Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1>CO>[CH3:12][N:13]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:1])=[O:30])[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1
Reactant: CN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCCC(=O)N(C)CCc1c[nH]c2ccccc12
Yield: 16231 %

Procedure:
30 ml of methanol and 10 mg of p-toluenesulfonic acid were added to 2.88 g of N-methyl-N-(4-carboxybutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-carboxybutanamido)ethyl]-indole). The mixture was refluxed for 5 hours. After the reaction was completed, the mixture was concentrated to about 10 ml. The concentrated mixture was diluted with an aqueous saturated sodium bicarbonate solution under cooling and then extracted with ethyl acetate. The extract was washed with water, dried and then concentrated to dryness. The residue thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane. 2.85 g of N-methyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. M.p. 101°-102° C. Yield: 95%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(F)c(C)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(F)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 6-fluoro7-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. Yellow solid, ISP MS: 379.4 (M+H)+
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15]>ClC(Cl)C>[N:2]1([C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15])[CH2:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCOC(=O)C1=CCN(C)CC1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1=CCN(C(=O)OC(C)Cl)CC1
Temperature: 25 °C

Procedure:
Ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate (47 g, 278 mmol) in dichloroethane (800 mL) was treated with α-chloroethyl chloroformate (50 g, 350 mmol) dropwise at 0° C. The mixture was warmed to room temperature, refluxed for 2 hours, and then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and the residue was purified via column chromatography (SiO2, ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 6.88 (m, 1H), 6.61 (q, 1H), 4.22 (q, 2H), 4.16 (m, 2H), 7.35 (d, 2H), 3.58 (m, 2H), 2.44 (m, 2H), 1.82 (d, 3H), 1.30 (t, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:6]=1)(=O)=O.[C-:30]#[N:31].[Na+]>C(#N)C.CS(C)=O>[N:14]1([CH2:13][CH2:12][O:11][C:9]2[CH:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:6]=[C:5]([C:30]#[N:31])[N:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: N#Cc1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
A mixture of 2-methanesulfonyl-4-(2-piperidin-1-yl-ethoxy)-6-(3-trifluoromethyl phenyl)-pyrimidine (50 mg, 0.12 mmol) and sodium cyanide (12 mg, 0.23 mmol) in acetonitrile (1.5 ml) with a few drops of DMSO was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was chromatographed over silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 95/5) to yield 31 mg of the above titled compound, yield: 70%. HPLC: 99.5%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=[O:11]>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([OH:11])([CH3:12])[CH3:9])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Fc1ccc(Br)nc1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2-bromo-5-fluoropyridine (1.0 g, 5.7 mmol) in diethyl ether (20 ml) under a nitrogen atmosphere at −78° C. was added sesBuLi (4.87 ml of a 1.4 M solution in heptanes, 6.8 mmol). The resulting dark orange solution was stirred for 30 minutes at −78° C. and acetone (0.84 ml, 11.4 mmol) was then added dropwise. After a further 1 hour the reaction temperature was raised to room temperature giving a clear yellow solution. This was quenched with water (2 ml), diluted with EtOAc (30 ml) and washed with water (2×20 ml), dried (MgSO4), filtered and concentrated. The residue was purified via silica FCC (using a gradient of eluents; 9:1 to 4:6 hexane/diethyl ether) to give the title product as colourless oil (395 mg, 45%).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:23]>O>[Br:23][CH2:3][CH2:2][CH:1]=[C:4]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: OC1(C2CC2)c2ccccc2Sc2ccccc21
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: BrCCC=C1c2ccccc2Sc2ccccc21
Reaction time: 0.5 h

