Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[CH3:22][C@:23]12CC[C@H]3[C@@H](CCC4[C@@H]3CCC(=O)C=4)[C@@H]1CCC2>O1CCOCC1>[CH2:22]([C@@H:10]1[CH2:11][C:12]2[C@H:17]([CH2:16][CH2:15][C:14](=[O:21])[CH:13]=2)[C@@H:18]2[C@@H:9]1[C@@H:6]1[C@@:4]([CH2:20][CH2:19]2)([CH3:5])[C@H:3]([CH2:2][OH:1])[CH2:8][CH2:7]1)[CH3:23]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@H]1CC[C@H]2CO
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@@H]3[C@H]1CC2
Solvent: C1COCCO1
Product: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@@H]3[C@H]12

Procedure:
xvi)—Following a procedure analogous to that described under iv of Example 1, the product obtained in the previous step (2.15 g) was converted to (7α,14β,7α)-7-ethyl-17-hydroxymethyl)estr-4-en-3-one (0.60 g), [α]D20=+68 ° (c=0.50, dioxane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][CH:17]2[CH2:16][CH2:15][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([N:13]([CH3:27])[CH3:12])[CH2:19][CH2:18]2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
970 mg C-(1H-Indol-3-yl)methylamine and 1.44 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (50 ml) under argon. Glacial acetic acid (13.2 mmol) and 1.82 g sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 72 hours at RT. For working up, the reaction mixture was concentrated, water (20 ml) and ether (30 ml) were added to the residue and the mixture was stirred vigorously. The aqueous phase was separated off, washed with ether (2×15 ml), adjusted to pH 11 with five molar sodium hydroxide solution and extracted with ethyl acetate (4×25 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product (2.11 g) was chromatographed over silica gel with methanol/triethylamine (199:1). 465 mg of the nonpolar diastereomer of N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained (m.p. 182-184° C.), from which the corresponding dihydrochloride was precipitated with chlorotrimethylsilane (443 μl) in 2-butanone/acetone (20 ml/50 ml) (498 mg; m.p. 164-168° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N+:26]([O-:28])=[O:27])=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=2[CH:25]=1.[OH:29]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N+:26]([O-:28])=[O:27])=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=2[CH:25]=1)=[O:29]
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccccn3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCS(=O)c3ccccn3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(2-pyridylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: N#Cc1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCCOc3cccc(C#N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
616 mg (1.91 mmol) of 1-t-butoxycarbonyl-4-(4-aminophenoxy)piperidine, 432 ml (1.91 mmol) of 3-(2-bromoethoxy)benzonitrile and 634 mg (3.82 mmol) of potassium iodide were dissolved in 20 ml of dimethylformamide. 2.64 g (19.1 mmol) of potassium carbonate was added to the solution, and they were stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure. After the treatment with ethyl acetate as extractant in an ordinary manner, the crude product was obtained. This product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:9]=1)[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:47][O:48][NH2:49]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([C:17]([NH:49][O:48][CH3:47])=[O:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:9]=1)[CH3:2]
Reactant: CON
Reactant: CCOCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Product: CCOCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)NOC)cc12

Procedure:
The title compound was prepared as in example 116, step 3, using 3-[(2-ethoxyethoxy)methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methyl morpholine, and O-methyl hydroxylamine hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.07 (t, J=6.95 Hz, 3H) 3.40 (q, J=6.99 Hz, 2H) 3.47-3.51 (m, 2H) 3.53-3.57 (m, 2H) 3.68 (s, 3H) 4.67 (s, 2H) 5.56 (s, 2H) 7.16 (t, J=8.97 Hz, 2H) 7.31-7.40 (m, 2H) 7.83 (s, 1H) 8.26 (s, 1H) 8.84 (s, 1H) 11.73 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]3[C:3]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:24][CH:23]=1
Reactant: COCn1nc2c(-c3ccncc3)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 20 °C
Yield: 75.1 %

