Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)C1C=CC=CC=1.C(Cl)(Cl)=O.N.[C:35]([N:45]1C[C@H](OC(Cl)=O)C[C@H]1C(OC)=O)(OCC1C=CC=CC=1)=[O:36]>C1(C)C=CC=CC=1>[C:1]([N:11]1[CH2:19][C@H:18]([O:20][C:35]([NH2:45])=[O:36])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)Cl)CN1C(=O)OCc1ccccc1
Agent: N
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](OC(N)=O)CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of equivalent quantities of N-carbobenzyloxy-trans-4-hydroxy-L-proline, methyl ester from Example 1, part b, and dimethylaniline is treated with a solution of phosgene in toluene. After standing overnight an equivalent quantity of ammonia is passed through the solution of trans-N-carbobenzyloxy-4-[(chlorocarbonyl)oxy]-L-proline, methyl ester. After standing for twelve hours at room temperature, the solution is washed with water, dried over magnesium sulfate, filtered and the solvent evaporated to give trans-N-carbobenzyloxy-4-[(aminocarbonyl)oxy]-L-proline, methyl ester.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].BrC1C=C([C@@H](N)C)C=CC=1>>[NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: C[C@@H](N)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: C[C@H](N)c1cccc(Br)c1
Product: C[C@H](N)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1

Procedure:
Intermediate 34 was prepared according to the procedures described in Intermediate 33 using (S)-1-(3-bromophenyl)ethanamine as the starting material. LC-MS (ESI) m/z 340.0 (M+H), RT=1.64 min (Method B).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.[CH3:28][O:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:24][O:23][C:14]1[CH:15]=[C:16]([O:19][CH2:20][O:21][CH3:22])[CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH3:28])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:25])([CH3:26])[CH:6]=[C:5]2[CH3:27]
Reactant: COCOc1ccc(-c2ccc3c(c2CCl)C(C)=CC(C)(C)N3)c(OC)c1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2, 262 mg, 0.675 mmol), 2-methoxyaniline (84 μL, 0.74 mmol) and potassium carbonate (151 mg, 1.09 mmol) was suspended in anhydrous N,N-dimethylformamide (4 mL) and the suspension was stirred at 80° C. overnight. After cooling down, ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture and separated. The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (196 mg) as a yellow amorphous product. (Yield 61%)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[F:31][C:32]([F:36])([F:35])[CH2:33]I>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH2:33][C:32]([F:36])([F:35])[F:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: FC(F)(F)CI
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(CC(F)(F)F)C3)cc1

Procedure:
Compound ha was synthesized using the general procedure described in Example 5 but by reacting (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1,1,1-trifluoro-2-iodoethane instead of benzyl chloroformate: LC-MS: m/z=+493 (M+H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[N:3]=1.C(O)(=O)C.[BH4-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1cccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(OCc2ccc(CC[N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
To a solution of 2-methyl-6-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (5.00 g, 18.5 mmol) described in Manufacturing Example 3-1-3 and acetic acid (5 mL) in dimethyl sulfoxide (50 mL) was added sodium borohydride (1.2 g, 29.6 mmol) under nitrogen atmosphere at room temperature while cooling appropriately, which was stirred for 10 minutes at room temperature. Water was then added dropwise. The mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5 then 1:2) to obtain the title compound (2.8 g, 56%).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9](O)[CH2:10][CH2:11][CH3:12].O>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOP(=O)(CC)CCO
Yield: 85.8 %

