Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[N:1]1([C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
To a solution of ethyl piperidine-3-carboxylate (4 g, 25.4 mmol) in THF (30 mL) and water (30.0 mL) was added Na2CO3 (6.74 g, 63.6 mmol). The resulting suspension was stirred at rt for 20 min. After this time, benzyl carbonochloridate (4.12 g, 24.17 mmol) was added dropwise. After addition, the stirring solution became milky, and a white precipitate formed. After stirring at rt for 2 h, the reaction was partitioned between EtOAc and water. The separated aqueous phase was extracted with EtOAc (2×). The combined organics were washed with water and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The oily residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex. The desired fractions were concentrated to afford the desired product, 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (5.68 g, 19.50 mmol, 77% yield) as a colorless oil. Anal. Calcd. for C16H21NO4 m/z 291.3, found: 292.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.28 (m, 5H), 5.26-4.97 (m, 2H), 4.34-4.06 (m, 3H), 4.06-3.91 (m, 1H), 3.13 (br. s., 1H), 2.96-2.81 (m, 1H), 2.46 (br. s., 1H), 2.15-1.96 (m, 1H), 1.78-1.56 (m, 2H), 1.49 (br. s., 1H), 1.33-1.17 (m, 3H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH3:11][C:12]1[C:17](/[CH:18]=[CH:19]/[CH:20]=[O:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:15]=[C:14]([CH3:29])[N:13]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:11][C:12]1[C:17](/[CH:18]=[CH:19]/[CH:20]([OH:21])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:16]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:15]=[C:14]([CH3:29])[N:13]=1
Reactant: Cc1cc(-c2ccc(F)cc2)c(/C=C/C=O)c(C)n1
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(C)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
82.2 μl (0.76 mmol) of methyl acetoacetate are added dropwise at 0° C. under a nitrogen atmosphere to 18.5 mg (0.8 mmol) of sodium hydride in 1 ml of tetrahydrofuran. After 15 minutes, 0.55 ml (0.77 mmol) of n-butylithium (1.5 M in hexane) is added dropwise at 0° C., the mixture is stirred for 15 minutes at 0° C. and 180 mg (0.7 mmol) of the compound from Example 31 are added dropwise in 3 ml of tetrahydrofuran. After 1 h, the mixture is hydrolyzed using saturated ammonium chloride solution and washed three times using dichloromethane, and the organic phases are dried and 0.25 g of oil are obtained after removing the solvent in vacuo.
Reaction SMILES: [CH2:1]([CH:7](C(O)=O)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]>C(#N)C>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCC(C(=O)O)C(=O)O
Solvent: CC#N
Product: C#CCCCCCC(=O)O

Procedure:
A mixture of 2-(hex-5-ynyl)malonic acid (2.2 g) and cuprous oxide (60 mg) in dry acetonitrile (40 ml) was stirred and refluxed, under nitrogen, for 6 hours. The solvent was removed in vacuo. 5% Aqueous hydrochloric acid was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. Oct-7-ynoic acid was obtained as an oil (1.5 g) and was used without further purification.
Reaction SMILES: [CH2:1]([O:13][C:14](=[O:20])[NH:15][S:16](Cl)(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[OH:33])([CH3:23])[CH3:22].C(N(CC)CC)C>C1COCC1>[CH3:31][CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[O:33][S:16]([NH:15][C:14](=[O:20])[O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:17])=[O:18])[CH3:32]
Reactant: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Oc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of n-dodecyl(chlorosulfonyl)carbamate (5.0 g, 15.2 mmoles) in 80 mL THF was added dropwise to a solution of 2,6-diisopropyl phenol (2.72 g, 15.2 mmoles) and excess triethylamine in 100 mL THF at room temperature under an atmosphere of N2. The mixture was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between 1N HCl and EtOAc. The organic layer was dried with MgSO4, filtered, and evaporated to give a clear oil. Chromatography (SiO2, 5% EtOAc/hexanes) gave 4.26 g of the title compound as a waxy solid, mp 32°-35° C.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([N:15]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:36][C@H:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[O:34][C:33]3=[O:42])=[CH:28][C:27]=2[F:43])C(OCC2C=CC=CC=2)=O)[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:14][CH:13]([NH:15][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:36][C@H:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[O:34][C:33]3=[O:42])=[CH:28][C:27]=2[F:43])[CH2:12]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N(C(=O)OCc3ccccc3)C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CNC3)c(F)c2)C(=O)O1
Reaction time: 5 h

