Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[CH2:8]([O:10][C:11](=[O:31])[N:12]([C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[C:21]=1[N+:28]([O-:30])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11](=[O:31])[N:12]([C:20]1[CH:25]=[C:24]([O:7][CH2:6][CH2:5][O:4][CH3:3])[N:23]=[C:22]([NH2:27])[C:21]=1[N+:28]([O-:30])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9]
Reactant: COCCO
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(OCCOC)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (21 mg) was added portion-wise to 2-methoxyethanol (0.5 ml). The resultant solution was added drop-wise to a solution of (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (100 mg) in THF (1.0 ml). The reaction mixture changed from yellow to deep red/orange solution and was left to stir at RT for 1 h. The orange mixture was concentrated in vacuo then partitioned between EtOAc (10 ml) and saturated NH4Cl solution (10 ml). The layers were separated and the organics were washed with water (10 ml) and brine (10 ml) then dried (MgSO4) and evaporated to provide the title compound as a crude yellow gum (111 mg). This was used directly in the next step with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].[ClH:15].[Cl:16][CH2:17][C:18]([CH3:25])([OH:24])[CH2:19][NH:20][CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>[OH-].[Na+]>[ClH:16].[ClH:15].[OH:24][C:18]([CH3:25])([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:17][NH:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(C)NCC(C)(O)CCl
Reactant: COc1cc(N)c2nccc(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COc1cc(NCC(C)(O)CNC(C)C)c2nccc(C)c2c1
Reaction time: 24 h

Procedure:
A stirred mixture of 10.7 g (0.057 mole) of 8-amino-6-methoxy-4-methylquinoline and 11.7 g (0.057 mole) of 3-chloro-2-methyl-1-(2-propylamino)propan-2-ol, hydrochloride was heated in an oil bath (150°) for 1 hr while 5.8 g (0.057 mole) of triethylamine was added, dropwise. The reaction mixture was stirred at 150° for 24 hrs, cooled, basified with 30 ml of 5% aqueous sodium hydroxide, then extracted with dichloromethane (3×100 ml). The organic extracts were combined, washed with water (2×200 ml), dried over anhydrous magnesium sulfate, then concentrated in vacuo to 50 ml. The solution was chromatographed on a column (60 cm× 7.5 cm) of silica gel (2.5 kg; activity III) using dichloromethane (10 l) followed by methanol-concentrated ammonium hydroxide (25:1) (7 l) as the eluent. The fractions (1 l each) 13-18 were combined then concentrated in vacuo to an oil. The oil was dissolved in ether (100 ml), and the solution was washed with water (2×200 ml), dried over anhydrous magnesium sulfate, then saturated with anhydrous hydrogen chloride. The solid that separated was collected on a filter, dried, then recrystallized from 300 ml of absolute ethanol; yield 4.6 g; mp 232°-234°, dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[C:15]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[NH2:25])C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:13])[C:15]3[C:16](=[CH:17][CH:18]=[C:19]([O:23][CH3:24])[C:20]=3[O:21][CH3:22])[NH:25][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=O)n(-c3ccc(Cl)cc3)c(=O)c2c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To p-chlorophenyl isocyanate (2.7 ml, 3.22 g, 20.97 mM) in pyridine (4.7 ml) at 0° C. was added a cold solution of 2-amino-5,6-dimethoxybenzoic acid ethyl ester (3.0 g, 13.32 mM) in pyridine (7.1 ml). The reaction mixture solidified shortly after the addition of the ester. The reaction mixture was allowed to go to room temperature but remained a solid. More pyridine (15 ml) was added and the pink slurry stirred at room temperature for three hours. The solvent was removed in vacuo to give a pink solid. The solid was triturated with 300 ml of 1N NaOH (4:1, MeOH:H2O) was added and the solution was heated at reflux for 2 hours. The solvent was removed in vacuo and the reddish solid partially dissolved in H2O (25 ml). The pH was adjusted to 5 with acetic acid and the resulting solid filtered, washed with H2O (~75 ml) and dried to give crude product as a pink solid. The crude product was triturated with MeOH. The insoluble solid was filtered to afford the title compound as a white solid; 2.66 g; mp 269°-273° C., CF3COOH(TMS), 7.10-7.77 (m, 6H, 7-H, 8-H, 9-H, 10-H, 12-H 13-H), 4.12 (s, 3H, 5 or 6-OCH3), 4.07 (s, 3H, 5 or 6-OCH3); M+ 332.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.COCCOC.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(Cc4c(F)cc5c(cnn5C)c4F)n3n2)cn1
Reaction time: 0.5 h

