Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[O:25])[C:9]([NH:11][CH:12]([C:17]([N:19]([CH3:22])[NH:20][CH3:21])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[N:37]#[C:38]Br>CO>[CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[O:25])[C:9]([NH:11][CH:12]([C:17]([N:19]([CH3:22])[N:20]([C:38]#[N:37])[CH3:21])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN(C)C(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)NC(=O)c1cnccn1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)c1cnccn1)C(=O)N(C)N(C)C#N
Reaction time: 4 h
Yield: 64.5 %

Procedure:
N2-[1-benzyl-2-(1-[(1,2-dimethylhydrazino)carbonyl]-3-methylbutylamino)-2-oxoethyl]-2-pyrazinecarboxamide (100 mg, 0.23 mmol) and sodium acetate (53 mg, 0.64 mmol) were dissolved in methanol (1 mL). Cyanogen bromide (49 mg, 0.46 mmol) was added and the solution was stirred for 4 h. Methanol was concentrated by rotary evaporation. The pH value was adjusted (5% NaHSO3) to 1-2. The solution was extracted by EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 1/1: Hexane/EtOAc, Rf=0.3) afforded N2-[1-benzyl-2-(1-[(2-cyano-1,2-dimethylhydrazino)carbonyl]-3-methylbutylamino)-2-oxoethyl]-2-pyrazinecarboxamide as pale yellow solid (67 mg, 65%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14]([N:17]1[CH2:22][C:21](=[O:23])[N:20]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=4)[CH2:27][CH2:26]3)[CH:19]([C:38]([OH:40])=[O:39])[CH2:18]1)(=[O:16])=[O:15])[CH:8]=[CH:7]2.[CH2:41](Cl)Cl>>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14]([N:17]1[CH2:22][C:21](=[O:23])[N:20]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=4)[CH2:29][CH2:30]3)[CH:19]([C:38]([O:40][CH3:41])=[O:39])[CH2:18]1)(=[O:16])=[O:15])[CH:8]=[CH:7]2
Reactant: Cc1cc(N2CCC(NN3C(=O)CN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)O)CC2)ccn1
Reactant: ClCCl
Agent: Cl
Product: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC1CCN(c2ccnc(C)c2)CC1

Procedure:
Methyl 1-[[4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate dihydrochloride (1.94 g) obtained in Example 127 was dissolved in methylene chloride (20 ml) and saturated aqueous sodium bicarbonate (20 ml) and partitioned. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure to obtain methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate. This material was dissolved in a 37% aqueous solution of formaldehyde (25.2 ml) and formic acid (12.8 ml), and reflux for 2 hours. The reaction mixture was cooled, made alkaline by adding saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried and then concentrated. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) and converted into a hydrochloride using a 4 N solution of hydrochloric acid in ethyl acetate (0.15 ml) to obtain the title compound (1.67 g) as a colorless non-crystalline powder.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:15][CH2:16][CH:11]([CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]#[N:10])[CH2:12][CH2:13]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: N#CC(c1ccccc1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of α-phenyl-4-piperidineacetonitrile hydrochloride (0.05 mole), 1-fluoro-4-nitrobenzene (0.06 mole) and potassium carbonate (0.15 mole) in DMF (200 ml) was stirred at 50° C. for four hours. Water and DIPE were added. The mixture was cooled. The precipitate was filtered off, washed with water and DIPE and dried, yielding 11.6 g of (±)-1-(4-nitrophenyl)-α-phenyl-4-piperidineacetonitrile (intermediate 12, melting point 118° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([Li])CCC.C(SCCCC)CCC.[C:22](/[C:24](=[CH:40]\[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][C:51]2[C:56]([Cl:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=2[Cl:59])=[CH:43][CH:42]=1)/[C:25]([N:27]([CH:37]1[CH2:39][CH2:38]1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[CH3:36])=[O:26])#[N:23]>C1COCC1.CCOCC>[C:22]([CH:24]([CH:40]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][C:51]2[C:52]([Cl:59])=[CH:53][C:54]([CH3:58])=[CH:55][C:56]=2[Cl:57])=[CH:43][CH:42]=1)[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:25]([N:27]([CH:37]1[CH2:38][CH2:39]1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[CH3:36])=[O:26])#[N:23]
