Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[OH:28][C:27]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:33])[N:23]1[CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −70° C., a 1.6 M butyllithium solution (3.99 mmol) in absolute diethyl ether was admixed dropwise with a solution of 0.56 g (3.56 mmol) of 3-bromopyridine in absolute diethyl ether. The color of the mixture changed to yellow, and a precipitate was formed. After 1 h at −70° C., a solution of 0.5 g (1.78 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide in 10 ml of absolute tetrahydrofuran was added dropwise. The reaction mixture was warmed to room temperature, stirred for another 1 h and then admixed with 10 ml of saturated ammonium chloride solution. The mixture was extracted three times with diethyl ether. The combined organic phases were washed once with saturated sodium chloride solution, dried and evaporated to dryness using a rotary evaporator. The colorless oily crude product was purified by chromatography. Elution was carried out using a dichloromethane/methanol gradient (0 to 3% methanol). The resulting colorless oil solidified on standing at room temperature. Yield: 0.34 g. M.p.: 97° C.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[C:25]1([C:30](Cl)=[O:31])[S:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:30]([C:25]1[S:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: O=C(Cl)c1cccs1
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)c1cccs1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (200 mg) in tetrahydrofuran (3 mL) were added triethylamine (100 μL) and 2-thenoyl chloride (100 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (273 mg, yield 92%) as colorless crystals. melting point 250° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([OH:33])=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CSc2nnnn2-c2ccccc2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3ccccc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylate (1.0 g, purity 80%, 1.42 mmol) in dichloromethane (50 ml) was cooled to 0° C. Titanium tetrachloride (0.62 ml, 5.6 mmol) was added in 1 min. After stirring for 1 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.55 g of (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylic acid-(purity 60%, yield 45.8%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].NC1C=CC(C(O)C)=C([Cl:46])C=1>>[Cl:46][C:19]1[CH:18]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[O:24])[CH:16]=[CH:15][C:14]=1[N:13]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(O)c1ccc(N)cc1Cl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,6-Dimethyl-3-nitro-2-pyridine (0.66 g, 3.8 mmol, step 2 of Example 1) and 4-amino-2-chloro-phenylethanol (0.72 g, 3.8 mmol, Eur. J. Med. Chem., 1996, 31, 133.).
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][S:12](Cl)(=[O:14])=[O:13])([O:8][CH3:9])=[O:7].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH2:16]([CH:10]([CH2:11][S:12]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)(=[O:14])=[O:13])[C:6]([O:8][CH3:9])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 1L round bottom flask was added the resultant compound from Example 3E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0° C. in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed, the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1 ; 1H NMR (CDCl3 ) delta 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H, J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDCl3) delta 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(O)c1cncc(Br)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)c1cc(Br)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine from Step 1 (3.1 mmol) in chloroform (10 mL) was added m-chloroperoxybenzoic acid 70% (1.5 eq) and the resulting mixture was stirred at room temperature for 18 hours. An excess of calcium hydroxide was added and after stirring for 5 minutes, the mixture was filtered through celite and the filtrate was evaporated. The crude material was chromatographed on silica gel eluting with 10% ethanol in methylene chloride (saturated with ammonia) to afford the 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide compound as a solid.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]1[C:42]([C:43](Cl)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]1[C:42]([C:43]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 1H), 7.47 (m, 2H), 7.44–7.39 (m, 3H), 7.25 (m, 2H), 7.09 (s, 1H), 7.03 (m, 2H), 6.95 (m, 1H), 6.83 (m, 1H), 5.75 (t, 1H, J=7.1 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.93 (m, 2H), 2.78 (s, 3H), 2.48 (m, 3H), 2.25 (m, 2H), 1.48 (m, 3H), 1.77 (m, 2H), 1.54 (m, 2H), 1.25 (d, 6H, J=7.3 Hz); ESMS m/e: 647.7 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([OH:13])=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:14]([NH2:16])[CH3:15].P(=O)(O)(O)O>O>[Br:8][C:6]1[N:7]=[C:2]2[N:16]([CH2:14][CH3:15])[C:11](=[O:13])[CH2:10][NH:9][C:3]2=[N:4][CH:5]=1