Procedure:
In a microwave vial were introduced under argon 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (23 mg, 0.112 mmol) and 6-chloro-3-(4,6-difluoro-1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine (Stage 284.1, 25 mg, 0.075 mmol) with 0.3 mL DME. The solution was degassed with argon, before adding PdCl2(PPh3)2 (1.5 mg) and 2 M K2CO3 (0.101 mL). The RM was then stirred at 80°-90° C. for 30 min. Additional 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.048 mmol) and PdCl2(PPh3)2 (1.5 mg) were added. The RM was then diluted with DCM and washed with sat. aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, evaporated to dryness and the residue was purified (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20) to afford the title compound as a beige crystalline powder (tR 3.91 min (conditions 3), MH+=380.2, 1H-NMR in DMSO-d6: 8.36 (s, 1H); 8.18 (s, 1H); 8.05 (s, 1H); 8.02 (d, 1H); 7.50 (m, 2H); 7.45 (s, 1H); 4.40 (s, 2H); 3.97 (s, 3H); 3.90 (s, 3H)).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]#[N:19])=[CH:14][C:15]=2[Br:17])[CH:10]=[C:9]1[CH:20](OCC)[O:21]CC)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Br:17][C:15]1[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[C:11]2[C:16]=1[NH:8][C:9]([CH:20]=[O:21])=[CH:10]2
Reactant: CCOC(OCC)c1cc2cc(C#N)cc(Br)c2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(Br)c2[nH]c(C=O)cc2c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
7-bromo-5-cyano-2-diethoxymethyl-indole-1-carboxylic acid tert-butyl ester (0.29 g, 685 μmol) was solved in THF (2 ml) and cooled to 0° C. Afterwards hydrochloric acid (37%, 1.35 g, 1.14 ml, 13.7 mmol) was added quickly, and the mixture was allowed to stir for 15 min at 0° C. and for 5 h at room temperature. The mixture was cooled (ice bath), saturated sodium carbonate solution (10 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product (0.18 g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield 7-bromo-2-formyl-1H-indole-5-carbonitrile (0.17 g, 100%) as an orange solid, MS (ISN) m/z=247.4 [(M−H)+], mp 117.5° C.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[CH:13][CH:14]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
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: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc(-c3cnn(C)c3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 36.2 %

Procedure:
To a solution of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (92 mg, 0.44 mmol) and sat. sodium carbonate (100 mg, 0.9 mmol) in toluene (20 mL, 0.2 mol) was added tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.01 mmol) under N2 at room temperature. The mixture was heated to reflux overnight. The mixture was stripped down and purified by preparative LC-MS to yield the desired product (50 mg, 37%). LCMS calculated for C24H29N8O2 (M+H): 461.2. found 461.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([N:19]3[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20]3)[C@@H:16]([OH:25])[C@H:15]2[OH:26])=[C:7]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>>[OH:26][C@@H:15]1[C@H:16]([OH:25])[C@@H:17]([N:19]2[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20]2)[CH2:18][C@H:14]1[N:11]1[CH:10]=[N:9][C:8]2[C:12]1=[N:13][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:42]([CH3:45])(=[O:44])=[O:43])=[N:6][C:7]=2[NH:27][CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CS(=O)(=O)Cl
Product: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCNS(C)(=O)=O)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
The title compound is prepared from (1R,2S,3R,5S)-3-[2-(2-Amino-ethylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol and mesyl chloride using a procedure analogous to that of Example 31. MS (ES+) m/e 632 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH:4]([CH3:9])[C:5]([NH:7]O)=[O:6].O>OS(O)(=O)=O>[CH3:9][C:4]1[C:5]([OH:6])=[N:7][O:10][C:3]=1[C:2]([F:12])([F:11])[F:1]
Reactant: CC(C(=O)NO)C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)noc1C(F)(F)F
Temperature: 75 °C
Yield: 43.7 %

Procedure:
4,4,4-Trifluoro-N-hydroxy-2-methyl-3-oxobutyramide (500 mg, 2.70 mmol) was dissolved in aq. 90% H2SO4 (5.5 mL). The mixture was heated to 75° C. for 90 min, and then allowed to cool to rt. Water (15 mL) was added, and the mixture was extracted with Et2O (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC (EtOAc/heptane/AcOH 20:80:1→25:75:1→33:66:1) yielded the title compound (197 mg, 44%). TLC: Rf=0.43 (EtOAc/heptane 1:1+1% AcOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][N:11]=2)[C:5]([C:18]#[N:19])=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[Cl:25]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:5]([C:18]#[N:19])=[C:6]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][N:11]=2)[N:7]=1
Reactant: Cc1cnc(COc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1cnc(COc2nc(N)nc(-c3ccc(Cl)o3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-(3,5-dimethyl-pyridin-2-ylmethoxy)-6-furan-2-yl-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 358 (M{37Cl}+H+, 30), 356 (M{35Cl}+H+, 100).
Reaction SMILES: C[O:2][C:3]1[C:4]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:5][C:6]2[C:7]([CH3:15])([CH3:16])[CH2:8][CH2:9][C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: CCC(=O)c1cc2c(cc1OC)C(C)(C)CCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reaction time: 0.5 h
Yield: 126.4 %