Procedure:
To a degassed mixture of crude 7-bromo-2-(methoxymethyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (620 mg, 1.85 mmol), 4-chlorophenylboronic acid (850 mg, 5.55 mmol) and K2CO3 (1.02 g, 7.4 mmol) in 1,4-dioxane (18 mL) and H2O (6.0 mL) under argon at 20° C. was added Pd(PPh3)4 (107 mg, 0.093 mmol). The reaction mixture was refluxed for 15 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (20 mL), then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 0-60% gradient of EtOAc in hexanes to obtain the title compound as a yellow solid (510 mg, 1.39 mmol). MS: [M+H]+=367.1. 1H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 5.32 (s, 2H), 6.62 (d, J=7.1 Hz 1H), 7.01-7.09 (m, 2H), 7.17-7.22 (m, 2H), 7.23-7.29 (m, 2H), 7.85 (d, J=7.1 Hz, 1H), 8.55 (d, J=4.40 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:57]3[CH2:58][CH2:59][CH:54]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=4[O:47][CH3:46])[CH2:55][CH2:56]3)=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Reactant: COc1ccccc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1C1CCN(C(=O)c2c(C)[nH]c3cc(Cl)ccc23)CC1
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 0.040 g (0.19 mmol) 6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol) N,N-diisopropylethylamine and 0.061 g (0.19 mmol) 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml dry N,N-dimethylformamide were added 0.038 g (0.20 mmol) 4-(2-methoxy-phenyl)-piperidine at room temperature. After stirring for 1 h the reaction mixture was quenched with 0.5 M aqueous sodium hydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.050 g; 69%) as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14]CC)=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[OH-].[Na+]>O.C(O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29](/[CH:32]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:30][CH:31]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.36 g) was added to an ethanol (30 ml) solution of ethyl diethylphosphonoacetate (1.4 g) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, to which was added 4-[(4-methoxyphenyl)oxy]benzenecarboaldehyde (1.2 g). The reaction mixture was stirred at room temperature for 2 hours, which was further stirred at 50° C. for 30 minutes. The reaction mixture was cooled, to which were added water (20 ml) and sodium hydroxide (0.5 g). The reaction mixture was stirred at room temperature for 2 hours, and concentrated. 2N Hydrochloric acid was added to the residue to become acidic, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.2 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:11]2[S:10][CH2:16][C:14](=[O:15])[N:13]=2)=[N:4][CH:5]=1
Reactant: Cc1cnc(CN)cn1
Reactant: O=C1CSC(=S)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CNC2=NC(=O)CS2)cn1
Temperature: 0 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 2-(aminomethyl)-5-methyl-pyrazine (3.69 g, 30 mmol) and Rhodanine (3.59 g, 27 mmol) in acetonitrile (100 mL) was added DIPEA (10.45 mL, 60 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.15 g, 30 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in acetonitrile (25 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air, 1.5 g (25% yield) of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-thiazol-4-one was isolated as a white solid: HRES(+) m/e calcd for C9H10N4OS (M+H)+223.0648, found 223.0648.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[OH-].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Br:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]1=[O:13]
Reactant: O=C1Nc2ccccc2CCC1Br
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(Br)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Bromo-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (300 mg) was added in one portion to a stirred suspension of potassium hydroxide (90 mg) and tetrabutylammonium bromide (40 mg) in tetrahydrofuran (10 ml) maintained at 0° under a nitrogen atmosphere. Stirring was continued for 5 minutes, then ethyl bromoacetate (200 mg) was added in one portion. The reaction mixture was allowed to warm to room temperature while stirring for an additional 3 hours. The tetrahydrofuran was removed under reduced pressure and the residue partitioned between water (5 ml) and ether (25 ml). The organic phase was washed with 2N hydrochloric acid (5ml), dried over magnesium sulfate, and the solvent removed under reduced pressure to give 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 114°-116°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[C:27](OC)=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH2:27][OH:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COC(=O)/C=C/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc(/C=C/C=C/CO)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 24, methyl (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienoate was subjected to reduction with diisobutylaluminum hydride to yield (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadien-1-ol, which was recrystallized from ethyl acetate to give colorless needles, m.p.149-151° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Sc2cccc(C(=O)O)c2)cc1
Reaction time: 24 h

Procedure:
A mixture of 3-[(4-nitrophenyl)thio]benzoic acid (11.2 g, 40.7 mmol) and 10% Pd/C (0.5 g) in ethanol (250 mL) was hydrogenated at atmospheric temperature and pressure for 24 h. The mixture was filtered through Celite and concentrated in vacuo to give the required aniline as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:17])[CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.I.[PH2](O)=O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([Br:17])=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Brc1ccc2cc3cc(Br)ccc3cc2c1
Temperature: 25 °C

