Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[C@H:12]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH2:13].C(OC(N[C@H](C(O)=O)CC1CCCCC1)=O)(C)(C)C.[C:42]([O:46][C:47]([NH:49][C@@H:50]([C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][CH3:54])=[O:48])([CH3:45])([CH3:44])[CH3:43]>>[C:42]([O:46][C:47]([NH:49][C@@H:50]([C:55]([NH:57][CH2:58][C:59]([NH:13][C@H:12]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:22])=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][CH3:54])=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: COC(=O)CCCCCNC(=O)[C@@H](N)CC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CC1CCCCC1)C(=O)NCCCCCC(=O)OC

Procedure:
After preparing N-(6-methoxy-6-oxohexyl)-3-cyclohexyl-L-alaninamide monohydrochloride from the title product of Example 36 by the methods of Examples 1 and 3, the title compound was prepared by coupling this material with the title product of Example 99 using the general mixed anhydride procedure of Example 1. Structure assignment of the product isolated by chromotography was supported by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9])=[C:4]([CH:21]=O)[CH:3]=1.CO.C[O-].[Na+].Cl>COC(=O)OC>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:11][CH2:12][CH2:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:21][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCN(CC(C)C)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCC1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
To a solution of methyl 5-(4-bromo-2-formyl-N-isobutylanilino)pentanoate (10.0 g) in dimethylcarbonate (250 ml) was added a methanol solution of 28% sodium methoxide (6.8 g) and the mixture was heated at 50° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to 0° C., neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain yellow oil of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (8.6 g). A suspension of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (5.0 g), 4-(2-butoxyethoxy)phenylboric acid (4.8 g) and potassium carbonate (5.6 g) in toluene (60 ml), ethanol (6.0 ml) and water (6.0 ml) was stirred for 30 minutes under an argon atmosphere. After addition of tetrakis(triphenyl)phosphine palladium (0.9 g), the mixture was heated at 105° C. for 3 hours under an argon atmosphere. The mixture was cooled, followed by addition of water, and extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain yellow oil of methyl 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (5.43 g). The oil was redissolved in THF (50 ml) and methanol (50 ml). To the solution was added aqueous 2N sodium hydroxide solution (23 ml), and the resulting mixture was heated at 90° C. for 3.5 days. The mixture was cooled to 0° C., followed by addition of water, and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diisopropylether-ethyl acetate to obtain yellow crystals of 8-[4-(2-butoxyethoxy)phenyl-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (1.04 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccc(Br)cc1
Reactant: OCCCCCCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCCCCO)c1ccc(Br)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
36.8 g (184.1 mmols) of N-ethyl-4-bromoaniline, 48.1 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 28.9 ml (1.2 equivalent) of 6-bromohexanol were mixed, and the mixture obtained was heated at 110° C. for 14 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was heated under reduced pressure (160° C./0.3 torr), and the components distilled out were removed to obtain 55.6 g of crude N-ethyl-N-(6-hydroxyhexyl)-4-bromoaniline (yield: 100%; a dark-brown oily liquid).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1C=[CH:29][CH:28]=[C:27]1P(C1OC=CC=1)C1OC=CC=1.CN1C(=O)CCC1.C([Sn](CCCC)(CCCC)CCCC)C=C>CCOC(C)=O>[CH2:29]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:28]=[CH2:27]
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: COC(=O)c1cc(Br)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 64 h
Yield: 774.4 %

Procedure:
Methyl 3-bromo-5-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}benzoate (Intermediate 104, 300 mg, 0.73 mmol), tris(dibenzylidineacetone)dipalladium (0) (26 mg, 0.03 mmol), trifurylphosphine (14 mg, 0.06 mmol) were weighed into a flask and placed under argon. NMP (3 ml) was added, followed by the dropwise addition of allyltributyl tin (0.25 ml, 0.80 mmol). The mixture was stirred at 100° C. After 64 h, the mixture was diluted with EtOAc and washed sequentially with water followed by brine. The organic phase was dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography on silica gel using 25% EtOAc/hexanes to give 174 mg of the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:12](I)=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:29])[C:27]#[CH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:28]#[C:27][C:26]([OH:29])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1ccccc1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)c(C#CC(O)(c2ccccc2)c2ccccc2)n1Cc1ccccc1
Yield: 83.9 %

