Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([OH:9])([CH3:8])[CH3:7].CC1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[C:13](C)([CH3:20])[CH:12]=1.C1CCCCC=1>O>[CH3:7][C:6]12[CH2:18][CH2:17][CH:14]([C:13]([CH3:20])([CH3:12])[CH2:8]1)[CH:15]([CH3:16])[O:9]2
Reactant: CC(C)O
Reactant: CC1=CC(C)(C)C(CCO)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1=CCCCC1
Product: CC1OC2(C)CCC1C(C)(C)C2
Temperature: 25 °C

Procedure:
Into a 500 ml reaction flask equipped with reflux head, thermometer and stirrer is added 50 g of 40% sulfuric acid and 50 g of anhydrous isopropyl alcohol. The resulting mixture is heated to reflux and 1,3,3-trimethyl-1-cyclohexene-4-ethanol, prepared according to Example II (50 g) (fraction 2 according to Example II) is added slowly to the reaction mass while maintaining the temperature thereof at 86°-88° C. The addition takes place over a period of one hour. At the end of the addition of the cyclohexene derivative, the reaction mass is cooled to room temperature and water is added. The reaction mass now exists in two phases. The phases are separated and the organic phase is washed with aqueous sodium carbonate and saturated sodium chloride. The organic phase is then distilled using a microdistillation set-up (micro Vigreux column) yielding the following fractions:
Reaction SMILES: CC1(C)C(C=CC2CCC/C(=C/[CH:17]=[C:18]3/[C:19](C)(C)[C:20]4[C:25](N/3CCCCS(O)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=4)/C=2OC2C=CC(OCCCCNCC3OC(O)C(N)C(O)C3O)=CC=2)=[N+](CCCCS([O-])(=O)=O)C2C1=CC=CC=2.[NH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1.C(=O)(OCC=CC1C=CC=CC=1)OC>C1COCC1>[C:20]1([CH:19]([N:73]2[CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:18]=[CH2:17])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C(C=CC2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Reactant: C1CCNC1
Agent: CC1(C)C(/C=C/C2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: COC(=O)OCC=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)N1CCCC1
Reaction time: 10 h
Yield: 81 %

Procedure:
A stock solution containing [(COD)Ir(η2-L1)(L1)] (Ir-2) (13.8 mg, 0.0100 mmol) and [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) in 1.0 mL of THF was prepared. From this solution, 0.10 mL was added to 0.40 mL of THF in a screw-capped vial with a small magnetic stirbar. Pyrrolidine (87.5 mg, 1.23 mmol) and methyl cinnamyl carbonate (183 mg, 0.950 mmol) were added to the reaction mixture by syringe. The reaction was conducted at room temperature for 10 h. 1H NMR analysis of the crude mixture indicated that the ratio of the branched to linear products was 99/1. The mixture was purified by flash column chromatography on silica gel (5% ethyl acetate in hexane) to give 148 mg (81%) of the title compound. HPLC analysis indicated that the enantiomeric excess of product was 98% [Daicel Chiralcel® OD-H (0.46 cm×25 cm); hexane/diethylamine=99.75/0.25; flow rate=0.6 mL/min; detection wave length=220 nm; TR=7.60 (minor), 8.10 (major) min]; =11.2 (major), 12.5 (minor) min]: [α]DRT=+85 (c 3.2, CHCl3); 1H NMR (400.13 MHz, CDCl3) δ 7.28-7.37 (m, 4H), 7.20-7.25 (m, 1H), 6.04 (ddd, J=17.2, 10.0, 8.8 Hz,1H), 5.20 (dd, J=17.2, 1.2 Hz, 1H), 5.00 (dd, J=10.0, 1.2 Hz, 1H), 3.58 (d, J=8.8 Hz, 1H), 2.45-2.54 (m, 2H), 2.33-2.42 (m, 2H), 1.76 (m, 4H); 13C NMR (100.5 MHz, CDCl3) δ 142.7, 141.0, 128.5, 127.6, 127.1, 115.1, 75.2, 53.0, 23.3.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10](OC)=[O:11])[N:7]=[N:6]1.[NH3:19]>>[CH:16]1[CH:15]=[C:14]([F:18])[C:3]([CH2:4][N:5]2[N:6]=[N:7][C:8]([C:10]([NH2:19])=[O:11])=[CH:9]2)=[C:2]([F:1])[CH:17]=1
Reactant: N
Reactant: COC(=O)c1cn(Cc2c(F)cccc2F)nn1
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
reacting methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV with ammonia to obtain rufinamide of formula I.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=[CH:32][C:33](Cl)=[O:34])[CH:22]=1>C(Cl)Cl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=[CH:32][C:33]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:34])[CH:22]=1
Reactant: O=C(Cl)C=Cc1cnc2ccccc2c1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cnc2ccccc2c1)NCCCSc1ccncc1
Yield: 83.8 %

