Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([C@H:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]([CH3:28])=[CH:5]2.Cl(O)(=O)(=O)=O>C(OC(=O)C)(C)(C)C>[C:4]([O:27][C@@H:21]([C:7]1[C:6]([CH3:28])=[CH:5][C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([Cl:1])[CH:3]=2)[C:8]=1[O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:15])=[O:16])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:9])([CH3:5])[CH3:3]
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(Cl)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 2.5 h
Yield: 170.3 %

Procedure:
To a solution of (S)-ethyl 2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (4.44 g, 9.99 mmol) in tert-butylacetate (100 mL) was added 70% perchloric acid (1.20 mL, 19.98 mmol). The reaction mixture was stirred for 2.5 hours and quenched with solid sodium bicarbonate and stirred for 45 minutes. Water and solid sodium bicarbonate were carefully added and stirred for another 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated bicarbonate solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give an pale orange oil (4.26 g). 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=7.2 Hz, 4H), 7.74 (d, J=10.2 Hz, 4H), 7.58 (s, 4H), 7.26 (s, 3H), 5.69 (s, 4H), 4.26-4.08 (m, 9H), 2.53 (s, 12H), 1.20 (s, 34H), 1.17 (t, J=7.1 Hz, 13H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C@@H:8]([CH2:12][CH:13]=[CH2:14])C(O)=O)([CH3:4])([CH3:3])[CH3:2].N[C@H]1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][CH2:8][CH2:12][CH:13]=[CH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(R)-allyl-succinic acid 4-t-butyl ester (5 g, 0.00234 mol), 9-(S)-amino-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-8-one (6,38 g, 0.00234mol) in 50 mL DMF added HOBT (3.47 g, 0.026 mol), DMAP (80 mg), N-methylmorpholine (2.84 g, 0.028 mol), and EDCI (6.69 g, 0.035 mol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (300 mL) and washed with brine (2×100 mL), saturated NaHCO3 (2×100 mL) and brine (1×100 mL), and dried (MgSO4). Removal of the solvents gave 9 g of crude product. Column chromatographic purification (50% EtOAc/CH2Cl2) gave 7.5 g of pure (3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17 ]octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-hex-5-enoic acid t-butyl ester, MS: 469(M+).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[C:32]([Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:33]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCN(Cc2ccc(N)cc2[Si](C)(C)C)CC1
Reactant: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c([Si](C)(C)C)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid (0.22 mmol) in dry pyridine (5 mL) is added 4-(4-methylpiperazin-1-ylmethyl)-3-trimethylsilylaniline (60 mg, 0.22 mmol) and EDCl (62 mg, 0.325 mmol). The resulting mixture is stirred at r.t. overnight. The solvent is removed on rotavap and the residue is partitioned between DCM and aq. NaHCO3. The combined organic layers from extraction are dried (Na2SO4), filtered, concentrated, and the resulting residue is purified by silica gel flash chromatography [eluted with 5% MeOH (pre-saturated with NH3) in DCM] to give the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1

Procedure:
A mixture of tert-Butyl-4-hydroxy-1-piperidine-carboxylate (2.0 g, 9.64 mmol) and 2-Fluoropyridine (0.93 mL, 10.6 mmol) in DMF (10 mL) is treated with 60% NaH in mineral oil (600 mg, 12.5 mmol) at RT. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a white powder; ES-MS: M+H=279.0: DtRet=2.82.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[C:18]=1[CH3:27])(=[O:3])[NH2:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[C:18]=1[CH3:27])(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C)c3C)c2cc1C(N)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1C(N)=O
Yield: 82.8 %

Procedure:
The title compound (840 mg) was obtained from 7-methoxy-4-chloroquinoline-6-carboxyamide (890 mg) and 4-nitro-2,3-dimethylphenol (940 mg), in the same manner as Production Example 7. Next, 6-carbamoyl-4-(2,3-dimethyl-4-nitrophenoxy)-7-methoxyquinoline (840 mg) was dissolved in tetrahydrofuran (25 ml) and methanol (25 ml), and the solution was subjected to catalytic reduction with palladium-carbon (840 mg) for 10 hours under a hydrogen atmosphere to obtain the title compound (639 mg).
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=3)[C@@H:14]([C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH2:13][C@@:12]2([CH2:41][CH:42]([CH3:44])[CH3:43])[C:34]([O:36]C(C)(C)C)=[O:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=3)[C@@H:14]([C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH2:13][C@@:12]2([CH2:41][CH:42]([CH3:43])[CH3:44])[C:34]([OH:36])=[O:35])=[O:10])=[CH:45][CH:46]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2cccc(-c3ccccc3)c2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2cccc(-c3ccccc3)c2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH3:15]
Reactant: O=Cc1cccs1
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Product: CC(COc1ccc2ccccc2c1Cl)NCc1cccs1
Yield: 62 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and thiophen-2-carbaldehyde in 62% yield as a pale yellow oil.
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]N)=[CH:9][CH:8]=2)[CH:6]=1.[Si]([O:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH:32]=O)[CH2:25][CH2:24]1)(C(C)(C)C)(C)C>C(O)C.O.C(O)C>[N:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][CH:32]=[C:31]3[CH2:30][CH2:29][CH:26]2[CH2:25][CH2:24][CH:23]([OH:22])[CH2:28][CH2:27]2)[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CCCC=O)CC1
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: OC1CCC(CCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Temperature: 140 °C

