Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][N+:8]([O-])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:32][CH:9]1[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[NH:11][C:10]1=[O:13])(=[O:31])[CH3:30]
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cccc(Cl)c2N1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Product: CC(=O)OC1N=C(c2ccccc2F)c2cccc(Cl)c2NC1=O
Yield: 50 %

Procedure:
A suspension of 9-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-4-oxide (1.475 g) in acetic anhydride (12 ml) was refluxed for 0.5 hour. The resultant clear solution was cooled in an ice-bath to afford precipitate. To the cooled suspension was added diisopropyl ether (20 ml) and the mixture was cooled further. The resultant precipitate was collected by filtration and washed with diisopropyl ether to give (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.84 g, 50.0% yield) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br>C(#N)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[N:15]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Yield: 88.1 %

Procedure:
1-N-Boc-1,2-cis-cyclohexyldiamine 5 (CAS 184954-75-4) (1.65 g, 7.7 mmol) was dissolved in 100 mL acetonitrile. Potassium carbonate (5.3 g, 39 mmol) and 1,4-dibromobutane (2.8 g, 13 mmol) were added and the reaction mixture was refluxed overnight. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-(2-pyrrolidin-1-yl-cyclohexyl)-carbamic acid tert-butyl ester as a yellow liquid (1.82 g, 88%), MS: m/e=269.4 [(M+H)+].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.[Cu]I>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(I)ccc1N
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: CCOCC
Product: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1N

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 1-tert-butyl-4-ethynylbenzene (25b, 158 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((4-tert-butylphenyl)ethynyl)-2-methyl benzene amine (26b) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((4-tert-butylphenyl)ethynyl)-2-methylbenzenamine (26b, 263 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29b). Reaction of 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methyl quinazolin-4(3H)-one (29b, 406 mg, 1 mmol) with 2,4-dihydroxybenzaldehyde (30d, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5d) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:15]3=[CH:16][C:17]4[NH:18][C:19]5[C:24]([C:25]=4[CH:26]=[C:14]3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:36]1[N:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]=[C:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:37]=1>CN(C)C=O>[C:48]1([C:38]2[N:39]=[C:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:41]=[C:36]([N:18]3[C:17]4[CH:16]=[C:15]5[C:7]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[C:8]6[C:13]([C:14]5=[CH:26][C:25]=4[C:24]4[C:19]3=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:12][CH:11]=[CH:10][CH:9]=6)[N:37]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: c1ccc(C2(c3ccccc3)c3ccccc3-c3cc4c(cc32)[nH]c2ccccc24)cc1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccccc3)nc(-n3c4ccccc4c4cc5c(cc43)C(c3ccccc3)(c3ccccc3)c3ccccc3-5)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6 g (14.6 mmol) of 12,12-diphenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 100 ml of dimethylformamide under a protective-gas atmosphere, and 0.76 g of NaH, 60% in mineral oil (19 mmol), is added. After 1 hour at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (4.3 g, 16 mmol) in 50 ml of dimethylformamide is added dropwise. The reaction mixture is then stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 8.1 g (12.7 mmol, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@@H:15]([O:16]C(C)(C)[O:18]2)[C@@H:14]([C:22]([OH:24])=[O:23])[O:13]1>C(O)=O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:13][C@H:14]([C:22]([OH:24])=[O:23])[C@@H:15]([OH:16])[C@H:19]1[OH:18]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(N)nc(I)nc31)O[C@@H]2C(=O)O
Solvent: O=CO
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H]1O
Yield: 84.9 %

Procedure:
A solution of 1.72 g (3.85 mmol) of (2S,1R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]octane-2-carboxylic acid (6.7) in 80 mL of 50% HCOOH was stirred at 80° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure, dissolved in H2O, and the solution was evaporated again. This process was repeated until there was no odor of formic acid in the residue. Recrystallization from water yielded 1.33 g (85%) 6.8 as a white solid, m.p. 221-223° C. dec. 1H NMR (300 MHz, DMSO-d6) δ8.31 (s, 1H, H-8), 7.68 (s, 2H, NH2), 5.90 (d, J=6.55 Hz, 1H, H-1′), 4.42 (m, 1H, H-2′), 4.35 (d, J=2.31 Hz, 1H, H-4′), 4.22 (m, 1H, H-3′).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.C(Cl)Cl.CCN(C(C)C)C(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CCCCCC.C1COCC1>[Cl:35][C:33]1[CH:32]=[C:31]([S:36]([N:3]2[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)(=[O:37])=[O:38])[CH:30]=[C:29]([Cl:28])[CH:34]=1
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)C1Cc2ccccc2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 80.2 %

