Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][C@@H:7]([CH3:9])[CH2:6][N:5]([C:10]2[CH:11]=[C:12]([C@@H:16]([NH2:18])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH2:4]1.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:9][C@H:7]1[O:8][C@@H:3]([CH3:2])[CH2:4][N:5]([C:10]2[CH:11]=[C:12]([C@@H:16]([NH:18][C:24](=[O:25])[CH:23]=[CH:22][C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[F:19])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH2:6]1
Reactant: C[C@@H]1CN(c2cccc([C@H](C)N)c2)C[C@H](C)O1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1CN(c2cccc([C@H](C)NC(=O)C=Cc3ccccc3F)c2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-1-[3-(cis-2,6-dimethyl-morpholin-4-yl)-phenyl]-ethylamine hydrochloric acid salt, Preparation 31 (50 mg, 0.16 mmol), 2-fluorocinnamic acid (30 mg, 0.18 mmol), EDC (65 mg, 0.33 mmol), DMAP (20 mg, 0.16 mmol), triethylamine (0.09 ml, 0.65 mmol) in dichloromethane (0.7 mL) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 70% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)[CH3:2].C([Li])(CC)C.[CH3:22][S:23]SC>C1COCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][C:6]=1[S:23][CH3:22])[CH3:16]
Reactant: CSSC
Reactant: CCCc1ccc(C(=O)N(CC)CC)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)N(CC)CC)c(SC)c1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a stirring solution of N,N-diethyl-4-propylbenzamide (2.0 g, 9.3 mmol) and N,N,N′N′-tetramethylethylenediamine (1085 mg, 9.4 mmol) in dry THF (93 mL) at −78° C. under Ar was added 0.78 M s-butyllithium in hexanes (12 mL). The reaction was stirred for 30 min and then methyl disulfide (1936 mg, 12.1 mmol) was added. The reaction was stirred for 5 min and then quenched with MeOH (1 mL) and brine. The reaction was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and conc in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0-30% EtOAc in hexanes) to yield 2.1 g (86%) of the product as a yellow oil. MS (ESI) 266 (M+H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[OH:38].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:38][C@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[N:27][C:19]=1[O:18][C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([S:14][CH3:13])[CH:16]=1
Reactant: N[C@@H]1CCCC[C@@H]1O
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@@H]2CCCC[C@@H]2O)c1
Reaction time: 18 h
Yield: 48.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1S,2R)-2-aminocyclohexanol hydroformate [8151/194/1] (128 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1R,2S)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]([CH2:4][C:5](O)=O)=[CH2:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:5][CH2:4][CH:2]([CH2:1][OH:9])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: NCc1ccccc1
Product: OCC1CCN(Cc2ccccc2)C1

Procedure:
This was prepared from itaconic acid and benzylamine by the procedure described by Feldkamp et al. J. Am. Chem. Soc.. (1961). 1519.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][C:16](=[O:19])[CH2:17]I.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:27])[NH:25][CH:26]=1>>[Cl:14][CH2:15][C:16](=[O:19])[CH2:17][O:27][C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=1
Reactant: O=c1ccc(Cl)c[nH]1
Reactant: O=C(CCl)CI
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(CCl)COc1ccc(Cl)cn1

Procedure:
A protected ketone derivative wherein R2 is a 5-chloro-2-pyridyl radical, for use as a starting material in the process of the invention, may be obtained by reacting epichlorhydrin with hydriodic acid and sodium iodide to give 1-chloro-3-iodopropan-2-ol, which is oxidised by Jones' reagent to the ketone, 1-chloro-3-iodopropan-2-one. The ketone is reacted with 5-chloro-pyrid-2-one to give 1-chloro-3-(5-chloropyrid-2-yloxy)propan-2-one, which is converted to the protected ketone derivative, ClCH2.CR3.CH2OR2 wherein R2 is a 5-chloro-2-pyridyl radical, which in turn is reacted with a trialkyl phosphite to give the required protected ketone starting material, (R1O)2.PO.CH2.CR3.CH2OR2.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.C1N=CN([C:16]([N:18]2[CH:22]=[N:21][CH:20]=[CH:19]2)=O)C=1.CCN(CCC[CH:31]([NH:33][C:34]1[CH:35]=[C:36](/C=C/C2C=CC=CC=2Cl)[N:37]=[C:38]2[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=12)C)CC>C1COCC1>[Cl:44][C:42]1[CH:43]=[C:38]2[C:39]([C:34]([NH:33][CH2:31][CH2:22][N:18]([CH3:16])[CH2:19][CH2:20][NH:21][C:8](=[O:10])[CH:7]=[CH:6][C:2]3[N:3]=[CH:4][NH:5][CH:1]=3)=[CH:35][CH:36]=[N:37]2)=[CH:40][CH:41]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Solvent: C1CCOC1
Product: CN(CCNC(=O)C=Cc1c[nH]cn1)CCNc1ccnc2cc(Cl)ccc12
Reaction time: 2 h
Yield: 31 %

