Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]1([CH2:8][C@H:9]([NH2+:11][CH2:12][C:13]#[CH:14])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C=O)C.O>[F:20][CH2:19][CH2:18][N:11]([C@H:9]([CH3:10])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:13]#[CH:14]
Reactant: C#CC[NH2+][C@H](C)Cc1ccccc1
Reactant: FCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN(CCF)[C@H](C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-aminium chloride (Sigma 100 mg, 0.578 mmol) in dry DMF (2 mL) was added sodium hydride (48.0 mg, 2 mmol). The reaction mixture was stirred at room temperature for 30 min, after which 1-bromo-2-fluoro ethane (0.85 mg, 0.603 mmol) was added. The reaction mixture was stirred over night, diluted with water (10 mL) and extracted with CH2Cl2 (3×15 mL). The organic phase was separated and washed with saturated NaHCO3 (15 ml) and brine (15 ml) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 80:20) and analyzed by NMR, HPLC and LC-MS.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CN(C=O)C>[C:20]1([CH:18]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]2=[O:14])[CH3:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Yield: 89 %

Procedure:
In the same way as that described in Example 1, Step 1, using Intermediate 1 (500 mg, 2.5 mmol), sodium hydride (110 mg of a 60% dispersion in mineral oil, 2.8 mmol), (1-bromoethyl)benzene (0.44 mL, 3.25 mmol) and DMF (12 mL). The title piperazinone (677 mg, 89%) was isolated as a colourless oil, which solidified on standing at 0° C. mp. 62-64° C. 1H NMR (250 MHz, CDCl3) δ1.40 (9H, s), 1.53 (3H, d, J=7.2 Hz), 2.80-2.90 (1H, m), 3.14-3.36 (2H, m), 3.56-3.71 (1H, m), 4.07 (1H, d, J=18.2 Hz), 4.22 (1H, d, 18.2 Hz), 6.08 (1H, q, J=7.2 Hz), 7.28-7.39 (5H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl.[NH2:28][OH:29].C(N(CC)CC)C>CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24](=[NH:25])[NH:28][OH:29])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C#N)cn3)cc(C)c21
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=N)NO)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
[6-(5-Cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.57 mmol) and hydroxylamine hydrochloride (99 mg, 1.4 mmol) were mixed in methanol (5.4 mL). To this was added triethylamine (0.28 mL, 2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed. The residue was dissolved in dichloromethane and washed with water. The organic layer was separated and the solvent was removed to give a residue. The residue was dried under high vacuum to give the title compound (174 mg, 79%) as a white solid. MS found (electrospray): (M+H)+=387.1.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc2cccc(Cl)c2nc1-c1cccnc1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (5.0 g, 22.2 mmol), Na2CO3 (3.51 g, 33.2 mmol) and 3-pyridylboronic acid (2.72 g, 22.2 mmol) in DME (60 mL) and water (30 mL) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (1.28 g, 1.11 mmol) was added and the mixture heated at 90° C. for 7 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (5.4 g, 91%) as a tan solid. δH (DMSO-d6) 10.15 (s, 1H), 9.15 (s, 1H), 8.94 (dd, J 2.3, 0.8 Hz, 1H), 8.77 (dd, J 4.9, 1.7 Hz, 1H), 8.31 (dd, J 8.3, 1.3 Hz, 1H), 8.20-8.19 (m, 1H), 8.18-8.16 (m, 1H), 7.75 (dd, J 7.9, 7.5 Hz, 1H), 7.62 (ddd, J 7.7, 4.9, 0.8 Hz, 1H). LCMS (ES+) 269 (M+H)+, RT 1.82 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring mixture of 5-methyl-pyridin-2-ylamine (1.0 g, 9.25 mmol) and pyridine (20 ml) in dry CH2Cl2 add phenylchloroformate (2.2 g, 13.9 mmol) and stir for 24 hours at room temperature. Add water and a solution of 1:1 EtOAc/hexanes and separate the organic layer. Wash the organic layer with 1N HCl three times and with brine once. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (5-methyl-pyridin-2-yl)-carbamic acid phenyl ester. Mass spec.: M+1=229 (AP+). B. 1′-(5-methyl-pyridin-2-yl-carbamoyl)-spiroisobenzofuran-1,4′-piperidine
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([F:17])=[C:11]([F:18])[CH:10]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:17])=[C:11]([F:18])[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7]1)[CH3:26]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(F)c(F)cc2c1=O
Temperature: 90 °C

