Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].O.Cl.C(OC(C)C)(C)C.C[O:13][C:14]([C:16]1[CH:38]=[CH:37][C:19]2[NH:20][C:21]([C:23]3[C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28](=[O:36])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15]>CO>[C:14]([C:16]1[CH:38]=[CH:37][C:19]2[NH:20][C:21]([C:23]3[C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28](=[O:36])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)([OH:15])=[O:13]
Reactant: COC(=O)c1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc2c1
Temperature: 10 °C

Procedure:
In a 50 ml round-bottomed flask under argon, dissolve 1 g of [4-(5-methoxycarbonyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained as in stage 2 of Example 205, in 15 ml of methanol, and then add 5.9 ml of a 1.2M aqueous solution of lithium hydroxide and reflux for 24 hours. Bring to dryness under reduced pressure, add water, cool to 10° C., and then acidify to pH 4-5 with a 1M aqueous solution of hydrochloric acid. The crude product is filtered, washed with water and then dried. The solid obtained is made into a paste with diisopropyl ether, filtered and rinsed. In this way, we obtain 919 mg of 4-(5-carboxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of a yellow powder, which is used as it is in the following stage with the following characteristics:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]12[CH2:15]C3C[CH:12]([CH2:14][CH:8](C3)[C:7]1=O)[CH2:13]2.CC(C)=O.[PH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.CCCCCC>[CH2:4]=[C:3]1[CH:12]2[CH2:13][CH:6]3[CH2:7][CH:8]([CH2:1][CH:2]1[CH2:15]3)[CH2:14]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [PH4+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (14 g; 39.17 mmol) in 100 ml of ether cooled to 0° C. under argon was added dropwise n-butyllithium (2.51 g; 39.17 mmol) in hexane (15.7 mml). An ice-bath was removed and the mixture was allowed to react at room temperature for 2 hours. After cooling the reaction mixture to 0° C., a suspension of 5.35 g (35.61 mmol) of 2-adamantanone in ether (25 ml) was added and the mixture was stirred at room temperature for 2 hours. Acetone was added to decompose the phosphonium salt, the reaction mixture was filtered and the residue was washed with ether. The combined organic layer was distilled in vacuo and the residue was redissolved in ether and cooled to 0° C. to yield 3.5 g (66.4%) of 2-methylene-adamantane (see J. Org. Chem. 1985, 54, 1375) (Formula III: R2 =R3 =H; R4 and R5 together are adamantanyl), as a low melting solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:21][O:20][CH:17]([O:18][CH3:19])[CH2:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: COC(CNc1ccc(OCc2ccccc2)cc1)OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(CNc1ccc(O)cc1)OC
Reaction time: 3 h