Procedure:
To a mixture of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, methyl ester hydrochloride (200 mg, 0.878 mmol) in a 1:1 mixture of CH2Cl2 and THF (2.5 mL each) was added dropwise DIPEA (0.88 mmol, 113 mg) followed by 3,5-dichlorobenzenesulfonyl chloride (0.922 mmol, 227 mg), a second equivalent of DIPEA and 4-DMAP (0.176 mmol, 22 mg). The reaction mixture was stirred at rt overnight when TLC (4:1 hexane:ethyl acetate) indicated disappearance of all starting material. The volatiles were removed in vacuo and the residue was purified by flash column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate to yield N-(3,5-dichlorobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, methyl ester (282 mg, 80%) as a white foam, homogeneous by TLC (Rf=0.55, 4:1 hexane:ethyl acetate);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[F:16][C:17]([F:44])([F:43])[C:18]([F:42])([F:41])[C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[CH2:25][CH2:26][CH2:27]I>CS(C)=O>[F:29][C:24]([F:30])([C:23]([F:31])([F:32])[C:22]([F:33])([F:34])[C:21]([F:35])([F:36])[C:20]([F:37])([F:38])[C:19]([F:39])([F:40])[C:18]([F:42])([F:41])[C:17]([F:44])([F:43])[F:16])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1ccc(OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
(E)-Methyl 3-(4-hydroxyphenyl)acrylate (166 mg, 0.93 mmol) was added to dry DMSO (10 mL) and stirred under nitrogen in a round bottom flask. Crushed sodium hydroxide (44 mg, 1.1 mmol) was added. After 30 minutes, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-11-iodoundecane (500 mg, 0.85 mmol) was added. The reaction was allowed to stir overnight. Washed with water and extracted with dichloromethane to yield an oil. This crude product was purified on a silica column using hexanes with increasing amounts of ethyl acetate as the eluent. A white solid was isolated (418 mg, 77% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.65 (d, J=16.0 Hz), 7.48 (d, J=8.75 Hz, 2H), 6.90 (d, J=8.75 Hz, 2H), 6.32 (d, J=16.0 Hz), 4.07 (t, J=5.90 Hz, 2H), 3.80 (3H), 2.40-2.20 (m, 2H), 2.18-2.05 (m, 2H).
Reaction SMILES: C([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:26]4[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]4)[CH:22]=[CH:23][C:24]=3[Cl:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:20][C:19]=1[CH2:18][C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH2:10][CH2:9][NH:8][C:13]=2[CH:14]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (2.4 g, 4.68 mmol) in methanol (15 mL) was added 10% palladium on charcoal (240 mg) and 0.05 mL conc. HCl. The reaction mixture was stirred under hydrogen atmosphere for 2 h then filtered through celite bed (which was washed with methanol). The resulting filtrate was concentrated to a residue which was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.6 g).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[CH2:14][CH2:15][CH2:16][C@H:11]2[CH2:10][NH:9]1)(C)C.[F:19][C:20]([F:54])([F:53])[C:21]1[CH:22]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39](Cl)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CO>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39]([N:9]3[C@H:8]([CH2:7][OH:6])[CH2:13][N:12]4[CH2:14][CH2:15][CH2:16][C@H:11]4[CH2:10]3)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:22]=[C:21]([C:20]([F:54])([F:19])[F:53])[CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2C[C@@H]3CCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a solution of (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrrolo[1,2-a]pyrazine (D82, 157 mg, 0.58 mmol) in 2.5 mL of toluene were added 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (238 mg, 0.45 mmol) (t-Bu3P)2Pd (46 mg, 0.09 mmol), a 25% aqueous solution of cetyltrimethylammonium chloride (26 μL), and, at last, 50% aqueous NaOH (54 μL). The reaction deoxygenated by freeze-pump-thaw cycles and then heated to 90° C. for 7 h. The reaction was checked by UPLC/MS, showing the expected product peak at 0.84 min, with m/z=767 (M+1) and 384 ((M+2)/2). The solution was diluted with EtOAc, washed with sat. NaHCO3 and brine. The sample was purified by flash chromatography (silica, cyclohexane:EtOAc 90:10 to 0:100). Isolated 251 mg of O-TBDMS protected intermediate. The intermediate was dissolved in 11 mL of MeOH and 0.55 mL of conc. HCl were added. The reaction was left at room temperature for 1 h. The product was isolated by SCX cartridge. Isolated 140 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.CN(C)[CH2:15][CH2:16][CH2:17][N:18]=C=NCC.C1(N)CC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:18][CH:17]1[CH2:15][CH2:16]1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-4-methylbenzoic acid (8.35 g, 33 mmol), I H-benzo[d] [1,2,3]triazol-1-ol (4.44 g, 33 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.31 g, 33 mmol), and cyclopropylamine (2.5 mL, 36 mmol) were dissolved in dichloromethane (20 mL) and stirred at RT for 16 h. The reaction was diluted with dichloromethane (100 mL), washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous) and 2× with 50 mL of 3 N HCl (aqueous). The organic layer was separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 254(M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
Trifluoroacetic acid (4.03 mL, 51.9 mmol) was added to a solution of ethyl ((1S)-5-{3-[(tert-butoxycarbonyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 262, 2.47 g, 6.54 mmol) in CH2Cl2 (32 mL). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure to give the product as a viscous oil (2.74 g, 94%). 1H NMR (400 MHz, CD2Cl2) δ 7.86 (b, 3H), 7.05 (d, 1H), 6.76 (d, 1H), 6.68 (dd, 1H), 4.15 (q, 2H), 4.08 (t, 2H), 3.49 (qt, 1H), 3.32-3.20 (m, 2H), 2.92-2.78 (m, 2H), 2.67 (dd, 1H), 2.45-2.32 (m, 2H), 2.16 (qt, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:6]1[C:7]([O:38][CH2:39][O:40][CH3:41])=[CH:8][C:9]([O:34][CH2:35][O:36][CH3:37])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](S(C)(=O)=O)=[N:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]>CS(C)=O>[CH:3]([C:6]1[C:7]([O:38][CH2:39][O:40][CH3:41])=[CH:8][C:9]([O:34][CH2:35][O:36][CH3:37])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](=[O:1])[NH:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1-c1ccc(CN2CCOCC2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(CN2CCOCC2)cc1
Temperature: 90 °C
Yield: 53 %

