Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[C:25]1(OB(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: OB(O)Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(Oc3ccccc3)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A suspension of 0.200 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate, 0.0906 g of phenylboric acid, 0.113 g of copper(II) acetate, 0.309 g of triethylamine, 0.700 g of 3 angstrom molecular sieves (powder) and 6 ml of dichloromethane is stirred vigorously at room temperature for 28 hours. The reaction mixture is clarified by filtration and concentrated by evaporation. The title compound is obtained as a yellowish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.44 (1:1 EtOAc-heptane); Rt=5.03.
Reaction SMILES: CN(CCCC1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)OCC2C=C(C#N)C=CC1=2)C.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:31](=[O:32])[O:30][CH2:29]2.FC1C=CC(Br)=CC=1.[Mg]>CCOCC>[OH:30][CH2:29][C:28]1[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:33]=1[C:31]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:32]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1CO

Procedure:
The preparation of citalopram and its hydrobromide salt from 5-bromophthalide and the properties of such compounds was first reported in U.S. Pat. No. 4,136,193, which corresponds to German Offenlegungsschrift No. 2,657,013. U.S. Pat. No. 4,136,193 discloses a synthesis of citalopram starting from 5-bromophthalide, which involves the use of two successive Grignard reactions. In a first reaction, a Grignard reagent prepared from p-fluorobromobenzene and magnesium turnings in ether was reacted with 5-bromophthalide to give 2-hydroxymethyl-4-bromo-4′-fluorobenzophenone. The latter was isolated as a crude oil before, in a second reaction, being added to N,N-dimethylaminopropylymagnesium chloride to give (4-bromo-2-(hydroxymethyl)phenyl)-(4′-fluorophenyl)-(3-dimethylaminopropyl)-methanol. The latter was dehydrated with 60 aqueous phosphoric acid to yield 1-(4′-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane, which was then refluxed with cupric cyanide in dimethylformamide to give citalopram.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])C.[CH3:14][N:15](C)[C:16](Cl)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:14][N:15]([CH3:16])[C:5]([N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCNCC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichloromethane and 1.5 mL of triethylamine at room temperature was added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2: dichloromethane/methanol=4/1 v/v.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C(=O)CBr)no1
Product: COC(=O)Cc1c(C(=O)c2cc(C)on2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromoacetyl-5-methylisoxazole (M. D. Amici et al., J. Org. Chem., 1989, 54, 2646).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[OH:46].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[C:7]=4[C:8]=3[CH:9]=2)[CH:34]=[CH:33][C:32]=1[OH:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(O)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.6 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.5 mg, 0.12 mmol) in toluene/ethanol (1:1, 8 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Methoxy-4-[6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenol as brown solid in 60% yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>ClCCl.N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][C:6]=1[C:7]([Cl:25])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)Cl)c1
Temperature: 35 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
5.5 g (18 mmol) of 2-acetyloxy-5-octanoylbenzoic acid are dissolved in 55 ml of dichloromethane with one drop of pyridine. 1.6 ml (21.5 mmol) of thionyl chloride are added dropwise and the mixture is stirred at 35° C. for 18 hours and then concentrated to dryness. 5.6 g of 2-acetoxy-5-octanoylbenzoyl chloride are obtained in the form of a red oil in a yield of 96%.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:26])[CH2:24][CH3:25]>C1COCC1.CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23]1([CH2:24][CH3:25])[CH2:4][O:26]1
Reactant: CCC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC1(c2ccc(Oc3ccc(Cl)cc3)cc2Cl)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
To a solution of sodium hydride (35.72 g, 1.49 mol) in THF (1 L) and dry DMSO (2 L) was added under argon drop wise at 5° C. a solution of trimethylsulfonium iodide (290.5 g, 1.42 mol) in dry DMSO (2 L). The mixture was stirred 1 hour at 5° C. followed by a dropwise addition of 1-[2-chloro-4-(4-chlorophenoxy)phenyl]propan-1-one (199.0 g, 0.65 mol) in DMSO (500 mL). The resulting mixture was then warmed to room temperature overnight and quenched with an aqueous solution of ammonium chloride and iced water, and then extracted with MTBE. The organic solvents were washed with water, dried and evaporated to give 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-ethyl-oxirane as a yellowish solid (216.0 g, 97%). 1H-NMR (CDCl3; 400 MHz) • • (ppm)=0.9 (t, 3H); 1.75 (m, 1H); 2.10 (m, 1H); 2.80 (d, 1H); 3.05 (d, 1H); 6.85 (d, 1H); 6.95 (m, 3H); 7.30 (d, 2H); 7.40 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:21])=[C:13]([C:16](OCC)=[O:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:21])=[C:13]([CH2:16][OH:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(I)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
A solution of ethyl 1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (6.5 g, 11.40 mmol) in anhydrous DCM (110 mL) was cooled to −55° C. and then DIBAL-H (22.80 mL, 22.80 mmol) (1M/toluene) was added dropwise in ˜20 min and the mixture was allowed to warm to 0° C. in 1 h and kept at 0° C. for 1 h. More DIBAL-H (12 mL, 12 mmol) was added and stirring at 0° C. continued for 1 h. The mixture was cooled to 0° C. and water (1.4 mL) was added slowly followed by 15% NaOH/water (1.4 mL) and water (3.5 mL). The mixture was stirred at RT for 15 min then filtered through a path of celite washing with dichloromethane. The filtrate was concentrated and co-evaporated with MeCN, dried in vacuo to provide (1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (5.0 g, 9.66 mmol, 85% yield) as an orange solid. 1H NMR and LCMS are consistent with proposed structure. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.80 (br s, 1 H), 2.83 (s, 3 H), 5.02 (d, J=2.15 Hz, 2 H), 5.40 (s, 2 H), 6.35 (d, J=3.51 Hz, 1 H), 6.92-7.12 (m, 3 H), 7.13 (d, J=3.51 Hz, 1 H); LCMS (m/z) ES+=415 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13](=[O:19])[C:14]2[S:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[CH2:6][CH:7]([CH:9]=[O:10])[O:8][C:4]=2[C:3]=1[Cl:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32](O)[CH2:33][OH:34]>C1C=CC=CC=1.O>[CH2:33]1[O:34][CH:9]([CH:7]2[CH2:6][C:5]3[CH:11]=[C:12]([C:13](=[O:19])[C:14]4[S:18][CH:17]=[CH:16][CH:15]=4)[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=3[O:8]2)[O:10][CH2:32]1
Reactant: O=CC1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C1OCCO1)C2
Reaction time: 3 h