Procedure:
Palladium(II) hydroxide (20% on carbon, 0.5 g) was added to a solution of (4-benzyloxyphenyl)-(2,2-dimethoxyethyl)amine (3.5 g) in ethanol (50 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 3 hours. The catalyst was filtered off and the filtrate was concentrated. The crude product was reacted further without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: c1ccncc1
Product: CN(C)CCCNc1ccccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 13 h
Yield: 99.9 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (3.24 g) was added to a solution containing 2-chloronitrobenzene (2.00 g) in pyridine (2.56 ml). After being stirred for 13 hours at 120-130° C., the reaction mixture was concentrated. The residue, with toluene added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.83 g) as orange oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2/[C:15](=[N:17]/[NH2:18])/[NH:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([O-])([O-])OCC>>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][N:18]=[CH:25][N:14]3[C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCn1c(=O)[nH]/c(=N\N)c2c1ncn2Cc1ccccc1
Reactant: CCOC([O-])[O-]
Product: CCCCCn1c(=O)n2cnnc2c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
(6Z)-7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 6-hydrazone (0.50 g, 1.5 mmol) was mixed with ethyl orthoformate (5 mL, 30 mmol). After being stirred at 60° C. for 1 h, the reaction mixture was concentrated in vacuum. The residue was treated with ether to yield the desired product as a white solid (0.25 g, 48.5%). LCMS calculated for C18H21N6O (M+H): 337.2. found: 337.1.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[N:55]=[C:54]([CH3:56])[C:53]([NH:57]C)=[CH:52][CH:51]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:57][C:53]4[C:54]([CH3:56])=[N:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:1])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CNc1ccc(OC)nc1C
Reactant: Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccc(OC)nc2C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with (6-methoxy-2-methyl-pyridin-3-yl)-methyl-amine (Asychem) to give the title compound. HR-MS (ES, m/z) calculated for C42H50Cl2N7O4 [(M+H)+] 786.3296, observed 786.3289.
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:15]1[CH:16]=[N:17][C:18]([F:29])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:20]=1)[CH2:11]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl.O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[C:15]([CH:10]3[CH2:11][CH:12]4[NH:8][CH:9]3[CH2:14][CH2:13]4)[CH:16]=[N:17][C:18]=2[F:29])=[CH:26][CH:25]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(c1cnc(F)c(-c3ccc(C#N)cc3)c1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1ccc(-c2cc(C3CC4CCC3N4)cnc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
Compound 16 (275 mg, 0.7 mmol) was dissolved in anhydrous CH2Cl2 (3 mL) and cooled in an ice-water bath. TFA (3 mL) was added in 30 min. After stirring at room temperature for 1 hr, the mixture was poured into a cold solution of NH4OH in water (1:1). The mixture was then extracted with CH2Cl2. The organic phase was washed with brine then dried over anhydrous Na2SO4 and evaporated to dryness. After flash chromatography on a silica gel column with CH2Cl2-MeOH, the free base was isolated as a clear oil (200 mg, 93%). 1H NMR (CDCl3): δ (ppm) 1.5-1.7 (m, 5H), 1.8-1.9 (m, 1H), 2.84 (dd, 1H, J=5.1, 9.0 Hz), 3.61 (br s, 1H), 3.82 (m, 1H), 7.6-7.8 (m, 4H), 8.09 (dd, 1H, J=2.4, 6.6 Hz), 8.14 (m, 1H). 13C NMR (CDCl3): δ (ppm) 29.6, 30.7, 31.9, 40.9, 44.6, 56.8, 63.2, 112.3, 118.9, 121.5 (d, J=112.2 Hz), 129.9 (d, J=13.2 Hz), 132.7, 139.3, 140.1, 141.6, 146.5 (d, J=57.9 Hz), 157.5, 160.7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:46])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:46])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white amorphous substance (348 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:13]3([OH:19])[CH2:18]COCC3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[N:3]=1.[O:27]1CC(=O)[CH2:28]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:13]3([OH:19])[CH2:18][O:27][CH2:28]3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[N:3]=1
Reactant: O=C1COC1
Reactant: CCn1c(C2(O)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Product: CCn1c(C2(O)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound (i-j) was prepared in an analogous fashion to (S)-4-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using 3-oxetanone as the starting material. 1H NMR (CDCl3, 500 MHz) δ ppm 5.70 to 4.70 (broad s, 2H), 5.20 (dd, J=12.1 Hz, 7.2 Hz, 2H), 4.95 (d, J=7.2 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 4.02 (dd, J=11.3, 3.2 Hz, 1H), 3.78 (dt, J=11.7 Hz, 7.2 Hz, 2H), 3.61 (td, J=11.9 Hz, 2.7 Hz, 1H), 3.47 (s, 2H), 1.46 (t, J=7.2 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=354/356 [M+H]+, RT=1.71 min.
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[C:14]2[C:8]([CH:9]=[C:10]([O:16][CH3:17])[O:11][C:12]2=[O:13])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].[Cl:18]N1C(=O)CCC1=O>CN(C=O)C>[NH:1]([C:5]1[CH:15]=[C:14]2[C:8]([C:9]([Cl:18])=[C:10]([O:16][CH3:17])[O:11][C:12]2=[O:13])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1cc2ccc(NC(=N)N)cc2c(=O)o1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1oc(=O)c2cc(NC(=N)N)ccc2c1Cl
Yield: 37.4 %

