Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=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.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cc(-c2ccc(C(=O)O)cc2)cnc1N
Temperature: 85.5 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6 mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.8 g, 70.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 90° C. over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45° C. The sticky solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12–13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 mL of water. The solids were discarded. The filtrate was cooled in an ice bath acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.5 g (83% yield) of 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid as a very dark solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH2:4].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.ClC1C(OC)=CC=C(Cl)C=1N[C:36](=[O:59])[N:37]([CH3:58])[C:38]1[CH:43]=[C:42]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)[N:41]=[CH:40][N:39]=1>O1CCOCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH:4][C:36](=[O:59])[N:37]([CH3:58])[C:38]1[CH:43]=[C:42]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([N:51]3[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]3)=[CH:49][CH:50]=2)[N:41]=[CH:40][N:39]=1
Reactant: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Agent: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2, 74 mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution in toluene (191 μl, 0.36 mmol, 1.35 eq.) under argon. The reaction mixture is stirred for further 6 h at room temperature under argon. Then, the solvent is evaporated and the colorless crystalline residue is taken up in dry toluene (2.5 ml). After the addition of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is stirred at 70° C. for 36 h under argon. After cooling the precipitate is filtered off, washed with toluene, methanol/ether 1:1, and ether to give a beige powder. The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min). The fractions containing the product are pooled, evaporated, and triturated with ether. The precipitate is filtered off, washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night to afford the title compound as colorless powder: m.p. 221° C. (dec.), ESI-MS: 546.1/548.0/550.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[S:27]1[CH2:31][CH2:30][N:29]=[CH:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:30][CH2:31][S:27][CH2:28]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: C1=NCCS1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCSC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to thiazoline via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide. MS (Q1) 459 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9]([C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(F)c1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1F

Procedure:
The title compound was prepared from rac-[(3-fluoro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 7) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 358.3 ((M−Si(CH3)2C(CH3)3)+H)+ (100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)[N:6]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].O>C(Cl)(Cl)Cl>[CH2:29]([S:31]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)[N:6]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: COC(=O)Cc1ccc(CCc2csc(N)n2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)OC)cc2)cs1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl {4-[2-(2-amino-1,3-thiazol-4-yl)ethyl]phenyl}acetate (2.00 g, 7.24 mmol) in chloroform (20 ml) was added N,N-diisopropylethylamine (6.3 ml, 36.2 mmol), and the mixture was cooled to 0° C. Ethanesulfonyl chloride (0.82 ml, 8.7 mmol) was added dropwise, and the mixture was stirred at 0° C. overnight. Iced water (40 ml) was added to the reaction mixture, and the mixture was stirred for 10 mins. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→1:0) to give methyl [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetate (1.76 g, yield 66%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>C(#N)C>[CH2:19]([O:18][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:14]([O:15][CH3:16])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:26][CH2:25][O:24][CH3:23])=[C:11]([NH2:17])[N:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Reactant: COCCN
Solvent: CC#N
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCNCCOC)c2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The compound obtained in Example 2-13 step (i) (500 mg) and (2-methoxyethyl)amine (303 mg) were dissolved in acetonitrile (5 ml) and stirred at 80° C. for 1 hour. The reaction mixture was cooled, filtered and purified by RPHPLC to give the titled compound as a white solid. Yield: 270 mg (55%); mp 99-100° C., MS APCI+ve 367 (M+H).
Reaction SMILES: C([NH:4][CH:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=O)C>Cl.O>[NH2:4][CH:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(CCCc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: NC(CCCc1ccccc1)C(=O)O

Procedure:
A stirred suspension of (±)-2-(acetylamino)-5-phenyl-pentanoic acid (0.5003 g, 0.002126 mol) in 2.8 M hydrochloric acid was refluxed for 2 hours, and the resulting brown solution was allowed to cool. A tan precipitate formed upon cooling. The solids were filtered off, and the filtrate was rotary evaporated to give a yellow gum. The gum was dissolved in hot water, gravity filtered, and allowed to cool. The mixture was made basic with 1 M sodium hydroxide to pH=5. The resulting precipitate was filtered off, washed with water, and dried in vacuo to give a yellow solid; yield 0.205 g (50%), mp=213-215° C.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].[Na].C[OH:22]>>[CH:1]1([CH2:4][C:5](=[O:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:18]([N+:15]([O-:17])=[O:16])[CH3:19])[CH2:3][CH2:2]1
Reactant: CC[N+](=O)[O-]
Reactant: CO
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1CC1
Agent: [Na]
Product: CC(C(C(=O)CC1CC1)c1ccc(Cl)cc1)[N+](=O)[O-]

