Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:31]([C:28]1[CH:27]=[C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:30][N:29]=1)=[O:33]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)on1
Temperature: 10 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
HOBt (44.6 mg, 0.33 mmol) and DIPEA (136.7 mg, 1.06 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (50 mg, 0.27 mmol) in DMF (1.0 mL). The reaction mixture was then cooled to 10° C. and EDCI.HCl (63.3 mg, 0.33 mmol) was added, followed by the addition 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (as TFA salt) (113.5 mg, 0.27 mmol). Then resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The crude product thus obtained was purified by column chromatography using neutral alumina as stationary phase and 100% ethyl acetate as the eluent to afford 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide as a solid in 20.3% yield. LC-MS purity: 98.075%, 1H NMR (DMSO-D6): δ 8.6 (s, 1H), 7.9 (m, 2H), 7.7 (m, 2H), 7.65 (m, 1H), 7.5 (m, 3H), 7.4 (s, 1H), 4.1 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[C:10]([N:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (1.75 g, 4.60 mmol) in methanol (50 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (13.8 mL, 13.8 mmol). The reaction was stirred at 25° C. for 18 h and then heated to 50° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and diluted with water (150 mL). The aqueous layer was brought to pH=1 by treatment with a 1N aqueous hydrochloric acid solution and then diluted with ethyl acetate (250 mL). The resulting precipitated product was collected by filtration. The filtrate was extracted with ethyl acetate (1×150 mL). The combined organics were then washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The two batches of product were combined to afford 1-trityl-1H-imidazole-4-carboxylic acid (1.55 g, 95.1%.) as a white solid: LR-MS for C23H18N2O2 (M+H)+ at m/z=355.
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH3:5])=C.CC=C(C)C.[Cl:11][SiH:12]([Cl:14])[Cl:13].[CH2:15](Cl)C=C>>[CH2:15]([Si:12]([Cl:14])([Cl:13])[Cl:11])[CH2:5][CH2:3][CH2:2][CH3:1]
Reactant: C=C(C)CC
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCCl
Agent: CC=C(C)C
Product: CCCCC[Si](Cl)(Cl)Cl

Procedure:
The process described in Example 2 is repeated, except that 1.5 liters of a mixture prepared from isomeric pentenes (10 percent by weight of 2-methylbutene-1, 82 percent by weight of 2-methylbutene-2 and 8 percent by weight of pentenes having an undetermined structure) and 10 ml of the catalytic solution are substituted for the trichlorosilane, allyl chloride and catalytic solution. About 98.6 percent of the trichlorosilane employed is reacted and 14.5 mol percent per hour of pentyltrichlorosilane is obtained. The product's purity is 92.5 percent by weight as determined by gas chromatography.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=1)[CH:12]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[N:7]1
Reactant: COC(=O)CCc1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)O)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ester 7 (0.31 g, 0.65 mmol) in THF (5 mL) was added a solution of LiOH (0.06 g, 1.40 mmol) in water (2 mL) and the resulting mixture was stirred at RT overnight. The volatiles were removed in vacuo. The residue was diluted with water (5 mL) and acidified to pH 1 with 2 M HCl. The acid 8 was isolated by filtration as a white solid and washed with water and dried overnight over KOH in a dessicator to yield 0.09 g (34%).
Reaction SMILES: [N+](C1C=CC(CCOC([NH:15][C:16]2[C:17]3[N:18]=[CH:19][N:20]([C:52]=3[N:53]=[CH:54][N:55]=2)[C@@H:21]2[O:51][C@H:48]([CH2:49][OH:50])[CH2:47][C@H:22]2[O:23][C:24](=[O:46])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=O)=CC=1)([O-])=O.C1CCN2C(=NCCC2)CC1.CC(O)=O>N1C=CC=CC=1>[C:31]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:23][C@@H:22]1[CH2:47][C@@H:48]([CH2:49][OH:50])[O:51][C@H:21]1[N:20]1[C:52]2[N:53]=[CH:54][N:55]=[C:16]([NH2:15])[C:17]=2[N:18]=[CH:19]1)=[O:46])(=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reaction time: 18 h

