Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]([F:9])([F:8])[C:5](Cl)=[O:6])[CH3:3].[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:5](=[O:6])[C:4]([F:9])([F:8])[N:2]([CH3:3])[CH3:1])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])([F:9])[F:8])[CH:18]=1
Reactant: CN(C)C(F)(F)C(=O)Cl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(F)(F)N(C)C)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(F)(F)N(C)C)c2)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of dimethylamino-α,α-difluoroacetyl chloride (10 mmol) in tetrahydrofuran (40 mL) is added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzyisulfone (10 mmol) in tetrahydrofuran. The solution is stirred overnight and the reaction progress is monitored by TLC. The solvent is removed and the residue is taken up in dichloromethane and washed with water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give the desired amide product.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:58])[CH2:31][C:32]1[C:33](=[O:57])[N:34]([CH2:55][CH3:56])[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[CH:36]=2>>[CH3:28][O:29][C:30](=[O:58])[CH2:31][C:32]1[C:33](=[O:57])[N:34]([CH2:55][CH3:56])[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:36]=2
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc21
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCCN)cc21

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester is replaced with [7-(4-tert-butoxycarbonylaminobutoxy)-1-ethyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>C(O)C.CCOCC>[OH:4][CH:2]([CH3:3])[CH2:1][NH:7][CH2:6][CH2:5][NH:8][CH2:1][CH:2]([OH:4])[CH3:3]
Reactant: NCCN
Reactant: CC1CO1
Solvent: CCO
Solvent: CCOCC
Product: CC(O)CNCCNCC(C)O
Temperature: 20 °C
Yield: 28.5 %

Procedure:
(IV-a): Propylene oxide (142.4 g, 2.4 mol) was added dropwise over a period of 11 hours to a solution of ethylenediamine (71.9 g, 1.2 mol) in 25 mL absolute ethanol and 10 mL of nitrogen purged distilled water at 90° C. After addition, the reaction was maintained for an additional hour, then cooled to room temperature (about 20° C.). The reaction solution was concentrated by rotary evaporation to give a milky white suspension which, upon dissolution in anhydrous ether, produced a white precipitate of N,N'-bis(2-hydroxypropyl)ethylenediamine in 28.5 percent yield. The product was crystallized from methanol/ethanol [m.p. 132° C., IR(Nujol):3250(OH); NMR(MeOHd4): δ3.8(m, 2H); 2.6(t, 8H); 1.2(d, 6H)].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)=O.C(N(CC)CC)C.[NH:21]1[CH2:29][CH2:28][CH2:27][C@H:22]1[C:23](OC)=[O:24]>O.CN(C)C=O>[N:4]1[C:3]2[C:8](=[O:10])[N:21]3[CH2:29][CH2:28][CH2:27][CH:22]3[C:23](=[O:24])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccnc2C(=O)N2CCCC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
36 g (0.26 mol) of 3-aminopyridine-2-carboxylic acid, 46.6 g (0.29 mol) of N,N'-carbonyldiimidazole and 200 ml of dimethylformamide are stirred at room temperature until the carbon dioxide evolution has finished, then the mixture is treated with 26.3 g (0.26 mol) of triethylamine and 43.1 g (0.26 mol) of methyl L-prolinate and stirred at room temperature for a further 1.5 hours. Subsequently, the solution is poured into water, extracted four times with chloroform, the combined chloroform extracts are dried over magnesium sulphate and then evaporated in vacuo. The oily residue is treated with 500 ml of glacial acetic acid, heated to boiling under reflux for 1 hour and then evaporated to dryness. By recrystallization from ethanol there is obtained 6a,7,8,9-tetrahydro-6H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11(5H)-dione of melting point 249°-250°.
Reaction SMILES: [CH2:1](O)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:10][C:11]1[N:12]=[N:13][C:14]([Cl:18])=[CH:15][C:16]=1Br.O.[C:20]1([CH3:26])[CH:25]=C[CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:14]1[N:13]=[N:12][C:11]([NH2:10])=[C:16]([C:23]2[CH:22]=[CH:21][C:20]([CH3:26])=[CH:25][C:1]=2[CH3:2])[CH:15]=1
Reactant: CCO
Reactant: Nc1nnc(Cl)cc1Br
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cc(Cl)nnc2N)c(C)c1
Temperature: 100 °C
Yield: 82 %