Procedure:
0.27 g of 7-guanidino-3-methoxyisocoumarin (1 mmole) was chlorinated with 0.15 g of N-chlorosuccinimide (1.1 mmole) in 5 ml DMF at r.t. overnight. The reaction mixture was evaporated to dryness, and purified by silica gel column chromatography which is eluted with methylene chloride and methanol (5:1) to give 0.1 g of 7-guanidino-3-methoxy-4-chloroisocoumarin (yield 34%). One spot on TLC, Rf=0.75 (Butanol:acetic acid:pyridine:water=4:1:1:2); NMR spectrum is similar to 7-guanidino-3-methoxyisocoumarin except no peak at 6.1 ppm; mass spectrum (FAB+), m/e=268 (M+ -Cl). Anal. Calc. for C11H11N3O3Cl2.1/2H2O: C, 42.17; H, 3.83; N, 13.41; Cl, 22.68. Found: C, 42.65; H, 3.72; N, 13,28; Cl, 22.32.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[NH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[O:21])=[C:4]([O:27][C:28]([F:31])([F:30])[F:29])[CH:3]=1.C(OCC)(OCC)O[CH2:34][CH3:35]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[O:18][CH2:34][CH3:35])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[O:21])=[C:4]([O:27][C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc(Br)cc2OC(F)(F)F)c2c(cc[nH]c2=O)N1
Agent: O=S(=O)(O)O
Product: CCOc1nccc2c1C(c1ccc(Br)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 7 h

Procedure:
7.30 g (13.19 mmol) of the compound from Example 34A are suspended in 150 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 7 hours, 15 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). 4.59 g (64% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7]N2CCN(C(OC(C)(C)C)=O)CC2)=[CH:5][CH:4]=1)#[N:2].[C:23]([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([N:25]1C=CN=C1)=[S:24].[CH2:35](Cl)Cl>C(O)(C(F)(F)F)=O.CO>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:32]2[CH2:33][CH2:34][N:30]([C:23](=[S:24])[NH2:25])[CH2:35][CH2:31]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCl
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1ccc(CN2CCN(C(N)=S)CC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A solution of tert-butyl 4-(4-cyanobenzyl)piperazine-1-carboxylate (336, 1.374 g, 4.56 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was added to a solution of thiocarbonyldiimidazole (1.21 g, 6.84 mmol, 1.5 equiv.) in dry DCM (20 mL) under N2 at 0° C. Obtained solid was diluted with MeOH (20 mL) and transferred to a pressure vial. Ammonia gas was bubbled in for 10 min and the flask was capped and stirred at 80° C. for two days. The reaction mixture was concentrated and purified by flash chromatography using 60% EtOAc in hexane as an eluent, to afford the title compound 337 (593 mg, 50% yield). MS: calc: 260.1; found: 261.2 (M+H)
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][C@H:14]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:19][C:16]1([CH3:20])[O:15][C@@H:14]([CH2:13][C:12]2[CH:21]=[CH:22][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:18][O:17]1
Reactant: [H][H]
Reactant: CC1(C)OC[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](Cc2ccc(O)cc2)O1
Yield: 99.8 %

Procedure:
A solution of (S)-4-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.00 g, 3.35 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on carbon (0.360 g, 0.34 mmol) and the resulting mixture hydrogenated under 1 atm of hydrogen pressure. The resulting mixture was filtered through a pad of Celite® and the pad of Celite washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenol (696 mg, 100%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)C(C)C)C.[C:38]1([C:44]2[NH:45][C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[N:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1C[O:59][CH2:58]C1>>[CH2:27]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH2:25][CH3:26])[CH2:18][C@@H:2]([NH:1][C:58]([N:52]1[CH2:51][CH2:50][CH:49]([N:47]2[C:46](=[O:55])[NH:45][C:44]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:48]2)[CH2:54][CH2:53]1)=[O:59])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4])[CH3:28]
Reactant: C1CCOC1
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Reactant: O=c1[nH]c(-c2ccccc2)nn1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Reaction time: 1 h