Procedure:
A solution of 5 (0.47 g, 1.3 mmol), 1,1-diphenylprop-2-yn-1-ol (0.66 g, 3.2 mmol), CuI (0.05 g, 0.3 mmol), Pd(PPh3)2Cl2 (0.18 g, 0.3 mmol), PPh3 (0.07 g, 0.3 mmol), and Et3N (4 mL) in anhydrous DMF (4 mL) was stirred for 16 hours at 70° C. under N2 atmosphere. The reaction mixture was partitioned between water and EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 6 as a pale yellow solid (0.49 g, 87%). 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.50-7.52 (m, 4H), 7.36 (s, 1H), 7.24-7.30 (m, 8H), 7.04 (m, 2H), 5.69 (s, 2H), 3.80 (s, 3H), and 3.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 185.16, 160.72, 144.07, 136.84, 128.91, 128.72, 128.33, 127.91, 127.79, 127.05, 126.23, 124.96, 116.97, 103.35, 75.37, 75.27, 52.15, and 50.38.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl)#[N:2].[CH3:25][C:26]([NH2:30])([C:28]#[CH:29])[CH3:27]>C(O)C>[C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:30][C:26]([CH3:27])([C:28]#[CH:29])[CH3:25])#[N:2]
Reactant: N#Cc1cc(NC(=O)c2ccc(F)cc2)ccc1OCC(O)CCl
Reactant: C#CC(C)(C)N
Solvent: CCO
Product: C#CC(C)(C)NCC(O)COc1ccc(NC(=O)c2ccc(F)cc2)cc1C#N

Procedure:
9 gm of 1-[2-cyano-4-(4-fluorobenzoyl-amino)phenoxy]-3-chloro-propan-2-ol were dissolved in 80 ml of ethanol, and 12.5 ml of 2-methyl-but-3-in-2-amine were added to the solution. After the mixture had been refluxed for 4 hours, the solvent was distilled off in vacuo, the residue was acidified with dilute HCl and washed with ether. The aqueous phase was made alkaline with NH4OH, the base precipitated thereby was extracted twice with ethyl acetate, and the organic phase was washed with H2O and dried over MgSO4. After the ethyl acetate had been distilled off, the crystalline residue was recrystallized twice from acetonitrile. 2.8 gm of colorless crystals of the base were isolated.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[Si](C)(C)C)C.FC(S(O[Si](C)(C)C)(=O)=O)(F)F.C[Si](C)(C)[CH2:36][C:37](=[CH2:45])[CH2:38][CH2:39][O:40][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH2:36]=[C:37]1[CH2:45][C:11]2([CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[O:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: C=C(CCO[Si](C)(C)C)C[Si](C)(C)C
Agent: CCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: C=C1CCOC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 1000 %

Procedure:
To a solution of 1-Boc-piperidone (2.39 g, 12 mmol) and ethoxytrimethylsilane (3.75 mL, 24 mmol) in 80 mL of CCl4 under stirring at 0° C. was added trimethylsilyl trifluoromethylsulfonate (217 μL, 1.2 mmol) and trimethyl-(2-methylene-4-trimethylsilyloxybutyl)silane (E. I. Marko et al., Journal of Organic Chemistry 1992, 57, 2211-2213) dissolved in in 23 mL of CCl4. After stirring at 0-5° C. for 6 h and overnight resting at 0° C., the reaction mixture was washed with water, dried on Na2SO4, filtered and the solvent was evaporated to dryness in vacuo. The residual 6.5 g of colourless oil was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc gradient from 99:1 to 85:15) to give 3.2 g of the title compound as colourless oil. Yield: 1000%
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:29][C:30]([O:32][CH2:33][C@@H:34]2[CH2:39][O:38][CH2:37][CH2:36][N:35]2C(OC(C)(C)C)=O)=[O:31])=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:17]=[CH:16]3)=[N:9][CH:8]=[N:7]2)[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([NH:29][C:30](=[O:31])[O:32][CH2:33][C@@H:34]2[CH2:39][O:38][CH2:37][CH2:36][NH:35]2)=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[N:17]=[CH:16]3)=[N:9][CH:8]=[N:7]2)[CH3:2]
Reactant: CCc1c(NC(=O)OC[C@@H]2COCCN2C(=O)OC(C)(C)C)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(NC(=O)OC[C@@H]2COCCN2)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Reaction time: 18 h
Yield: 97.1 %