Procedure:
To the above crude alcohol (25.2 g) was added glacial acetic acid (120 ml). The mixture was cooled on an ice-bath and a mixture of glacial acetic acid (60 ml) and 47% hydrobromic acid (30 ml) was added. The mixture was stirred for 30 minutes, poured into water (600 ml) and extracted with diethyl ether (3×200 ml). The combined organic phases were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 19.5 g of crude 9-(3-bromo-1-propylidene)-9H-thioxanthene. Rf =0.35 (SiO2 ; THF/heptane=1:9).
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O:18]CC)=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:2].[OH-].[K+].Cl>C(O)C.O>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([C:16]([OH:18])=[O:17])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 90.9 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl 4-ethylpiperidine-1,4-dicarboxylate (Intermediate 21-step 2, 10.0 g, 63.69. mmol) in 50 ml ethanol was added potassium hydroxide (8.0 g, 95.5 mmol) and the contents were refluxed for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, acidified with 5% HCl and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (8.2 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, 1H); 2.82 (s, 2H); 2.92-2.95 (m, 1H); 3.46-3.52 (m, 3H); ES Mass: 280 (100%), [M+Na].
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].N1C=CC=CC=1.Cl[C:33]([O:35][CH3:36])=[O:34]>ClCCl>[Cl:25][C:8]1[CH:9]=[C:10]([F:24])[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:5])=[O:4])[C:33](=[O:34])[O:35][CH3:36]
Reactant: COC(=O)Cl
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl

Procedure:
To a mixture of the title compound of Example 1, Step H (0.32 g, 0.7 mmol) and pyridine (0.5 mL) in dichloromethane (5 mL) was added a solution of methyl chloroformate (0.09 g, 0.95 mmol) in dichloromethane (1 mL) at room temperature. After completion of the reaction (2 h), the solvents were removed in vacuo and the title compound of Step A, a compound of this invention, was isolated by flash chromatography (0.31 g, 95%) as a white solid melting at 108-115° C. 1H NMR (CDCl3) δ 7.40 (m, 2H), 5.42 (m, 1H), 5.36 (dd, 1H), 4.92 (dd, 1H), 4.60 (m, 1H), 4.04 (m, 1H), 3.82 (s, 3H), 3.60 (dd, 1H), 2.64 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:25][CH2:24]1
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: OC1CCNCC1
Solvent: CC(C)O
Product: O=C(CN1CCC(O)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 26.4 %

