Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(N(C(C)C)CC)(C)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:28][CH2:27][N:29]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCNc1ccccc1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (15 gm) and methylene chloride (105 ml) was cooled to 5-10° C. under nitrogen atmosphere. Diisopropylethyl amine (26.7 gm) was added to the resulting mass for 5 minutes at 5-10° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (7.8 gm) in one portion at 5-10° C. and then thionyl chloride (9.1 gm) was added at 5-10° C. The resulting mixture was stirred for 7 hours followed by evaporation of methylene chloride under vacuum. The resulting residue was dissolved in ethyl acetate (200 ml) followed by washings with 5% sodium hydroxide solution (65 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (25 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 19.3 gm of laquinimod (HPLC Purity: 98.41%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.O>CN(C=O)C>[Br:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[S:3][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: Brc1csc(Br)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(c2nc(Br)cs2)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
1 g (4.12 mmol) of 2,4-dibromothiazole was dissolved in 10 ml of DMF, 1.06 g (7.82 mmol) of piperidin-4-one hydrochloride and 2.3 ml (16.47 mmol) of triethylamine were added, and the mixture was stirred at 80° C. for 3 days. The reaction mixture was stirred into 300 ml of water and extracted by shaking with EA. The organic phase was dried over sodium sulfate, filtered and evaporated. The purification was carried out by means of flash chromatography on silica gel.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH3:9])[CH2:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:12][C:13]([CH3:15])=O.OP(O)(O)=O>C1COCC1>[CH3:9][C:6]1[C:7](=[C:13]([CH3:15])[CH3:12])[CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: CC1=CC(C(C)C)=CC1
Reactant: CC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=CC(C(C)C)=CC1=C(C)C
Reaction time: 0.5 h

Procedure:
3-isopropyl-1methyl-1,3-cyclopentadiene (39 g, 0.32 mol) was added at low temperature to a suspension of 12.8 g (0.32 mol) of sodium hydroxide in 200 mL of dry THF. After 30 min stirring, the reaction mixture was treated with 23.8 mL (0.32 mol) of acetone. The resulting solution was kept below room temperature overnight. Then the resulting mixture was neutralized with a 10% aq. solution of H3PO4, extracted with hexane (3×100 mL) and washed with water until neutral pH. The organic phase was separated, dried with MgSO4 and concentrated. The residue was distilled at 80° C./10 mmHg. Yield 25.96 g (50%).
Reaction SMILES: [CH3:1][C:2]1([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:7][CH2:6][N:5]([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:5]5[CH2:6][CH2:7][C:2]([CH3:1])([O:29][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:37]([CH3:39])[CH3:38])[CH2:3][CH2:4]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(C)(O[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Yield: 93 %

Procedure:
A solution of Intermediate 79e (160 mg, 0.291 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 176 mg, 0.437 mmol) and DIPEA (150 mg, 1.16 mmol) in DMF (4 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with EtOAc and washed with water (2×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound (210 mg, 93%). LCMS (Method 4): Rt 5.32 min, m/z 805 [MH+].
Reaction SMILES: [CH2:1]([C:8]1[C:9](=O)[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CN=1.Cl.[NH2:25][OH:26]>>[OH:26][N:25]1[C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:10]
Reactant: NO
Reactant: Cc1cc(C)c(Cc2ccccc2)c(=O)o1
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1cc(C)n(O)c(=O)c1Cc1ccccc1
Yield: 30.4 %