Procedure:
The procedure of Example IX using 24.3 g of 1-cyclopropyl-3-(p-chlorophenyl)prop-2-en-1-one, 11 ml of nitroethane and 1.5 g of sodium in 120 ml of methanol, gives 25 g of 1-cyclopropyl-3-(p-chlorophenyl)-4-nitropentanone as an oily residue which is used in the crude state for the remainder of the operations.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:16]([O:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[O:31][CH3:32])[C:17]#[CH:18]>C(OCC)(=O)C>[CH:1]1([CH2:7][NH:8][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([O:31][CH3:32])[C:20]([O:19][CH2:16][C:17]#[CH:18])=[C:28]([O:29][CH3:30])[CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: NCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1c(OC)cc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of 3.6 g of cyclohexylmethylamine, 3.5 g of triethylamine and 10 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 75 ml of ethyl acetate and 7.4 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.7 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 1 of the present invention) represented by the formula:
Reaction SMILES: [N:1]1[C:2]([CH2:10]O)=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: OCc1nc2ccccn2n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a brown suspension of [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol (870 mg, 5.83 mmol) and triphenylphosphine polymer bound (2.94 g, 8.75 mmol) in dichloromethane (18 mL) was slowly added carbon tetrabromide (2.9 g, 8.75 mmol) at 0-5° C. The ice bath was removed after 5 min and the reaction mixture was stirred at RT overnight. The solvent was evaporated, the brown residue was suspended in ethyl acetate (100 mL) and the organic phase was washed with water (3×50 mL) and brine (1×50 mL). The aqueous layers were back-extracted with ethyl acetate (1×100 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as colorless waxy solid (1.35 g with 90% purity, 5.7 mmol, 98.2%) which was used without further purification for the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Cl>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cccc(CCl)c1
Reactant: O=C1CCNCC1
Product: COc1cccc(CN2CCC(=O)CC2)c1

Procedure:
1-(3-Methoxybenzyl)-4-piperidone is prepared from 4-piperidone and 3-methoxybenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:18][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Yield: 106.2 %

Procedure:
A mixture of 4-nitro-phthalonitrile (4.00 g), 4-methoxy-phenol (3.46 g) and potassium carbonate (6.39 g) in acetone (64 ml) was heated to reflux for 2 h. Reaction mixture was cooled and filtered. Filtrate was concentrated and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1N, 50 ml), water, and then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the product (6.14 g). 1H NMR (200 MHz, CDCl3) δ 6.70 (d, J=7.8 Hz, 1H), 7.21 (m, 2H), 6.96 (m, 4H), 3.84 (s, 3H).
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:23][CH2:24][CH3:25])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:9][C:8]=1[O:23][CH2:24][CH3:25])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4-dimethyl-6-ethoxy-1-tert-butyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-55, 0.023 g, 0.066 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(F)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(F)c2)N1
Yield: 101.9 %

Procedure:
Analogous to the procedure described for Compound 1A, Step B, 5-[4-(3-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.17 g, 8.71 mmol) was reduced with NaBH4 (165 mg, 4.35 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2) provided 5-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.23 g). 1H NMR (CDCl3) δ 7.27 (m, 1H), 6.94 (m, 3H), 6.38 (m, 1H), 3.82 (m, 1H), 3.66 (m, 1H), 2.79 (m, 1H), 2.67 (m, 1H), 2.33-2.21 (m, 3H), 1.92 (d, 1H), 1.75-1.40 (m, 5H); MS 252.2 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[ClH:20].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:20].[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=2)[NH2:8])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cccc(NCCN2CCOCC2)c1