Procedure:
Ethanol (8 mL), a 2M aqueous sodium carbonate solution (4 mL), 2,4-dimethylbenzeneboric acid (650 mg, 4.3 mmol) and tetrakistriphenylphosphine palladium complex (456 mg, 0.39 mmol) were added to a solution of 3-amino-4-bromo-6-chloropyridazine (822 mg, 3.9 mmol) in toluene (40 mL), and the mixture was heated at 100° C. for 2 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (759 mg, 82%) as a pale brown powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][NH:9][C@H:8]([C:16](OC)=[O:17])[CH2:7][C:6]2=1.[BH4-].[Na+].C(O)C>O>[OH:17][CH2:16][C@@H:8]1[CH2:7][C:6]2[C:5]3[C:13](=[CH:14][CH:15]=[C:3]([F:2])[CH:4]=3)[NH:12][C:11]=2[CH2:10][NH:9]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.1 %

Procedure:
A mixture of 0.577 g of methyl (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride, 0.32 g of sodium borohydride, 20 ml of ethanol and 10 ml of water is stirred at room temperature for 21 hours, and then further refluxed for 3 hours. After the reaction, insoluble materials are removed by filtration and washed with hot ethanol. The filtrate and washings are combined and concentrated. Water is added to the residue, and crystalline precipitates are collected by filtration and dried, whereby 286 mg of (3S)-3-hydroxymethyl-6-fluoro-1,2,3,4-tetrahydro-β-carboline are obtained as colorless needles. Yield: 65%
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:33])[O:22][C@@H:23]1[CH2:28][C@H:27]([CH3:29])[CH2:26][CH2:25][C@H:24]1[CH:30]([CH3:32])[CH3:31].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:21]([O:22][C@@H:23]2[CH2:28][C@H:27]([CH3:29])[CH2:26][CH2:25][C@H:24]2[CH:30]([CH3:32])[CH3:31])=[O:33])=[CH:7][CH:8]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)Cl
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.361 mmol, example 9 (step 3) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl carbonochloridate (76.5 μL, 0.361 mmol) in DCM (1 mL) was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as an off-white oil. MS (ESI, positive ion) m/z: 460 (M+H).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+].Cl>CO>[OH:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCOc1ccc(COc2cccc3c2CC(CC(=O)OCC)C3O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCOc1ccc(COc2cccc3c2CC(CC(=O)O)C3O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
In 10 ml of methanol was dissolved 380 mg of ethyl 1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetate obtained in Example 100 and, 2.5 ml of a 5% sodium hydroxide solution was added thereto followed by stirring at room temperature for 8 hours. The system was rendered acidic with 20% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed subsequently with water and then a saturated saline aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate-hexane to obtain 230 mg of 1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>COCCO.O>[N:29]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: [N-]=[N+]=NCCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
9.83 g (22 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene are dissolved in 100 ml of 2-methoxyethanol, a solution of 2.86 g (44 mmoles) of sodium azide in 10 ml of water is added, and the mixture is boiled for one hour. The reaction mixture is processed as described in Example 5, and the product is recrystallized twice from ethanol. 7.40 g (82%) of the aimed compound are obtained; m.p.: 73°-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:31])[C:11](=[O:30])[CH:12]=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])=[O:16])=[C:4]([F:32])[CH:3]=1.Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:31])[C:11](=[O:30])[CH:12]=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[O:16])=[C:4]([F:32])[CH:3]=1
Reactant: C[C@@H](CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](O)CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
To a solution of (S)-2-(4-bromo-2-fluorophenylamino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.074 g, 0.14 mmol) in THF (1.50 mL) was added 1 M aqueous HCl (1.4 ml, 1.4 mmol). The reaction was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 (3×) and saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude white solid. Purification of the crude product by trituration with Et2O and isolation of the resulting solid provided (S)-2-(4-bromo-2-fluorophenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.030 g; 52% over two steps) as a white solid. MS ESI (+) m/z 414, 416 (M+) Br pattern detected; 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.42 (dd, 1H), 7.28 (m, 1H), 6.81 (t, 1H), 6.28 (d, 1H), 3.88 (m, 1H), 3.70 (dd, 1H), 3.58 (dd, 1H), 3.38 (s, 3H), 1.11 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[CH2:33][C:34]#[N:35])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[CH2:33][C:34]2[N:39]=[N:40][NH:41][N:35]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)CC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)Cc1nn[nH]n1