Procedure:
Subsequently, a mixture of 2,6-dibromoanthraquinone (22.41 g, 61.23 mmol), acetic acid (250 mL), 56-58% hydriodic acid (100 mL), and 50% hypophosphorous acid (55 mL) was refluxed for 5 days. The mixture was then cooled to room temperature and poured into ice water (800 mL). Thereafter, the precipitate was filtered and washed with water and ethanol. The precipitate was then re-crystallized from toluene (620 mL) to give 14.49 g of pale yellow flake-like crystals of 2,6-dibromoanthracene (Compound 24).
Reaction SMILES: Cl.[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[O:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[C:24]([CH3:26])=[CH2:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:29]([O:28][C:23](=[O:27])[CH:24]([CH3:26])[CH2:25][N:19]1[CH2:20][CH2:21][O:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:16][CH:15]=2)[CH2:18]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CN(CC(C)C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 140 °C
Yield: 50.7 %

Procedure:
To a suspension of 2-(4-octyloxy-phenyl)-morpholine hydrochloride (0.17 g; 0.5 mmol) in DMF (5.00 mL) was added tert-butyl methacrylate (0.17 mL; 1.0 mmol) and DBU (0.23 mL; 1.5 mmol) The resulting mixture was heated at 140° C. in a sealed flask overnight. After cooling to RT the reaction mixture was partitioned between 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 2-methyl-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.11 g).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][CH2:49][OH:50]>CN(C)C=O>[OH:50][CH2:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:36])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (360 mg, 0.70 mmol) (Example 22 (a)) was dissolved in dimethylformamide (2.1 ml) . Sodium iodide (15 mg, 1 mmol), triethylamine (142 mg, 1.4 mmol) and 3-chloro-1-propanol (132 mg, 1.4 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 3 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (3 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the dichloromethane solution and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (6 ml). The aqueous solution was washed with ether (6×3 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 192 mg (68%), FAB MS: 405(M+1). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Cl:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:30]2[CH:29]=[C:28]([Cl:27])[CH:33]=[CH:32][N:31]=2)=[O:35])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cc(Cl)ccn1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cc(Cl)ccn2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-chloro-pyridine-2-carboxylic acid.
Reaction SMILES: O[CH:2]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl.C1(C)C=CC=CC=1>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(O)c2nccs2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2nccs2)cc1
Yield: 83.6 %

Procedure:
The product of Step 1 (4.00 g, 16.05 mmol) was taken up in DCE (80 ml) with triethylsilane (25.6 ml, 160 mmol), and trifluoroacetic acid (24.72 ml, 321 mmol) was added. The reaction was stirred at reflux overnight. The reaction was diluted with toluene and evaporated to dryness. The residue was taken back up in EtOAc, washed with aqueous saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-(1,3-thiazol-2-ylmethyl)benzoate (3.13 g, 13.42 mmol, 84% yield) as a pale yellow gum that crystallized upon standing. MS ESI: [M+H]+ m/z 234.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=1.[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH2:30][NH2:31])=[C:27]([CH3:29])[CH:28]=2)[CH:20]=[CH:19][N:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH2:30][NH:31][C:13](=[O:15])[C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[CH:12][N:11]=3)=[C:27]([CH3:29])[CH:28]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(-c2cnc(CN)c(C)c2)ccn1
Reactant: O=C(O)c1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(-c2cnc(CNC(=O)c3ccc(-c4cnccn4)cn3)c(C)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(pyrazin-2-yl)picolinic acid 41-4 (20 mg, 0.1 mmol), (2′,5-dimethyl-3,4′-bipyridin-6-yl)methanamine 81-5 (21 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (38 mg, 0.1 mmol) in DMF (1.0 mL) was added DIEA (0.053 mL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-42′,5-dimethyl-[3,4′-bipyridin]-6-yl)methyl)-5-(pyrazin-2-yl)picolinamide 81 as a white solid. MS m/z 397.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.60 (t, 1H), 9.54 (d, 1H), 9.52 (d, 1H), 8.99 (d, 1H), 8.91 (m, 1H), 8.82-8.80 (m, 2H), 8.66 (d, 1H), 8.33 (d, 1H), 8.20 (d, 1H), 7.87 (s, 1H), 7.79 (b, 1H), 4.81 (d, 2H), 2.64 (s, 3H), 2.51 (s, 3H).