Procedure:
414 g (3 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 8) are at 85° C. dissolved in 400 ml of toluene and admixed with 888 g (12 mol) of butanol. At a reaction temperature of about 100° C., the water formed is removed by azeotropic distillation to leave 500 g (86% of theory) of butyl ethyl(2-hydroxyethyl)phosphinate.
Reaction SMILES: O[C@@H:2]1[C@H:13]2[C@H:9]([N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:14])[CH2:12]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.ClCCl.C(N(S(F)(F)[F:31])CC)C>>[F:31][C@H:2]1[C@H:13]2[C@H:9]([N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:14])[CH2:12]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@@H]2[C@H]1c1ccccc1[C@@H]2O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C[C@H]2[C@H](F)c3ccccc3[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3aR,4R,8bS)-4-hydroxy-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (0.200 g, 0.691 mmol) in dichloromethane (1 equiv., 3 mL, 0.69 mmol) was added at 0° C. diethylaminosulfur trifluoride (0.913 mL, 6.91 mmol). The solution was stirred at 0° C. for 30 min. The reaction mixture was carefully quenched with NaHCO3 sat. and extracted with dichloromethane. The organic layer was dried and concentrated. The residue was purified by flash chromatography (0-80% ethyl acetate in cyclohexane) to give the desired product F28 (0.150 g, 74%). LCMS (method A): 1.65 min; ES+: 605 (2M+Na+).
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[CH:1]1([C:7]2[CH:14]=[CH:13][C:20]([C:19]([OH:22])=[O:21])=[CH:9][C:8]=2[C:15]([F:16])([F:17])[F:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
A mixture of 4-cyclohexyl-3-(trifluoromethyl)benzonitrile (Preparation 118A, 8 g, 31.6 mmol), acetic acid (30 mL), conc. hydrochloric acid, 37% (30 mL) and water (60 mL) was stirred at 110° C. under nitrogen (oil bath temp.) for 20 h. After water (100 mL) was added, the mixture was cooled. The solid was filtered, washed with water (3×15 mL) and dried to give 4-cyclohexyl-3-(trifluoromethyl)benzoic acid (7 g, 25.7 mmol, 81% yield) as a brownish solid. The compound had an HPLC retention time=3.80 min. (condition C); LC/MS M+1=273.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 2.5 h
Yield: 100 %

Procedure:
22.3 g of methyl 4'-methyl-(1,1'biphenyl)-2-carboxylate were dissolved in 900 ml of tetrachloromethane under a nitrogen flow. Then there were added 17.8 g of 1-bromo-2,5-pyrrolidinedione and a catalytic amount of dibenzoyl peroxide. After stirring for 2.5 hours at reflux temperature under a nitrogen atmosphere, the reaction mixture was cooled and filtered. The filtrate was evaporated, yielding >30 g (100% ) of methyl 4'-(bromomethyl)[1,1'-biphenyl]-2-carboxylate as a crude residue (interm. 44).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C=O)C.[Cu]I.[Pd].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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 120 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)-palladium(0) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 120° C., after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35% EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47%). 1H NMR (CDCl3, 300 MHz): δ 8.04 (s, 1H), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H)+, calc. 269.
Reaction SMILES: CO.O.[OH-].[Li+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:11]([O:13]C)=[O:12].Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccn2)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To 154 mL of a 50/50 solution of MeOH and H2O was added lithium hydroxide monohydrate (13.85 g, 330 mmol). The solution was stirred until all of the salt dissolved, at which point methyl 3-methoxy-4-pyridin-2-ylbenzoate (8.02 g, 32.9 mmol) was added. The mixture was heated at reflux and stirred overnight. The reaction mixture was cooled to rt, neutralized with 6N HCl, and acidified to pH 4 with 1N HCl. A colorless solid crashed out of solution and was filtered to give 3-methoxy-4-pyridin-2-ylbenzoic acid as a colorless solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (d, 1H), 7.92–7.84 (m, 3H), 7.69–7.65 (m, 2H), 7.40–7.36 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[C:11](N)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CC(C)CC[O:18]N=O.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.ClCCl>[CH3:1][S:2][C:3]1[NH:12][C:11](=[O:18])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: CC(C)CCON=O
Reactant: CSc1nc(N)c2c(n1)CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1nc2c(c(=O)[nH]1)CCCC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ylamine (5.09 g; 23.145 mmol), 3-methyl-1-nitrosooxybutane (11.6 ml; 86.79 mmol) and trifluoroacetic acid (23.2 ml; 300.89 mmol) are dissolved in chloroform (300 ml), the pale-yellow solution is warmed to 60° C. and stirred for 2 h. The reaction mixture is diluted with dichloromethane and extracted with 10% K2CO3. The aqueous phase is separated off and back-extracted once with dichloromethane, NaCl is subsequently added, and the mixture is extracted again with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered and evaporated. The crude product obtained in this way is adsorbed onto sorbent and purified by chromatography on a SI50 silica-gel column of a Combiflash Companion XL. After evaporation of the product fractions, the crystalline residue is triturated with diethyl ether, filtered off by suction and dried in vacuo; yield: 2.0 g (57%), crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH3:44][C:37]1([CH3:45])[CH2:36][C@H:35]([NH:34][C:32]2[C:31]([F:46])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][OH:18])=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[CH:7]=3)[N:33]=2)[CH2:43][C@H:42]2[N:38]1[CH2:39][CH2:40][CH2:41]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: Cn1nnn(-c2cc(N)ccc2OCCO[Si](C)(C)C(C)(C)C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)ccc2OCCO)c1=O
Yield: 20 %