Procedure:
Compound 10 (160 mg, 0.208 mol) was co-evaporated twice with abs. pyridine and then dissolved in abs. pyridine (2 ml). DBU (158 mg, 1.04 mmol) was added, the mixture kept at r.t. for 18 h, then AcOH (62 mg, 1.04 mmol) added, and the soln. evaporated. The residue was diluted with CHCl3 (80 ml) and washed with a 10% citric acid soln. (2×50 ml), the aq. phase reextracted with CHCl3, the combined org. layer dried (MgSO4), evaporated, and co-evaporated with toluene, and the residue precipitated by MeOH and washed with Et2O: 103 mg (86%) of 12. UV (CH2Cl2: 259 (4.16). 1H-NMR ((D6)DMSO): 8.33, 8.13 (2s, H—C(8), H—C(2)); 7.68 (t, NH(CH2)5CO); 7.25 (s, NH2); 6.05 (d, H—C(1′)); 5.60 (m, H—C(2′)); 5.11 (t, OH—C(5′)); 4.32 (m, H—C(4′)); 3.65, 3.47 (2m, 2 H—C(5′)); 2.95 (q, 1 CH2 of NH(CH2)5CO); 2.6, 2.15 (2m, 2 H—C(3′)); 2.34, 2.00 (2t, 2 CH2 of NH(CH2)5CO, 2 H of Me(CH2)12Co); 1.65-1.15 (m, 28 H, 2 CH2 of NH(CH2)5CO, Me(CH2)12CO); 0.83 (t, Me(CH2)12CO). Anal. calc. for C30H50N6O5 ½ H2O (583.76): C 61.72, H 8.81, N. 14.39; found C 62.04, H 9.07, N 13.85.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:20])=[C:13]([NH:18][CH3:19])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:31][C:32](=O)[O:33]CC)(=[O:30])=[O:29])=[CH:25][CH:24]=1>CC(O)=O>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([F:20])=[C:13]([NH:18][CH3:19])[CH:14]=4)[C:9]3=[O:21])=[CH:4][CH:3]=2)=[O:33])(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)cc1)CC2
Solvent: CC(=O)O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of 2-(4-aminophenyl)-7-fluoro-6-(methylamino)-3,4-dihydroisoquinolin-1(2H)-one (62 mg, 0.22 mmol) in HOAc (4 mL) at 100 C, ethyl 5-chlorothiophen-2-ylsulfonylcarbamate (119 mg, 0.44 mmol) was added. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by RP-HPLC to give the titled compound as a powder (25 mg). ES-MS (M+H)+=509, 511 (Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1([CH3:33])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:12]1=[O:32].[CH2:34]([NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH3:35]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:36]([CH2:34][CH3:35])[CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:7])=[CH:4][C:3]=1[C:11]1([CH3:33])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:12]1=[O:32]
Reactant: CCNCc1cccnc1
Reactant: COc1ccc(CN2C(=O)C(C)(c3cc(C(=O)O)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Product: CCN(Cc1cccnc1)C(=O)c1ccc(Cl)c(C2(C)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1

Procedure:
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoic acid, in the racemic form, is treated with N-ethyl-3-pyridylmethylamine (document WO 01/074775, example 201a) and b)). 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoic acid, in the racemic form, is described in the document WO 01/074775, in example 101. After silica chromatography, elution being carried out with a dichloromethane/methanol 90/10 mixture, the expected compound, in the racemic form, is obtained crystallized from methanol (white powder).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=1)=[O:16])[CH2:6]2.ClC1C(Cl)=C(Cl)C(Cl)=C2C=1[CH2:38][N:39](C(C(C)C)C(O)=O)C2.[OH-].[K+].S(OC(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)(=O)(=O)C>C(O)C.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17][CH:18]([C:38]#[N:39])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=1)=[O:16])[CH2:6]2
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1
Reactant: CC(C)C(C(=O)O)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1
Agent: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1