Procedure:
A 20 g portion of the above ester was suspended in 400 ml of dimethylformamide, 27.3 g of potassium carbonate was added and this mixture was stirred at 90° C. A 61.8 g portion of ethyl iodide was added and this mixture was stirred at 90° C. for 24 hours and then evaporated. The residue was dissolved in water and then extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated in vacuo. The residue was recrystallized from ethanol, giving 16.15 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (80 mg, 245 μmol), 6-chloronicotinonitrile (50 mg, 368 μmol) and anhydrous K2CO3 (102 mg, 735 μmol) in DMF (2 mL) was heated at 100° C. overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine and then dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 429 (M+H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:16][OH:17]>N1C=CC=CC=1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:16][OH:17])[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=NO)c1ccc(NS(C)(=O)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 4′-(Methylsulfonylamino)acetophenone (13-5, 5 mmol) and hydroxylamine hydrochloride (0.695 g, 10 mmol) in pyridine (5 mL) was heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc several times. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant to 4′-Methylsulfonylamino)acetophenone oxime (13-8, LJO-299).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.[OH-].[Na+].[CH3:25][NH2:26]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:26]([CH3:25])[CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN2c3ccc(Cl)cc3C(c3ccco3)=NCC2C1

Procedure:
3.4 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine in 100 ml of methanol are left to react with 0.8 g of sodium hydroxide in 1 ml of water and 2.5 g of methylamine at 95° C. in an autoclave for 5 hours. The reaction mixture is then worked up in the customary manner and the reaction product is purified by chromatography on aluminium oxide of activity level II, using methylene chloride/chloroform, and the fractions containing the product of medium polarity are separated off and the 1,2,3,4,4a,5-hexahydro-9-chloro-3-methyl-7-(2-furyl)-pyrazino[1,2-a]-[1,4]benzodiazepine obtained therefrom is dissolved in isopropanol and converted into its salt with alcoholic hydrochloric acid. This salt crystallises from isopropanol as the dihydrochloride hemihydrate with 0.1 mol of isopropanol. Melting point: >240° C., yield: 0.8 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:21]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCN(CCC(=O)O)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 40 h

Procedure:
To a solution of 2.5 g (11.2 mmol) 3-benzyloxycarbonylamino-propionic acid in 30 ml DMF and 30 ml THF are added 1.34 g (33.6 mmol, 60% suspension in mineral oil) NaH and the mixture is heated at 60° C. for 3 h. After cooling down 1.42 ml (16.8 mmol) allyl bromide are added. After stirring for 40 h at rt the mixture is diluted with 10% citric acid and extracted three times with EtOAc. The combined organic layers are washed with water, dried with sodium sulfate and the volatiles are removed in vacuo. The residue is chromatographed on silica gel (hexane/EtOAc 3:1), yielding the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]([CH2:20][CH2:21]O)[CH3:19]>>[CH3:17][N:18]([CH2:20][CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: CN(C)CCO
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCCN(C)C

Procedure:
Following General Procedure C′ above, and using N-(3-chlorophenylacetyl)alanine (from Example D′ above) and 2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 0.1:2:0.79 NH4OH:EtOH:CHCl3 as the eluant.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:40][CH3:41])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[O:40][CH3:41]
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5ccc(C(C)=O)s5)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (35.39 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 59% (75 mg, 0.136 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH:45]1[CH2:49][CH2:48][N:47]=[C:46]1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH:57][CH3:58])=[CH:52][CH:51]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:57]([CH2:56][C:53]3[CH:54]=[CH:55][C:50]([C:46]4[NH:47][CH2:48][CH2:49][N:45]=4)=[CH:51][CH:52]=3)[CH3:58])=[O:22])[CH:16]=2)[CH3:13])(=[O:10])=[O:11])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cc(Br)cc2Cl)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.14 mmol), EDCI (33 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) in DMF (0.5 mL) was added a solution of 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (28 mg, 0.13 mmol) and DIPEA (0.025 mL, 0.14 mmol) in DMF (0.5 mL). The reaction was heated to 60° C. for 5 h, then concentrated and diluted with DCM. The solution was washed with saturated aqueous NH4Cl(2×2 mL) and saturated brine (2 mL), and dried over MgSO4. The filtrate was shaken with Ambersep resin for 48 h, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(N(C)C)=O)=NC(N(C)C)=O.[C:28](O)(=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A solution of Intermediate 35 (21.06 g), 1,1′-azobis(N,N-dimethylformamide) (64.11 g) and p-anisic acid (23.03 g, Tokyo Kasei Kogyo) in tetrahydrofuran (400 ml) was added with tri(n-butyl)phosphine (35.6 ml) at room temperature and stirred at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, then added with ethyl acetate (200 ml) and successively washed with saturated aqueous sodium hydrogencarbonate twice (200 ml each) and 0.1 N aqueous sodium hydroxide (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (32.92 g).
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])#[N:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:5][CH2:4][C:3]([C:1]#[N:2])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(C)(C#N)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(C)(C#N)COS(=O)(=O)c1ccc(C)cc1
Yield: 66.8 %

