C. Split ratio: 100:1. Carrier gas: He, Flow: 2.0 mL/min, Mode: Constant flow. Oven parameters: 0 min, 50° C.; 2.0 min, 50° C.; 5.33 min, 100° C.; 15.83 min, 270° C. Injection volume: 1 μL, Syringe wash solvent: acetonitrile. MS conditions: Volt: 70 EV, Scan range: m/z=50˜550)
Reaction SMILES: C(C[CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.NC[C:35]1[O:36][C:37]([CH3:40])=[N:38][N:39]=1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:11])[CH3:10])[C:6]([NH:5][CH2:4][C:35]3[O:36][C:37]([CH3:40])=[N:38][N:39]=3)=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: Cc1nnc(CN)o1
Product: Cc1nnc(CNC(=O)[C@@H](NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)C(C)(C)C)o1

Procedure:
Compound 113 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-aminomethyl-5-methyl-1,3,4-oxadiazole. LCMS (+ESI) m/z=489.3 [M+H]+. 1H NMR (CDCl3) δ 7.90 (d, J=9.3 Hz, 1H), 7.46-7.52 (m, 1H), 7.28-7.32 (m, 1H), 7.19-7.26 (m, 1H), 6.91 (br, 1H), 4.82 (s, 2H), 4.74-4.79 (m, 1H), 4.58-4.63 (m, 1H), 4.28 (d, J=9.3 Hz, 1H), 3.94 (t, J=5.6 Hz, 2H), 3.17 (br, 2H), 2.51 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:17](=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[NH:24][C:25]([C@@H:27]([NH2:31])[CH2:28][O:29][CH3:30])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[NH:24][C:25]([C@@H:27]([NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[C:17](=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[C:2]([CH3:1])[CH:3]=3)[CH2:28][O:29][CH3:30])=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCCC1=O
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H](NC(=O)c1ccc(N2CCOCCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoic acid, (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([OH:7])=[O:6].[CH:13](O)=O>O>[CH3:12][N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: CNc1ccc(C(=O)O)cc1N
Reactant: O=CO
Solvent: O
Product: Cn1cnc2cc(C(=O)O)ccc21
Temperature: 85 °C
Yield: 84 %

Procedure:
To a stirred solution of 3-amino-4-(methylamino)benzoic acid (9 g, 1.0 eq) in 50 mL water, was added 50 mL formic acid and heated at 85° C. overnight. The mixture was cooled, concentrated in vacuo, and dissolved in water. Then 2N HCl was added to adjust pH to 1-3. The suspension was filtered and washed with water to give the product (9.7 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.37 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=[CH:7]2.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc2cccc(Br)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2cccc(Br)c2c1
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of 5.73 (21.6 mmoles) of 8-bromo-2-naphthoic acid, methyl ester (VIII) in 50.0 mL of ethanol was added 21.6 mL (216 mmoles) of 10N NaOH at room temperature. After 1 hour, an excess of 1N HCl was added. The precipitate was collected, washed with 1N HCl and air dried to give 5.40 g (yield: 99%) of 8-bromo-2-naphthoic acid; 1H-NMR: δ13.35 (bs, 1H), 8.80, (s, 1H), 8.11 (m, 3H), 7.98 (d, J=8.0 Hz, 1H), 7.59 (dd, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=O)(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][O:33][C:34]2([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:30]=[N:29][CH:28]=[N:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([N:37]2[CH2:38][CH2:39][C:34]([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)([O:33][CH2:32][CH2:31][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:35][CH2:36]2)=[O:24])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCn2cncn2)(c2cccnc2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCn3cncn3)(c3cccnc3)CC2)c(C)c1
Yield: 24 %