Procedure:
The ester, m-phenoxybenzyl 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoate is hydrolyzed to 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoic acid using KOH in ethanol/water, which is reacted with α-cyano-m-phenoxybenzyl mesylate to yield α-cyano-m-phenoxybenzyl 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoate.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[N:17]([O-])=O.[Na+]>O>[ClH:1].[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15][NH2:17])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1csc2ccc(N)cc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1csc2ccc(NN)cc12
Temperature: 25 °C

Procedure:
12.1 g of 3-butyl-5-aminobenzothiophene hydrochloride are mixed with 50 ml of H2O and 50 ml of concentrated HCl, and a solution of 3.6 g of NaNO2 in 40 ml of water is added dropwise at -5°. The solution obtained is added dropwise to a mixture, cooled to -15° C., of 28.4 g of S2Cl2.2H2O and 50 ml of concentrated HCl. After warming the reaction mixture to room temperature, the precipitate which has separated out is filtered off, washed with cold concentrated HCl and put into ice-water and the mixture is covered with a layer of ether and rendered alkaline with 20% strength NaOH. The ethereal phase is washed and dried and acidified with HCl/ether; the precipitate is boiled up in ethyl acetate and filtered off. Melting point: 168°-170° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=O)[CH2:13][NH2:14])=[CH:6][CH:5]=1.[S-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:18][C:17]([SH:16])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(CCC(=O)CN)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCc2cnc(S)[nH]2)cc1
Yield: 19.2 %

Procedure:
A solution of 4-(4-methoxyphenyl)-2-oxo-1-aminobutane, hydrochloride (8.6 g, 37.7 mmole) and potassium thiocyanate (3.6 g, 37.7 mmole) in acetic acid (100 ml) was heated under reflux for 20 minutes. The reaction was cooled, diluted with water and the product was filtered and recrystallized from ethyl alcohol and dried to give the product as a solid (1.7 g, 19%).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:24]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH2:24][NH:6][CH3:5]
Reactant: O=Cc1c[nH]c2c(Cl)cccc12
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2c(Cl)cccc12
Yield: 92 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-chloro-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (440 mg, 92%) was obtained as an off white solid: MS (ES) m/e 195.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:22]([NH2:24])[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1.[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C.O>C(O)CCC>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:24][CH:22]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]3[C:5]([CH:6]=2)=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:23])[N:29]=[CH:28][N:27]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O
Product: CC(Nc1ncnc(N)c1C#N)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanamine (300 mg, 0.86 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (135 mg, 0.86 mmol) in n-butanol (5.2 mL) was added diisopropylethyl amine (336 mg, 2.6 mmol) at 25° C. The reaction mixture was stirred for overnight at 110° C. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated it. The residue was purified by column chromatography on neutral alumina using 0-5% MeOH in DCM. It was further purified by reversed-phase HPLC to give 4-amino-6-((1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6): δ 1.380 (d, 3H, J=6.8 Hz), 3.215 (s, 3H), 5.240-5.310 (m, 1H), 7.256 (br s, 2H), 7.718-7.828 (m, 2H), 7.934-7.950 (m, 3H), 8.123 (dd, 1H, J=1.2 Hz, 7.6 Hz), 8.336 (dd, 1H, J=2.4 Hz, 9.6 Hz). 8.678 (s, 1H), 9.117 (d, 1H, J=2.8 Hz); LC-MS (ESI) m/z 464.2 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)=[N+:2]=[N-:3].[C:12]1(=[O:19])[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:1]=[N+:2]=[N-:3])[C:13]2[C:12](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:26][C:25]=1[NH2:27])=[O:28])[CH3:21]
Reactant: CCOC(=O)CC(=N)N
Reactant: [N-]=[N+]=Nc1ccccc1C=O
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1ccccc1N=[N+]=[N-]
Yield: 58 %

