Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:35][CH:36]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCN)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Agent: I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methylisothiourea hydriodide (0.39 g, 1.0 mmol) was added to a solution of 13 (0.49 g, 1.07 mmol) in THF (8 mL) containing diisopropylethylamine (0.18 mL, 2 mmol). The reaction mixture was stirred at reflux for 2.5 h and at room temperature overnight. After this time, the solvent was removed under reduced pressure. The brown residue was washed with ether (2×30 mL) and methylene chloride (2×10 mL). The residue was dissolved in a minimal volume of methanol (approx. 2 mL) and poured into water. The precipitate was collected, washed with water and dried overnight to give crude 11 (0.5 g) as a yellow solid. The compound II (0.4 g, 54%) was purified by flash chromatography on silica gel (eluent: chloroform/methanol/ammonium hydroxide=10:1:0.1) as a yellow solid. [α]D25=−20.4° (c=1.0, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt](=O)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(Br)cc1C=Cc1cccc(Br)c1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(Br)cc1CCc1cccc(Br)c1

Procedure:
The product from step (iii) (8.5 g) and platinum(iv)oxide (0.87 g) in toluene (150 ml) was stirred under 1 atmosphere of hydrogen for 72 hours. The mixture was filtered and the filtrate evaporated under reduced pressure. Yield 6. 1 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:23][N:22]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Yield: 90.5 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid (1.052 g, 0.003922 mol) was allowed to react with hydroxylamine hydrochloride (0.3245 g, 0.00467 mol) in the presence of sodium carbonate (0.498 g, 0.00470 mol) in absolute ethanol to give 1.006 g of 4-hydroxyimino-4-(4′-methyl-biphenyl-4-yl)-butyric acid as a white solid; mp 176.5-177.5° C.
Reaction SMILES: C(O)(=O)C.[S:5]([O-:9])(=[O:8])(=[O:7])[CH3:6].C([O:17][CH:18]([CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:19][S:20]([CH2:23][CH2:24][CH2:25][N+:26]([CH3:29])([CH3:28])[CH3:27])(=[O:22])=[O:21])C1C=CC=CC=1>[C].[Pd].O>[S:5]([O-:9])(=[O:8])(=[O:7])[CH3:6].[OH:17][CH:18]([CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:19][S:20]([CH2:23][CH2:24][CH2:25][N+:26]([CH3:27])([CH3:29])[CH3:28])(=[O:22])=[O:21]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCC[N+](C)(C)C)OCc1ccccc1
Agent: [Pd]
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CS(=O)(=O)CCC[N+](C)(C)C
Yield: 88.1 %

Procedure:
Into a mixed solvent consisting of 50 ml of acetic acid and 5 ml of water is dissolved 1.4 g of 3-[(2-benzyloxy-3-octadecyloxypropyl)sulfonyl]propyltrimethylammonium mesylate and the solution is shaked in the presence of palladiumcarbon under hydrogen streams. The catalyst is then removed by filtration and the filtrate is concentrated. The resulting residue is treated with acetone to give 1.07 g of the captioned compound as powder.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:41][NH2:42].CO>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1)NO
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(3-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 109) (410 mg, 1.04 mmol) in dichloromethane (10 ml) was treated with 1,1′-carbonyidiimidazole (169 mg, 1.04 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (418 μl, 3.12 mmol) was added and the reation mixture was stirred for 18 hours. The reaction mixture was then treated with methanol (5 ml) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×30 ml) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 (dichloromethane:methanol) gradually changing to 95:5 (dichloromethane:methanol) to afford a white waxy solid. The solid was recrystallised from ethyl acetate to afford the title compound as a white solid (128 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[CH:37]=[CH:36][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]2)=[CH:27][CH:26]=1.CO.CCOC(C)=O>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[CH:37]=[CH:36][C:28]([CH2:29][N:30]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]4)=[CH:27][CH:26]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: O[C@H]1CCN(Cc2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Cl)c4s3)cc2)C1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of 98 (2.44 g, 5.30 mmol) and bromide 97 (1.3 g, 5.07 mmol) in dry toluene (30 mL) was added Pd(PPh3)4 (290 mg, 0.25 mmol). The reaction mixture was heated to reflux for 1.5 h, cooled to room temperature and the solvent was removed under reduced pressure. The resultant solid was purified by column chromatography, eluents EtOAc-Hexane (1:1) then MeOH/EtOAc (20:80), to afford title compound 99 (1.24 g, 71% yield) as a white solid. MS (m/z): 345.1/347.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:17][C:18]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:19]=1[C:20]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29]OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:21]>CN(C=O)C.CCOC(C)=O.O>[Cl:17][C:18]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][C:19]=1[C:20]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][N:12]2[C:11]([CH3:14])=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:13]2)[CH2:25][CH2:24]1)=[O:21]