Procedure:
A stirred mixture of 4-(1,2,4-triazol-4-yl)phenylhydrazine hydrochloride (930 mg, 3.5 mmol) in ethanol/water (25 ml, 4:1), under nitrogen, was slowly treated with a solution of 4-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]butyraldehyde (1 g, 3.5 mmol) in ethanol (5 ml). The reaction mixture was heated at 140° C. for 18 hours in a sealed tube, cooled and evaporated. The residue was purified by column chromatography on silica using methanol/dichloromethane as eluent to afford the title compound as a mixture of cis and trans isomers (1 g, 92%). MS, ES+, m/z=311 for (M+H)+, δ(250 MHz, d6-DMSO) 1.07-1.88 (11H, m), 2.71 (2H, t, J=7 Hz), 3.70-3.78 (1H, m), 4.26 (1H, d, J=3 Hz), 7.21-7.32 (2H, m), 7.47 (1H, d, J=9Hz), 7.76 (1H, d, J=2Hz), 9.02 (2H, s), 11.10 (1H, br s).
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[CH2:3][C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][C:7]([Cl:10])([CH3:9])[CH3:8].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[Cl:1][C:2]#[C:3][C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][C:7]([Cl:10])([CH3:8])[CH3:9]
Reactant: CC(C)(Cl)CCC(C)(C)CC(Cl)(Cl)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(Cl)CCC(C)(C)C#CCl
Yield: 78.9 %

Procedure:
25.2 g of 1,1,1,6-tetrachloro-3,3,6-trimethylheptane is heated with 0.60 g of tricaprylmethylammonium chloride ("Aliquat" 336) and 50 ml of 40% aqueous sodium hydroxide solution under vigorous agitation to 80° C. for 22 hours. The mixture is then allowed to cool, combined with 60 ml of dichloromethane, the organic phase is separated and dried over calcium chloride. The solvent is thereafter removed under vacuum, and the residue is distilled, thus obtaining 14.7 g of 1,6-dichloro-3,3,6-trimethyl-1-heptyne as a yellow oil, bp 39°-43° C. under 1 mbar.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34]CF)[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1.[F:39][CH2:40][CH2:41][CH2:42]CN=[N+]=[N-]>>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34][CH2:42][CH2:41][CH2:40][F:39])[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCF)nn3)cc21
Reactant: [N-]=[N+]=NCCCCF
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCCCF)nn3)cc21

Procedure:
is prepared according to the procedure for compound 12, with the exception that 4-fluorobutylazide is used in place of the 2-fluoroethylazide.
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][C:10]1[CH:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]2=[O:21]>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][C:10]1[CH:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]2([CH3:1])[OH:21]
Reactant: C[Mg]Cl
Reactant: O=c1c2cc(Cl)ncc2oc2c(F)cc(Br)cc12
Solvent: C1CCOC1
Product: CC1(O)c2cc(Cl)ncc2Oc2c(F)cc(Br)cc21
Reaction time: 2 h

Procedure:
Methyl magnesium chloride, 22 wt % in tetrahydrofuran (6.14 mL, 18.26 mmol) was added to a solution of 7-bromo-3-chloro-9-fluoro-5H-chromeno[2,3-c]pyridin-5-one (3.0 g, 9.13 mmol) in THF (40 mL) at 0° C. After 2 hours, the reaction was quenched with saturated aqueous ammonium chloride (250 mL) and diluted with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude product 7-bromo-3-chloro-9-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol which was used directly in the next reaction. MS m/z=346.0 [M+H].
Reaction SMILES: [CH2:1]([S:6]([NH:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH:12]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:1]([S:6]([NH:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH:12]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Temperature: 100 °C
Yield: 54.6 %