Procedure:
At room temperature aqueous sodium hydroxide (1.0 M aqueous solution, 7 mL) was added to a dimethylsulfoxide solution (7 mL) of the crude product (1.01 g), which was obtained in the previous step, containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methanesulfonyl-4H-[1,2,4]triazole (F45-05). The reaction mixture was heated at 90° C. for 5.5 hours while stirring, cooled to room temperature, extracted with ethyl acetate, and the extract was washed twice with water and then saturated sodium chloride solution. The extract was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. The solvent was distilled off under reduced pressure to obtain a pale yellow foam. Reprecipitation purification was carried out (chloroform, diethyl ether), and the solids were washed with diethyl ether and dried under reduced pressure to obtain 5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-morpholin-4-ylmethylphenyl)-2,4-dihydro-[1,2,4]triazole-3-one (F45-06, pale yellow solid, 469 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][N:15]([C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:43]([O:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52]C)=[O:51])=[CH:48][CH:47]=1)=[O:44]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:43]([O:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=2)=[O:44])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 300 mg of tert-butyl {[4-(3-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2 mL of THF were added 0.136 mL of triethylamine and 167 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka), followed by stirring at room temperature for 2 hours. It was washed with water, and extracted with ethyl acetate, and the organic layer was then washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 8 mL of THF, 8 mL of isopropanol, and 4 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. After neutralizing by addition of 4.1 mL of 1 M hydrochloric acid, the reaction mixture was concentrated under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 387 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C=O
Reaction time: 3 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (2.11 g, 8.89 mmol), Et3N (6.2 ml, 44.5 mmol), DMSO (6.3 ml, 88.9 mmol) in CH2Cl2 (20 ml) was added SO3-pyridine (4.25 g, 26.7 mmol). After 3 h stirring, the mixture was concentrated in vacuo and diluted with Et2O (200 ml). The resulting mixture was washed with 1 N HCl (100 ml) and brine (100 ml), dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinecarbaldehyde (1.40 g, 67%) as a yellow oil. 1H-NMR (CDCl3) δ1.45-1.52 (m, 9 H), 2.49 (m, 2 H), 3.75-3.88 (m, 2 H), 4.29-4.42 (m, 1 H), 9.54 and 9.60 (s, each, total 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:23])=[C:14]([F:22])[C:15]([N+:19]([O-])=O)=[C:16]([O:17][CH3:18])[C:11]=3[NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1>[Zn]>[NH2:19][C:15]1[C:14]([F:22])=[C:13]([F:23])[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:25])[C:9](=[O:24])[NH:10][C:11]=2[C:16]=1[O:17][CH3:18]
Reactant: COc1c([N+](=O)[O-])c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(Br)cc1F
Agent: [Zn]
Product: COc1c(N)c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(Br)cc1F
Yield: 91.6 %

Procedure:
Intermediate I-12a was prepared from 1-(4-bromo-2-fluoro-phenyl)-6,7-difluoro-4-methoxy-5-nitro-1,3-dihydro-benzoimidazol-2-one (2 g, 0.00478 mol) and zinc powder (1.9 g, 0.0287 mol) using procedures analogous to those described above for the preparation of Intermediate I-11a to afford 1.7 g of the product (95% yield). H1NMR (DMSO-d6, 300 MHz): δ 11.52 (s, 114), 7.83 (dd, 1H), 7.62-7.55 (m, 2H), 4.99 (s, 2H), 3.75 (s, 3H).