Procedure:
To a solution of 1-(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one (Intermediate 12, 2.07 g, 7.9 mmol) in CH2Cl2 (40 mL) at 0° C. was added BBr3 (8.9 mL, 1M in CH2Cl2 8.9 mmol) dropwise. After 30 min, the reaction was quenched with ice-H2O, and extracted with EtOAc. The organic layer was washed with brine, dried-over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2% EtOAc-hexane) to give the title compound as a white solid (2.6 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[C:9]([C:13]1[C:14](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:15][N:16]2[C:21]=1[C:20]([CH3:22])=[N:19][N:18]=[C:17]2[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[F:31])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[C:14]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)=[N:15][N:16]2[C:21]=1[C:20]([CH3:22])=[N:19][N:18]=[C:17]2[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[F:31])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4c(F)ccc(F)c4F)nnc(C)c3c2C(C)(C)C)cc1
Reactant: Cn1ncnc1CO
Product: Cc1nnc(-c2c(F)ccc(F)c2F)n2nc(OCc3ncnn3C)c(C(C)(C)C)c12

Procedure:
This compound was prepared using the procedure described in Example 7, step e, using (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (prepared as described in EP-A-170073) instead of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol, and using toluene-4-sulfonic acid 3-tert-butyl-4-methyl-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-yl ester instead of toluene-4-sulfonic acid 3-tert-butyl-7-(2,5-difuorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester. Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 1.55 (9H, s), 3.07 (3H, s), 3.84 (3H, s), 5.38 (2H, s), 7.04 (1H, m), 7.41 (1H, m), 7.86 (1H, s); MS (ES+) m/e 432 [MH]+.
Reaction SMILES: C([O-])=O.[NH4+].C[N:6](C)/[CH:7]=[CH:8]/[C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[CH:11][CH:10]=1.CC(O)=O>O>[C:15]1([NH2:16])[C:14]2[C:9](=[CH:10][CH:11]=[N:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CN(C)/C=C/c1ccncc1C#N
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nccc2ccncc12
Temperature: 115 °C
Yield: 27.8 %

Procedure:
810 g of ammonium formate are added to 253 g of 4-((E)-2-dimethylaminovinyl)nicotinonitrile in a 4 liter vessel. 300 ml of AcOH are then added, and the mixture is heated at 115° C. for 20 h. The mixture is cooled, 5 liters of water are added, and the mixture is extracted 10× with 0.5 liter of CH2Cl2. The aqueous phase is adjusted to ˜pH 10 using 160 g of NaOH. The aqueous phase is extracted with MTB ether, the organic phase is separated off and dried over sodium sulfate. Removal of the solvent and drying gives 59 g of 2,7-naphthyridin-1-ylamine, M˜145.16 g/mol, M+H found 146, NMR corresponds.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)(C)C>[NH2:11][C:8]1[CH:9]=[CH:10][C:3]([Cl:2])=[C:4]([CH:7]=1)[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: N#Cc1cc(N)ccc1Cl
Temperature: 120 °C
Yield: 91.4 %

Procedure:
Conc. HCl (15.6 ml) was added dropwise to 2-chloro-5-nitrobenzonitrile (3.38 g, 18.5 mmol) and SnCl2.2H2O (18.9 g, 83.9 mmol, 4.5 eq.) in isopropanol (35 ml). The mixture was heated at 120° C. for 2 h and then cooled to room temperature and made basic using aq. NaOH. The mixture was extracted with dichloromethane, dried over Na2SO4 and filtered through silica gel. Concentration under reduced pressure gave 5-amino-2-chlorobenzonitrile (2.58 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].[NH:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([NH:7][CH2:8][C:9]([N:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1)=[O:11])=[O:6]
Reactant: OC1CCNC1
Reactant: O=C(O)CNC(=O)c1ccc(Cl)c(Cl)c1
Product: O=C(NCC(=O)N1CCC(O)C1)c1ccc(Cl)c(Cl)c1