Procedure:
A mixture of 400 mg (1.04 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-propan-1-one, 205 mg (1.25 mmol) CDT, 0.2 mL (1.15 mmol) ethyldiisopropylamine and 50 mL THF was stirred for 1 h while cooling with an ice bath and stirred for 1 h at RT, then combined with 270 mg (1.11 mmol) 5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one and refluxed for 4 h. The reaction mixture was evaporated down under reduced pressure, the residue was combined with saturated NaHCO3 solution and exhaustively extracted with DCM. The combined organic phases were dried, evaporated down under reduced pressure and the residue was purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])C=2OC)[CH2:10][CH2:9]1)=O)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].C[CH2:34][O:35]CC>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:22][O:21][C:17]1[C:18]([O:35][CH3:34])=[CH:19][CH:20]=[CH:15][C:14]=1[C:11]1([CH:28]=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOCC
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2(C=O)CCNCC2)c1OC
Reaction time: 0.75 h

Procedure:
4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50 mL, 650 mmol) and stirred for 45 minutes. The entire solution was poured into ether (900 mL) and allowed to stand overnight. Filtration yielded 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as fine white needles, m.p. 123° C. Anal. Calcd for C14H19NO3 :CF3CO2H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:20])O)([CH3:16])([CH3:15])[CH3:14].O1CCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:20])[N:10]([CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)O
Reactant: CNCC(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 1-(4-fluorophenyl)-2-methylamino ethanol (the compound of Preparation Example 17) (9.7 g) and t-butylbicarbonate (10.0 g) in a mixed solvent of tetrahydrofuran solution (100 mL) and an aqueous solution of saturated sodium bicarbonate (50 mL) was stirred at room temperature for 1.5 hours. The solution was diluted with ethyl acetate, and washed with water and saturated sodium chloride water. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained by evaporating the solvent at reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (9.5 g) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[C-]#N.[CH2:16]([NH:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19]>C(C(C)=O)C(C)C>[CH2:16]([N:20]([CH2:21][CH3:22])[C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)=[O:11])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCC
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Agent: [C-]#N
Solvent: CC(=O)CC(C)C
Product: CCCCN(CC)C(=O)NC(C)(C)c1ccc(Cl)cc1
Yield: 86.2 %

Procedure:
A solution of 3.9 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 20 ml of methyl isobutyl ketone was added to 2.2 g of N-n-butylethylamine. The solvent was then removed by distillation under reduced pressure and the resulting crystals were recrystallized from n-hexane to obtain 5.1 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:34])[NH2:2]
Reactant: [NH4+]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2cccc(C(=N)N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and ammonium carbonate (192 mg, 2.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. Methylene chloride (150 mL) was added to the mixture. The methylene chloride solution was washed with 10% K2CO3 (2×50 mL) and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and the solvent again removed in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white solid (112 mg, 48%). 1H-NMR (300 MHz, DMSO-d6) δ 2.23 (s, 3 H), 5.11 (s, 2 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 6.88 (s, 1 H), 7.58 (t, 1 H, J=6.5 Hz), 7.61 (t, 1 H, J=12.2 Hz), 7.66 (d, 1 H, J=3.9 Hz), 7.73-7.95 (m, 5 H), and 9.40 (br s, 4 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O4SCl: 431.1 (M+H), 453.1 (M+Na). Found: 431.0, 452.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:31]1C=C(S(Cl)(=O)=O)C=C[CH:36]=1>>[CH2:31]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:36]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)cc1

Procedure:
4-[3-(3-Fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=413.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-fluoro-benzensulfonyl chloride and yielded 4-[3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.