Procedure:
A suspension of 1.11 g of 3-({4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-benzyloxycarbonyl-amino)-azetidine-1-carboxylic acid benzyl ester (1.88 mmol) and 200 mg Pd/c 10% in methanol was stirred under hydrogen for 5 h. The Pd/C was filtered and the filtrate evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[Cl:1])=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3sccc3Cl)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4sccc4Cl)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A mixture of 2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (59 mg, 0.21 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.15 mL, 1.05 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and semi-preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide (45 mg, 51%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=7.0 Hz, 1H), 8.22 (dd, J=8.0, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.16 (d, J=5.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.18-3.09 (m, 2H), 2.68-2.60 (m, 2H) 2.56 (s, 3H), 2.12-1.95 (m, 3H), 1.62-1.44 (m, 4H), 1.21-1.10 (m, 1H); MS (ESI+) m/z 416 (M+H); HPLC>99% (AUC), tR=12.97 min.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=O.Br.O=C(C12CN(CC1)CCC2)C=O.C(=O)(O)O.[NH2:31][NH:32][C:33]([NH2:35])=[NH:34].Cl.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:35][C:33]1[N:32]=[N:31][CH:3]=[C:4]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][CH2:7]3)[N:34]=1
Reactant: O=C(CBr)C12CCCN(CC1)C2
Reactant: N=C(N)NN
Agent: Br
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: Nc1nncc(C23CCCN(CC2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
(±) 5-(α-Bromoacetyl) -1-azabicyclo[3.2.11octane hydrobromide (1.0 g, 3.2 mmol) was converted into (±) 2-oxo-2-(1-azabicyclo[3.2.1 ]oct-5-yl) ethanal hydrobromide as described in Example 1. The crude aldehyde was immediately treated with a suspension of aminoguanidine bicarbonate (0.46 g, 3.38 mmol) in water (15 ml) and the solution was acidified to pH4 with 5M HCl. After stirring overnight at room temperature the reaction mixture was saturated with potassium carbonate then extracted into chloroform. The combined organic extracts were dried over sodium sulphate, concentrated in vacuo and the residue chromatographed on neutral alumina in a gradient of 0-8% methanol in chloroform. This afforded the title compound (E2) as a solid (95 mg, 15%) which was converted into the oxalate salt m.p. 184° C. (dec) (from methanol-ether)..
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:34]([C:36]1([OH:40])[CH2:39][NH:38][CH2:37]1)[CH3:35]>>[CH2:34]([C:36]1([OH:40])[CH2:39][N:38]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:16]3[CH2:15][N:14]([C:12]([C:10]4[O:11][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][N:9]=4)=[O:13])[CH2:17]3)=[CH:26][CH:25]=2)[CH2:37]1)[CH3:35]
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Reactant: CCC1(O)CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2)C1
Yield: 30 %

Procedure:
Using a similar protocol as described in Example 70 employing 71A and 70A as starting materials afforded 185 mg (30%) of 71 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (t, 3H), 1.76 (q, 2H), 3.02 (d, 2H), 3.26 (d, 2H), 3.58 (s, 2H), 4.29 (m, 1H), 4.61 (m, 1H), 4.72 (m, 1H), 5.10 (m, 2H), 6.71 (d, 2H), 7.21 (d, 2H), 7.51 (t, 2H), 7.55 (t, 1H), 8.13 (d, 2H), MS (APCI+) m/z 435 [M+H]+, LC purity: 94%.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH:28]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])/[CH:34]=[CH:33]/[C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)/C=C/c1cccnc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 60 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with trans-3-(3-pyridyl)acrylic acid under the conditions described in example 86 to yield 60% of the desired product.
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].Br[C:23]1[N:32]=[C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][N:25]2[N:24]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][N:25]2[N:24]=[C:23]([C:2]#[C:1][C:3]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[N:4]=3)[N:32]=[C:26]2[CH:27]=1
Reactant: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Reactant: Clc1ccn2nc(Br)nc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C#Cc3nc4cc(Cl)ccn4n3)nc2N2CCCC2)cc1
Temperature: 75 °C
Yield: 28.6 %