Procedure:
Urocanic acid (138 mg, 1 mmol) was dissolved in dist THF, and a condensing agent CDI (200 mg, 1.3 mmol) was added to this solution. The solution was stirred. After two hours, 2Q (278 mg, 1 mmol) dissolved in dist THF was added and continued to be stirred. After reaction overnight, the reaction solution was filtered through a Kiriyama funnel. The filtrate was concentrated under a reduced pressure to give a yellow oil and this oil was purified by HPLC. Yield: 31%.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C[C@@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
The method of Part B of Example 4 was used to hydrogenate 2-chloro-3-nitro-N-[(1R)-1-phenylethyl]quinolin-4-amine (24.35 g, 73.3 mmol) with the modifications that the reaction was stopped after one hour, and magnesium sulfate was added to the mixture before filtration. 2-Chloro-N4-[(1R)-1-phenylethyl]quinoline-3,4-diamine (21.0 g) was isolated as an amber oil.
Reaction SMILES: [CH:1](=O)[CH2:2]CCCC.C(=O)CCCCCC.[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH3:18]>>[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH2:18][CH2:1][CH3:2]
Reactant: CCCCCC=O
Reactant: CCCC(CO)(CO)CO
Solvent: CCCCCCC=O
Product: CCCCCC(CO)(CO)CO

Procedure:
2-n-Butyl-2-hydroxmethyl-propan-1,3-diol and 2-n-pentyl-2-hydroxymethyl-propan-1,3-diol were prepared from n-hexanal and n-heptanal respectively in a manner analogous to that described for the synthesis of 2-n-propyl-2-hydroxymethyl-propan-1,3-diol.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][O:12][CH2:11][CH:10]1[O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:18]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[K+].[OH2:27].Cl>OCC(CO)O>[CH2:1]([O:8][CH:9]1[CH2:13][O:12][CH2:11][CH:10]1[O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:18]([OH:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: COc1ccc(C#N)cc1OC1COCC1OCc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: OCC(O)CO
Product: COc1ccc(C(=O)O)cc1OC1COCC1OCc1ccccc1
Reaction time: 1 h

Procedure:
2.8 g (8.6 mmol) of 3-(4-benzyloxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A8) and 4.8 g (86.0 mmol) of potassium hydroxide are heated at 140° C. for 3 h in 30 ml of glycerol. The mixture is treated with 70 ml of water and acidified by dropwise addition of 40 ml of 2 N hydrochloric acid with ice-cooling. The mixture is subsequently stirred for 1 h, filtered and the precipitate is washed with ice water. For further purification, the product is chromatographed on silica gel [toluenelethyl acetate =2:1]. The product-containing fractions are concentrated and the residue is crystallized from isopropanol. 2.1 g of the title compound of m.p. 153-156° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]1[O:16][CH2:15][CH:14]2[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]2[CH2:12]1.[H][H]>CCOC(C)=O.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1c(C2CN3CCN(C(=O)OC(C)(C)C)CC3CO2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1C1CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO1

Procedure:
9aS)-tert-Butyl 3-(2-methyl-3-nitrophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.45 g, 3.84 mmol) was dissolved in EtOAc (30 ml) then added 10% Pd/C (0.409 g) and stirred under a balloon of hydrogen overnight. The catalyst was filtered off and solvent evaporated to yield the title compound. LC-MS (IE, m/z): 348 [M+1]+
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[C:12]([NH:15][C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:14])[CH3:13].[C:29]([N:37]1[CH2:42][CH2:41][CH2:40][C:39]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=2)([CH2:43][CH2:44][CH2:45]OS(C)(=O)=O)[CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[OH2:8].[OH2:14].[ClH:57].[C:12]([NH:15][C:16]1([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18][N:19]([CH2:45][CH2:44][CH2:43][C:39]2([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=3)[CH2:40][CH2:41][CH2:42][N:37]([C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:38]2)[CH2:20][CH2:21]1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: CC(=O)NC1(Cc2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)NC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 90 °C
Yield: 105.3 %

