Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[C:24](=O)[CH2:23][O:22]4)[C:8]1=[O:28].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+].[OH-].[Na+]>CO.O1CCCC1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[C:24](=[N:30][OH:31])[CH2:23][O:22]4)[C:8]1=[O:28]
Reactant: NO
Reactant: O=C1COc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)C(=NO)CO3
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To a solution of 1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione (0.25 g, 0.66 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) were added hydroxylamine hydrochloride (0.92 g, 13.3 mmol) and sodium acetate (1.09 g, 13.3 mmol). The reaction mixture was stirred for 48 h at ambient temperature. To the reaction mixture was added 1 N sodium hydroxide to adjust pH>9. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic solution was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford 1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione 5-oxime (0.25 g, 96%) as a colorless solid: mp 82-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.00-7.50 (br, 1H), 7.49-6.83 (m, 5H), 6.52-6.46 (m, 1H), 5.10-4.93 (m, 3H), 4.76-4.69 (m, 1H), 4.30-5.19 (m, 1H), 3.95-3.66 (m, 4H), 2.08-1.60 (m, 4H); MS (ES+) m/z 392.9 (M+1), 414.9 (M+23).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].C(OCC)C.[Br:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[Cl-].[NH4+]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH2:1][CH2:2][CH3:3]
Reactant: CCC[Mg]Cl
Reactant: O=Cc1cccc(Cl)c1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(O)c1cccc(Cl)c1Br
Temperature: 25 °C
Yield: 62 %

Procedure:
Under an argon atmosphere, zinc chloride (0.68 g, 4.97 mmol) was added to a 2.0 M solution of n-propyl magnesium chloride in diethyl ether (12.42 mL, 24.93 mmol), and the mixture was stirred at room temperature. After stirring for 0.5 hours, a solution of 2-bromo-3-chlorobenzaldehyde (4.36 g, 19.87 mmol), which had been obtained in Reference example 7 (7b), in tetrahydrofuran (10 mL) was added dropwise thereto. After stirring for 2 hours under ice cooling, a saturated aqueous ammonium chloride solution (20 mL) was added thereto. The mixture obtained was extracted with ethyl acetate (20 mL×2). After that, the organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=5/1) to give the title compound as a white solid (3.23 g, yield 62%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]#[N:11])[CH2:4]1>[Ni].CCO>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][NH2:11])[CH2:4]1
Reactant: COC1CCCN(CC#N)C1
Agent: [Ni]
Solvent: CCO
Product: COC1CCCN(CCN)C1
Reaction time: 22 h

Procedure:
A mixture of nitrile 282 (3.5 g, 22.7 mmol) and Raney Nickel (50% w/w suspension in water, 8 g) in EtOH (100 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 22 h. The mixture was filtered through Celite, the solid washed with EtOH (60 mL) and the solvent evaporated to give diamine 283 as a crude colourless oil (3.48 g, 97%) which was used without further purification: HRMS (FAB+) calcd for C8H19N2O (MH+) m/z 159.14974, found 159.14976.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[C:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:31]=[CH:30][C:10]=1[C:11]1[C:20](=O)[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[O:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:33]=[C:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH:31]=[CH:30][C:10]=1[C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2coc3cc(OCc4ccccc4)ccc3c2=O)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
To an ice cooled solution of 2′,7-dibenzyloxy-4′-(t-butyldimethylsilyloxy)-isoflavone (0.564 g, 1 mmol) in 10 mL of THF was added 1.6 M lithium borohydride solution in THF (3 mmol) dropwise. The reaction mixture was allowed to come to RT gradually and then stirred for ca. 2 hrs. After disappearance of the starting material (TLC) the reaction was quenched with 1N HCl (pH 4). The reaction was further stirred at room temperature followed by refluxing at 60° C. for ca. 2 hours. The reaction mixture was extracted with DCM:water (2×15 mL:15 mL). The organic layers were combined and washed with 1N NaHCO3 (2×15 mL), dried over sodium sulfate and evaporated at 20° C. to obtain an oily residue. The residue was chromatographed over silica using DCM:hexanes (1:1). The organic fractions were evaporated to provide 0.247 g (45%) of white solid: mp 105-107° C.; TLC Rf0.75 in DCM:hexanes (2:1); 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.32 (m, 10H, 2×CH5), 7.22-7.20 (d, 1H, J=8.4 Hz, Ar—H5), 7.03-7.01 (d, 1H, J=8.4 Hz), 6.63 (s, 1H, CH═), 6.58-6.55 (m, 2H, Ar—H3′/H5′), 6.49-6.46 (m, 2H, Ar—H6/8), 5.11 (s, 2H, Ph-CH2), 5.07 (s, 2H, Ph-CH2), 4.89 (s, 2H, OCH2), 0.93 {s, 9H, Si(CH3)3}, 0.17 {s, 6H, Si(CH3)2}; 13C NMR (100 MHz, DMSO-d6) δ 199.6, 159.7, 157.5, 156.8, 154.7, 137.7, 137.5, 129.7, 129.2, 129.1, 128.6, 128.5, 128.4, 128.3, 128.1, 121.5, 121.4, 117.5, 112.8, 108.9, 105.9, 102.8, 70.5, 69.9, 68.3, 26.3, 18.7; analysis calcd. for C35H38O4Si.0.25H2O: C, 75.71; H, 6.99. found: C, 76.0; H, 6.70.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](S(C)(=O)=O)[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2].[CH3:31][NH:32][CH3:33]>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:22]1[N:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=1
Reactant: CNC
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)(=O)=O)n3)s2)o1
Solvent: CN(C)C=O
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(N(C)C)n3)s2)o1