Procedure:
3-[[[[[5-ethyl-4-[[1-(phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-6-yl]amino]carbonyl]oxy]methyl]-4-morpholinecarboxylic acid, (3S)-1,1-dimethylethyl ester (14.0 g, 22.3 mmol) was dissolved in methylene chloride (250 mL) and treated with trifluoroacetic acid (40 mL). The resulting solution was stirred for 18 h, then neutralized by the addition of saturated aqueous sodium carbonate. The organic phase was separated and dried over magnesium sulfate. Filtration and concentration of the filtrate gave 11.4 g of [5-ethyl-4-[[(1-phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester as a yellow oil. This material was re-dissolved in methylene chloride (100 mL) and treated with 1M hydrochloric acid in ether (21.7 mL, 21.7 mmol). The solution was stirred for 30 min then concentrated under reduced pressure. Drying of the residue under high vacuum (0.5 mmHg) overnight afforded 11.6 g (92%) of [5-ethyl-4-[[(1-phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester hydrochloride as an off-white solid.
Reaction SMILES: BrCCBr.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH:13]([CH3:15])[CH3:14].[C:16]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17].Cl>CCOCC>[C:16]([N:21]1[CH2:22][CH2:23][C:24]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH:13]([CH3:15])[CH3:14])([OH:27])[CH2:25][CH2:26]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(C)Oc1ccccc1Br
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: BrCCBr
Solvent: CCOCC
Product: CCOC(=O)N1CCC(O)(c2ccccc2OC(C)C)CC1
Temperature: 22 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a suspended solution of Mg chips (10.07 g, 0.414 mol) in anhydrous ether (150 mL) at 22° C. under argon was added ca. 0.15 mL of 1,2-dibromoethane. Then 43.7 g (0.200 mol) of XIV in 200 mL of ether was added dropwise. After 50% of the aryl halide was added, the reaction began to reflux vigorously. The flask was cooled in an ice bath. After the refluxing had subsided somewhat, the ice bath was removed and the remaining aryl halide was added over a 1.5 h period. The resultant Grignard reagent was cooled in a dry ice/ether bath for 2 h and then treated with 34.0 mL (0.221 mol) of 98% 1-carbethoxy-4-piperidone. Upon complete addition of ketone, the reaction mixture was allowed to warm to 22° C. and stirred for 2 h. The reaction was then quenched with cold aqueous ammonium chloride which resulted in an emulsion. Addition of 1M aqueous HCl solution separated the two layers. The aqueous phase was extracted with additional ether and the combined organic solution was washed with 10% aqueous sodium bisulfite, 1.0M HCl, saturated NaHCO3, and dried (K2CO3). Filtration concentration yielded 56.36 g of XV as a yellow viscous oil which was carried on without further purification The structure of this oil was supported by 1H NMR.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=[O:9])=[C:6]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)[CH:5]=1.Cl.S(Cl)([Cl:23])=O>O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[C:8](=[O:9])[N:16]([CH3:19])[CH2:15][CH:14]([CH2:18][CH2:17][Cl:23])[O:13][C:6]=2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(Oc2cc(Cl)ccc2C(N)=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=O
Yield: 58.9 %

Procedure:
To a solution of 10.4 g (0.26 mole) of sodium hydroxide in 150 ml of water was added 32 g (0.13 mole) of 4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was adjusted to pH 6 with concentrated hydrochloric acid and filtered and the filtrate concentrated. The residue was boiled with 100 ml of isopropyl alcohol and the mixture filtered. The filtrate was concentrated and heated at reflux with 98 g (0.83 mole) of thionyl chloride for 1 hr. The excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 70 ml of chloroform and the solvent evaporated under reduced pressure. The residue was redissolved in 75 ml of chloroform and 40 ml of triethylamine was added gradually. The mixture was heated at reflux for 1 hr. The solvent was evaporated under reduced pressure to give a dark-brown solid. The solid was dissolved in ethyl acetate and the resulting solution washed twice with 200 ml of water and twice with 250 ml of 20% sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 21 g (59%) of dark-brown solid. The solid was crystallized from isopropyl alcohol to give the title compound, m.p. 85°-87° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8]([NH:10][C:11](=[N:14][CH3:15])SC)#[N:9]>N1C=CC=CC=1>[C:8]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])=[N:14][CH3:15])#[N:9]
Reactant: CN=C(NC#N)SC
Reactant: NCCCCCO
Solvent: c1ccncc1
Product: CN=C(NC#N)NCCCCCO

