Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1Br.[CH3:20][N:21]1CCCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: Cc1cn(-c2cc(Br)c(N)c(C(F)(F)F)c2)c(C)n1
Reactant: CN1CCCC1=O
Product: Cc1cn(-c2cc(C#N)c(N)c(C(F)(F)F)c2)c(C)n1

Procedure:
To a stirred solution of 1-(4-amino-3-bromo-5-trifluoromethylphenyl)-2,4-dimethylimidazole (4.61 g) in 1-methyl-2-pyrrolidone (50 cm3) was added cuprous cyanide (3.7 g) and the mixture was heated at 150° for 2 days. The mixture was then cooled and the solvent evaporated in vacuo. A solution of ammonia in water (100 cm3 s.g. 0.88) was added and the aqueous phase was extracted with chloroform:methanol, 20:1 (3×100 cm3). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform: methanol, 50:1. Combination and evaporation of appropriate fractions gave a solid which was recrystallised from methanol/ethyl acetate to give microcrystals of 1-(4-amino-3-cyano-5-trifluoromethylphenyl)2,4-dimethylimidazole, (1.1 g), m.p. 208°-10°.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:22]([NH2:24])=[O:23])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO.C(Cl)Cl>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:22]([NH2:24])=[O:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1
Reaction time: 8 h

Procedure:
10% Palladium on carbon (75 mg, 0.07 mmol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-[(1-methyl-1H-imidazol-4-yl)methyl]- (60 mg, 0.10 mmol) in MeOH/CH2Cl2 (1:1, 4 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction was stirred under a balloon of hydrogen overnight, filtered through a pad of celite and concentrated to yield 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-N6-[(1-methyl-1H-imidazol-4-yl)methyl]- (60 mg, 0.09 mmol, 90%) as a bright yellow solid. Mixture of atrope diastereomers. LCMS: m/e 633 (M+H)+, ret time 1.73 min, column C, 2 minute gradient.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:26][F:27])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]2[CH:12]=[C:13](C(F)(F)C(F)(F)C(F)(F)F)[CH:14]=[CH:15][C:5]=2[O:4]1.F[CH2:29][C:30]1(CF)C=C(C(NC)=O)C2C=C(C(F)(F)C(F)(F)C(F)(F)F)C=CC=2O1>>[CH2:29]([O:11][C:9]([C:7]1[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:26][F:27])[CH:8]=1)=[O:10])[CH3:30]
Reactant: CNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccccc21

Procedure:
Using 2,2-bis(fluoromethyl)-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid, an oily product of 2,2-bis(fluoromethyl)-6-heptafluoropropyl-N-methyl-2H-1-benzopyran-4-carboxamide as in Example 7 (3).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[C:20]([NH:1][C:2](=[S:10])[NH:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:21])[C:19]1[CH:18]=[CH:22][CH:11]=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2
Reactant: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CCOC2
Temperature: 50 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
tert-Butyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.099 g, 0.39 mmol, 1 equiv.) and PhCONCS (0.06 mL, 0.4 mmol, 1 equiv.) were dissolved in THF (2 mL) and stirred at 50° C. for 16 h. The solvent was removed and the product was purified by preparatory HPLC (0-30% EtOAC:hexanes). The product was isolated as a white solid (0.131 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 14.75 (s, 1H), 9.21 (s, 1H), 7.92 (dd, J=5.2, 3.3 Hz, 2H), 7.64-7.57 (m, 1H), 7.54-7.46 (m, 2H), 4.71 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 1.63 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 173.72, 165.23, 164.54, 147.15, 133.48, 131.81, 129.36, 129.04, 127.77, 125.77, 117.76, 82.36, 65.20, 64.71, 28.51, 27.38.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]COC)=[C:4]([O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH:3]=1.O1CCOCC1.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: COCOc1ccc(Br)cc1OC1CCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Br)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To 7.26 g (25.3 mmol) of 4-bromo-2-cyclobutoxy-1-methoxymethoxybenzene obtained in Reference Example 5-(c) was added 30 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 100 ml of water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 3.07 g of the title compound as a pale yellowish oil. (Yield: 50%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[C:21]([CH2:29][C:30](=O)[CH3:31])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:30]([CH3:31])=[CH:29][C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Product: Cc1cc(-c2ccccc2)nn1-c1nc(Nc2ccc(Cl)cc2)c2ncn(C)c2n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and benzoylacetone.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(Br)ccc2ccc(O)nc12
Product: COc1c(Br)ccc2ccc(Cl)nc12
Yield: 84 %

