Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17]([OH:20])[CH2:18][OH:19].CCCCCC.C(OCC)(=O)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:19][CH2:18][CH2:17][OH:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 80 °C

Procedure:
In a 50 mL, 3-neck RBF equipped with a magnetic stirrer, reflux condenser, and thermo pocket were sequentially charged 4-fluoro nitrobenzene (2.00 g), Cs2CO3 (9.21 g) and ethylene glycol (20 mL). The reaction mixture was heated to 80° C. for 30 minutes. The reaction was monitored on TLC using Hexane:Ethyl acetate (7:3) as mobile phase. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into cold water. Solid precipitate was filtered and washed with water. Solid was dried under reduced pressure at 45° C. for 1 hr. 2.70 g of 2-(4-nitrophenoxy)ethanol was obtained as a solid and was taken for the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[CH:17]1[CH:22]=[N+:21]([C@@H:23]2[O:27][C@H:26]([CH2:28][O:29][P:30]([O:33][P:34]([O:37][CH2:38][C@H:39]3[O:43][C@@H:42]([N:44]4[C:48]5[N:49]=[CH:50][N:51]=[C:52]([NH:53]CCN)[C:47]=5[N:46]=[CH:45]4)[C@H:41]([OH:57])[C@@H:40]3[OH:58])([OH:36])=[O:35])([OH:32])=[O:31])[C@@H:25]([OH:59])[C@H:24]2[O-:60])[CH:20]=[C:19]([C:61]([NH2:63])=[O:62])[CH:18]=1.C1(N=C=NCCN2CCOCC2)CCCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>O.[OH-].[Na+].CC(C)=O>[CH:17]1[CH:22]=[N+:21]([C@@H:23]2[O:27][C@H:26]([CH2:28][O:29][P:30]([O:33][P:34]([O:37][CH2:38][C@H:39]3[O:43][C@@H:42]([N:44]4[C:48]5[N:49]=[CH:50][N:51]=[C:52]([NH2:53])[C:47]=5[N:46]=[CH:45]4)[C@H:41]([OH:57])[C@@H:40]3[OH:58])([OH:36])=[O:35])([O-:32])=[O:31])[C@@H:25]([OH:59])[C@H:24]2[OH:60])[CH:20]=[C:19]([C:61]([NH2:63])=[O:62])[CH:18]=1.[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: NCCNc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H]([n+]3cccc(C(N)=O)c3)[C@H]([O-])[C@@H]2O)[C@@H](O)[C@H]1O
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reaction time: 5 h

Procedure:
A 16 mg quantity of biotin was suspended in 1 ml of water containing 22 mg of nicotinamide 6-(2-aminoethylamino) purine dinucleotide prepared as in Example 1. A few drops of 0.1 N sodium hydroxide was added to aid dissolution of the biotin. A 240 mg quantity of 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho-p-toluene sulfonate was added to the resulting solution and brought into solution by dropwise addition of 0.1 N hydrochloric acid. The reaction mixture was allowed to incubate at room temperature for 5 hours and was then poured into 10 ml of acetone at -10° C. The oil which formed was separated, washed twice with from 5 to 10 ml of ether and dissolved in from 1 to 2 ml of water. The resulting material was purified by electrophoresis on paper as in Example 1. Two fluorescent bands appeared after spraying with sodium cyanide, one having migrated toward the cathode and the other toward the anode. The latter band, which contained the NAD-biotin conjugate, was eluted with water and stored at -20° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][CH:16]=[C:17]([CH:20]=1)[C:18]#[N:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 109.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-fluorobenzoic acid (215 mg) and 5-methyl-6-piperazin-1-ylnicotinonitrile (202 mg), the title compound (433 mg) was obtained.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][CH2:34][C:33]1=[O:40]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:33](=[O:40])[CH2:34][N:35]([CH2:11][C@H:9]([NH:10][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[C@@H:7]2[CH2:8][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[O:6]2)[C:36]([CH3:39])([CH3:38])[CH2:37]1
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 93.4 %

Procedure:
A solution of 192 mg of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (0.54 mmol) and 181 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (0.76 mmol) in toluene (7 ml) was stirred at 110° C. for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/ethyl acetate=5/1) to obtain 299 mg of the title compound (yield: 93%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[CH:7]=2)[CH2:21][CH2:20]1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: CN1CCNCC1
Product: CC1CCN(c2cc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Yield: 100.8 %

Procedure:
The procedure of Example 4, step (b) was followed using 150 mg (0.589 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 327 μL (2.95 mmol) of 1-methylpiperazine at 142° C. for 21 h to afford 189 mg (100%) of the title compound as a yellow semisolid: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 319.2 (M+H), found 319.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCC(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: Cc1ccc(Cl)c(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(N(CCCC(F)(F)F)c2cc(Cl)ncn2)c1
Temperature: 50 °C