Procedure:
To a solution of 396 mg (1.64 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 0.27 ml (1.97 mmol) of triethylamine in 20 ml of methylene chloride, 500 mg (1.96 mmol) of 3-quinolineacryloyl chloride hydrochlride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder was washed with ether and dried to obtain the desired compound (480 mg, yield: 83.8%, pale yellow powder).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.C(OCC)(=O)C>[N:27]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][CH:11]([CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:3]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(-n4cncn4)ncn3)CC2)CC1
Temperature: 140 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (190 mg, 0.50 mmol), 1,2,4-triazole (69 mg, 1.0 mmol), cesium carbonate (488 mg, 1.5 mmol) were added in NMP (5 mL) and heated to 140° C. for 1.5 hours. The reaction crude were cooled down to r.t. and diluted with ethyl acetate (10 mL), washed with water (5 mL, ×1) and brine (5 mL, ×1). The organic phase was dried over magnesium sulfate, filtered and concentrated on rotavapor. The crude mixture was purified by preparative TLC with 50% ethyl acetate:hexane to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCCCCC>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:39])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (60.6 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.64 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (59.5 mg, 68%) as white powder.
Reaction SMILES: [CH2:1](Cl)[CH3:2].[N:4]1([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[CH2:6][CH2:5][N:4]([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8]1)[CH3:2]
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCN5CCNCC5)C(=O)SC4C)ccc32)cc1OC
Reactant: CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1CCN(CCCOC(=O)N2N=C(c3ccc4c(c3)CCCN4C(=O)c3ccc(OC)c(OC)c3)C(C)SC2=O)CC1

Procedure:
1.3 g of ethyl chloride dissolved in 10 ml of toluene are added dropwise with stirring to a solution of 10 g of 3-(3-piperazinopropoxycarbonyl)-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 1.8 g of triethylamine in 100 ml of toluene, and the mixture is stirred with heating for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[3-(1-ethyl-4-piperazinyl)-propoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[OH2:14]>C(Cl)(Cl)(Cl)Cl.CC#N>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[C:11]([CH3:13])[N:12]=[C:3]([C:2]([OH:14])=[O:1])[CH:4]=1)=[O:7]
Reactant: O
Reactant: COC(=O)c1cc(C)nc(CO)c1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C)nc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a stirring mixture of 51.6 mg (0.283 mmol) of methyl 2-(hydroxymethyl)-6-methylisonicotinate in 1.6 mL of CCl4, 1.6 mL of CH3CN, and 2.4 mL of H2O was added 348 mg (1.63 mmol) of NaIO4, and 8.8 mg (0.0424 mmol) of RuCl3.(H2O)n. After 2 h, 6 mg of RuCl3.(H2O)n was added, and after 2.5 h the mixture was filtered through Celite twice with EtOAc and MeOH. The solution was concentrated and then reconcentrated with MeOH (2×) to remove H2O. Crude 4-(methoxycarbonyl)-6-methylpicolinic acid was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:26]2[C@@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1Cl
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@@H]2C)ccc1Cl