Procedure:
N-(n-pentanesulfonyl)-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide (38.9 g) was mixed with 200 ml of tetrahydrofuran, 200 ml of ethanol and 800 ml of water. Sodium hydrosulfite (214.2 g) was added all at once to the mixture with stirring. Immediately, the mixture was placed on an oil bath at 90° C. and refluxed for 40 minutes. The mixture was then cooled down and separated into aqueous and organic layers. The organic layer was concentrated, and water was added to the resulting residue. The precipitate thus formed was separated by filtration, and washed subsequently with water and ethyl acetate. Ethanol (520 ml) was added to the resulting solid, and the mixture was refluxed at 100° C. to dissolve the solid completely. Water (230 ml) was added to the heated solution, and the mixture was cooled with stirring for 1 hour. The resulting crystals were separated through filtration, washed with a solution of ethanol/water (7:3) and dried to give pale-yellow crystals (19.9 g) of N-(n-pentanesulfonyl)-4-amino-3-(2,4-dichlorobenzylamino)benzamide (31).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([N:15]([CH3:21])[C:16](=O)[CH2:17][CH2:18][CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:16]([N:15]([CH3:21])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]([N:2]([CH3:28])[CH3:1])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)N(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The title compound from step 1 (200 mg, 0.528 mmol) was dissolved in abs. THF (15 mL). LiAlH4 (39 mg, 1.06 mmol) was added in argon. The batch was boiled for 7 h with reflux. The batch was then cooled to room temperature, mixed with THF (12 mL) and H2O (5 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in a vacuum.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:8]([CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9][CH2:10][S:22]1
Reactant: ClCC[NH2+]CC1CCCC1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CCCC2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Si:15]([O:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B (2.5 g, 13.3 mmol) in methylene chloride (50 mL) was added t-butyldimethylsilyl chloride (3.0 g, 20 mmol) and DIPEA (4.7 mL, 27 mmol). The reaction was stirred at RT for 16 h, poured into dilute aq. HCl and extracted twice with ether. The organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (5% ethyl acetate in hexanes) to afford the title product. (4.2 g) as a oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)=[O:35])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([C:34]([N:36]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]5)=[O:35])[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CNC1)N1CC[C@H](O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CC[C@H](O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (75 mg, 0.19 mmol), azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone (65 mg, 0.38 mmol), and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to afford 460 as an off-white solid (32 mg, 30%). LCMS (Method I): RT 2.33 min, [M+H]+ 546. 1H NMR (400 MHz, CDCl3): δ 7.98-7.93 (1h, m), 7.71-7.70 (1 H, m), 7.22 (2 H, s), 4.49 (2 H, s), 4.31 (4 H, s), 3.83-3.81 (8 H, m), 3.52-3.50 (9 H, m), 3.32-3.30 (2 H, m), 2.04-1.88 (3 H, m), 1.40 (3 H, t, J=7.47 Hz)
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(N(CCCC)CCCC)CCC.C(C(C)=[O:25])C>>[O:25]1[CH:2]([C:1]([OH:8])=[O:7])[CH:3]1[C:4]([OH:6])=[O:5]
Reactant: CCC(C)=O
Reactant: O=C(O)CCC(=O)O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(O)C1OC1C(=O)O
Temperature: 150 °C

Procedure:
A reaction vessel was charged with 442 parts Epoxy B, 442 parts Epoxy E, 116.0 parts succinic acid, 110 parts methyl ethyl ketone, and 3 parts tri-n-butylamine (catalyst). The temperature was raised to 150° C., while removing sufficient MEK (100 parts) to maintain controlled reflux at this temperature. The reaction maintained at 150° C., for 1.5 l hours and then poured into a poly(tetrafluoroethylene) lined tray and allowed to cool to ambient temperature. The resulting solid resin had an acid number of 32.0 and an epoxy content of 0.03 meq./g.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].[C:30]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][N:42]([C:45](O)=O)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)(O)=O>>[CH2:1]([N:3]([CH2:30][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:37][CH:38]=1)[C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2]
Reactant: O=C(O)c1ccc(C2CCN(C(=O)O)CC2)cc1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid text-butyl ester (60 mg) according to an analogous synthetic method to Example 337 described below, the title compound (35 mg) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=3[C:15]3=[N:23][O:24][C:25]([CH3:26])=[C:14]3[C:13]2=[O:27])[N:7]=1)C.CO.[OH-].[Na+].Cl>O.C1COCC1>[Cl:22][C:17]1[C:16]2[C:15]3[C:14](=[C:25]([CH3:26])[O:24][N:23]=3)[C:13](=[O:27])[N:12]([C:8]3[N:7]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1cccc(-n2c(=O)c3c(C)onc3c3c(Cl)cccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(-c1cccc(CC(=O)O)n1)c1cccc(Cl)c21
Temperature: 25 °C
Yield: 101.6 %

Procedure:
Heat [6-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-pyridin-2-yl]-acetic acid ethyl ester (0.359 g, 0.9 mmol), MeOH (4.5 ml), THF (0.5ml), and 1N NaOH (1.8 ml, 1.8 mmol) at 50° C. for 2 h. Cool to room temperature, dilute with H2O, and acidify (conc. HCl) to less than pH 3. Extract with EtOAc twice and wash the combined extracts (H2O then brine), dry (MgSO4), filter, and concentrate giving the title compound (0.338 g, 100%). Use this material without further purification. Mass Spectrum (FIA) (m/z) 370.0 [M+1]