Procedure:
4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12) (0.28 g, 1.1 mmol) and 1,1,1-trifluoro-4-bromobutane (0.32 g, 1.67 mmol) were dissolved in NMP (2 ml). Anhydrous potassium carbonate (0.31 g, 2.2 mmol) was added and the mixture heated to 50° C. for three hours. Following an aqueous work-up the product was obtained by column chromatography on silica gel using EtOAc-isohexane mixtures. (0.3 g, 75%). M/z 364 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Br:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[Br:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:17]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: O=C(Cl)c1ccccc1Br
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2Br)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2-bromobenzoyl chloride according to the procedure of Example 19 to yield 5-(2-bromobenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 206.5°-208.5° C. after purification from ethanol.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][CH:32]=[O:33])=[CH:25][CH:24]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:33][CH:32]([CH2:31][CH2:30][S:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([F:34])([F:21])[F:35])=[CH:24][CH:25]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
3.77 Grams of methyl acetoacetate were dissolved in 5 ml of water, and 4.50 g of a 30% aqueous sodium hydroxide solution was added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with 50% sulfuric acid. Thereafter, 0.31 g of sodium acetate and 0.81 g of tetrabutylammonium bromide were added thereto and 14.7 g of a toluene solution containing 39.8% of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at 45°-50° C. for 6 hours and then at room temperature for 12 hours. After the mixture had been neutralized with a 50% sulfuric acid, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 6.82 g of crude 4-hydroxy- 6-(4-trifluoromethylphenylthio)-2-hexanone (purity, 92.6%). The crude product was further recrystallized from diisopropyl ether to obtain 6.04 g of a purified product. The yield of the purified product was 82.7%. It had a melting point of 73.0°-74.5° C.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]#[N:19])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]#[N:19])[CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: Cc1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1C#N
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(3′-cyano-4′-methylbiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 18, step (i), 154 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (145 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the mixture was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:1) to afford the sub-titled compound (127 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:22][CH2:23][C:24]1[C:25]([CH2:30]Cl)=[CH:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][Cl:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Reactant: ClCc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a cooled solution of 4-tert-butyl-2-(5-hydroxybenzofuran-2-yl)thiazole (0.8 g) in tetrahydrofuran (16 ml), sodium hydride ((60% in mineral oil) 0.152 g) was added below 10° C. After being stirred for 30 minutes, α,α'-dichloroxylene (2.05 g) was added to the mixture. After subsequently being stirred at ambient temperature for 30 minutes, the mixture was refluxed for 9.5 hours. After the solvent was removed under reduced pressure, the residue was subjected to column chromatography on silica gel (25 g) and eluted with a mixture of n-hexane and toluene (1:1). The fractions containing object compound were combined and concentrated under reduced pressure to give an oil of 4-tert-butyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (0.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.C([O:32][C:33]1[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:35](Cl)=[O:36])(=O)C.[OH-].[Na+].Cl>C(Cl)Cl>[OH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:36]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 20.36 g (91.71 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 200 ml of dry methylene chloride, add 42.33 g (391.92 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 11.87 g (117.57 mmol) of triethylamine and a solution of 15.52 g (78.38 mmol) of acetylsalicyloyl chloride dissolved in 20 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 200 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 21.66 g (81%) of 4-[2-(2-hydroxy-benzoylamino)benzoylamino]butanoic acid as a white solid.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].BrC1C=CC2C3N(CCOC=2C=1)C=C(C1N(C(C)C)N=CN=1)N=3.B1(C2CCN([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])CC=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:71]([O:70][C:68]([N:27]1[CH2:28][CH:29]=[C:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH:11]=[C:10]([C:9]2[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][N:8]=2)[N:19]=4)[CH2:25][CH2:26]1)=[O:69])([CH3:74])([CH3:73])[CH3:72]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 80 °C
Yield: 96 %