Procedure:
The desired target compound was synthesized under reaction conditions analogously to the process described for Example 61 (see below) from (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] and tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine G]. Yield: 24%. MS, Rt=3.3 min, m/z=627.4 [MH]+
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1)([CH3:3])=[CH2:2].[H][H]>CCO.C1COCC1.[Pd]>[CH:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)C)c3o2)cc1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
7-Isopropenyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran 116 (0.28, 0.95 mmol) was hydrogenated over an atmosphere of hydrogen with 10% Pd/C (0.05 g) in EtOH/THF (10 ml). After 2 hr, the reaction was filtered through celite and concentrated to give 117 as a solid (0.27 g, 95%).
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH3:27])[CH2:6][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 83, 60.0 mg, 0.17 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 38.0 mg (69%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[S:19][CH:20]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[C:4]([CH3:15])[C:3]([C:16]3[N:17]=[C:18]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[S:19][CH:20]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:9][CH2:10]1
Reactant: Cc1cc(N2CCC(=O)CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(N2CCC(O)CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of N-(4-(2,6-dimethyl-4-(4-oxopiperidin-1-yl)phenyl)thiazol-2-yl)isonicotinamide (33 mg, 0.081 mmol) in methanol (5 mL) was added NaBH4 (33 mg, 0.78 mmol). The mixture was stirred for 30 min at rt. Then saturated aqueous NH4Cl solution (2 mL) was added to quench the reaction. The mixture was extracted with EtOAc (5×2 mL). After removal of solvent, the residue was purified on a silica gel column (EtOAc) to provide N-(4-(4-(4-hydroxypiperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide as yellow solid (29.8 mg, 90%). MS (ESI) m/z 409.2 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[F:18].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([N:1]2[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]2)=[C:11]([F:18])[CH:12]=1)#[N:15]
Reactant: O=C(O)c1c[nH]cn1
Reactant: N#Cc1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-n2cnc(C(=O)O)c2)c(F)c1
Temperature: 120 °C

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid (500 mg), 4-fluoro-3-fluorobenzonitrile (0.93 g), and N,N-diisopropyl-ethyl amine (3.6 mL) in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=1.85 min; Mass spectrum (APCI): m/z=232 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC.C(O)(C)C>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: c1ccc(CO[C@@H]2CCC[C@H]2c2ccn[nH]2)cc1

Procedure:
The 5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1H-pyrazole prepared in Example 148b was optically resolved with CHIRALPAK AD-H (Daicel Corp.; hexane/isopropanol=9:1) to yield the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([NH:20]S(C(C)(C)C)=O)[CH3:19])=[CH:14][CH:13]=1)=[N:7]2.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[N:43][N:44](C(OC(C)(C)C)=O)[CH:45]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CCOCC.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1.C(O)C.O>[C:27]1([C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][C:8]3[C:3]([CH:4]=2)=[C:2]([C:41]2[CH:42]=[N:43][NH:44][CH:45]=2)[N:11]=[CH:10][CH:9]=3)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of N-{1-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]ethyl}-2-methylpropane-2-sulfinamide (2-3, 0.10 g, 0.22 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.12 g, 0.39 mmol), cesium carbonate (0.21 g, 0.64 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.013 g, 0.025 mmol) in a 7/3/1 mixture of dioxane/ethanol/water (3 mL) was heated to 100° C. in a microwave for 10 minutes. The crude reaction mixture was treated with HCl in ether (3 mL). After 30 minutes, the reaction was concentrated and purified by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA, Sunfire C18) to give (1R)-1-{4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]phenyl}ethanamine (2-4) as a white solid. MS (M+H)+: 428
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:7])[CH3:6]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:17]=[C:16]([CH:15]=[CH:14][C:3]=1[O:4][C:5]([CH3:7])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:6])[NH2:18]
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1Cl)c1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ccc(N)cc1Cl)c1ccccn1
Reaction time: 6 h
Yield: 62.8 %