Procedure:
A benzene mixture (250 ml.) containing 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde (3.2 g., 0.01 mole), p-toluenesulfonic acid (0.2 g.) and ethyleneglycol (15 ml.) is heated under reflux for three hours. The water formed in the reaction is co-distilled with the benzene and is removed by a Dean-Stark apparatus. After three hours, the reaction mixture is cooled, washed twice with dilute sodium bicarbonate (2×50 ml.) once with water (50 ml.) and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give the 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde ethyleneacetal.
Reaction SMILES: CO.C(OC(=O)[C:7](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])C.[C-:22]#[N:23].[K+]>O>[C:22]([CH:13]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=[O:9])#[N:23]
Reactant: [C-]#N
Reactant: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)OCC
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC(CC(=O)O)c1ccc(O)cc1
Temperature: 70 °C
Yield: 72.3 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (6 mL) and water (1 mL). To the stirred solvent was added 2-(4-hydroxy-benzylidene)-malonic acid diethyl ester (1 g, 3.8 mmol), followed by potassium cyanide (0.492 g, 7.6 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.6 g, yield: 72.3%); MS (ESI, 120 eV): m/z=190.0 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 12.69 (s, 1H), 9.58 (s, 1H), 7.22-7.24 (d, 2H), 6.75-6.78 (d, 2H), 4.28-4.40 (m, 1H), 2.77-3.12 (m, 2H).
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:23])C=CC.[CH3:24][OH:25]>ClCCl>[O:25]=[CH:24][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:23]
Reactant: CO
Reactant: CC=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Agent: O=[O+][O-]
Solvent: ClCCl
Product: O=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Reaction time: 1.25 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 75 minutes while stirring through a solution, cooled to -70°, of 12.0 g of (RS)-2-(2-buten-1-yl)-6-phenyl-1-indanone in 180 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.04 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 120 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 1.2 g (97%) of (RS)-2-(2-oxoethyl)-6-phenyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH:10](=O)[CH:11]=O>C(O)(=O)C.C([O-])(=O)C.[Na+].O>[N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=2[N:1]=[CH:11][CH:10]=1
Reactant: O=CC=O
Reactant: Nc1cccc(O)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cccc2nccnc12
Temperature: 60 °C