Procedure:
A solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (0.22 g, 0.049 mmol) and dimethylamine (2M in THF, 0.073 ml, 0.15 mmol) in DMF (1 ml) is heated at 70° C. for 18 hours. The solvent is removed and the product is purified by chromatography on silica eluting with ethyl acetate to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:10].[CH2:25]([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH3:10])=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(Cl)ccc2C(C)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
N-(1-(2-bromo-4-chlorophenyl)ethyl)-4′-chloro-[1,1′-biphenyl]-4-amine (129 mg, 0.31 mmol), 4-(ethoxycarbonyl)phenylboronic acid (89 mg, 0.46 mmol), Pd(dppf) Cl2 (34 mg, 0.05 mmol), and K2CO3 (106 mg, 0.76 mmol) in wet DMF (3 mL) was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc, washed with water for and saturated aqueous NaHCO3, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>CS(C)=O>[CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(CN(C)S(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 25) (0.042 mmol) was dissolved in dry DMSO (0.5 mL), added DIPEA (0.25 mL) and propane-1-sulfonyl chloride (0.050 mmol) and then stirred at 40° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:27][NH2:28])[CH3:26]>>[CH2:25]([O:27]/[N:28]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH3:26]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CCON
Agent: Cl
Product: CCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 61 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-ethylhydroxylamine hydrochloride in 61% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6), δ ppm 9.31 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.34 (q, 2H), 2.32 (s, 3H), 1.24 (t, 3H). LCMS (method B): [MH]+=348, tR=2.59 min.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH:17](=O)[CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH3:19])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC=O
Reactant: c1ccc([C@@H]2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN1CCC[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1 g (6.2 mmol) of commercially available (S)-3-phenylpiperidine was dissolved in dichloromethane and 0.37 ml acetic acid (6.51 mmol). After addition of 0.5 ml of propanal (6.93 mmol) and 1.97 g of sodium triacetoxyborohydride (9.3 mmol), the reaction mixture was stirred at room temperature for 18 h. Water was added, the layers separated, and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield 1.1 g of (S)-3-phenyl-1-propyl-piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24]>CN(C=O)C.O>[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][C:20]2[O:21][C:20]3[C:22](=[CH:23][C:17]([Cl:16])=[C:18]([OH:24])[CH:19]=3)[C:11]3([C:6]4[C:7](=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]=4[Cl:13])[C:8](=[O:9])[O:10]3)[C:22]=2[CH:23]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC2(c3cc(Cl)c(O)cc3Oc3cc(O)c(Cl)cc32)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 98.1 %