Procedure:
A mixture of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (93 mg, 0.272 mmol) and 4-hydroxypiperidine (138 mg, 1.35 mmol) in isopropanol (5 mL) was heated at reflux for 1 h. The solvent was evaporated in vacuo and the crude reaction mixture was purified by preparative LCMS to afford 2-(4-hydroxypiperidin-1-yl)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (26 mg, 26% yield). LCMS calculated for C21H22N4O2 (M+H): 363.43. found 363.40. 1H-NMR (CD3CN, 400 Mhz) δH: 9.55 (1H, br.), 9.25 (1H, s), 8.40 (1H, m), 8.00-8.05 (2H, m), 7.85-7.90 (1H, m), 7.65-7.80 (3H, m), 7.40-7.48 (1H, m), 3.65 (1H, m), 3.22 (2H, s), 2.85-3.15 (OH and 2H, br. and m), 2.40-2.50 (2H, m), 1.82-1.92 (2H, m), 1.55-1.68 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].I([O-])(=O)(=O)=[O:15].[Na+]>CO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:15])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CSCc1ccc(O)c(C(C)=O)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(CS(C)=O)ccc1O
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of 2'-hydroxy-5'-(methylthiomethyl)acetophenone (2.20 g, 11.0 mmol) in 70 mL MeOH cooled in an ice bath was added a solution of sodium metaperiodate (2.49 g, 12.1 mmol) in 115 mL water. The resulting cloudy mixture was stirred two hours with cooling then partially concentrated in vacuo to remove methanol. The remaining aqueous mixture was extracted with chloroform (3×125 mL). The extract was washed with 50 mL water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give crude product which was recrystallized from n-butylchloride to give 1.39 g (60%) product, as a pale yellow solid, mp 95°-97° C.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]([N:12]=C=O)([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]>O>[ClH:1].[CH2:2]([C:5]([NH2:12])([CH2:6][CH2:7][CH3:8])[CH2:9][CH2:10][CH3:11])[CH2:3][CH3:4]
Reactant: CCCC(CCC)(CCC)N=C=O
Agent: Cl
Solvent: O
Product: CCCC(N)(CCC)CCC
Temperature: 90 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Into a three-necked flask equipped with a mechanical stirrer, a dropping-funnel, a thermometer and a condenser, were introduced 200 ml of water and 90 ml of concentrated hydrochloric acid (d=1.19). The acid solution was heated to 90° C and then, under vigorous stirring, 105 g of 1,1-di-n-propyl-n-butylisocyanate, prepared as previously described, were slowly added. The operation of addition lasted one hour after which the reaction medium was heated for a further 4 hours at a temperature between about 95° and 100° C. The mixture was then cooled to about 0° C and the colourless crystals so obtained were filtered off dried by exposure to the air and then in a dessicator in the presence of potassium hydroxide. In this manner, 99 g of 1,1-di-n-propyl-n-butylamine hydrochloride were isolated in the form of a white crystalline powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[C:20]([OH:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:21][C:20]2[C:19]([F:22])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=2[F:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 10.8 g of 4-acetoxybenzoyl chloride in dry acetonitrile was treated with 10 g of pentafluorophenol, and stirred at 0° C. whilst 4.4 ml of pyridine was added dropwise. The solution was permitted to warm to room temperature then heated to reflux temperature until the reaction was complete. Solvent was evaporated in vacuo and the residue obtained partitioned between ethyl acetate and water. The organic solution was washed with further portions of water and brine and dried over magnesium sulphate. Evaporation afforded 18 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCc1ccncc1Br
Product: CCCc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-propylpyridine (Intermediate 49), the title compound was obtained as a dark orange sticky solid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:23][C:24]1[C:28]([C:29]2[CH:30]=[C:31](C3C(C)=CC=C4C=3C=CC=N4)[C:32]3[NH:36][C:35](=[O:37])[NH:34][C:33]=3[CH:38]=2)=[C:27]([CH3:50])[O:26][N:25]=1>>[CH3:23][C:24]1[C:28]([C:29]2[C:38]3[NH:36][C:35](=[O:37])[NH:34][C:33]=3[CH:32]=[C:31]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:16])[CH:30]=2)=[C:27]([CH3:50])[O:26][N:25]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc(-c2c(C)noc2C)c2[nH]c(=O)[nH]c2c1

Procedure:
4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one was synthesized using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:23]1[C:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1.C(N(C(C)C)C(C)C)C.C(OC([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][CH:60]2[CH2:62][CH2:61]2)[CH2:55][CH2:54]1)=O)(C)(C)C.C>CN(C)C=O>[CH:60]1([N:59]([CH:56]2[CH2:57][CH2:58][NH:53][CH2:54][CH2:55]2)[C:32](=[O:34])[C:31]2[CH:30]=[CH:29][C:28]([C:27]3[O:23][CH:24]=[N:25][CH:26]=3)=[CH:36][CH:35]=2)[CH2:62][CH2:61]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (6.10 g) is added to a solution of 4-oxazol-5-yl-benzoic acid (3.00 g) and ethyldiisopropylamine (5.56 mL) in N,N-dimethylformamide (50 mL) at room temperature. The solution is stirred for 10 min prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (4.57 g). The resulting mixture is kept at room temperature over night. The mixture is treated with activated charcoal and filtered through a pad of basic aluminum oxide. The pad is washed with N,N-dimethylformamide/methanol (9:1) and the combined filtrates are concentrated in vacuo. The residue is dissolved in 1,4-dioxane (35 mL), a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) is added and the resulting mixture is stirred at room temperature for 2 h. The solvent is evaporated and the residue is taken up in water. The resulting mixture is washed with dichloromethane, basified with NaOH solution and extracted with dichloromethane. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to afford the title compound. LC (method 1): tR=0.70 min; Mass spectrum (ESI+): m/z=312 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[C:26]([F:29])([F:28])[F:27])[CH2:15][C@H:14]1[CH3:30])(=[O:12])=[O:11])[C:5]#[N:6].[OH:31]S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[C:26]([F:28])([F:27])[F:29])[CH2:15][C@H:14]1[CH3:30])(=[O:11])=[O:12])[C:5]([NH2:6])=[O:31]
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C#N)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of (R)-3-chloro-4-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)benzonitrile (290 mg, 0.626 mmol) in H2SO4 (3 mL) and TFA (6 mL) was stirred at rt overnight. To this was added ice-water. The precipitate was collected by filtration and washed with water to give the desired product as a white solid (267.5 mg, 89%). HRMS: calcd for C19H18ClF4N3O3S+H+, 480.07663. found (ESI-FTMS, [M+H]1+), 480.07642.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=1[CH2:43]Cl>>[Br:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=1[CH2:43][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: Cc1ccc(CCl)c(Br)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2Br)cc1