Procedure:
A mixture of 7-bromo-8-methoxy-2-quinolinol (4c) (2.22 g, 8.7 mmol) and POCl3 (7 mL) was heated under reflux for 1.5 hours. After neutralization with NaHCO3 and extraction with AcOEt, the residue was dissolved in CHCl3 and filtered through silica gel to remove the brown polar impurities. The product (1.99 g, 84% yield) was obtained as white crystals upon recrystallization from AcOEt-Hexanes. mp 130-132° C.; 1H NMR (400 MHz, CDCl3), 8.06 (d, J=8.8 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.17 (s, 3H).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC=C(CSCCO)C=2)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:17]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccccc1-c1cccc(CSCCO)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (2.1 g, 6.64 mmol, 1 eq.) in anhydrous THF was treated with phenol (0.88 g, 9.30 mmol, 1.4 eq.), triphenylphosphine (2.44 g, 9.30 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (1.88 g, 1.83 mL, 9.30 mmol, 1.4 eq.). When complete, the reaction was worked up as described leaving a yellow oil
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1[N:19]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:18][C:2]=1[CH3:10]
Reactant: NC(=S)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Product: COC(=O)Cc1nc(-c2ccccc2)sc1C
Yield: 70 %

Procedure:
The title compound (827 mg) was prepared from 1.0 g (4.78 mmol) of methyl 4-bromo-3-oxo-pentanoate and 2.6 g (19.14 mmol) of thiobenzamide according to the method of Intermediate 42 followed by purification via silica gel flash column chromatography using hexanes/EtOAc (3:1) as eluent: low resolution MS (ES) m/e 270 (MNa+), 248 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:18][CH3:19])=[N:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)=[O:8].[SH:20][C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:18][CH3:19])=[N:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1ccc(NC(=O)CCCCCBr)c(SC)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(NC(=O)CCCCCSc2nc3ccccc3o2)c(SC)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Triethylamine (196 mg, 1.94 mmol) was added to a THF (3 ml) solution of this aminopyridine (301 mg, 1.62 mmol), and a THF (1 ml) solution of 6-bromohexanoyl chloride (345 mg, 1.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=4:1) to obtain 453 mg (yield 77%) of 6-bromo-N-[2,6-bis(methylthio)-3-pyridyl]hexanamide as a colorless powdery crystal (melting point: 117 to 119° C.). To a DMF (4 ml) solution of this amide (100 mg, 0.28 mmol) and 2-mercaptobenzoxazole (42 mg, 0.28 mmol) were added 18-crown-6 (7 mg, 0.03 mmol) and potassium carbonate (46 mg, 0.33 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 83 mg (yield 70%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:30][C:29]3[C:24](=[C:25]([O:37]C)[C:26]([O:35][CH3:36])=[C:27]([O:33][CH3:34])[C:28]=3[O:31]C)[CH2:23]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C(O)=O)=CC=CC=1C(O)=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)(O)[O-].[Na+]>O.C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:30][C:29]3[C:28](=[O:31])[C:27]([O:33][CH3:34])=[C:26]([O:35][CH3:36])[C:25](=[O:37])[C:24]=3[CH2:23]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(Cc3ccccc3)CC1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCN3CCN(Cc4ccccc4)CC3)C2)C1=O
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a mixture of 4-benzyl-1-[8-(4,5,6,7-tetramethoxyindan-2-yl)octyl]piperazine (676 mg), 2,6-pyridinedicarboxylic acid (647 mg), THF (14 ml), and water (7 ml) was dropwise added a solution of CAN (2.83 g) in water (7 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from hexane-ethyl acetate to yield the entitled compound (380 mg) as crystals.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])C=1C(O)=O>C1C=CC=CC=1.CN(C=O)C>[F:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cc(F)c(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of oxalyl chloride (36.5 g, 0.29 mol) in dry benzene (50 ml) was added dropwise to a stirred solution of compound 24 (25.5 g, 0.14 mol) and dry DMF (40 drops) in dry benzene (500 ml) at room temperature. The mixture was stirred at room temperature overnight and the excess of oxalyl chloride and benzene were removed in vacuo.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH:12]1([C:18]([O:20][CH:21]([O:23][C:24](ON2C(=O)CCC2=O)=[O:25])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC(OC)(C)C.CC(C)=O.O>[CH:12]1([C:18]([O:20][CH:21]([O:23][C:24]([NH:11][CH2:10][C@H:2]2[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]2)=[O:25])[CH3:22])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C1CCCCC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (780 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl cyclohexanecarboxylate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 22 (200 mg, 26% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.99 (m, 2H), 1.20-1.44 (br. m, 11H), 1.58-1.81 (m, 7H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.27-2.35 (m, 1H), 2.79-2.90 (m, 2H), 6.66 (q, J=5.6 Hz, 1H), 7.48 (t, J=6.0 Hz, 1H), 12.05 (br. s, 1H). MS (ESI) m/z 378.13 (M+Na)+; 354.15 (M−H)−.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][C:6]#[CH:7]>CO>[C:1]([OH:9])(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][C:6]#[CH:7]
Reactant: C#CCC/C=C/C(=O)OCC
Solvent: CO
Product: C#CCC/C=C/C(=O)O
Yield: 88.5 %