Procedure:
2-[1-(2-Chloro-4-nitrophenoxy)-1-methylethyl]pyridine (800 mg, 2.74 mmol) was dissolved in ethyl acetate (50 ml). The mixture was purged with nitrogen, and platinum on activated carbon (10%, 100 mg) was added. The mixture was hydrogenated for 6 hours using a burette filled with hydrogen. The system was degassed and purged with nitrogen, and the catalyst removed by filtration. The filtrate was concentrated in vacuo, and the residue purified by chromatography, eluting with 20% to 30% ethyl acetate in iso-hexane. The appropriate fractions were evaporated to give 3-chloro-4-(1-methyl-1-pyridin-2-ylethoxy)aniline as a straw-coloured oil (452 mg, 63%); NMR Spectrum (DMSO-d6, 400 MHz, CDCl3) 1.63 (s, 6H), 3.41 (bs, 2H), 6.25 (dd, 1H), 6.35 (d, 1H), 6.65 (d, 1H), 7.11 (ddd, 1H), 7.63 (ddd, 1H), 7.77 (d, 1H), 8.50 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:26][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCc2cnc3c(N)nc4cc(/C=C/C(=O)O)ccc4c3c2)c(C)c1

Procedure:
(E)-3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)acrylic acid was prepared from (E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)acrylate (from Example 80) following the procedures described for Example 68. 1H NMR of TFA salt (DMSO-d6): δ 12.66 (s, 1H), 9.09 (s, 1H), 8.88 (s, 1H), 8.66 (d, 1H), 7.95 (d, 1H), 7.91 (s, 1H), 7.75 (d, 1H), 7.10 (d, 1H), 6.77-6.71 (m, 2H), 6.68 (dd, 1H), 3.70 (s, 3H), 3.16 (t, 2H), 3.00 (t, 2H), 2.30 (s, 3H). LRMS [M+H]=414.2
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:14]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:27])=[CH:21][CH:22]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(O)(c3ccccc3)CC2)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A solution of 4-hydroxy-4-phenyl piperidine (221 mg, 1.25 mmol) in DMSO (1 mL) was treated with tert-butyl-4-fluorobenzoate (196 mg, 1.00 mmol) and powdered potassium carbonate (173 mg, 1.25 mmol), stirred vigorously at 125° C. for 16 hours, cooled to room temperature, diluted with diethyl ether, washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 354 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[C:26]4=[N:27][C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:29]([N+:32]([O-])=O)[C:30](=[O:31])[N:25]4[CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:32][C:29]1[C:30](=[O:31])[N:25]2[CH2:24][CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][CH:12]([CH3:13])[CH2:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=4)[N:20]=3)[C:26]2=[N:27][C:28]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)c([N+](=O)[O-])c3=O)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(CN)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)c(N)c3=O)n1
Reaction time: 2 h

Procedure:
To a solution of 9-{2-[2-(3-azidomethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (61 mg, 0.11 mmol) in 1 mL methanol was safely added 10 mg palladium on carbon (10%) and stirred over an atmosphere of hydrogen delivered by a balloon. After 2 h, the reaction was filtered through a bed of Celite and solvent removed under reduced pressure. Product was purified on silica. M+1=483 1H NMR (CDCl3) d (3H, 1.19 ppm), m (2H, 2.20 ppm), dd (1H, 2.76 ppm), dd (1H, 2.96 ppm), s (2H, 3.84 ppm), m (6H, 4.08 ppm), q (1H, 4.30 ppm), d (1H, 4.95 ppm), m (4H, 7.13 ppm), t (1H, 7.28 ppm), t (1H, 7.36 ppm), t (2H, 7.45 ppm), d (2H, 7.80 ppm), d (1H), 8.03 ppm).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:9]1([CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:15]#[N:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccccn1
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
To a cold (0° C.) solution of 2-chloropyridine (4.8 mL, 50 mmol) and benzyl cyanide (5.8 ml, 50 mmol) in 120 ml of DMF, was added with potassium t-butoxide (11.2 g, 100 mmol), under N2. The reaction mixture was reacted for 3 hours and then partitioned between EtOAc and H2O. The resulting layers were separated and the EtOAc layer was washed sequentially with NaHCO3 and brine, dried over Na3SO4, filtered and concentrated in vacuo. The crude material was purified by recrystallization (hexanes/EtOAc).