Procedure:
Analogously to Method D, 1.45 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.80 g of 2-bromo-1-chloromethyl-4-methylbenzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.56 (1:1 EtOAc-heptane); Rt=6.53.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:19]=3)[S:13][C:6]=12.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[N:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:19]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:32]=1
Reactant: O=c1ncc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1CCN1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution the compound 415 (81 mg, 0.16 mmol) in ethanol (1 mL) and water (0.5 mL) was added NH4Cl (9 mg, 0.16 mmol) and iron powder (73 mg, 1.30 mmol). The mixture was stirred at 80° C. for 45 min, filtered through celite, and the solvent was evaporated to give title compound (416). MS (m/z): 468.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1>C(Cl)Cl>[F:13][C:2]([F:1])([F:14])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CCC(O)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Product: CCC(=O)c1ccc(C(F)(F)F)nc1
Yield: 96 %

Procedure:
Dissolve 1-[6-(trifluoromethyl)-3-pyridyl]propan-1-ol (2.010 g, 9.796 mmol) in DCM (40 mL). Add 3,3,3-Triacetoxy-3-iodophthalide (4.712 g, 10.776 mmol), and stir for 16 hours. Dilute with DCM (100 mL). Wash with 0.5 N NaOH (100 mL). Dry the organic extracts over Na2SO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound (1.910 g, 96% yield) as a white solid. 1H NMR (400.43 MHz, d6-DMSO) δ 9.21 (dd, J=0.5, 1.4 Hz, 1H), 8.51-8.49 (m, 1H), 8.03 (dd, J=0.7, 8.1 Hz, 1H), 3.12 (q, J=7.1 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:17](OC)=[O:18])([CH3:4])([CH3:3])[CH3:2].ClCCl.CC(C[AlH]CC(C)C)C>O>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[CH2:17][OH:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2cc(C(C)(C)C)[nH]c12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(CO)c2[nH]1
Yield: 72.2 %

Procedure:
To a solution of methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (6.15 g, 22.3 mmol) and dichloromethane (30 ml) was added DIBAL-H (1.0 M, 20 mL, 20 mmol) at 78° C. The mixture was stirred for 1 h before water (10 mL) was added slowly. The resulting mixture was extracted with EtOAc (120 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-tert-butyl-5-nitro-1H-indol-7-yl)methanol (4.0 g, 73%), which was used in the next step directly.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[NH:23][C:24](=[S:28])[S:25][C:26]=1[CH3:27]>>[CH3:21][C:22]1[N:23]([CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:24](=[S:28])[S:25][C:26]=1[CH3:27]
Reactant: Cc1[nH]c(=S)sc1C
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2c(C)c(C)sc2=S)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 92 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 4,5-dimethylthiazole-2(3H)-thione. m/e+ 380 for C21H22N3S2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.08 (dd, J=1.4, 9.1 Hz, 1H), 4.83 (s, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 156.250, 149.085, 145.149, 144.391, 137.642, 131.159, 129.347, 128.748, 128.217, 127.929, 122.090, 121.794, 116.828, 113.612, 30.301, 21.308, 18.449, 14.688, 11.374 ppm.