Procedure:
A solution of ethyl (E)-hept-2-en-6-ynoate (1.8 g) in 50% aqueous methanol containing 5% sodium hydroxide was stirred at ambient temperature overnight. The methanol was removed under reduced pressure and the resulting aqueous phase was extracted with dichloromethane. The aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid and re-extracted with dichloromethane. These organic extracts were washed with brine, dried over anhydrous magnesium sulphate and then evaporated in vacuo to leave (E)-hept-2-en-6-ynoic acid as a white solid (1.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH3:2].[N+:15]([CH3:18])([O-:17])=[O:16]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH2:18][N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=CC1COC(C)(C)O1
Product: CCOC(=O)CC(C[N+](=O)[O-])C1COC(C)(C)O1

Procedure:
WO03/022853 in Example I provides a Wittig route which employs triethyl phosphono acetate (TEPA) to obtain 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethyl ester. The subsequent Michael addition to 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethyl ester, presents limitations in that it produces a nitromethane adduct, i.e. 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-4-nitro-butyric acid ethyl ester, with a syn:anti ratio of approximately 8:2. Subsequent reduction followed by Nef/cyclization reactions yields the (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol seriously contaminated with its exo-diastereoisomer, i.e. (3R,3aR,6aS) hexahydro-furo[2,3-b]furan-3-ol, with a ratio endo:exo of around 8:2. Although this process does not possess several of the disadvantages attached to the Knoevenagel process, it does not produce pure endo-diastereoisomer since there is no purification step available, such as crystallization, to remove the undesired exo-diastereoisomers that have been formed during the Michael addition in the anti configuration.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([N:14]2[CH2:17][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=4[N:19]=3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.CN1C(=O)CCC1.[O:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>CCOC(C)=O>[CH3:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:18]([CH:16]3[CH2:17][N:14]([C:9]4[C:8]([O:41][CH:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[N:13][CH:12]=[CH:11][N:10]=4)[CH2:15]3)=[N:19][C:20]=2[CH:26]=1
Reactant: Cc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Reactant: OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C3CN(c4nccnc4OC4CCOCC4)C3)nc2c1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
To a mixture of cesium carbonate (0.223 g, 0.684 mmol) and 2-(1-(3-chloropyrazin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole (0.103 g, 0.344 mmol) was added NMP (1 mL) and tetrahydro-2H-pyran-4-ol (0.20 mL, 2.1 mmol). The reaction mixture was heated to 100° C. for 1 h, heated to 130° C. for 2 h, and heated to 150° C. for 21 h. The reaction was diluted with EtOAc, and the organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (60% to 100% EtOAc in hexanes) gave 5-methyl-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.061 g, 0.17 mmol, 49% yield) as a pale yellow foam. [M+1] 366. IC50 (uM) 0.2388.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9](SC)[C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1>[Ni].O.C(O)(C)C>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1C(=O)Nc2cccc(-c3ccccc3)c21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2)N1

Procedure:
A stirring solution of 3.5 g. (0.014 mole) of 4-phenyl-3-methylthioindolin-2-one in 75 ml. of tetrahydrofuran was treated portionwise with 20 g. of a commercial Raney nickel/water suspension. The mixture was filtered through Celite and the filtrate was concentrated to give a yellow solid. The solid was recrystallized to give a yellow solid. This solid was recrystallized from benzene to yield 1.6 g. (57%) of product as an off-white solid. An analytical sample was prepared from isopropanol; m.p. 192°-194° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:35](Cl)=[O:36].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:32]([Cl:31])[CH:33]=4)=[CH:18][N:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2c(Oc3ccc(N)cn3)cccc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ccc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Yield: 87.3 %

Procedure:
[4-(5-Aminopyridin-2-yloxy)indole-1-yl]acetic acid ethyl ester (0.715 g, 2.30 mmol) was dissolved in THF (10 mL). To the solution were added triethylamine (0.320 mL, 2.30 mmol), then 3,4-Dichlorobenzoyl chloride (0.481 g, 2.30 mmol), and the resulting solution was stirred for 30 minutes at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate and n-hexane to yield 0.972 g of the title compound as a white powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1.Cl>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[NH:16][C:14]([C:12]1[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:10][CH2:9][C:8]=3[N:11]=1)=[O:15])=[O:25])=[CH:34]2
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCN1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (110 mg) was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 μl) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 85:15 mixed solvent of dichloromethane and methanol, and water were added to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale yellow foamy substance. This product was suspended in 1N hydrochloric acid (0.3 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (63 mg) as a pale yellow foamy substance.