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: COc1ccc(-c2cc(C)n[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C)n(C[C@H]3CC[C@H](NC(=O)c4cc(C(F)(F)F)ccc4Cl)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(4-Methoxyphenyl)-3-methyl-1H-pyrazole (91 mg, 0.483 mmol) was dissolved in dry DMF (2 ml). The flask was flushed with N2 and the solution was treated with NaH (BO % in mineral oil) (19.33 mg, 0.483 mmol) and stirred at RT for ˜10 mins. Trans-methanesulfonic acid 4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexylmethyl ester (Intermediate G) (100 mg, 0.242 mmol) was added and the mixture was heated to 50° C. for 4 hours. After cooling to RT, the mixture was diluted with EtOAc/H2O (20 ml) and transferred to a separating funnel. The organic layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil. Purification of the crude product by chromatography on silica eluting with EtOAc/iso-Hexane afforded the title compound as a white solid; LCMS Rt=1.39 min, [M+H]+ 506.3; Method 2 minLC—30_v002. 1H NMR (400 MHz, CDCl3) δ 7.9 (1H, s), 7.7 (1H, d), 7.6 (1H, d), 7.55 (1H, d), 6.95 (2H, d), 6.25 (1H, s), 5.95 (1H, d), 4.0 (1H, m), 3.95 (2H, d), 3.85 (3H, s), 2.3 (3H, s), 2.2 (2H, d), 2.1 (1H, m), 1.8 (2H, d), 1.25 (4H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][C:9](Cl)=[C:10]([Br:12])[CH:11]=1)=[O:5])[CH3:2].[OH:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[N:8][C:7]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(Cl)nc1C
Reactant: OCC1CC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc(Br)c(OCC2CC2)nc1C
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-6-chloro-2-methyl-3-pyridinecarboxylic acid ethyl ester (CAN 41598-77-0) (0.7 g, 2.5 mmol), hydroxymethylcyclopropane (0.57 mL, 6.2 mmol) and DBU (0.94 mL) was heated for 15 min in a microwave oven to 100° C. The reaction mixture was cooled to room temperature and partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with a cyclohexane:ethyl acetate gradient to yield the title compound as light yellow solid, MS (ISP) 314.0, 316.0 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([CH:25]=[O:26])=[N:21][C:22]=1[O:23][CH3:24].O>COCCOC>[CH3:24][O:23][C:22]1[N:21]=[C:20]([CH:25]=[O:26])[CH:19]=[CH:18][C:17]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1nc(C=O)ccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(C=O)ccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
Tetrakistriphenylphosphine palladium (403 mg), phenylboronic acid (510 mg) and a 2 M sodium carbonate solution (3.5 mL) were sequentially added to a solution of 5-bromo-6-methoxypyridine-2-carbaldehyde (753 mg) in 1,2-dimethoxyethane (23 mL) in a nitrogen atmosphere, and the mixture was stirred at 80° C. for three hours. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→1:1) and further purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to give 6-methoxy-5-phenylpyridine-2-carbaldehyde (445 mg, 60%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[N+:18]=[N-:19]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Under nitrogen, a solution of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene (1.2 g, 0.0037 mol), NaN3 (0.6 g, 0.0092 mol) and DMF (25 ml) was heated at 100° C. After 18 hours, the solution was cooled, poured into H2 0, and filtered to yield 0.8 g of product. The filtrate was extracted with ethyl acetate (2×). The organic layers were dried, filtered and concentrated to dryness to yield an additional 0.4 g of product (75%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 73.8 %

Procedure:
A mixture of 722.7 mg (2.70 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 100.1 mg (2.70 mmol) of 4-phenoxyaniline and 312.1 mg (2.70 mmol) of pyridine hydrochloride in 30 mL of 2-ethoxyethanol is heated at 110–120° C. for 3 hours. After cooling, the mixture is diluted with water, neutralized with an aqueous solution of saturated sodium carbonate, and extracted with ethyl acetate. The separated organic layer is washed with brine and dried over sodium sulfate. Removal of the solvent yields a solid residue which is purified by flash chromatography (elution with 99:1 methylene chloride/methanol), giving 831.0 mg (73.9%) of the product as a deep yellow solid, mp 220–222° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C)c(OS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 93 %