Procedure:
A mixture of 5-aminopentan-1-ol (20 g.) and N-cyano-N',S-dimethylisothiourea (L25 g.) in pyridine (130 ml) was heated on a steam-bath for 14 hours, evaporated to dryness, and the residue recrystallised from chloroform/methanol to give N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (15.7 g). A recrystallised sample had m.p. 116°-119°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[OH:11].O[CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.CN1CCCC1=O>[Br:18][C:14]1[CH:13]=[C:12]([CH:10]([O:11][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1
Product: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
A mixture of 1H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9 g), 4-hydroxy-1-methylpiperidine (4.86 g) and para-toluenesulfonic acid (24 g) in chlorobenzene (60 mL) and N-methylpyrrolidone (6 mL) is heated under reflux for 120 h in a Dean Stark apparatus. Solvent is removed by evaporation. To the residue is added water which is made alcaline by addition of sodium hydroxyde solution, then extracted with ethyl acetate. The pooled organic extracts are washed with water, treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated in diethyl ether to give 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:28]([Zn+])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C:16]1[CH:15]=[C:14]([C:20]([F:22])([F:21])[F:23])[C:13]2[N:12]([CH3:24])[C@H:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Product: CN1c2c(cc(Cc3ccccc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a colorless oil from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45) and benzyl zinc bromide. MS (ES+): 347 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[OH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C(=O)O)cc1O
Reaction time: 4 h

Procedure:
A solution of 9.75 g of 4-amino-3-hydroxybenzoic acid and 9.75 ml of triethylamine in 90 ml of dimethylformamide is heated to 80° C. 20 g of the N-hydroxysuccinimide ester of N-tert.-butoxycarbonylglycine are added and the reaction mixture is kept at 80° C for 4 hours.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[F:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Li]>C1COCC1>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]2[CH:32]=[CH:33][CH:34]=[C:21]([F:20])[CH:22]=2)[CH2:7]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: [Li]c1ccccc1Oc1cccc(F)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (0.65 g, 2.37 mmol) in THF (4 mL) at −20° C. was added dropwise the solution of 2-(3-fluorophenoxy)phenyllithium prepared in Step 2 above. After the addition was complete, the resulting solution was allowed to warm to rt slowly, and left at rt for 1 h. The reaction was quenched with 1N HCl (˜6 mL), and extracted with Et2O (4×10 mL). The combined organic layers were washed with sat'd aq NaHCO3 and brine, and dried over Na2SO4. Removal of the solvent left the crude ketone (1.49 g, quantitative), which was used for next step without further purification.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:7]1[N:11]2[CH2:12][C@H:13]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[N:9][CH:8]=1)(=[O:6])[CH3:5]>O1CCCC1>[F:32][C:26]1[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=1[C@H:13]1[CH2:12][N:11]2[C:7]([C:4]([OH:6])([CH3:1])[CH3:5])=[CH:8][N:9]=[C:10]2[C@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)O)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Methylmagnesium bromide (3.0 M in ether; 90 μL, 0.27 mmol) was added to a solution of tert-butyl (6S,9R)-3-acetyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (22 mg, 0.05 mmol) in tetrahydrofuran (1 mL) at 0° C., and the reaction mixture was allowed to warm to ambient temperature. After 30 min, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (15 mg). MS 422.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>C(O)C>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH:17][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4]
Reactant: Cc1cccc(N)c1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Solvent: CCO
Product: Cc1cccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c1
Yield: 63.3 %

Procedure:
2-Chloro-N-(2-chloro-4-sulphamoylphenyl)-acetamide (28.3 g) and m-toluidine (31.8 g) were heated 7 hours at 175°C (oil bath) and worked up as in Example 15 to yield 22.4 g product, m.p. 185°-189°C (ethanol).