Procedure:
2 g of 3-benzyl-4,6-dimethyl-2-pyrone, 6 g of 2-aminopyridine and 1 g of hydroxylamine-hydrochloride were heated for 8 hours to 70° C. After working up as described in Example 1, 0.65 g (30%) of 1-hydroxy-3-benzyl-4,6-dimethyl-2-pyridone were obtained; melting point 148° C (Calc.: 6.1 % N, found 6.1 % N).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCc1ccccn1
Solvent: c1ccncc1
Product: CC(=O)OCCCc1ccccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
2-Pyridinepropanol (2.0 g, 14.6 mmol) was dissolved in pyridine (5 ml), and acetic anhydride (3.0 g, 29.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2.5 hrs, and subjected to a silica gel (75 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (2.6 g, 99%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:24](/[F:32])\[CH2:25][CH:26]1SCCCS1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C[O+:39](C)C.CC(C)=O.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl.O>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:32])[CH2:25][CH:26]=[O:39])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[O+](C)C
Reactant: CC(C)(C)[Si](OCCCC/C=C(/F)CC1SCCCS1)(c1ccccc1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCC=C(F)CC=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the dithialane prepared in 3F (0.424 g, 0.86 mmoles) in dry methylene chloride (4 ml) was added at room temperature trimethyloxonium tetrafluoroborate (0.125 g, 0.86 mmoles) and the mixture was stirred for 1 hr. Then a 9:1 mixture of acetone and water (2 ml) containing calcium carbonate (0.172 g, 1.72 mmoles) was added and the mixture was stirred overnight at room temperature. The precipitate was filtered off and after dilution with saturated brine the mixture was extracted three times with ether. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the expected aldehyde as an oil which was used after drying under high vacuum (0.366 g, 92%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[S:11](Cl)(=[O:13])=[O:12]>O1CCCC1>[CH3:2][C:1]([NH:5][S:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)(=[O:13])=[O:12])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of t-butylamine (8.35 g, 0.114 mol) in dry tetrahydrofuran (THF) (20 mL) cooled to 0° C. was added dropwise 2-thiophenesulfonyl chloride (5.0 g, 27.4 mmol). After the addition was completed, the reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was extracted with ethyl acetate (3×80 mL) and the combined extracts were washed with water, dried over molecular sieves and concentrated. The residue was chromatographed on silica, eluting with 25% ethyl acetate-hexane, to yield 5.62 g (94%) of solid: mp 80°-82° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH2:30])[CH:29]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:29]=1
Reactant: Cc1ccc(F)cc1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1ccc(F)cc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (5-fluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.11 (s, 3H), 2.17 (s, 3H), 4.39 (d, J=1.6 Hz, 2H), 7.77-7.88 (m, 2H), 7.09-7.20 (m, 3H), 7.34 (d, J=9.8 Hz, 1H), 7.45 (s, 1H), 7.64 (t, J=7.5 Hz, 1H), 8.43 (d, J=2.8 Hz, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:61])[NH2:60]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:60][N:59]([CH3:61])[CH3:58])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)N
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-hydrazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.43 (m, 2H) 1.53-1.92 (m, 8H) 2.92 (s, 6H) 3.32 (s, 3H) 3.96 (s, 3H) 4.14 (t, J=13.0 Hz, 2H) 4.42-4.52 (m, 1H) 7.44-7.52 (m, 2H) 8.20-8.27 (m, 2H) 8.49 (br. s., 1H). [M+H] calc'd for C24H31F2N7O3 504. found 504.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[ClH:27].[CH2:28]([NH:30][CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1)[CH3:29].C1C2C(=CC=CC=2)CCC1=O.C(N)C.[Na]>C(O)C>[ClH:27].[CH2:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39][CH2:40][CH:31]1[N:30]([CH2:28][CH3:29])[CH:14]1[CH2:15][CH2:16][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([C:18]#[N:19])[CH2:12][CH2:13]1
Reactant: CCNC1CCc2ccccc2C1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Agent: CCN
Agent: Cl
Agent: O=C1CCc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN(C1CCC(C#N)(c2ccc(OC)c(OC)c2)CC1)C1CCc2ccccc2C1
Reaction time: 72 h

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (3 mmol), triethylamine (3 mmol), 2-ethylamino-1,2,3,4-tetrahydronaphthalene hydrochloride prepared by reductive amination of 3,4-dihydro-2-(1H)-naphthalenone with ethylamine and sodium cyanoborhydride, (3 mmol) in ethanol was stirred 72 hours and worked up as in Example 17. ##STR22##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25]
Reactant: CCOC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (168 mg, 31%) in the same manner as described in the above example 6 (20) from ethyl 3-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.41 g, 1.36 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30].O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c(OC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c(OC)c1
Yield: 87.9 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (100 mg, 0.24 mmol, prepared in Synthetic Example 24) in DMF (2 ml) was added hydrazine monohydrate (80%, 50 μl, 1.25 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(2,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (87 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccnc1N
Solvent: ClCCl
Product: CC(=O)Nc1cccnc1N
Yield: 56.6 %

Procedure:
2,3-Diaminopyridine (28 g, 0.256 mole) and acetic anhydride (30 mL, 0.38 mole) were stirred at room temp in methylene chloride (770 mL) for 30 min. The mixture was concentrated in vacuo to a brown solid. Recrystallization from methylene chloride/hexane (10/1) gave off-white crystals (21.9 g, 57%) of 3-acetamido-2aminopyridine. This acetamide was combined with 3-chloro-2,4-pentanedione (20 g, 0.146 mole) in abs. ethanol (350 mL) and stirred under reflux for 20 hrs. After cooling, the mixture was diluted with methylene chloride (300 mL) and washed with water (3×300 mL). The organic phase was dried over magnesium sulfate and concentrated to a green solid. Recrystallization from methylene chloride/hexane (1/1) gave the title compound as green crystals (7.3 g, 21%, m.p. 173°-175° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)O1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]1([CH2:12][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(Cc1ccccc1)N1CCc2cc(-c3ccncc3)ccc21
Temperature: 100 °C
Reaction time: 60 h
Yield: 50.5 %

