Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1>>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: CC(=O)Nc1ccc(NC2CCN([C@H](C)CCN)CC2)cn1

Procedure:
Using general procedure A with N-(5-amino-pyridin-2-yl)-acetamide (Bae, Jong Woo; et al., Tetrahedron Lett., 41, 2, 2000, 175-178) (1.00 g, 6.62 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.16 g, 6.95 mmol) and then using general procedure J afforded N-{5-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-pyridin-2-yl}-acetamide as a white solid (1.05 g, 52% over 2 steps).
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[N:16]=[C:15]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:33])=[C:28](F)[C:29]=3[Cl:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[C:14]=1[F:38]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:28]2[C:29]([Cl:31])=[C:30]3[C:25]([C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22][N:21]3[C:15]3[C:14]([F:38])=[C:13]([NH2:12])[C:18]([F:19])=[C:17]([F:20])[N:16]=3)=[CH:26][C:27]=2[F:33])[CH2:9]1
Reactant: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Reactant: NC1CNC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c1F
Yield: 50.2 %

Procedure:
To 1 ml dimethylsulfoxide solution of 70 mg of 3-aminoazetidine dihydrochloride and 250 mg of triethylamine at 80° C. was added 150 mg of 1-(4-amino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, and the solid content was collected by filtration, washed with ethanol, and dried to obtain 85 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:33])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:34])[CH:5]=1)([CH3:3])[CH3:2].[C:35]1([CH2:41][O:42][C:43](=[O:48])[CH2:44][CH2:45][CH2:46]O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH:1]([C:4]1[C:9]2[C:10](=[O:33])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:20]=[C:19]([C:29]([F:30])([F:31])[F:32])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:34][CH2:46][CH2:45][CH2:44][C:43]([O:42][CH2:41][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:48])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Reactant: O=C(CCCO)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture of 4-isopropyl-6-hydroxy-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (9.95 g; 19.3 mmol), 4-hydroxybutanoic acid phenylmethyl ester (4.49 g;23.16 mmol), DEAD (4.03 g; 23.16 mmol) was dissolved in 193 ml of THF at 0° C. and then (Ph)3P (6.068 g; 23.16 mmol) was added at 0° C. The above mixture was stirred overnight at room temperature, concentrated in vacuo, and the residue was purified by column chromatography (2×, silica gel; 12-50% ethyl acetate/hexane; methylene chloride/hexane, 1/4-30/1) to afford 4.55 g (34%) of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2 CH2Ph) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([Br:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirring suspension of 7-benzyl-8-bromo-3-methylxanthine (10.06 g, 30.0 mmol) in anhydrous dimethylsulfoxide was added sodium hydride (864 mg, 36.0 mmol). After stirring at room temperature for 30 min, (R)-5-acetoxy-1-chlorohexane (5.9 g, 33.0 mmol) was added. After stirring at 70-75° C. for 12 hours, the mixture was cooled to room temperature, quenched with water (600 ml) and stirred at room temperature for 4 hours. The precipitate was filtered to provide (R)-1-(5-acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (12.31 g, 86% yield) as a beige powder.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]O.Cl>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: Cc1ccccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccccc1C
Yield: 82 %

Procedure:
A solution of 2-methylbenzoic acid (18a) (5 g, 36.8 mmol) in MeOH.HCl (2.4M, 50 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure to give compound 18b (4.5 g, 82% yield), which was used without purification.
Reaction SMILES: C1([C:9]([O-:11])=[O:10])C(C)=CC=CC=1O.[K+].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:13]([CH2:14][C:9]([OH:11])=[O:10])(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Agent: [K+]
Product: O=C(O)CC(=O)c1ccccc1
Yield: 9.4 %

Procedure:
By operating as in Example 1, starting from 6.75 g of potassium meta-cresolate and from 5.5 g of acetophenone, 0.55 g of benzoylacetic acid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7][CH2:6]2.BrN1C(=[O:21])CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:9]=1[C:8]([OH:7])=[O:14])=[O:21]
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C=O)c(C(=O)O)cc1OC
Yield: 59.4 %