Procedure:
A mixture of 3-ethynyl-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (75 mg, 266 μmol, Eq: 1.00), 2-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine (67.9 mg, 292 μmol, Eq: 1.1) and triethylamine (40.3 mg, 55.5 μl, 398 μmol, Eq: 1.5) in tetrahydrofuran (2 ml) was purged with argon, then copper (I) iodide (1.01 mg, 5.31 μmol, Eq: 0.02), bis(triphenylphosphine) palladium(II) chloride (3.73 mg, 5.31 μmol, Eq: 0.02) and triphenylphosphine (1.39 mg, 5.31 μmol, Eq: 0.02) were added, the vessel was capped and heated for 18 hours to 75° C. Still starting material. The mixture was cooled, purged with argon and another portion of copper (I) iodide (1.01 mg, 5.31 μmol, Eq: 0.02), bis(triphenylphosphine) palladium(II) chloride (3.73 mg, 5.31 μmol, Eq: 0.02) and triphenylphosphine (1.39 mg, 5.31 μmol, Eq: 0.02) was added and the mixture was stirred again over night at 75° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 7-chloro-2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylethynyl]-[1,2,4]triazolo[1,5-a]pyridine (33 mg 26.8%) as an orange oil. MS: m/e=434.4 (M+H+)
Reaction SMILES: [Cl-].[Li+].[B:3].[Mg].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[OH-:10].[Ca+2:11].[OH-:12]>[Cl-].[Na+].O>[B:3]([O-:6])([O-:12])[O-:10].[B:3]([O-:6])([O-:12])[O-:10].[B:3]([O-:6])([O-:12])[O-:10].[B:3]([O-:6])([O-:12])[O-:10].[Ca+2:11].[Ca+2:11].[Ca+2:11].[Ca+2:11].[Ca+2:11].[Ca+2:11].[OH2:6].[OH2:6].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Ca+2:11]
Reactant: [B]
Reactant: [OH-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: [O-]B([O-])[O-]

Procedure:
A brine containing 0.77% lithium in the form of lithium chloride, and 0.28% boron, as well as magnesium and sulfate impurities, was treated with a slurry of slaked lime to a pH of 11.2 to precipitate magnesium as magnesium hydroxide and then treated with a sufficient amount of a 20% solution of calcium chloride to form calcium tetra borate (CaB2O4.6H2O), and gypsum. At pH 11.2, only gypsum precipitated and boron was reduced to 0.15%B due to a dilution effect. Upon concentrating the brine by evaporation, to 40% Li, calcium tetraborate hydrate precipitated and the boron was maintained at 0.13%B.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:10]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]([CH3:25])[N:17]=[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:19]=3)[N:12]=2)[C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:8][C:6]1[CH:7]=[C:2]([CH:26]2[CH2:28][CH2:27]2)[C:3]2[N:4]([N:10]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]([CH3:25])[N:17]=[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:19]=3)[N:12]=2)[C:5]=1[CH3:9]
Reactant: OB(O)C1CC1
Reactant: Cc1c(Cl)cc(Br)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cl)cc(C2CC2)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Temperature: 100 °C
Reaction time: 0.07 h
Yield: 22.8 %