Procedure:
To a solution of 5-bromo-1-(phenylacetyl)indoline (15.98 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12.4 g) in 1,2-dimethoxyethane (500 mL) were added [1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.24 g) and potassium phosphate (32.2 g) at ambient temperature and the mixture was stirred at 100° C. for 60 hours. The mixture was evaporated in vacuo to remove 1,2-dimethoxyethane and the residue was dissolved in a mixture of ethyl acetate (600 mL) and water (300 mL). The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 1-(phenylacetyl)-5-(4-pyridinyl)indoline (8.02 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16]1[C@H:25]2[C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[C:10]([C:13]([N:17]3[CH:16]4[CH:25]([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Reactant: O=C(O)c1csc(-c2ccnc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(-c2ccnc(F)c2)c1)N1CCCC2CCCCC21
Yield: 26.4 %

Procedure:
5-(2-Fluoro-pyridin-4-yl)-thiophene-3-carboxylic acid (0.05 g, 0.22 mmol) was dissolved in acetonitrile (2 mL) together with cis, trans-decahydroisoquinoline (0.134 mL, 0.90 mmol), triethylamine (80 μL, 0.60 mmol) and HATU (0.085 g, 0.22 mmol) and the resulting mixture was stirred over the weekend. The crude material was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as an oil (0.02 g). LCMS m/z 345.22 [M+H]+ R.T.=11.64 min (Analytical Method 2).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(OC(=O)[NH:39][CH2:40][C@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)(C)(C)C>>[NH2:39][CH2:40][C@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH2:29][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=3[CH3:13])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:31])[CH:15]=2)[C:20](=[O:24])[N:19]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC[C@@H]3CN)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (R)-1-pyrrolidine-2-ylmethyl-carbamic acid tert-butyl ester hydrochloride. The product was purified using SCX ion-exchange chromatography (eluting with methanol followed by 3N ammonia in methanol), followed by HPLC.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[C:34]([Cl:36])[C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]3)[C:15]2=[O:33])=[C:11]([Cl:37])[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:29]([Si:26]([CH3:28])([CH3:27])[O:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([N:16]2[CH2:17][CH2:18][CH:14]([CH2:13][C:12]3[C:11]([Cl:37])=[CH:10][C:9]([OH:8])=[CH:35][C:34]=3[Cl:36])[C:15]2=[O:33])[CH2:20][CH2:21]1)([CH3:31])([CH3:30])[CH3:32]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1

Procedure:
Add a solution of 3-(4-benzyloxy-2,6-dichloro-benzyl)-cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (8.5 g 15.1 mmol) in 25 mL tetrahydrofuran to 0.5 g Pearlman's catalyst and hydrogenate the resulting mixture under a balloon of hydrogen gas 2 hr. Filter through Celite® and concentrate to get a solid. Purify by silica gel chromatography using hexanes/ethyl acetate to recover 4.4 g (61%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[Cl-].[CH3:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]=[N+:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:17]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[CH3:14])[CH:3]=1
Reactant: Cc1ccccc1C=[N+]1CCOCC1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: [Cl-]
Product: Cc1ccccc1C(c1cc(Cl)c2ccccc2c1O)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-chloro-1-naphthol and 4-(2-methyl-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([OH:22])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9].CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([O:22][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Reactant: CS(=O)(=O)OCCc1ccccn1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCc2ccccn2)c1OCCC(C)c1ccc(F)cc1
Yield: 89 %

Procedure:
Example 7c (500 mg, 1.31 mmol) was reacted with 2-pyridin-2-ylethyl methanesulfonate (2.0 eq.) as described under General Procedure F to give the title compound as an oil (410 mg, 89%). 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=4.1 Hz, 1H), 7.58 (dt, J=7.7, 1.8 Hz, 1H), 7.17-7.10 (m, 4H), 6.97-6.90 (m, 2H), 4.37 (t, J=6.6 Hz, 2H), 3.85 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.10 (t, J=6.5 Hz, 2H), 2.98-2.91 (m, 1H), 2.26 (s, 3H), 2.14 (s, 3H), 1.96-1.88 (m, 2H), 1.25 (d, J=7.0 Hz, 3H). MS (ES+) m/z 485.9 (M+H+).