Procedure:
A mixture of 0.44 g of 4-(acetylamino)-4-benzylpiperidine p-toluenesulfonate, 0.50 g of the compound obtained in step B of EXAMPLE 1 and 0.53 g of K2CO3 in 5 ml of DMF is heated at 90° C. for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with 2 N NaOH and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (99/1; v/v to 93/7; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.38 g of the expected product, m.p.=158° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([OH:15])([C:18]([F:20])([F:19])[F:17])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)c1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)(CC(C)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
4.4 g of 2-oxo-4-phenylvaleric acid ethyl ester is dissolved in 40 ml of tetrahydrofuran and mixed at −78° C. with 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at −78° C., another 20 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran is added. It is stirred for 1.5 hours at 0° C., ethyl acetate and saturated common salt solution are added, the organic phase is separated, and it is washed with saturated common salt solution and water. Then, it is dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 95-100° C./0.04 hPa, is obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]([OH:15])[OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+].O1CCOCC1>[CH2:20]([O:19][C:17]([NH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]([OH:15])[OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccc(B(O)O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccc(B(O)O)cc1)C(=O)O)OCc1ccccc1

Procedure:
3.0 g (14.4 mmol) of 2-amino-3-(4-boronophenyl)propionic acid were dissolved in 120 ml 0.4 N NaOH solution and diluted with 120 ml 1,4-dioxane. 2.05 ml benzyl chloroformate (14.4 mmol) in 15 ml 1,4-dioxane were added slowly at −15° C. The reaction mixture was allowed to come to room temperature over night and the organic solvent was removed under reduced pressure. After extracting the acidified remaining aqueous phase with ethyl acetate and drying this organic phase over Na2SO4 the solvent was removed under reduced pressure. The crude product was recrystallized from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25].CCN(CC)CC>ClCCCl>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25]
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with (3-chloro-4-isocyanato-phenyl)-acetic acid ethyl ester in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 d under reflux conditions to give the title compound as brown gum. MS: m/e=565.3 [M+H+].
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:43]([OH:51])(=[O:50])[CH:44]([CH2:46][C:47]([OH:49])=[O:48])[OH:45].[H][H]>O1CCCC1.[Pd].CCOCC>[CH2:21]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:50][C:43](=[O:51])[CH:44]([CH2:46][C:47]([OH:49])=[O:48])[OH:45])=[O:15])[CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: C=CCCCCCCCCC=CCCCN(C(=O)OCc1ccccc1)c1ccccc1C(=O)Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCCCCCCCC=CCCCNc1ccccc1C(=O)OC(=O)C(O)CC(=O)O