Procedure:
A mixture of 8-bromo-6-chloro-5-methyl-2-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 70.6 μmol, Eq: 1), cyclopropyl-boronic acid (9.1 mg, 106 μmol, Eq: 1.5) and cesium carbonate (46.0 mg, 141 μmol, Eq: 2) in dioxane (0.75 mL) and water (0.075 ml) was stirred for 4 min. Dichloro1,1′-bis(diphenylphosphino)ferrocene palladium(II) (11.6 mg, 14.2 μmol, 0.2 Eq) was added, and the mixture was heated at 100° C. for 30 min in a microwave oven. The mixture was separated by preparative HPLC to give the desired product (6.2 mg, 22%) as a white solid. MS: m/z=386.4 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Solvent: C1CCOC1
Product: Clc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
1.19 g (5 mmol) of 2-bromo-5-chloro-nitrobenzene were dissolved in 50 ml THF. At a temperature of −45° C. 15 ml of a 1M vinyl magnesium bromide solution in THF were added under nitrogen in such a way that the temperature did not exceed −40° C. After complete addition the dark solution was stirred for 30 min at −40° C. The reaction mixture was quenched with 10 ml aqueous saturated ammonium chloride solution and extracted twice with diethyl ether. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (100 g silica gel; heptane/EtOAc 19:1) to yield 562 mg (49%) of 7-bromo-4-chloro-1H-indole as an orange oil. MS (EI) 229.0 (80), 231.0 (100), 233.0 (30) (M)+.
Reaction SMILES: [Br-].[CH3:2][CH2:3][CH2:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@@H](CCCC2)CC3)CC1)C.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:89][O:90][C:91]1([CH:98]=[CH:97][C:96]([O:99][CH3:100])=[CH:95][CH2:94]1)C=O.C([Li])CCC>C1(C)C=CC=CC=1.CCOCC.[C].[Pd]>[CH3:2][CH2:3][CH2:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6].[CH3:89][O:90][C:91]1[CH:98]=[CH:97][C:96]([O:99][CH3:100])=[CH:95][CH:94]=1
Reactant: COC1=CCC(C=O)(OC)C=C1
Agent: [Pd]
Agent: CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(OC)cc1

Procedure:
The intermediate product obtained in Example 24, i.e., 5β-cholane alcohol, 10 m mol, was subjected to tosylation and treated with lithium bromide, thus forming 8 m mol of 5β-cholane bromide. 5β-cholane bromide was made to react with 12 m mol of triphenylphosphine in toluene, thereby preparing 7.8 m mol of 5β-cholane-triphenylphosphonium bromide. This product, 7.5 m mol, was reacted with 7.5 m mol of p-dimethoxybenzaldehyde in ether in the presence of butyl lithium. The product resulting from this reaction was hydrogenated, by using palladium carbon as catalyst, whereby 7.0 m mol of 5β-cholane-p-dimethoxybenzene was obtained. This compound, 6.8 m mol, was treated with sodium in liquid ammonia, thus forming 5.1 m mol of 5β-cholane-cyclohexyl-1,4-dione. This product, 4.5 m mol, was made to react with 10 m mol of malononitrile. The reaction product was treated with bromine, thereby preparing 1.2 m mol of 5β-cholanetetracyanoquinodimethane, which is identified with the following formula: ##STR54##
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH:9]([CH2:16]CC)[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].Cl>CCOCC>[CH3:7][O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CCCC(CCCC(=O)O)OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COC(C)CCCCO
Reaction time: 12 h
Yield: 60.9 %

Procedure:
15.3 g of LiAlH4 was added to 330 ml of dry ether, and under stirring, a solution of 53 g of the above 5-methoxycaprylic acid in 60 ml of dry ether was dropped at below 10° C. in 2 hours. After the dropping, the mixture was raised in temperature for 2 hours of stirring at 15°-20° C. After standing for 12 hours, 5%-hydrochloric acid was added to the mixture for acidification while keeping the temperature below 15° C. The mixture was then subjected to extraction with ether. The ether extract was washed successively with water, 5%-NaOH aqueous solution and water, followed by drying with anhydrous MgSO4, distilling-off of the solvent and vacuum distillation to obtain 24.5 g of 5-methoxy-1-hexanol which provided the following IR data:
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25])(=[O:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:25])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
A mixture of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (1.50 g, 5.12 mmol, Amine-1, single enantiomer), 2-acetamidoisonicotinic acid (1.01 g, 5.63 mmol), HBTU (2.33 g, 6.14 mmol) and triethylamine (3.57 mL, 25.6 mmol) in dichloromethane (51 mL) is stirred at room temperature for 15 hours. The reaction mixture is poured into water (50 mL) and extracted with dichloromethane (50 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give 1.30 g (66% yield) of the title compound as a white solid.