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [5-(4-bromo-2-bromomethyl-phenoxy)-2-chloro-phenyl]acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:29])[C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:37]1(B(O)O)[CH2:39][CH2:38]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:29])[C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]([C:30]3[CH:35]=[CH:34][C:33]([CH:37]4[CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(Br)cc2)cc1
Product: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(C3CC3)cc2)cc1

Procedure:
Using the compound obtained in Example 239 and cyclopropylboronic acid (0.066 g), and by the reaction and purification in the same manner as in Example 242, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C@@H:10]([C@@:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH3:22])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[C:11]([OH:13])=[O:12])[N:3]=1.[CH:33](=O)[CH3:34]>>[CH2:33]([N:20]1[C@@:14]([C@H:10]([O:9][C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:11]([OH:13])=[O:12])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:15]2[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=2[N:17]([CH3:22])[C:18](=[O:21])[CH2:19]1)[CH3:34]
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Reactant: CC=O
Product: CCN1CC(=O)N(C)c2ccccc2[C@@]1(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O

Procedure:
(±)-(S*)-((5S*)-4-ethyl-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared starting from (±)-(S*)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (Example 49) and acetaldehyde in analogy to Example 127. LC-MS1: tR=0.75 min, [M+1]+=461.16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: Oc1cc(Cl)ccc1Br
Reactant: CC(Br)C(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(Oc1cc(Cl)ccc1Br)C(=O)N(C)C
Reaction time: 8 h

Procedure:
2-Bromo-5-chlorophenol (8 g), 2-bromo-N,N-dimethylpropionamide (6.66 g) and anhydrous potassium carbonate (2.6 g) in methyl iso-butyl ketone (100 ml) were refluxed with stirring overnight. The mixture was cooled to 50° and washed with 5% sodium hydroxide (2×20 ml) and then water (2×50 ml). The organic solution was dried and evaporated under reduced pressure to yield a pale red oil, which solidified on cooling. Recrystallisation from 50% aqueous ethanol gave the title compound, m.p. 76°-77°. Compounds 2, 9, 10 to 13, 17 and 21 were made by a similar procedure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(Cl)(Cl)Cl>[C:15]1([C:13]2[N:1]=[C:2]3[N:6]([CH:12]=2)[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nc2c(s1)CCCC2
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cn3c4c(sc3n2)CCCC4)cc1

Procedure:
0.1 m. Quantities of 2-amino-4,5,6,7-tetrahydrobenzothiazole and α-bromoacetophenone in 100 ml. of chloroform are heated at reflux for 2 hours. After cooling, the solid is filtered off and slurried in 1 l. of water containing 40 g. of ammonium acetate. This suspension is heated to boiling over a 2-hour period and allowed to cool. The product is collected, washed with water and dried. The yield of product is 19.8 g. melting at 158°-160° C. and having the formula: ##STR20##
Reaction SMILES: [OH:1][CH:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5]O.[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.C(OCC)C>C(Cl)Cl>[OH:1][CH:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][C:25]#[N:27]
Reactant: CCN(CC)CC
Reactant: COCC1CN(c2ccc3nc(C(O)CCCO)sc3c2)C(=O)O1
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCC1CN(c2ccc3nc(C(O)CCCC#N)sc3c2)C(=O)O1
Reaction time: 0.5 h

Procedure:
2.8 g of the 3-[2-(1,4-dihydroxybutyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone thus obtained was dissolved in 20 ml of anhydrous methylene chloride and 1 ml of anhydrous triethylamine was added to the solution. 0.6 ml of methanesulfonyl chloride was slowly added to the solution under cooling with ice. After stirring for 30 min, 100 ml of diethyl ether was added to the reaction mixture. An insoluble matter was filtered off and then the solvent was distilled off. The resulting crude product was dissolved in 15 ml of dimethyl sulfoxide. 1.5 g of potassium cyanide was added to the solution and a reaction was conducted at 80° C. for 8 h. After cooling the reaction liquid followed by ordinary treatment and purification, 1.5 g of the titled compound was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH2:22])=[O:21]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH:22][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:21]
Reactant: NC(=O)NCc1cccc(Cl)c1
Reactant: N#CCC(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)NC(=O)NCc1cccc(Cl)c1
Reaction time: 4 h
Yield: 84.8 %