Reactant: Brc1ccccn1
Reactant: [Li]CCCC
Reactant: Cc1cc(Cl)c(OCCOc2ccc(/C=C(\C#N)C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Solvent: CCCCSCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(Cl)c(OCCOc2ccc(C(Cc3ccccn3)C(C#N)C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a THF solution (0.5 M) of 2-bromopyridine (2.8 eq.) was added, at −78° C., n-butyl lithium (1.6 M hexane solution, 2.8 eq.) dropwise over 15 min. The resulting yellow suspension was stirred at −78° C. for a further 15 min before an ether solution (0.5 M) of cuprous iodide (1.4 eq.) and dibutyl sulfide (2.8 eq.) was added over 15 min. The resulting reaction mixture was allowed to stir at −78° C. for 15 min and then at 0° C. for 15 min. Finally, to this was added dropwise at 0° C., a THF solution (0.1 M) of (2E)-2-cyano-N-cyclopropyl-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-(2,3-dimethylbenzyl)acrylamide (Example 1, Step 2, 1 eq.). The resulting emerald green suspension was stirred at 0° C. for 15 min and then at RT for 2 h. The reaction was quenched with 3:1 (v:v) sat. aq. NH4Cl:conc. aq. NH4OH solution and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by way of column chromatography (SiO2, 10:1→1:1 (v/v) Hex:EtOAc). The title compound was isolated as a mixture of diastereomers.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC([O:11][C:12]1[C:15](=[O:16])[C:14](=O)[C:13]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])C>C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:14]2[C:15](=[O:16])[C:12](=[O:11])[C:13]=2[Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1c(N2CCN(C)CC2)c(=O)c1=O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
1-Methylpiperazine (0.65 g, 6.49 mmols) was added to a stirred, cooled (ice/H2O bath) solution of 4-(2-propoxy)-3-(tri-n-butylstannyl)-cyclobut-3-ene-1,2-dione (2.53 g, 5.90 mmols) in diethyl ether (80 mL). Stirring was continued with cooling for 1 hr and then at ambient temperatures for 1 hr. The mixture was concentrated and the residue chromatographed on SiO2 with ethyl acetate-methylene chloride (35:65) to afford the title compound (2.1 g, 76% yield) as a golden viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4]/[C:5](/[C:13]([O:15]C)=[O:14])=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:21]=1[CH:22]=O>>[CH3:1][O:2][C:3](=[O:17])/[C:4](=[CH:22]/[C:21]1[C:20]([O:19][CH3:18])=[CH:27][C:26]([O:28][CH3:29])=[CH:25][C:24]=1[O:30][CH3:31])/[C:5](/[C:13]([OH:15])=[O:14])=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:1][O:2][C:3](=[O:17])/[C:4](=[CH:22]\[C:21]1[C:20]([O:19][CH3:18])=[CH:27][C:26]([O:28][CH3:29])=[CH:25][C:24]=1[O:30][CH3:31])/[C:5](/[C:13]([OH:15])=[O:14])=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COC(=O)C/C(=C\c1ccccc1)C(=O)OC
Product: COC(=O)C(=C/c1c(OC)cc(OC)cc1OC)/C(=C\c1ccccc1)C(=O)O
Product: COC(=O)C(=C\c1c(OC)cc(OC)cc1OC)/C(=C\c1ccccc1)C(=O)O

Procedure:
(E)-3-Methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester and 2,4,6-trimethoxybenzaldehyde are treated in the same manner as in Example 1-(1) to give (E)-2-[(E)-2,4,6-trimethoxybenzylidene]-3-carboxy-4-phenyl-3-butenoic acid methyl ester (foam) and (E)-2-[(Z)-2,4,6-trimethoxybenzylidene]-3-carboxy-4-phenyl-3-butenoic acid methyl ester (m.p. 208°-210° C.).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@@H](N)CO
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@@H](C)O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (R)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 350 mg 6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=181.5-184.4° C.).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:11][C@@H:12]1[C@H:17]2[CH2:18][O:19][C@H:15]([O:16]2)[C@H:14]([CH:20]=C)[C@H:13]1[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+]>C(O)C.C(O)C.O>[CH2:4]([O:11][C@@H:12]1[C@H:17]2[CH2:18][O:19][C@H:15]([O:16]2)[C@H:14]([CH2:20][OH:1])[C@H:13]1[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=C[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Reaction time: 0.5 h

