Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH2:28]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH2:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>CN(C=O)C.[Pd].ClCCl.CO.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>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([CH2:28][CH2:29][CH3:30])[CH:3]=3)[S:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with allyltri-n-butyltin, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-para-cresol in DMF, then hydrogenation with palladium on charcoal in dichloromethane and methanol. ES-MS m/e (%): 412 (M+H+, 100).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.O=[C:12]1[CH2:17][CH2:16][N:15](C(OCCCC)=O)[CH2:14][CH2:13]1.Cl>C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:9][C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1Br
Reactant: CCCCOC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: Brc1cccc2c3c([nH]c12)CCNC3
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of (2-bromophenyl)hydrazine hydrochloride (2.24 g, 10.0 mmol; Aldrich) and tent-butyl 4-oxopiperidine-1-carboxylate (1.99 g, 10.0 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) in a sealed tube and stirred at 100° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between NaOH (1.0 M, 200 mL) and CH2Cl2 (3×200 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-80% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.86-2.94 (m, 2H), 3.24 (t, J=5.9 Hz, 2H), 4.04 (t, J=1.5 Hz, 2H), 6.89 (t, J=7.8 Hz, 1H), 7.21 (dd, J=7.6, 0.8 Hz, 1H), 7.33 (dd, J=8.0, 0.8 Hz, 1H); MS (APCI) m/z 292/294 (M+CH3CN+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][OH:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:14][OH:15])[CH2:9][CH2:10]2)=[O:25])[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: OCC1(c2ccc(Cl)cc2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(CO)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL flask was taken 500 mg of [4-(4-chloro-phenyl)-piperidin-4-yl]-methanol (2.44 mmol, 1.0 equiv), 591 mg of (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (2.44 mmol, 1.00 equiv), 1.29 g BOP (2.92 mmol, 1.2 equiv), 1.36 mL TEA (9.75 mmol, 4.00 equiv) and 15 mL NMP. A stir bar was placed in the flask and the mixture stirred overnight at room temperature under N2. The crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-hydroxymethyl-piperidin-1-yl]-ethanone. MS (ES) M+H expected=450.0, found=450.3
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[S:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[S:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: C=Cc1cc2c(nn1)SCCO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)SCCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.2 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]oxathiino[3,2-c]pyridazine (200 mg, 1.11 mmol) in 1,4-dioxane/water (10 ml/2 ml) was treated with an aqueous solution of osmium tetroxide (4% w/v, 1 ml) and sodium periodate (0.55 g), initially stirred in an ice-bath for 1.5 hours, then allowed to warm to room temperature. After 1.5 hours the mixture was treated with sodium bicarbonate solution, evaporated to dryness and dissolved in 1,4-dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (20 g), and chromatographed, eluting with 0-100% ethyl acetate in hexane, to afford a pale yellow solid (63 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[C:3]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(C2(O)CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1cc(Br)c(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(4-bromo-1-methyl-1H-pyrazol-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:23][CH2:22][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:20]([F:21])=[C:12]3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[N:43]=2)[C:27]1=[O:49].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[F:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]2[CH2:22][CH2:23][N:10]([C:6]3[N:5]=[CH:4][CH:3]=[C:2]([C:30]4[CH:29]=[C:28]([NH:41][C:42]5[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[N:43]=5)[C:27](=[O:49])[N:26]([CH3:25])[CH:31]=4)[C:7]=3[CH:8]=[O:9])[C:11](=[O:24])[C:12]=12
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Reactant: Cc1nccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1nccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3C=O)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 57.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (150 mg, 0.43 mmol), 213b (147 mg 0.43 mmol), Pd(dppf)Cl2 (35 mg, 0.043 mmol), sodium acetate (71 mg, 0.86 mmol), K3PO4 (182 mg, 0.86 mmol), water (0.5 mL), and acetonitrile (15 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2.5 h. After cooling to room temperature the reaction was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 213c as a yellow solid (130 mg, 57%). MS-ESI: [M+H]+ 528.2.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][C:8]([Cl:30])=[C:9]3[C:14]([C:13](=[O:15])[O:12][C:11]([C:16]4[N:17]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=4)=[N:10]3)=[C:5]2[NH:4][N:3]=1.C(#N)C.O.[CH:35]([NH2:38])([CH3:37])[CH3:36]>[Cl-].[Na+].O>[CH:35]([NH:38][C:13]([C:14]1[C:9]([NH:10][C:11]([C:16]2[N:17]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:12])=[C:8]([Cl:30])[CH:7]=[C:6]2[C:5]=1[NH:4][N:3]=[C:2]2[Br:1])=[O:15])([CH3:37])[CH3:36]
Reactant: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)Nc2c(Cl)cc3c(Br)n[nH]c3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
To a suspension of 120 mg (0.24 mmol) of the above 3-bromo-5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 2.4 mL of a mixture acetonitrile:H2O 4:2 (v/v) is added 60 μL (0.71 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:2) affords 56 mg (42%) of a white solid; LC/MS:568/570 (M+H)+, m.p.: 217-218° C.
Reaction SMILES: C(Cl)(=O)C.[C:5]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[C:20]3[CH:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[CH:23]=[CH:24][C:19]=3[S:18][C:17]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:16]=3[CH2:15]2)[CH2:10][CH2:9]1)(=O)[CH3:6]>C(Cl)(Cl)Cl>[CH2:5]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[C:20]3[CH:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[CH:23]=[CH:24][C:19]=3[S:18][C:17]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:16]=3[CH2:15]2)[CH2:12][CH2:13]1)[CH3:6]
Reactant: CC(=O)N1CCN(C2Cc3ccc(F)cc3Sc3ccc(C(C)C)cc32)CC1
Solvent: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN1CCN(C2Cc3ccc(F)cc3Sc3ccc(C(C)C)cc32)CC1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 5.0 g 3-fluoro-8-isopropyl-10-piperazine-10,11-dihydrodibenzo(b,f)thiepin in 20 ml chloroform is stirred and treated dropwise with 2.2 g acetyl chloride. The mixture is then left overnight at room temperature. Then, the separated hygroscopic hydrochloride of the product is filtered with suction, suspended in water and the base released by an excess of 20% sodium hydroxide solution and isolated by extraction with chloroform. Processing of the extract yields 5.4 g (95%) crude base of 10-(4-acetylpiperazino)-3-fluoro-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin which crystallizes from a mixture of benzene and petroleum ether and melts in a pure state at 164.5°-166° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](O)=[O:8].[BH4-].[Na+]>S(Cl)(Cl)=O.C(COC)OC>[Br:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: OCc1cc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
Under a nitrogen atmosphere, a suspension of 2-bromo-5-phenylthiophene-3-carboxylic acid (11d) (260 mg, 0.92 mmol) in thionyl chloride (2 mL) was refluxed for 30 minutes. The reaction mixture was concentrated in vacuo and co-evaporated with toluene to provide an oil which was slowly added to a solution of sodium borohydride (81 mg, 0.92 mmol) in anhydrous dimethoxyethane (8 mL) under a nitrogen atmosphere at 10° C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated in vacuo. Water (8 mL) was added to the residue, followed by acetic acid (1.5 mL) to ensure sodium borohydride decomposition. The mixture was basified with 28% ammonium hydroxide until pH 8 and extracted with ethyl dichloromethane (2×10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness to provide the desired alcohol (11e) (220 mg, 0.82 mmol, 89%) as a pink oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].O1CCCC1>O>[C:12]([NH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1c(C)cccc1C(=O)O
Temperature: 80 °C
Reaction time: 13 h
Yield: 38 %