Procedure:
535 mg (3.8 mM) of (+)-2-cyano-2-methylhexanol ([α]D26 +0.66 degree (c 1.823, ether)) and 911 mg (11.4 mM) of dry pyridine were stirred at room temperature, and 724 mg (3.8 mM) of p-toluenesulfonyl chloride was added thereto, followed by 7 hours of reaction. After the reaction, 3 ml of 2N-hydrochloric acid was added thereto, followed by extraction with diethyl ether. the resultant organic layer was washed with a small amount of 2N-hydrochloric acid and distilled water, followed by drying on sodium sulfate, distilling-off of the solvent and purification by silica gel column chromatography (developer solvent: methylene chloride) to obtain 748 mg of 2-cyano-2-methylhexyl p-toluenesulfonate (yield: 63.3%).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]([NH:10][C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:9])[CH3:8]>C(OCC)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:11]2[O:21][CH2:6][C:7]([CH3:8])([CH3:9])[N:10]=2)[CH:17]=1
Reactant: COc1ccc(Br)cc1C(=O)NC(C)(C)CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1ccc(Br)cc1C1=NC(C)(C)CO1
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Thionyl chloride (36.5 ml) was added dropwise to N-(1-hydroxy-2-methylpropan-2-yl)-5-bromo-2-methoxybenzamide (36.34 g). The resulting solution was stirred for 15 minutes and mixed with diethyl ether. The diethyl ether was decanted off and the resulting residue dissolved in 20% NaOH solution. The aqueous solution was extracted with diethyl ether. The extract was washed with brine, dried (MgSO4) and evaporated to give 2-(5-bromo-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (32.02 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:8][CH:7]=1.I.[NH2:20][C:21]1[C:22]([C:29]([NH:31][C:32](=[NH:35])SC)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1>C(O)C>[NH2:20][C:21]1[C:22]([C:29]([N:31]=[C:32]([NH2:35])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[CH:8][CH:7]=2)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)C(=O)COc1ccc(CCCCN)cc1
Agent: I
Solvent: CCO
Product: CN(C)C(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-dimethylacetamide 29 (67 mg, 0.27 mmol) in absolute ethanol (1 mL) was stirred at 65° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (10 mg, 0.29 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 3 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-dimethylacetamide as a yellow solid (35 mg, 28% yield). This solid was dissolved in methanol (2 mL) and added to 4 N aqueous HCl (4 drops). Concentration in vacuo gave 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidino]butyl}phenoxy)-N,N-dimethylacetamide hydrochloride (30, PSA 16313). mp 130-132° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 1.69 (m, 4H), 2.60 (m, 2H), 2.95 (s, 3H), 3.10 (s, 3H), 3.35 (m, 2H), 4.75 (s, 2H), 6.80 (d, 2H), 7.10 (d, 2H). m/z (ESI): 463 [C20H27ClN8O3+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])#[N:2].[H][H]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccccc1/C=C\C(=O)O
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccccc1CCC(=O)O
Yield: 90.7 %

Procedure:
A slurry of (Z)-3-(2-cyanophenyl)acrylic acid (Example 323a, 4.75 g) in ethanol (50 mL) was added to 5% Palladium (0.292 g) in ethanol (50 mL) and hydrogenated under 2.0 bar hydrogen pressure for 2 h. The reaction mixture was filtered and the filtrate evaporated to dryness to afford the sub title compound as a solid (4.36 g).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C.[C-:23]#[N:24].[K+]>O>[C:23]([CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:24]
Reactant: [C-]#N
Reactant: OC(CCl)Cc1cccc(C(O)c2ccccc2)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC(O)Cc1cccc(C(O)c2ccccc2)c1
Yield: 71.4 %

Procedure:
A mixture of 11.97 g of 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol, 120 ml of ethanol, 2.4 ml of water and 2.66 g of potassium cyanide was refluxed for 3 hours and then evaporated to dryness. The residue was taken up in 200 ml of methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 75-25 methylene chloride-ethyl acetate mixture which was evaporated to obtain 7.8 g of 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in the form of an orange amorphous solid soluble in chloroform and insoluble in water.