Procedure:
The general displacement procedure was described herein was used with 1-(5-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (382 mg, 1.1 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (350 mg, 1.1 mmol) and pTsOH.H2O (398 mg, 2.1 mmol) in IPA (10 mL) at reflux to give the product (113 mg, 21% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 95:5) as eluent.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1)#[CH:29]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:29]#[C:28][C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Reactant: C#CC1=CCCCC1
Solvent: CCCCCCC
Solvent: ClCCl
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)C1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (81.5, 54%); 1H NMR δ (CDCl3): 7.8 (d, J=8.05 Hz, 1H), 7.4-7.19 (m, 8H), 6.37-6.3 (m, 1H), 5.6 (s, 2H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 312.
Reaction SMILES: CCO/[CH:4]=[C:5](/[CH:7]=O)\[CH3:6].[NH2:9][C:10]1[N:14]=[C:13]([SH:15])[NH:12][N:11]=1>>[CH3:6][C:5]1[CH:4]=[N:9][C:10]2[N:11]([N:12]=[C:13]([SH:15])[N:14]=2)[CH:7]=1
Reactant: CCO/C=C(\C)C=O
Reactant: Nc1n[nH]c(S)n1
Product: Cc1cnc2nc(S)nn2c1

Procedure:
The title compound was prepared from 3-ethoxymethacrolein and 3-amino-5-mercapto-1,2,4-triazole as previously described by M. Kunstlinger and E. Breitmaier in Synthesis, 1983, 44-47. 1H NMR (DMSO-d6) d 2.31 (s, 1H) 8.45 (s, 1H) 8.68 (s, 1H). MS (APCI) calcd for C6H6N4S: 166.21; found (M+H+) 167.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH2:10]Cl)[C:7]=1[O:8][CH3:9]>CO.[Pd].[C]>[Cl:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(CCl)cnc(C)c1Cl
Agent: [Pd]
Solvent: CO
Product: COc1c(C)cnc(C)c1Cl
Yield: 79.7 %