Procedure:
A mixture of 1.51 g of 2-amino-3-methylbenzoic acid, 1.0 g of acetic anhydride and 20 ml of tetrahydrofuran was stirred at 80° C. for 13 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate to obtain 0.72 g of 2-acetylamino-3-methylbenzoic acid of the formula:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].C(ON=O)(C)(C)C>C(O)(=O)C.C1COCC1>[F:9][C:8]([F:10])([F:11])[C:6]1[CH:5]=[C:4]2[C:3]([S:12](=[O:14])(=[O:13])[NH:15][C:16]3[C:17]2=[CH:18][CH:19]=[C:20]2[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]2)=[CH:2][CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
2-Amino-N-quinolin-8-yl-4-trifluoromethyl-benzenesulfonamide (Example Compound 35) (50 mg, 0.14 mmol) was dissolved in acetic acid/THF (1:1; 2 ml) and cooled to 0° C. Tert-butylnitrite (16.2 μl, 0.14 mmol) was added and the mixture was stirred for 1 h keeping the temperature between 0° C. -5° C. The reaction was quenched with water (3 ml), while keeping the temperature between 0° C. -5° C., and the organic phase was extracted with EtOAc (10 ml). The combined organic phases were washed with sat. sodium bicarbonate and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (11 mg, 23%)
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][NH:10][CH2:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].CCN(CC)CC.C(OC([N:28]([C:36]1[C:41]([C:42]2[O:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:45][N:46]=2)=[N:40][C:39](Br)=[CH:38][N:37]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([S:3]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][N:10]([C:39]3[N:40]=[C:41]([C:42]4[O:43][C:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[N:45][N:46]=4)[C:36]([NH2:28])=[N:37][CH:38]=3)[CH2:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)N1CC2CNCC2C1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC2CN(c3cnc(N)c(-c4nnc(-c5ccccc5)o4)n3)CC2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
2-ethylsulfonyl-3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (36.34 mg, 0.1779 mmol) and Et3N (54.01 mg, 74.39 μL, 0.5337 mmol) were added to a solution of tert-butyl N-tert butoxycarbonyl-5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-ylcarbamate (100 mg, 0.1779 mmol) in DMF (2 mL) and the resulting solution heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL) and washed successively with water (2×5 mL) followed by brine (1×5 mL). The organic layer was concentrated in vacuo to leave a solid. The solid was dissolved in CH2Cl2 (10 mL) and trifluoroacetic acid (405.7 mg, 274.1 μL, 3.558 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and the reaction mixture then concentrated in vacuo to an oil. The oil was redissolved in CH2Cl2 (20 ml) and concentrated in vacuo to leave a solid. The solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the product (34.4 mg, 40% yield); 1H NMR (400 MHz, DMSO) d 1.25 (t, 3H), 3.1-3.2 (m, 4H), 3.25-3.3 (m, 2H), 3.4-3.45 (m, 2H), 3.5-3.7 (m, 4H), 6.75 (s, 2H), 7.6-7.65 (m, 3H) and 8.05-8.1 (m, 2H) ppm; MS (ES+) 442.1
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:35][CH2:36][CH3:37])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 68 %