Procedure:
The titled compound was prepared from (3,4-dichloro-benzoylamino)-acetic acid (preparation #14) and pyrrolidin-3-ol according to the general procedure G. m/z: (M+H)+ 317.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:16][NH:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.[F:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:16][N:15]([C:31]4[N:32]=[CH:33][C:28]([F:27])=[CH:29][N:30]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Nc1ccc(F)c(C23CNCC2CSC(NC(=O)c2ccccc2)=N3)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(F)c(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Yield: 66.6 %

Procedure:
A solution of N-[7a-(5-amino-2-fluoro-phenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (705 mg, 1.90 mmol), 5-fluoro-2-chloropyrimidine (1.01 g, 7.61 mmol), and diisopropylethylamine (1.66 mL, 9.52 mmol) are heated in 1,4-dioxane (20 mL) to reflux for 4 hours under nitrogen. The reaction is cooled, diluted with water, and extracted with ethyl acetate (3×). The organic layers are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo to give crude product. The crude product is purified over silica gel with a 25 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (590 mg, 66%). ES/MS (m/e): 467 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][C:15](=[O:17])[NH:14][S:13]1(=[O:19])=[O:18])[CH:8]=[C:7]([CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH:6]=[CH:5]2.[CH3:29]CN(C(C)C)C(C)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:29][O:25][C:24](=[O:26])[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][CH2:20][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([N:12]3[CH2:16][C:15](=[O:17])[NH:14][S:13]3(=[O:19])=[O:18])=[C:2]([OH:1])[CH:3]=2)[CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(C)(C)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-2,2-dimethylpentanoic acid (Example LCE840, 63 mg, 0.13 mmol) in MeOH at 0° C. is added DIEA (0.032 mL, 0.13 mmol). After is stirred for 2 min, trimethylsilyldiazomethane (2M, 0:07 mL) is added drop wise. The reaction mixture is stirred for 15 min and concentrated give the title compound: Retention time=1.28 min (Method A); (M−H)−=419.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13]([OH:30])=[CH:12][C:11]=1[OH:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CCCCCC>[CH2:1]([O:30][C:13]1[CH:12]=[C:11]([O:31][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([Br:9])=[CH:15][C:14]=1[C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl bromide (0.36 ml, 3 mmol) was added suspension of 4-bromo-6-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol (Example 2) (0.55 g, 1.5 mmol) and cesium carbonate (0.85 g, 2.6 mmol) in DMF (5 ml) and the mixture stirred for ˜18 hrs, at room temperature. Water (100 ml) was added and the mixture extracted with diethyl ether (2×30 ml). The combined extracts were washed with water (4×75 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown gum. Trituration with hexane gave 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole as an off-white solid, dried in vacuo, (0.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCc1cccc(N)c1
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A solution of (E)-4-(3-nitrophenyl)but-3-en-2-one (15 g, 78 mmol) in EtOAc (150 mL) was added Pd/C (1.7 g), H2 was bubbled in, the reaction mixture was stirred at 40 psi H2 for 4 hrs. The mixture was filtrated, and the filtrate was concentrated to give 4-(3-aminophenyl)butan-2-one (12 g, 94% yield). 1H NMR: (400 MHz, CDCl3) δ 7.08 (t, 1H), 6.63 (s, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 2.76 (t, 2H), 2.71 (t, 2H), 2.1 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@@H]1OC(=O)CC1.C(C1OC(=O)CC1)=CCCCCCCCC>>[CH2:1]=[CH:2][CH:3]=[CH:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC/C=C\[C@H]1CCC(=O)O1
Agent: CCCCCCCCC=CC1CCC(=O)O1
Product: C=CC=CC=CCCCC

Procedure:
japonilure--4-(decen-1-yl)-butyrolactone
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:8]1(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[C:6]([C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#N)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(C#N)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.189 mL, 2.43 mmol) was added to a mixture of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (500 mg, 2.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.579 mL, 3.31 mmol) in chloroform (8.8 mL) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, and was then partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, and the dried solution was filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in pyridine (5.5 mL). The reaction mixture was heated to 120° C. for 4 hours, and was then cooled to ambient temperature. The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed sequentially with water and saturated aqueous sodium chloride solution. The washed solution was dried over anhydrous sodium sulfate, and the dried solution was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash-column chromatography (using a gradient elution of 0-100%, ethyl acetate/hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 6.55 (br s, 1H), 4.05 (m, 2H), 3.55 (t, J=5.6 Hz, 2H), 2.34 (br s, 2H), 1.46 (s, 9H).