Reactant: CCN
Reactant: O=C(O)CNc1ncc(Br)nc1Br
Agent: O=P(O)(O)O
Solvent: O
Product: CCN1C(=O)CNc2ncc(Br)nc21
Temperature: 90 °C

Procedure:
The 2-((3,5-dibromopyrazin-2-yl)amino)acetic acid and ethylamine (4 equiv, 70 wt % solution) were combined in water and the mixture was stirred at 90° C. The reaction mixture was cooled to 80° C. and treated with phosphoric acid (4 equiv), and the mixture was cooled to room temperature and the solids were collected by filtration. The product was dried to obtain 7-bromo-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as a solid. MS (ESI) m/z 256.9
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[O:29][CH:30]=1>>[CH3:39][C:35]1[CH:34]=[C:33](/[CH:32]=[CH:31]/[C:28]2[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=3)[N:27]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Cc1cccc(/C=C/c2nc(CCl)co2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CC(O)CO)cc3)co2)c1
Yield: 60.3 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (154 mg), 65% oily sodium hydride (21 mg) and 4-(chloromethyl)-2-[(E)-2-(3-methylphenyl)ethenyl]-1,3-oxazole (131 mg), the same reaction as Example 2 was carried out to yield the titled compound (156 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15]O)=[CH:12][CH:11]=1)[CH3:8].C([O-])([O-])=O.[Na+].[Na+]>Cl>[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[CH:12][CH:11]=1)[CH3:8]
Reactant: NCCS
Reactant: CN(C)Cc1ccc(CO)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C)Cc1ccc(CSCCN)o1
Reaction time: 20 h
Yield: 56 %

Procedure:
Cysteamine hydrochloride (5.7 g; 0.05 mol) was dissolved in conc. hydrochloric acid (20 ml). Upon ice-cooling, 5-(dimethylamino)methyl-2-furanemethanol (7.75 g; 0.05 mol) was added. The reaction mixture was left to stand at 0° C. for 20 hours, added with a Na2CO3 excess, extracted with ether and filtered. The filtrate was evaporated to obtain an oily residue which after distillation in vacuo (p.e. 105°-107°; 0.1 mm) gave the pure product (6.0 g; 56% yield).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([OH:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:17]([CH3:32])[N:16]=1.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:18]2[C:19]([O:21][S:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:13])(=[O:11])=[O:10])=[N:20][C:15]([NH2:14])=[N:16][C:17]=2[CH3:32])=[C:24]([O:30][CH3:31])[CH:25]=1)(=[O:11])=[O:10]
Reactant: COc1cc(O)ccc1Cc1c(C)nc(N)nc1O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)c2c(C)cc(C)cc2C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Mesitylenesulfonyl chloride (5.25 g) was added to a mixture of the product from step (iii) (5 g), TEA (7 ml) and DMAP (120 mg) in DCM (100 ml) and stirred at rt for 24 h. DMF (10 ml) was added and the mixture heated under reflux for 12 h. Another portion of 2-mesitylenesulfonyl chloride (2 g) was added and heated under reflux for a further 24 h. The mixture was partitioned between DCM/water, the organics separated, washed with aq NaHCO3 soln, brine, dried and evaporated under reduced pressure. The residue was triturated with ether/isohexane and filtered to afford the subtitle compound, 9.515 g.
Reaction SMILES: [C:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[CH2:2].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH3:17])[CH:19]=[CH:20]3)=[O:29])=[CH:8][CH:9]=1)([C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH3:17])[CH:19]=[CH:20]3)=[O:29])=[CH:12][CH:11]=1)=[CH2:2]
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Reactant: C=C(c1ccc(N)cc1)c1ccc(N)cc1
Product: C=C(c1ccc(NC(=O)c2ccc3c(ccn3C)c2)cc1)c1ccc(NC(=O)c2ccc3c(ccn3C)c2)cc1

Procedure:
Compound 702 was prepared according to the procedure described in Scheme IV from 4,4′-(ethene-1,1-diyl)dianiline and 1-methylindole-5-carboxylic acid. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 2H), 7.93 (s, 2H), 7.79 (dd, J=1.7, 8.5 Hz, 2H), 7.66 (dd, J=1.7, 6.8 Hz, 4H), 7.42 (d, J=2.3 Hz, 2H), 7.39 (d, J=8.5 Hz, 4H), 7.15 (d, J=2.3 Hz, 2H), 6.61 (d, J=2.9 Hz, 2H), 5.44 (s, 2H), 3.86 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][O:66][C:67](=[O:75])[CH2:68][CH:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1>C(Cl)Cl>[CH3:65][O:66][C:67](=[O:75])[CH2:68][CH:69]1[CH2:70][CH2:71][N:72]([C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])[CH2:73][CH2:74]1