Procedure:
3.76 g of 98% cyanoacetic acid and 14 ml of acetic anhydride were heated for 1 hour at 65° C. A solution of 7.73 g of (3-chlorobenzyl)urea in 55 ml THF was added and the mixture kept for 4 hours at 65° C. The THF was removed in vacuo and the residue diluted with 50 ml of toluene. The solid was collected and washed to give the title compound (8.94 g) as a white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([CH2:31][C:32]([O-])=[O:33])[CH2:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][C:27]5([OH:26])[CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C([O-])CC1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1(O)CCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (20.5 mg, 68.2%), MS (ISP) m/z=443.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0744 mmol) and 2-(1-hydroxycyclobutyl)acetate acid prepared previously by saponification of the corresponding ethyl 2-(1-hydroxycyclobutyl)acetate using lithium hydroxide or another base in the presence of a solvent mixture such as tetrahydrofuran, water and methanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:19][OH:20])[N:4]=1.I[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COC(=O)CCNCCOc1cc(CO)nc(CO)c1
Reactant: COCCOCCOCCI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCN(CCOc1cc(CO)nc(CO)c1)CCC(=O)OC
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a solution of 284 mg of methyl 3-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-propanoate in 28 ml of acetonitrile was added 356 mg of 1-iodo-2-[2-(2-methoxy-ethoxy)-ethoxy]-ethane and 330 μl of diisopropylethylamine. The mixture was heated at 80° C. for 3 days and then concentrated under reduced pressure and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-40g), using a gradient of 5 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 165 mg of methyl 3-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate were obtained. LC/MS (B): tr=0.44 min; [M+H]+: m/z 431.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19](Cl)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19]([O:20]/[C:19](/[C:18]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:17]=2)=[CH:8]\[C:7]2[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC3CCCC3)c2)cc1OC1CCCC1

Procedure:
The compound was obtained starting from 3,5-dichloro-4-methyl-pyridine and 3-cyclopentyloxy-4-methoxybenzoyl chloride following the procedure of Example 31.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C([O-])=O)[CH3:25]>O1CCCC1.O>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-thiophenecarboxylic acid (6.48 g, 50.57 mmol) in tetrahydrofurane (100 ml) at 5. was added 1,1′-Carbonyldiimidazole (8.61 g, 53.09 mmol) by portions. The mixture was allowed to warm to room temperature, and the stirring was continued for 1 hour. The reaction mixture was added into a suspension mixture of magnesium chloride (4.86 g, 51.07 mmol) and pottasium 3-ethoxy-3-oxopropanoate (12.91 g, 75.85 mmol) in tetrahydrofurane (50 ml). After being stirred at 50. for 2 hours and at room temperature overnight, the reaction mixture was poured into water, and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/hexane, 15/85) to give ethyl 3-oxo-3-(2-thienyl)propanoate (7.83 g, 78% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.CC1(C)C(C)(C)OB([C:52]2[CH:57]=[CH:56][N:55]=[C:54]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[CH:53]=2)O1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:52]3[CH:57]=[CH:56][N:55]=[C:54]([N:58]4[CH2:59][CH2:60][NH:61][CH2:62][CH2:63]4)[CH:53]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Agent: OCc1ccc(B(O)O)cc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccnc(N5CCNCC5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced by 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine. LCMS, [M+H]+=485.3. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=5.1 Hz, 1H), 7.22-7.28 (m, 2H), 7.07-7.13 (m, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 6.53 (s, 1H), 6.50 (d, J=5.9 Hz, 1H), 3.98 (t, J=5.7 Hz, 2H), 3.80 (t, J=6.9 Hz, 2H), 3.47-3.59 (m, 4H), 2.95-3.04 (m, 4H), 2.77 (t, J=7.3 Hz, 2H), 2.53 (t, J=6.5 Hz, 2H), 2.16-2.27 (m, 5H), 2.00 (br. s, 3H), 1.85 (quin, J=6.7 Hz, 2H).