Procedure:
Alternatively, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride can be prepared whereby 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (2.1 g, 5.4 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (2.59 g, 8.3 mmol) and potassium carbonate (1.92 g, 13.9 mmol) were mixed with DMF (13 mL) and purged with argon. PdCl2dppf.DCM (310 mg, 0.42 mmol) was added, purging repeated and the mixture heated to 80° C. for 18 h. After cooling the reaction mixture was filtered through Celite®, washing with ethyl acetate, and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 2% methanol in ethyl acetate) to give 4-[2(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.56 g, 96%). LCMS RT=4.79, [M+H]+=477. 1H NMR 400 MHz (CDCl3) δ: 8.45 (1H, d, J=8.46 Hz), 7.89 (1H, s), 7.73 (1H, s), 7.19 (1H, dd, J=8.37, 1.80 Hz), 7.04 (1H, d, J=1.87 Hz), 6.15 (1H, s), 6.04-5.96 (1H, m), 4.51-4.43 (4H, m), 4.09 (2H, d, J=3.68 Hz), 3.64 (2H, t, J=5.64 Hz), 2.52 (2H, s), 1.59 (6H, d, J=6.63 Hz), 1.49 (9H, s)
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:7]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=2)[CH2:8][C:9](=O)[N:10]=1)[CH2:2][CH2:3][CH3:4].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([CH:5]1[NH:10][CH2:9][CH2:8][N:7]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NC(=O)Cn2cc(-c3ccccc3OC)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC1NCCn2cc(-c3ccccc3OC)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
The product from Step 1.e. (6.13 g, 20.5 mmol) (compound vi where R3 is n-butyl, R4 is 2-methoxyphenyl, and R5 and R6 are H) was dissolved in THF (100 ml) and treated with 1M BH3H/TF (82.0 ml, 82.0 mmol) at room temperature for about 2 hours and then refluxed for about 3 hours. The mixture was cooled to room temperature and 4N HCl (50 ml) was added dropwise. The mixture was stirred at room temperature for about 2 hours then made basic by careful portionwise addition of solid K2CO3. Product was extracted with EtOAc (3×50 ml). The EtOAc layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (about 50 ml), concentrated HCl (1.75 ml) was added and the solution was again concentrated under reduced pressure. The product was crystallized from MeOH/Et2O to yield 6.76 g (92%) of the desired product. Mass spec. 286.3 MH+, NMR (300 MHz DMSO-d6, 30° C.) 10.0–11.5 (2H, s broad), 8.05–8.15 (1H, d,d), 8.0–8.1 (1H, s), 7.35–7.5 (1H, t), 7.15–7.3 (1H, d), 7.0–7.15 (1H, t), 4.8–4.95 (1H, m), 4.4–4.65 (2H, m), 3.9–4.0 (3H, s), 3.65–3.8 (1H, m), 3.5–3.65 (1H, m), 2.45–2.65 (1H, m), 2.1–2.35 (1H, m), 1.5–1.7 (2H, m), 1.25–1.5 (2H, m), 0.85–1.0 (3H, t).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:20]([C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[C:24]=1[NH2:25])(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([C:23]1[C:24]([NH:25][C:17]([C:15]2[N:16]=[C:12]([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[S:13][CH:14]=2)=[O:19])=[C:26]([CH3:32])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1csc(C2CCCCC2)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(C3CCCCC3)n2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
POCl3 (1.4 mL, 14.9 mmol) was added drop wise at −35° C. over 5 min, to a stirred solution of 2-cyclohexylthiazole-4-carboxylic acid (117, 1.5 g, 7.1 mmol) and 2-acetyl-5-methoxy-6-methylaniline (1.27 g, 7.1 mmol) in dry pyridine (40 mL). After 1 h, the reaction mixture was successively warmed up to room temperature for 2.5 h, evaporated and neutralized with an aqueous solution of sodium bicarbonate. The precipitate was filtered, washed with water and dried to give 2.6 g (95%) of the title compound 118: m/z=373 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH2:14][CH2:15][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:17][NH2:18]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH2:14][O:13][CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: COCCC(CN)c1cnc(C(F)(F)F)nc1
Product: COCCC(CNC(=O)c1cccc(Cl)c1Cl)c1cnc(C(F)(F)F)nc1

Procedure:
From 2,3-dichlorobenzoic acid and 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butan-1-amine. LCMS (MH+): m/z=422.0, tR (minutes, Method F)=2.73
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([O:34][CH2:35][C@@H:36]1[CH2:38][O:37]1)[CH:28]=[CH:27]2>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:38][C@H:36]([OH:37])[CH2:35][O:34][C:29]5[CH:28]=[CH:27][C:26]6[C:31](=[CH:32][CH:33]=[C:24]([Br:23])[CH:25]=6)[CH:30]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: Brc1ccc2cc(OC[C@@H]3CO3)ccc2c1
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc4cc(Br)ccc4c3)CC1)O2

Procedure:
Compound 217 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-{[(6-bromo-2-naphthyl)oxy]methyl}oxirane and conditions outlined in procedure Y. M.p.=104-105° C.; 400 MHz 1H NMR (CDCl3) δ: 7.94-7.85 (m, 3H), 7.70-7.56 (m, 3H), 7.54-7.47 (m, 1H), 7.23-7.17 (m, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.26-4.18 (m, 1H), 4.17-4.08 (m, 2H), 3.04-2.94 (m, 1H), 2.96 (s, 2H), 2.90-2.78 (m, 2H), 2.76-2.66 (m, 2H), 2.56 (t, J=11.4 Hz, 1H), 2.24-2.12 (m, 2H), 2.00-1.85 (m, 2H); LCMS: 660 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:13]Br>C(OCC)C>[Br:13][CH:8]1[C:9](=[O:12])[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1
Reactant: BrBr
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCOCC
Product: CCOC(=O)C1CCC(=O)C(Br)C1

Procedure:
11.65 g (68.45 mmol) ethyl-4-oxo-cyclohexanecarboxylate are dissolved in 200 ml diethyl ether and cooled to −13° C., at this temperature 3.5 ml (68.45 mmol) bromine are slowly added dropwise. The reaction mixture is extracted with water, with 10% sodium hydrogen carbonate solution and then again with water, then it is dried on magnesium sulphate and the solv. is eliminated completely i. V.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=2)[CH2:11][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2cccc(Br)c2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2cccc(Br)c2)CC1)c1ccccc1
Yield: 53.4 %

Procedure:
0.108 g (0.0004 mol) of 1-(3-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.08 g (53.5%) of 1-(3-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.