Procedure:
The above 3-chloro-5-(chloromethyl)-4-methoxy-2-methylpyridine (550 mg) was dissolved in 10 ml of methanol, and 10% Pd carbon (50 mg) was then added to the solution. Normal-pressure contact hydrogenation was performed on the mixture under cooling on ice for 3 hours. Thereafter, the catalyst was removed by filtration, and methanol was then distilled away under reduced pressure. The residue was extracted with chloroform. The organic layer was washed with a saturated sodium bicarbonate solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel chromatography (ethyl acetate-hexane), so as to obtain the title compound (365 mg) as an oily substance.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([CH:21]([CH3:23])[CH3:22])[N:16]=2)[N:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].CB(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1.O>[CH:21]([N:17]1[C:18]([CH3:20])=[CH:19][C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:24])=[N:3]2)=[N:16]1)([CH3:23])[CH3:22]
Reactant: Cc1cc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)nn1C(C)C
Reactant: O=C([O-])[O-]
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CB(O)O
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(Cc2cc(C)n(C(C)C)n2)c2cccc([N+](=O)[O-])c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
A flask was charged with 1,4-dioxane/H2O (30 mL/5 mL). The flask was cooled to 0° C. and vacuum was applied for 20 minutes. A second flask was charged with 3-bromo-1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.95 g, 5.16 mmol), K2CO3 (2.85 g, 20.6 mmol), diacetoxypalladium (0.0579 g, 0.258 mmol), methylboronic acid (0.926 g, 15.5 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.264 g, 0.516 mmol). The second flask was evacuated with and back filled with nitrogen three times. The cold degassed dioxane/H2O was added to the second flask, which was evacuated and back filled with argon 5 times. The reaction mixture was heated to 80° C. for 3 hours. The reaction was cooled to ambient temperature and filtered, and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO3 (30 mL), dried (Na2SO4) and concentrated to give 1.34 g (83%) of the title compound, which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:9].[H-].[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]Cl)[CH2:30][CH2:29]1)=[O:27].[Cl-].[NH4+]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][N:28]([C:26](=[O:27])[C:25]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:29][CH2:30]2)[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:9]
Reactant: O=C(Nc1ccccn1)c1nc2ccccc2[nH]1
Reactant: COc1ccc(C(=O)N2CCN(CCCl)CC2)cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)N2CCN(CCn3c(C(=O)Nc4ccccn4)nc4ccccc43)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
In an argon atmosphere, N-(2-pyridyl)benzimidazole-2-carboxamide (1.40 g) was dissolved in DMSO (20 ml), and 60% sodium hydride (0.28 g) was added and stirred at room temperature for 1 hr. A solution (7 ml) of 2-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]ethyl chloride (1.90 g) in DMSO was added dropwise and allowed to react overnight at room temperature under agitation. The reaction solution was poured into an aqueous solution of ammonium chloride and extracted with chloroform. The chloroform layer was dried over Na2SO4 and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (1.60 g) as amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1.CCCCCC>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:9]1[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]([CH3:13])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1.1 g (3.25 mmol) of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-imidazole in 30 mL of dry THF was cooled in a −78° C. bath and 1.7 mL of 2.5 M n-BuLi in hexane was dropwise added. After stirring the solution for 1 h it was added with a canula to 0.623 mL of ethyl chloroformate in THF cooled in a −78° C. bath. The cold bath was removed and the reaction was stirred for 1 h then quenched with water. The mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-20% EtOAc-hexane to isolate the desired product.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C([SnH](CCCC)CCCC)CCC.[Li].Br[C:37]([C:39]([F:42])([F:41])[F:40])=[CH2:38]>O1CCCC1.[Cu]I>[CH2:18]([Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[C:37]([C:39]([F:42])([F:41])[F:40])=[CH2:38])[CH2:19][CH2:20][CH3:21]
Reactant: C=C(Br)C(F)(F)F
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Cu]I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C(F)(F)F)[Sn](CCCC)(CCCC)CCCC
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 74.8 %

Procedure:
A 2M solution of LDA in tetrahydrofuran (7.5 ml, 15 mmole) was added to tetrahydrofuran (5 ml) at −5° C. To this solution was added tri-n-butylstannane (4.36 g, 15 mmole) dropwise and the mixture was left to stir for 20 min. In a second flask, copper(I)iodide (1.43 g, 7.5 mmoles) was suspended in tetrahydrofuran (5 ml). The flask was cooled to −10° C. and the lithium tri-n-butylstannane solution was then transferred dropwise via a syringe to the copper(I)iodide suspension. The mixture was stirred at −10° C. for 0.5 h, cooled to −78° C. then treated dropwise with 2-bromotrifluoropropene (1.32 g, 7.5 mmole). Stirring was continued for a further 0.5 h followed by 1 h at room temperature. Volatiles were removed in vacuo and the residue was dissolved in ether (100 ml), filtered and the solvent was removed to give an oil. Purification was by distillation. The fraction boiling at 114° C./4.6 mbar was collected to give the title compound (2.16 g, 75%).