Procedure:
Upon heating a solution of 7.4 of 2-azidobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-4-(2-azidophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 209° C. (ethanol) is obtained. Yield: 58% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.Cl[CH2:12]I.C([Zn]CC)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:10]2)=[CH:4][CH:3]=1
Reactant: ClCI
Reactant: C=COc1ccc(Br)cc1
Agent: CC[Zn]CC
Solvent: ClCCCl
Product: Brc1ccc(OC2CC2)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a 0° C. solution of 1-bromo-4-vinyloxy-benzene (31.75 g, 159.51 mmol) and chloroiodomethane (101.3 g, 574.2 mmol) in 1,2-dichloroethane (410 mL), slowly add diethylzinc (1 M in heptane, 380 mL) over 1 hr while maintaining the temperature below 5° C. Stir the white mixture at 0-5° C. for 2 hours. Quench the reaction slowly at 5° C. with aqueous saturated ammonium chloride (400 mL, exothermic) and separate the layers. Extract the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers, wash with saturated ammonium chloride (400 ml), dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (33 g, 97%) as an oil: GCMS: 212.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:35]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:35])=[O:24]
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(OC(=O)c2ccco2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (6.20 g) is dissolved in ethyl acetate (100 mL). DBU (2.20 g) and dimethyl sulphate (1.83 g) are added sequentially. The reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords furan-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 3.75 (3H, s), 6.30 (1H, dd), 6.45 (1H, d), 6.55 (2H, m), 7.15 (1H, d), 7.60 (1H, d).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)C4CC4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (0.65 g, 210 mmol) in acetonitrile (50 mL). After stirring for 30 min, cyclopropanecarbonyl chloride (0.24 g, 2.31 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (100 mL) to afford N-{[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]methyl}cyclopropylcarboxamide (0.36 g, 50%) as a white solid: mp 262-264° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 8.63 (t, J=5.7 Hz, 1H), 7.65-7.47 (m, 3H), 5.18-5.11 (dd, J=5.0 and 13.2 Hz, 1H), 4.46 (d, J=17.3 Hz, 1H), 4.38-4.31 (m, 3H), 3.00-2.85 (m, 1H), 2.65-2.30 (m, 2H), 2.04-1.99 (m, 1H), 1.64-1.54 (m, 1H), 0.69-0.65 (m, 4H); 13C NMR (DMSO-d6) δ 172.82, 172.69, 170.96, 168.03, 140.08, 134.76, 131.66, 130.70, 128.30, 121.64, 51.54, 46.15, 31.16, 22.59, 13.47, 6.27; Anal. Calcd. For C18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 62.97; H, 5.55; N, 12.33.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[C:6]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[CH:5]=[C:4]([C:32]2[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:33]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.C(N(CC)CC)C.Cl[C:52](Cl)([O:54]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:13]1([NH:12][C:10]([N:9]2[CH2:8][C:7]3[C:6]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)=[CH:5][C:4]([C:32]4[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:33]=4[O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[N:3][C:2]=3[NH:1][C:52]2=[O:54])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNC(=O)NC2CCCCC2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(C(=O)NC2CCCCC2)C(=O)N3)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-{2-amino-3-({[(cyclohexylamino)-carbonyl]amino}methyl)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate(0.039 g, 0.065 mmol), which was obtained in the step (1) of Example 23-3, and triethylamine (15.0 mL, 0.389 mmol) in tetrahydrofuran (10.0 mL) was added dropwise a solution of triphosgene (0.019 g, 0.065 mmol) in tetrahydrofuran (5.0 mL) under an argon atmosphere. The mixture was stirred at 0° C. for 2 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue (white solid) was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give tert-butyl 3-{3-[(cyclohexylamino)carbonyl]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl}-1-piperidinecarboxylate (0.021 g, yield; 52%).