Procedure:
To a solution of N-(2-tert-butyl-1-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (27 mg, 0.054 mmol) in anhydrous DMF (1.2 mL) were successively added NH4Cl (35 mg, 0.65 mmol) and NaN3 (43 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 h at 110° C. in the microwave, at which stage 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to provide N-(2-tert-butyl-1-(2-hydroxy-3-(2H-tetrazol-5-yl)propyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 539.0.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:24][CH2:23]1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][N:19]([C:2](=[O:1])[CH3:4])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:26][CH2:27]1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (114 mg, 0.211 mmol) in DCM (2.11 mL) at 0° C. was treated with pyridine (0.051 mL, 0.63 mmol) and acetic anhydride (0.040 mL, 0.42 mmol). The reaction mixture was stirred for 30 min at 0° C. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered, and purified by HPLC Method B, using a 40% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (39.7 mg, 32.3%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.96 (m, 2H), 2.12 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.73 (t, J=5.9 Hz, 0.8H), 2.83 (t, J=5.9 Hz, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.80 (m, 4H), 4.45 (dt, J=7.0, 3.6 Hz, 1H), 4.57 (app d, 2H), 6.05 (m, 1H), 6.86 (m, 1H), 6.96 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.15 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 468.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:13][CH2:14][CH2:15][N:16]([C:18](=[O:65])[CH2:19][O:20][C@@H:21]2[C:29]3([CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C@:37]4([C:58]5[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=5)[O:41][CH2:40][N:39]([C:42](=[O:57])[C:43]5[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=5)[CH2:38]4)[CH2:31][CH2:30]3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[CH3:17])[CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:66]1([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[NH:72][C:73](=[O:93])[O:74][CH:75]1[CH2:80][CH2:79][N:78]([CH2:81][CH2:82][N:83]([CH3:92])[C:84](=[O:91])[CH2:85][CH2:86][CH2:87][CH2:88][CH:89]=O)[CH2:77][CH2:76]1>>[C:66]1([C:94]2[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=2)[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[NH:72][C:73](=[O:93])[O:74][CH:75]1[CH2:80][CH2:79][N:78]([CH2:81][CH2:82][N:83]([C:84](=[O:91])[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:13][CH2:14][CH2:15][N:16]([C:18](=[O:65])[CH2:19][O:20][C@@H:21]3[C:29]4([CH2:30][CH2:31][N:32]([CH2:35][CH2:36][C@:37]5([C:58]6[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=6)[O:41][CH2:40][N:39]([C:42](=[O:57])[C:43]6[CH:44]=[C:45]([C:53]([F:54])([F:56])[F:55])[CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=6)[CH2:38]5)[CH2:33][CH2:34]4)[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[CH3:17])[CH3:12])=[O:10])=[CH:4][CH:3]=2)[CH3:92])[CH2:77][CH2:76]1
Reactant: CN(CCCN(C)C(=O)Cc1ccc(N)cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(CC(=O)N(C)CCCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Yield: 31.9 %

Procedure:
The compound (194 mg, 0.219 mmol) obtained in Example 57b and the compound (102 mg, 0.219 mmol) obtained in Example 4g were used to give the title compound (95 mg; yield, 32%) as a white solid according to the method described in Example 41b.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→50% ethyl acetate in hexanes) affording the desired product (75) as a solid. ESMS: MH+ 590.6
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.25 mmol) in dichloromethane (0.6 ml) was added methanesulfonyl chloride (0.20 ml, 0.25 mmol) at room temperature. Stirring for 20 h was followed by partitioning between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5 ml-portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (46 mg, 77%) as white solid. MS m/e: 476 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:9]1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: O=C(O)C(O)c1cccc(Br)c1
Reactant: Nc1ccccc1N
Product: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (20 g) and ortho-phenylenediamine (9.36 g) in 5N aqueous hydrochloric solution (100 mL) is heated under reflux for 4 h and cooled back to room temperature. The precipitate is separated by filtration, rinsed with acetonitrile and dried under vacuum with phosphorus pentoxide et give 1H-benzimidazol-2-yl(3-bromophenyl)methanol as a white crystalline solid used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]#[N:26])[C:9]=1[S:27][C:28]([F:31])([F:30])[F:29].[CH2:32]=[O:33].O.[CH:35](O)([CH3:37])[CH3:36]>C(OCC)(=O)C>[Cl:24][C:14]1[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:8]([NH:7][CH2:32][O:33][CH2:36][CH2:35][CH3:37])=[C:9]([S:27][C:28]([F:31])([F:30])[F:29])[C:10]([C:25]#[N:26])=[N:11]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: C=O
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOCNc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
Potassium carbonate (6.6 g, 47.5 mmol) was added to a solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)3-cyano-4-trifluoromethylthiopyrazole (5.0 g, 11.87 mmol) in iso-propanol, and stirred for five minutes before paraformaldehyde (0.75 g) was added. The resulting mixture was stirred at 20C for three days, then diluted with isopropanol (20 ml) and added to water and ethyl acetate. The organic layer was dried (sodium sulfate) and evaporated to give 1-(2,6-dichloro-4-trifluoromethylphenyl-3-cyano-5-1-propyloxymethylamino-4-trifluoromethylthiopyrazole (Compound number 14, 5.3 g).