Reactant: COC(=O)CC1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (581 mg, 1 mmol) in methylene chloride (10 mL), HATU (Aldrich, 500 mg, 1.3 mmol) was added followed by the addition of DIPEA (0.35 mL, 2.2 mmol) and piperidin-4-yl-acetic acid methyl ester (Oakwood, 205 mg, 1.3 mmol). The mixture was stirred at rt for 3 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 586 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7](N)[CH:6]=1)[CH3:2].N(OCCC(C)C)=O.C(I)[I:29]>C(#N)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7]([I:29])[CH:6]=1)[CH3:2]
Reactant: ICI
Reactant: CCOC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester (3.7 g, 14.45 mmol) was added to 50 mL of acetonitrile, and the mixture was stirred at room temperature. Isoamyl nitrite (9.7 mL, 72.27 mmol) was slowly added, followed by methylene iodide (7.0 mL, 86.7 mmol). The reaction mixture was slowly heated to 60° C. for 30 minutes, then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by liquid chromatography (30% to 100% methylene chloride/hexanes) to give 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester, MS (M+H)=368.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:10]([C:11]3([OH:17])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)[CH:9]=[C:10]([C:11]3([OH:17])[CH2:16][CH2:15][CH2:14][N:13]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C3(O)CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCCC(O)(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 80 h
Yield: 33.2 %

Procedure:
A mixture of 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidin-3-ol (154 mg, 0.35 mmol), N,N-dimethylglycine (43 mg, 0.42 mmol), EDCl (74 mg, 0.39 mmol), HOBt (52 mg, 0.39 mmol), and N,N-diisopropylethylamine (183 μL, 1.05 mmol) in DMF (3.0 mL) was stirred at rt for 80 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 61 mg (33%) of the desired product. ES-MS m/z 525.52 [M+H]+, HPLC RT (min) 2.04.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([O:12]S(C)(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:27])[F:28])=[CH:25][CH:24]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: CCOC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
1-ethoxycarbonyl-4-mesyloxypiperidine (13.6 g), trifluoromethoxyphenol (4.0 g), tetrabutylammonium chloride (1.2 g) and potassium carbonate (7.72 g) were suspended in water (20 mL) and the suspension was refluxed for 3 hours. The reaction solution was cooled to room temperature, and then the reaction product was extracted with toluene (24 mL). The extract was washed with water (20 mL×2), and then the solvent was concentrated under reduced pressure to obtain a target compound as a light yellow oily substance. The yield amount was 12.03 g (%). The obtained target compound was used, for the subsequent reaction without being purified.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)([CH3:10])([CH3:9])[CH3:8].[NH2:18][CH2:19][C@@H:20]([OH:22])[CH3:21]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[C:7]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][NH:18][CH2:19][C@@H:20]([OH:22])[CH3:21])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: C[C@H](O)CN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: C[C@H](O)CNCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 2583 mg (18.69 mmol) potassium carbonate, 2780 mg (12.46 mmol) 4-bromobutyric acid tert.-butyl ester and 184 mg (0.50 mmol) tetra-n-butylammonium iodide to a solution of 936 mg (12.46 mmol) (2S)-1-aminopropan-2-ol in 10 ml THF. Stir the reaction mixture for 48 h at room temperature. After filtering-off the inorganic salts, concentrate the filtrate by vacuum evaporation. Take up the residue in dichloromethane and chromatograph on silica gel (solvent: dichloromethane/methanol/35% aqueous ammonia solution 9:1:0.1). 810 mg (30% of theor.) of the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][C@H:9]2[N:21]([CH3:32])[C:22](=[O:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([C:61](O)=[O:62])[CH2:60][CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22](=[O:31])[N:21]([C@H:9]2[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:61]([CH:57]4[CH2:60][CH2:59][CH2:58]4)=[O:62])[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:32])=[CH:29][CH:28]=1
Reactant: O=C(O)C1CCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3CCC3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 27.6 mg (0.06 mmol) 4-fluorophenyl (3S,4R)-4-(4-chlorophenyl)-1-(piperidine-4-carbonyl)pyrrolidin-3-yl(methyl)carbamate, 0.52 mL (0.072 mmol) HATU (0.136 M in DMF), 12 mg (0.072 mmol) cyclobutanecarboxylic acid and 46.5 mg (0.36 mmol) DIPEA in 1.5 mL DMF was shaken at room temperature over night. The mixture was subjected to preparative HPLC chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 12.5 mg (39%) of the title compounds as off-white solid. MS m/e: 542.3 [M+H]+.