Procedure:
3-Fluoronitrobenzene and 2-morpholin-4-yl ethylamine were added, and the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 and then treated with 4 M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain 3-[N-(2-morpholin-4-ylethyl)amino]aniline hydrochloride. F: 222.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH3:12].[CH2:14]1COCC1.C[Li].Cl>CCOCC>[C:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])=[CH2:14]
Reactant: C1CCOC1
Reactant: COc1ccc(C(C)=O)c(OC)c1
Agent: Cl
Agent: [Li]C
Solvent: CCOCC
Product: C=C(C)c1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.57 g of 1-(2,4-dimethoxyphenyl)ethanone are dissolved in 100 ml of ether and 50 ml of THF under nitrogen. 55 ml of 1.6M methyllithium in ether are added at −50° C. and the mixture is left stirring for 2 hours between −60° C. and −40° C. and then for 30 minutes between −40° C. and 0° C. and for 3 hours at RT. It is cooled to 0° C. and 70 ml of 2N HCl are added. After separation of the phases by settling, the aqueous phase is extracted with ether and the organic phase is then dried over Na2SO4. This solution is concentrated and the residue is then taken up in 150 ml of THF and 75 ml of 2N HCl are added. After stirring for 4 hours at RT, 100 ml of water are added and this mixture is then extracted with ether. The organic phase is washed with Na2CO3, with water and then dried over Na2SO4 and concentrated. The residue is chromatographed on silica, eluting with a DCM/pentane mixture (70/30 and then 60/40). 5 g of the expected compound are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([O-])=[O:13])[N:4]=1.[OH-].[NH4+:18]>>[F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:18])=[O:13])[N:4]=1
Reactant: [NH4+]
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Agent: [OH-]
Product: NC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Temperature: 100 °C

Procedure:
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (250 mg, 1 mmol) and 10 mL of ammonium hydroxide were added in a 20 mL sealed tube. The reaction mixture was heated to 100° C. and reacted for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (240 mg) as a white solid. The product was used directly in the next reaction without purification.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[CH:11]1[CH:12]=[CH:13][C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[S:16])=[CH:9][CH:10]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccccc1)c1ccc(NC(=S)Nc2ccccc2)cc1

Procedure:
Triethylamine (0.07 mL, 0.5 mmol) and phenyl isothiocyanate (2.1 mL, 11 mmol) were added sequentially to a solution of 4 (2.48 g, 10 mmol) in dry THF (10 mL). After heating under reflux for 48 h, all volatiles were removed under vacuum, and the resulting crude material was purified by flash chromatography on silica gel (hexanes/acetone, 3:1) to afford N-phenyl-4-[[(phenylamino)thioxomethyl]amino]benzenesulfonamide (5, also called LED209) (1.34 g, 35%) as a white solid, mp 160-162° C. 1H NMR (CD3COCD3, 300 MHz) δ 9.35 (br s, 1H), 9.30 (br s, 1H), 8.98 (br s, 1H), 7.80-7.72 (m, 4H), 7.51-7.47 (m, 2H), 7.38-7.33 (m, 2H), 7.28-7.16 (m, 5H), 7.08-7.04 (m, 1H); 13C NMR (CD3COCD3, 75 MHz) δ 180.2, 143.9, 138.9, 138.2, 135.2, 129.3 (2C), 129.1 (2C), 127.9 (2C), 125.8, 124.6 (3C), 122.8 (2C), 120.8 (2C).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][O:15][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-BOC-3-piperidinemethanol (0.50 g, 0.002 mmole) in DCM (10 mL) was added dropwise pyridine (2.42 mL, 0.03 mmole) followed by the addition of methanesulfonyl chloride (0.774 mL, 0.01 mmole). The reaction mixture continued stirring at RT overnight. The reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc (3×5 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield a crude oil, 68, which was used in the next step without further purification. LRMS: 193 (M+-BOC group).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]O.S([O-])(=O)(=O)C.[CH2:21]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:15])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCOCCOCCOCCOCc1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of tetrahydrofuran (140 mL) containing sodium hydride (0.43 g, 18 mmol) was added dropwise a solution of non-polydispersed tetraethylene glycol (3.5 g, 18 mmol) in tetrahydrofuran (10 mL) and the reaction mixture was stirred for 1 h. Then mesylate of non-polydispersed tetraethylene glycol monobenzylether 40 (6.0 g, 16.5 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed, CH2Cl2, 250 mL) and the filtrate was washed H2O, dried MgSO4, and evaporated to dryness. The resultant oil was chromatographed (silica, ethyl acetate/methanol, 10:1) and chromatographed (silica, chloroform/methanol, 25:1) to afford the non-polydispersed title compound as a clear oil (2.62 g, 34% yield).