Procedure:
A stream of ozone (0.36 mmol/min) was passed through a solution of 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-vinyl-β-D-glucopyranose (8, 3.36 g, 12.8 mmol) in ethanol (100 ml) for 43.5 minutes. The solution of the ozonide was transferred to a three-necked round bottomed flask equipped with a thermometer and a dropping funnel containing a solution of NaBH4 (3.87 g, 102 mmol) in ethanol/water 1:1 (35 ml). The solution of NaBH4 was added dropwise in such a manner to keep the temperature below 20° C. (cooling on ice bath). After stirring for 45 min Amberlite IR 120, H+ (100 ml) was added. After stirring for another 30 minutes, the ion exchange resin was filtered off and rinsed with water. The solution was evaporated and co-concentrated with methanol (3×80 ml). The residue was a colorless syrup obtained in 96% (3.28 g) yield. This syrup was flash chromatographed using ethyl acetate/pentane 2:1 and ethyl acetate as eluent to give 9 in a 63% (2.14 g) yield as a crystalline compound. In some runs the crude syrup crystallized and was recrystallized from chloroform: mp. 111°-113°; [α]D20 =41.4° (c; 2.05, CH3OH). 13C-NMR (50 MHz, D2 O):δ139, 130.1, 129.8 (Ph); 102.0 (C-1);, 80.5 (C-4), 76.1 (C-3), 72.9 (OCH2Ph), 67.4 (C-5), 66.2 (C-6), 61.7 (C-2'), 49.0 ppm (C-2). Anal. Calc. for C14H18O5 : C, 63.15; H, 6.81. Found: C, 63.14; H, 6.79.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](Br)=[O:4].[C:7]1([C:13]#[C:14][C:15]2[N:20]=[C:19]([NH2:21])[CH:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:16]=2[C:26]2[CH:27]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:32]([N:34](CC)CC)C.CN>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH3:32][NH:34][CH:2]([CH3:6])[C:3]([NH:21][C:19]1[CH:18]=[C:17]([C:22]([F:25])([F:23])[F:24])[C:16]([C:26]2[CH:27]=[N:28][CH:29]=[N:30][CH:31]=2)=[C:15]([C:14]#[C:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:20]=1)=[O:4]
Reactant: CCN(CC)CC
Reactant: Nc1cc(C(F)(F)F)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Reactant: CC(Br)C(=O)Br
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CNC(C)C(=O)Nc1cc(C(F)(F)F)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Under stirring at 0° C. 2-bromopropanoyl bromide (44 μl, 0.42 mmol) is added dropwise to a mixture of 6-(2-phenylethynyl)-5-pyrimidin-5-yl-4-(trifluoromethyl)pyridin-2-amine C3d (95 mg, 0.28 mmol), triethylamine (59 μl, 0.42 mmol), DMAP (0.3 mg, 3 μmol) and dioxane (1.4 ml). The mixture is warmed to RT and stirred for 1 h. Methylamine (solution in THF 2 mol/l, 1.4 ml, 2.8 mmol) is added and stirring continued for 6 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 45 mg (38%). HPLC-MS: M+H=426; tR=1.27 min (*Method—1).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[CH2:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10])[CH:4]=[CH2:5]>CO.O>[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[CH2:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(OCC=C)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc(OCC=C)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.5 ml) was added to a mixture of methyl 2,4-bis-allyloxy-5-isopropylbenzoate (450 mg, 1.55 mmol) in methanol (6 ml) and water (2 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 2,4-bis-allyloxy-5-isopropylbenzoic acid (418 mg, 98%) as an off-white solid. 1H NMR (DMSO-d6) 12.16 (1H, br s), 7.58 (1H, s), 6.66 (1H, s), 6.07 (2H, m), 5.51 (1H, dm), 5.44 (1H, dm), 5.28 (2H, m), 4.68 (2H, m), 4.64 (2H, m), 3.17 (1H, m), 1.15 (6H, d). MS: [M+Na]+ 299.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[NH:20][C:21]3[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:29]([O:31][CH2:32][CH3:33])=[O:30].[Cl:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:28])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:36]4[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=4[Cl:34])=[CH:25][CH:26]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)nn4)cc3)c(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C(F)(F)F)cc5Cl)nn4)cc3)c(Cl)cc21