Procedure:
2,3-Diaminophenol (2 g) in 10 ml acetic acid and 20 ml 4M sodium acetate and a solution of oxalaldehyde (4.8 g) dissolved in 20 ml water were combined and the resulting mixture was heated at 60° C. for 1.5 h. After cooling to RT water (100 ml) was added and the mixture extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated to give quinoxalin-5-ol. MS (ESI+) for m/z 147 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][C:37]([NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4])([CH3:41])[CH3:40]
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Reactant: CC(C)(N)CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NC(C)(C)CO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 49 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 49%. Melting point: 181-182° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([OH:9])=O.[Cl-].[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([NH3+:32])[CH3:31])=[CH:26][CH:25]=1)=[O:23]>>[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([NH:32][C@H:30]([C:27]1[CH:28]=[CH:29][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][CH:26]=1)[CH3:31])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Reactant: O=C(O)c1c(Cl)sc(Cl)c1Cc1cccc(Cl)c1
Agent: [Cl-]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2Cc2cccc(Cl)c2)cc1

Procedure:
2,5-Dichloro-4-(3-chlorobenzyl)thiophene-3-carboxylic acid from Example 6, Step 1 (1.90 g, 5.91 mmol) was reacted with (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 under conditions similar to Example 1, Step 10. The crude product was purified by Combi Flash chromatography system (2-5% EtOAc/toluene in 20 min.) to afford the desired product as a white solid. MS (−APCI): m/z 480 (M−1)−.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:16]([OH:18])=O)=[N:9][C:10]=2[O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>>[OH:22][CH2:21][C:20]([NH:19][C:16]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:18])([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 133 b) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=401.1 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[Cl:8][CH2:9][NH2:10]>C1(C)C=CC=CC=1>[Cl:8][CH2:9][NH:10][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4]
Reactant: NCCl
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: COCC(C=O)NCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloromethylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-chloromethylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].O>CC(C)=O>[CH:17]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH2:10])=[CH:18][CH3:19]
Reactant: C=CCBr
Reactant: C=CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1ccccc1OC=CC
Yield: 98.7 %

Procedure:
200 g of 3-(2-hydroxyphenyl)propene, 226 g of potassium carbonate and 180 g of allyl bromide were stirred in 490 ml of acetone at reflux temperature for 23 hours and then cooled. One liter of water was added and the resultant layers were separated. The aqueous layer extracted with two volumes of diethyl ether, dried and stripped of solvent to give 256 g of 3-(2-propenyloxyphenyl)propene which was subsequently rearranged as described in Example 56 to the 2,6-di-propenylphenol intermediate. 52.2 g of said intermediate was dissolved in 500 ml of THF and chilled to -5° C. 300 ml of one molar borane was added over 15 minutes (maximum temperature not exceeding 18° C.), after which the mixture was stirred for 36 hours and chilled to 0° C. 80 ml of water was added over a 5 minute period, after which 120 ml of 5N sodium hydroxide was added all at once. When the temperature of the reaction mixture reached 1° C., 81 ml of 30% hydrogen peroxide was added over a 25 minute period and the mixture stirred for one hour and then concentrated. An additional 500 ml of water and 250 ml of ethyl acetate were added which, following workup, gave about 54 g of the desired 2,6-di(3-hydroxypropyl)phenol intermediate, m.p. 176°-187° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH2:6][CH2:5][N:4]([CH:9]([C:11]([OH:13])=[O:12])[CH3:10])[C:3]1=[O:14].O=[C:16]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:11]([CH:9]([N:4]1[C:3](=[O:14])[CH:2]([NH:1][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][S:7][CH2:6][CH2:5]1)[CH3:10])([OH:13])=[O:12]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C(=O)O)N1CCSCC(N)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1CSCCN(C(C)C(=O)O)C1=O
Yield: 74.8 %

Procedure:
6-Amino-4-N-(1-carboxyethyl)perhydro-1,4-thiazepin-5-one (0.05 g) is suspended in 1 ml of methanol. Ethyl 2-keto-4-phenylbutyrate (0.24 g) and acetic acid (0.02 g) are added. A 1M solution of sodium cyanoborohydride (0.75 ml) is added dropwise over a period of twenty hours. After removal of methanol, the reaction mixture is taken up in water and loaded onto a column of Dowex-50 (on the proton cycle). After thorough washing with water, the column is developed with 5% pyridine solution. Lyophilization of the eluent afforded the crude product (0.08 g), which is purified by preparative thin layer chromatography on silica gel (9:1 chloroform-methanol containing 5% formic acid). The product is obtained as an oil (0.07 g). The NMR spectrum is consistent with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,4-dichlorobenzene and isolated as white solid (6.6 mg, 37%). MS (m/e): 441.4 (MH+).