Procedure:
A warm solution of N-carbobenzyloxy-2-(4,14-pentadecadienylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered. The solution is evaporated and the residue is crystallized from acetic acid to yield the title compound as white crystals.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl.[OH-].[Na+].C(C(C)=O)C(C)C>O1CCCC1.C(OCC)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:12]([CH3:18])[C:13](=[O:17])[C:14]([CH3:16])=[CH:15][C:10]=1[C:8]([NH:7][O:6][CH2:5][CH2:4][OH:3])=[O:9]
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-vinyloxy-ethoxy)-amide (500 mg, 915 μmol) and hydrogen chloride (1 mL) in tetrahydrofuran (5 mL) was stirred overnight. Sodium hydroxide (1M, 2.00 mL) was then added, and after a further 10 minutes methyl isobutyl ketone (3 mL) and ethyl acetate (3 mL) were added to the mixture. The layers were separated and the organic solution was washed with 50% brine (4 mL), then evaporated (approximately half the material was lost by spillage). The residue was taken up in methyl isobutyl ketone (3 mL) and ethyl acetate (1 mL) and the mixture was heated to reflux. Upon cooling to 50° C. the mixture went cloudy and isohexane (5 mL) was added. This caused solid to crystallize and the mixture was cooled to 20° C., followed by a further addition of isohexane (5 mL). The solid was then filtered, washed with isohexane (1 mL) and dried in a vacuum oven at 40° C., to provide the title compound, 140 mg.
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH2:17][CH2:18][C:19]#[N:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3].[CH:21](N)([CH3:23])[CH3:22].[H][H]>[Pd]>[CH:21]([NH:20][CH2:19][CH2:18][CH2:17][C:4]1([C:2]([NH2:1])=[O:3])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 500 g. of 9-aminocarbonyl-9-(2-cyanoethyl)fluorene, 1500 ml. of isopropylamine and 100 g. of 5% palladium on carbon was placed in a one gallon high pressure hydrogenation bomb. The bomb was pressurized with hydrogen to a pressure of 1500 psi, and the reaction mixture was then stirred at 100° C. for ten hours, and for an additional eight hours at room temperature. The reaction mixture was filtered to remove the hydrogenation catalyst, and the solvent was removed from the filtrate by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was extracted several times with 1N hydrochloric acid. The acidic extracts were combined, made alkaline by the addition of sodium hydroxide, and the alkaline mixture was extracted with fresh ethyl acetate. The organic layer was separated, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 9-(3-isopropylaminopropyl)-9-aminocarbonylfluorene as a solid residue. The solid was dissolved in methanol and treated with anhydrous hydrogen chloride. The crystalline product which formed was recrystallized from chloroform to afford 391 g. of 9-(3-isopropylaminopropyl)-9-aminocarbonylfluorene hydrochloride. Yield 60%. m.p. 216.5°-217° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C:23]4([C:27]5[CH:28]=N[CH:30]=[CH:31][C:26]=5[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.FC(F)(F)C(O)=O.[F:47][C:48]1[C:53]2[O:54][C:55]3[C:60]([C:61]4([C:65]5[CH:66]=[N:67][CH:68]=[CH:69][C:64]=5[C:63]([NH2:70])=[N:62]4)[C:52]=2[CH:51]=[C:50]([C:78]2[CH:83]=[CH:82][N:81]=[C:80]([F:84])[CH:79]=2)[N:49]=1)=[CH:59][C:58]([C:71]1[C:72]([F:77])=[N:73][CH:74]=[CH:75][CH:76]=1)=[CH:57][CH:56]=3.C(=O)=O>>[F:47][C:48]1[C:53]2[O:54][C:55]3[C:60]([C:61]4([C:65]5[CH:66]=[N:67][CH:68]=[CH:69][C:64]=5[C:63]([NH2:70])=[N:62]4)[C:52]=2[CH:51]=[C:50]([C:78]2[CH:83]=[CH:82][N:81]=[C:80]([F:84])[CH:79]=2)[N:49]=1)=[CH:59][C:58]([C:71]1[C:72]([F:77])=[N:73][CH:74]=[CH:75][CH:76]=1)=[CH:57][CH:56]=3.[O:54]1[CH2:55][CH2:60][CH:61]=[C:52]([C:9]2[N:14]=[C:13]([F:15])[C:12]3[O:16][C:17]4[C:22]([C@@:23]5([C:27]6[C:26](=[CH:31][CH:30]=[CH:2][CH:28]=6)[C:25]([NH2:32])=[N:24]5)[C:11]=3[CH:10]=2)=[CH:21][C:20]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:18]=4)[CH2:53]1
Reactant: O=C(O)C(F)(F)F
Reactant: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Agent: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(-c2ccnc(F)c2)nc3F)c2cnccc21
Agent: O=C=O
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(C2=CCCOC2)nc3F)c2ccccc21

Procedure:
The titled compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using 3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine 2,2,2-trifluoroacetate (14d) and in step 4. 1-Fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)spiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine 2,2,2-trifluoroacetate (14e, 77 mg) was subjected to chromatography using supercritical CO2 (additives 26% MeOH with 20 mM NH3) on a Chrialcel ADH column (21×250 mm, 5 μm) eluting at a flow rate 65 ml/min (100 bar pressure, 40° C. column temperature). The first peak (retention time=5.3 min) provided (S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine (Example 14-A; >99% ee), and the second peak (retention time=7.0 min) provided (R)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine (Example 14-B; TFA salt; >99% ee).