Temperature: 110 °C
Yield: 20.1 %

Procedure:
A solution of ethyl 6-chloro-7-(4-(6-chloropyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.131 g, 0.268 mmol), 2-chloro-4-(trifluoromethyl)phenylboronic acid (0.0903 g, 0.402 mmol), and 20% aqueous sodium carbonate (0.426 ml, 0.805 mmol) in toluene (2 ml) was degassed with argon, then tetrakis(triphenylphosphine)palladium (0.0155 g, 0.0134 mmol) was added and the reaction was heated to 110° C. for 16 hours. The reaction mixture was loaded directly onto silica gel and purified eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (0.034 g, 0.0538 mmol, 20.0% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[S:38][C:37]3[C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][C:34]([C:45]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:46]=4[CH:47]=[N:48][N:49]5CCCCC(OCC)=O)=[N:33][C:32]=3[CH:31]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21].[CH3:63][S:64]([N:67]1[CH2:72][CH2:71][N:70]([CH2:73][C:74]2[S:82][C:81]3[C:80]([N:83]4[CH2:88][CH2:87][O:86][CH2:85][CH2:84]4)=[N:79][C:78]([C:89]4[C:90]5[C:94]([CH:95]=[CH:96][CH:97]=4)=[N:93][N:92]([CH2:98]CCCC(OCC)=O)[CH:91]=5)=[N:77][C:76]=3[CH:75]=2)[CH2:69][CH2:68]1)(=[O:66])=[O:65]>C(#N)C>[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[S:38][C:37]3[C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][C:34]([C:45]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:46]=4[CH:47]=[N:48][N:49]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:33][C:32]=3[CH:31]=2)[CH2:25][CH2:24]1)(=[O:21])=[O:22].[CH3:63][S:64]([N:67]1[CH2:68][CH2:69][N:70]([CH2:73][C:74]2[S:82][C:81]3[C:80]([N:83]4[CH2:84][CH2:85][O:86][CH2:87][CH2:88]4)=[N:79][C:78]([C:89]4[C:90]5[C:94]([CH:95]=[CH:96][CH:97]=4)=[N:93][N:92]([CH2:98][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:91]=5)=[N:77][C:76]=3[CH:75]=2)[CH2:71][CH2:72]1)(=[O:65])=[O:66]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCOC(=O)CCCCn1cc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(S(C)(=O)=O)CC5)cc4n3)cccc2n1
Reactant: CCOC(=O)CCCCn1ncc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(S(C)(=O)=O)CC5)cc4n3)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCCn1cc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(S(C)(=O)=O)CC5)cc4n3)cccc2n1
Product: CCOC(=O)CCCCCCn1ncc2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(S(C)(=O)=O)CC5)cc4n3)cccc21
Yield: 27 %
Yield: 16 %

Procedure:
The title compound 0115-5 (110 mg, 27%) and 0116-5 (60 mg, 16%) were prepared from 0114 (280 mg, 0.55 mmol) , ethyl 7-bromoheptanoate (133 mg, 0.65 mmol) and potassium carbonate (152 mg, 1.10 mmol) in acetonitrile (25 mL) using a procedure similar to that described for compound 0115-3 and compound 0116-3 (Example 1):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:4]=1[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O.I[C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:4]=1[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1
Reactant: COc1cc(OC)c(CSc2ccccc2B(O)O)c(OC)c1
Reactant: Oc1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(CSc2ccccc2-c2cccc(O)c2)c(OC)c1
Yield: 79 %

Procedure:
To a mixture of 1.05 g 2-(2,4,6-trimethoxybenzylthio)phenylboronic acid (3.14 mmol), 1.07 g 3-iodophenol (4.9 mmol) and 0.195 g Pd catalyst was added 40 ml toluene followed by 15 ml 2M Na2CO3. The mixture was refluxed under nitrogen overnight. The mixture was extracted with ethyl acetate. The organic was washed with water, brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica flash chromatography (hexane:ethyl acetate 80:20) to afford 0.948 g product (2.48 mmol, 79% yield).