Procedure:
To a solution of methyl 3-hydroxy-4-methylbenzoate (3.0 g, 18.1 mmol) in pyridine (20 mL) was added methanesulfonyl chloride (2.80 mL, 36.1 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (4.11 g, yield 93%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.C1(C=CC(O)=CC=1)O.[Na].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:34][CH2:33][C:30]1[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][CH:31]=1)[C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCC1N2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A suspension of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (170 mg, 0.80 mmol; Example 4A), hydroquinone (9 mg, 0.08 mmol), and -32% sodium in paraffin (79 mg, 1.1 mmol; Aldrich) in anhydrous dimethyl sulfoxide (800 μL) was sealed in a septum-capped reaction tube. After thoroughly evacuating and purging the vessel with nitrogen, 2-methyl-5-vinylpyridine (143 mg, 1.2 mmol, International Publication No. WO2001/017968) was added, and the reaction was stirred at 100° C. for 48 hours. The thick mixture was cooled to room temperature, poured into water (5 mL), and extracted with ethyl acetate (3×). The combined organic phases were washed with water, filtered through diatomaceous earth, dried (Na2SO4), concentrated, and purified by chromatography on silica (0-5% gradient of concentrated aqueous ammonium hydroxide in acetonitrile). The resulting material was purified further by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.10-1.26 (m, 1H), 1.84-2.06 (m, 4H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86 (dd, J=16, 4.6, 1H), 2.97 (ddd, J=14, 5.4, 5.4, 1H), 3.09 (ddd, J=14, 9.0, 6, 1H), 3.75-3.86 (m, 1H), 4.14 (ddd, J=15, 9.0, 5.4, 1H), 4.30 (ddd, J=15, 6, 5.4, 1H), 4.44 (d, J=4.6, 1H), 6.90 (d, J=8.3, 1H), 7.10 (d, J=7.9, 1H), 7.17 (d, J=8.3, 1H), 7.20-7.25 (m, 2H), 7.75 (d, J=2.1, 1H); MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([O:8][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1ncc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 2-aminopyrimidin-5-ol (0.500 g, 4.50 mmol) in dry MeOH (10 mL), K2CO3 (0.622 g, 4.50 mmol) and benzyl bromide (0.535 mL, 4.50 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, then dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel using 50% ethyl acetate in petroleum ether. The desired fractions were concentrated to give 5-(benzyloxy)pyrimidin-2-amine as an off-white solid (0.222 g 25%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.06 (s, 2H), 6.21 (s, 2H), 7.28-7.30 (m, 5H), 7.45 (s, 2H). LCMS: RT 1.060 min; 202.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:23][NH:22][CH2:21]C[C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:24](=[O:29])([O:27][CH3:28])OC.C(N(C(C)C)CC)(C)C>C1COCC1.CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[CH2:23][N:22]([C:24]([O:27][CH3:28])=[O:29])[CH2:21][C:16]=3[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)OC
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1Cc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nc2C1
Temperature: 60 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
A solution of N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.020 g, 0.063 mmol) in anhydrous THF (2.0 mL) was treated sequentially with dimethyl carbonate (0.006 g, 0.063 mmol) and diisopropylethylamine (0.025 mL, 0.095 mmol). The reaction was heated to 60° C. and allowed to stir for 5 hours. The reaction was cooled to room temperature, then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a EtOAc/Hexanes gradient affording the final product in 64% yield (0.015 g, 0.040 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1)([CH3:29])[CH3:28]
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 79 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (80 mg, 0.26 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (78 mg, 79%) which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[F:63][C:57]([F:62])([C:58]([F:59])([F:61])[F:60])[CH2:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][CH:39]([NH:38][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[OH:41])=[CH:51][CH:52]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (153 mg, 0.801 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 g, 0.801 mmol) and 1-hydroxybenzotriazole monohydrate (123 mg, 0.801 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (0.30 g, 0.763 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered using a glass filter filled with silica gel, and the filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.284 g, 66%) as colorless crystals.