Procedure:
A mixture of 1.17 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.41 g of 4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy acetic acid ethyl ester, 1.66 g of anhydrous potassium carbonate and 0.1 g of potassium iodide in 15 ml of anhydrous acetone and 15 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The solvent was removed in vacuo, 50 ml of 0.1N hydrochloric acid was added to the residue and the product was extracted with methylene chloride. The dried, over sodium sulfate, extract was concentrated in vacuo and the crude product was crystallized from methanol to yield 2.1 g, mp 45°-46°, (68% yield) of [4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30].O>O1CCCC1>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCCOC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1
Temperature: 70 °C

Procedure:
4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (300 mg, 1.1 mmol) and N-ethyldiisopropylamine (0.56 ml, 3.4 mmol) were dissolved in tetrahydrofurane (11 ml) and 2-methoxyethyl chloroformate (0.19 ml, 1.4 mmol) were added over 5 min. Then the mixture was heated to 70° C. for 3 h. The mixture was cooled to room temperature, water added and extracted twice with ethyl acetate. TRhe combined organic phases were dryed with Na2SO4 and evapprated to dryness. The title compound was obtained as off-white solid (52%). MS: m/e=368 (M+H+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:27][C:23]1[N:22]=[C:21]([CH2:20][NH:7][C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:11]=[N:10][CH:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(CN(C(=O)OC(C)(C)C)c2cncc(N3CCNCC3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CNc2cncc(N3CCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6-methyl-pyridin-2-yl methyl)-(3,4,5,6-tetrahydro-2H-[1,2′]-bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4l (196.9 mg, 0.51 mM) in methylene chloride (2 mL) was treated with trifluoroacetic Acid (0.39 mL, 5.12 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution and the pH of the aqueous layer brought to approximately 10 using 1N NaOH. The reaction mixture was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, dried (Na2SO4), and concentrated to dryness to afford the desired product I-4m.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16])=[O:4].[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]([N:5]([CH3:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16])=[O:4]
Reactant: CNC
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C(=O)CCl
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])cc1N(C)C(=O)CN(C)C
Yield: 81 %

Procedure:
2-Chloro-2'-methoxy-N-methyl-5'-nitroacetanilide (D86) (1.01 g, 3.9 mmol) and dimethylamine (33% in IMS, 2 ml) were stirred in ethanol (10 ml) for 3 days. After evaporation to dryness in vacuo, the crude product was partitioned between 2M HCl and ethyl acetate. The aqueous portion was basified with potassium carbonate solution, and extracted with chloroform. The extract was dried (Na2SO4) and evaporated in vacuo to give the title compound as a dark oil (0.85 g, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Yield: 94.6 %

Procedure:
0.2 g (0.00105 mol) of 1-benzyl-4-hydroxypiperidine and 0.26 ml (0.00184 mol) of triethylamine were dissolved in 10 ml of toluene and treated with 0.11 ml (0.00084 mol) of 2-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.262 g (95%) of 1-benzyl-piperidin-4-yl 2-chloro-benzoate was obtained as white crystals; m.p. 143°-144°.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-].Cl>O1CCOCC1>[CH3:25][CH:22]1[CH2:21][CH2:20][CH:19]([C:17]([N:10]([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[C:9]2[CH:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:18])[CH2:24][CH2:23]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (20 mg, 0.045 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (0.5 ml) and then LiOH 1N (135 ul, 0.135 mmol) was added. After 4 hours of stirring at room temperature, the reaction mixture was acidified to pH 3-4 with a 10% solution of hydrochloric acid and then the solvents were removed. It was further diluted in cold water (1 ml) and filtered out to give 16 mg (84%) of 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 41).