Reaction SMILES: [Mg].[CH2:2]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14]Br)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].C1O[C:19]2([C:24](=O)[CH2:23][CH2:22][CH2:21][CH:20]2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)OC1.Cl.C1C[O:37]CC1>>[CH2:2]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][C:23]2[CH2:22][CH2:21][CH:20]([CH:26]3[CH2:31][CH2:30][C:29](=[O:37])[CH2:28][CH2:27]3)[CH2:19][CH:24]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: O=C1CCCC(C2CCCCC2)C12OCCO2
Reactant: CCCCCC1CCC(CCBr)CC1
Agent: Cl
Agent: [Mg]
Product: CCCCCC1CCC(CCC2=CCC(C3CCC(=O)CC3)CC2)CC1
Reaction time: 12 h

Procedure:
To the Grignard reagent which was prepared from 4.80 g (198 mmol) of dried magnesium and 50.0 g (191 mmol) of 2-(4-n-pentylcyclohexyl)bromoethane in 500 ml of THF, was added dropwise 200 ml of solution of 40.0 g (168 mmol) of bicyclohexanedione monoethylene ketal in THF at room temperature, and the mixture was stirred at the same temperature for 12 hours. The reaction solution was added to 500 ml of 0.5N hydrochloric acid, the product thus formed was extracted with ether, the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=3/1), the solvent was distilled off, the residue was refluxed in 200 ml of formic acid for 3 hours, 200 ml of water was added to the reaction solution, the product thus formed was extracted with toluene, the extract was washed with water, saturated aqueous sodium bicarbonate solution, and water in this turn, and then dried over magnesium sulfate. After the solvent was distilled off and the residue was purified by column chromatography (eluent: heptane/ethyl acetate=1/1), the solvent was distilled off, and the residue was recrystallized from ethanol to give 15.0 g of 4-(4-(2-(4-n-pentylcyclohexyl)-ethyl)-3-cyclohexenyl)-cyclohexanone. Yield of this compound based on bicyclohexanedione monoethylene ketal was 24.9%.
Reaction SMILES: C1(C)C=CC=CC=1.C(OC([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)OC(C)(C)C)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CCc2cc(N)ccc2O1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Into the ethyl 2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetate toluene solution of Example 3 (7 L) was added 1480 g of trifluoroacetic acid. The solution was warmed to 60° C. for 2 h. After distilling-off about 2 L of toluene under reduced pressure (T≦60° C.), the mixture was cooled to room temperature. About 10 L of 10% (w/w) of aqueous sodium bicarbonate was added slowly to the well-stirred mixture until the pH was above 7. The mixture was stirred for 20 min and the aqueous fraction separated. The aqueous fraction was extracted with 3×1 L of toluene. The combined organic fractions were washed with 3 L of brine, dried over 200 g of anhydrous sodium sulfate, and filtered. The volume of solvent was reduced to 6 L by distillation under reduced pressure (T≦60° C.) to provide a toluene solution of ethyl 2-(6-aminochroman-2-yl)acetate.