Procedure:
Treatment of tetrachlorophthalic anhydride (5 g, 17.49 mmol) and 4-chlororesorcinol (6.32 g, 43.73 mmol), according to the procedure described in Example 1 Step 1, provided 10.31 g of crude product. Suspension of a 9.25 g portion of this in DMF:water (1:1) followed by filtration, provided 9.70 g (2:1 DMF complex 17.16 mmol, 92.3% yield) of 2′,4,5,6,7,7′-hexachloro-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one that was isolated as an orange solid. 1H NMR (300 MHz; DMSO d6) δ 11.13 (S, 2H), 7.31 (s, 2H), 6.89 (s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 35.4 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (0.663 g, 1.81 mmol) (from example 99, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.073 g, 1.81 mmol) dissolved in water (1 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.111 mL, 1.81 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 4 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9 mL, 54.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (214 mg, 35%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-1.77 (m, 2H), 1.82-2.15 (m, 2H), 2.75-3.00 (m, 2H), 3.00-3.15 (m, 2H), 3.40-3.80 (m, 3H), 4.00-4.42 (m, 1H), 4.42-4.80 (m, 1H), 5.64 (s, 1H), 6.83-7.05 (m, 3H), 7.22-7.31 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[C:14](Cl)=O.C(O)C>ClCCl.CN(C)C=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[F:1])[CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(F)cc1F
Reaction time: 0.75 h
Yield: 97.3 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6 mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (100 mL), and to this solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (12.23 g). 1H NMR (CDCl3): δ 7.85-7.73 (m, 1H), 7.06-6.94 (m, 1H), 4.38 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[C:19](O)(=[O:31])/[CH:20]=[CH:21]/[C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:21]=[CH:20][C:19]([NH:6][CH:5]([C:4]([O:3][CH3:2])=[O:18])[CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)=[O:31])[CH:30]=[CH:29][C:27]=1[OH:28]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(Cc1c[nH]c2ccc(O)cc12)NC(=O)C=Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
As mentioned above, 5-hydroxy-L-tryptophan methyl ester hydrochloride (350 mg, 1.29 mmol) and ferulic acid (251 mg, 1.29 mmol) were dissolved in a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml), and the solution was maintained at 0° C. To this solution were added triethylamine (198 μl, 1.4 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 217 mg, 1.4 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI HCl, 217 mg, 1.4 mmol), the solution temperature was gradually raised from 0° C., and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (20 ml). The ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: chloroform:methanol=3:1) to give 3-(3-methoxy-4-hydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3-yl)-1-methoxycarbonylethyl]-2-propenamide (413 mg, yield 78.0%) as a powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([C:24]([F:27])([F:26])[CH3:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.Cl.C(OCC)C>CN1CCCC1=O.C(OCC)(=O)C>[ClH:16].[F:26][C:24]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23])([F:27])[CH3:25]
Reactant: Cc1c(Cl)ncnc1C(C)(F)F
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncnc1C(C)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-6-(1,1-difluoroethyl)-5-methylpyrimidine (Intermediate 46, 134 mg, 0.697 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (NMP) (3 mL) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was heated at 100° C. for 1 hour, allowed to cool to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4, 25+M, collect all) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure. The residue was triturated with DCM and the solid collected by filtration (53 mg), dissolved in methanol (2 mL), treated with 1M HCl in diethyl ether (0.16 mL, 0.160 mmol) and the resulting mixture was evaporated under reduced pressure. The resulting solid was dried under high vacuum at 40° C. for 18 hours to give the title compound as a white solid (53 mg);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13]([CH:20]=O)=[N:14][NH:15]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][C:32]3[N:35]=[C:20]([C:13]4[C:12]5[C:16](=[CH:17][CH:18]=[CH:19][C:11]=5[O:10][C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=5)[NH:15][N:14]=4)[NH:36][C:31]=3[CH:30]=2)[CH2:27][CH2:28]1
Reactant: O=Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(Oc6ccc([N+](=O)[O-])cn6)c45)[nH]c3c2)CC1

Procedure:
The formation of the tide compound is carried out using 4-(5-nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=383.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.[Li].C(O)C>CCOCC>[N:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:18]3[CH2:17][CH:16]=[CH:15][CH2:14][C:13]=3[CH2:12][CH:11]2[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC1Cc2ccccc2C1CCCN1CCCCC1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: OC1CC2=C(CC=CC2)C1CCCN1CCCCC1

Procedure:
The crude 1-(3-piperidinopropyl)-2-indanol (~0.2 M) is dissolved in 300 ml ether and added to 2 liters liquid ammonia. Lithium ribbon (50 g) is added in small portions over a period of 30 minutes. After stirring 11/2 hours, absolute ethanol is added dropwise until the color is discharged (~1 liter added over a period of 4 hours). The ammonia is allowed to evaporate and the residue is then diluted to 4 liters with water; two ether extracts yield 62 g of crude diene which becomes partially crystalline on standing.