Procedure:
A mixture of 5,6-dimethoxy-3H-isobenzofuran-1-one (10 g, 51.5 mmoles), obtained as described in example 1, under N2 in CCl4 (250 ml), N-bromo-succinimide (13.88 g, 77.25 mmoles) and benzoyl peroxide (320 mg, 1.23 mmoles) was kept under reflux for 2 hours, then cooled, filtered and washed with a 10% Na2SO3 solution (200 ml), then with water, anhydrified and brought to dryness. The residue was taken up with 5% HCl (100 ml) and kept under reflux for 4 hours, then the solution was cooled, basified with NaOH, washed with ethyl acetate and slowly re-acidified to give a precipitate which was filtered, washed with water, dried on P2O5 under vacuum to give 6.43 g of the title compound (yield: 60%).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].Cl.CN(C)CCCN=C=NCC.[C:20](O)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C1CSC(=O)C1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a stirring solution of 1.71 g (14.75 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 2.22 ML (17.2 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-dimethylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4.96 g (17.7 mmol) of linoleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is recrystallized from pentane at -78° C. to give a solid which melts upon warming to room temperature giving 1.67 g (30%) of 4-hydroxy-3-[(Z,Z)-1-oxo-9,12-octadecadienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]([NH2:36])=[O:35].Cl.C(OCC)C>O1CCOCC1>[NH:1]([C:8]1[C:13]([CH2:14][NH:33][C:34]([NH2:36])=[O:35])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)CC(O)COc1ccc(Nc2ncc(CNC(N)=O)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 ml). Urea (12 mg, 0.19 mmol) and ethereal hydrogen chloride (1.0M; 0.19 ml, 0.19 mmol) were added, and the suspension was heated at 100° C. for 20 hours. Diethyl ether (20 ml) was added, and the precipitated solid collected by filtration. The solid was dissolved in 10% methanol solution in DCM (3 ml), and loaded on a Varian Mega Bond Elut column. The column was eluted with 0-2.5% methanol solution in DCM containing 0.5% aqueous ammonia solution. Concentration of the appropriate fractions and trituration of the residue with diethyl ether gave the product as a white crystalline solid (20 mg, 28%). NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.07 (d, 2H), 4.74 (br d, 1H), 5.85 (s, 2H), 6.62 (t, 1H), 6.80 (d, 2H), 6.98 (t, 1H), 7.27 (dd, 2H), 7.54 (d, 2H), 7.77 (d, 2H), 7.88 (s, 1H), 8.88 (s, 1H), 9.88 (s, 1H); MS (MH+): 452.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:22][C:23]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[O:25][N:24]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:32][C:29]2[CH:30]=[CH:31][C:26]3[O:25][N:24]=[C:23]([CH3:22])[C:27]=3[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1noc2ccc(N)cc12
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1ccc2onc(C)c2c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 3-methylbenzo[d]isoxazol-5-amine (Step 33.3). tR: 5.40 min (HPLC 1); tR: 1.20 min (LC-MS 2); ESI-MS: 439 [M+H]+ (LC-MS 2); Rf=0.77 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1>CCO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])/[C:8]/2=[CH:20]\[C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)/C(=C/c1ccc(F)cc1)C(=O)N2

Procedure:
To a solution of methyl-2-oxindole-5-carboxylate (4.764 g) in EtOH (100 mL) was added 4-fluoro-benzaldehyde (4.72 mL) in one portion, followed by piperidine (790 μL). The mixture was refluxed for 3 hours and the yellow precipitate was collected by filtration. The yellow product was used for the next step without further purification.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17](=O)[C:18](=[CH:30]N(C)C)[CH2:19][N+:20]([O-:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:30][C:18]2[CH2:19][N+:20]([O-:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:36]=[CH:35][C:16]=3[C:17]=2[N:5]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2

Procedure:
In two equal portions 28 g (150 mmole) of guanidine carbonate and 38 ml (150 mmole) of a 4.09M methanol solution of sodium methoxide was added over a 2 hr period to a solution of 7.0 g (20 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide in 210 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red solid. Recrystallization from a mixture of methanol and ethyl acetate gave the product as fine yellow needles, m.p. 320°-323° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4](F)[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([NH:17][CH:14]2[CH2:16][CH2:15]2)[CH:3]=1
Reactant: NC1CC1
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)cc1F
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(Cl)c(Cl)cc1NC1CC1
Temperature: 105 °C

Procedure:
A solution of 4,5-dichloro-2-fluorobenzenesulphonamide (3 g) in dioxane (30 mL) to which cyclopropylamine (3 mL) has been added is heated at 100-110° C. in a hermetically closed vessel for 24 hours. The solvent and the excess of amine are removed by distillation under reduced pressure and the residue is dissolved in methanol (20 mL). The methanolic solution is cooled on an ice bath, and water (60 mL) is added. The precipitate obtained (the title product) is collected by filtration, washed with water and dried. It is used in the following Step without being otherwise purified.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([S:21]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][N:11]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(COCC2CC2)cn1
Product: O=S(=O)(Nc1ccc(COCC2CC2)cn1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.06 g) and 3-chloro-benzenesulfonyl chloride (0.078 g) as an amorphous off-white solid (0.059 g). MS (ESI−): 351.1 ([M−H]−)
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:32]([N:34]([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:22][CH:23]=1)[CH2:35][CH3:36])[CH3:33]
Reactant: CCNCC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added diethylamine (36 μL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 37.6 mg of the title compound (67%).
Reaction SMILES: [I:1]I.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1>O.[NH4+].[OH-]>[I:1][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[OH:3])[C:8]([OH:10])=[O:9]
Reactant: II
Reactant: O=C(O)c1ccc(O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(O)c(I)c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O was added at once to a solution of 4-hydroxybenzoic acid (0.58 g; 4.18 mmol) in 25% NH4OH (22 ml). The reaction mixture turn instantly from black to colourless upon stirring at room temperature. This was evaporated under reduced pressure, diluted to 5 ml with H2O and acidified to pH˜5 with 10% citric acid. The solid formed was filtered off, washed with H2O (2×5 ml) and dried to give title compound (0.91 g; 89%), as colourless solid. 1H-NMR (DMSO-d6) 6.9 (d, 1H, J=8.5 Hz); 7.75 (dd, 1H, J=2, 8.5 Hz); 8.17 (d, 1H, J=2 Hz); 11.4 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29]CC)=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([OH:29])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Yield: 95.1 %

Procedure:
Ethyl 2-[4-(3-bromophenoxy)phenyl]-1-cyclohexyl-benzimidazole-5-carboxylate (1.0 g) obtained in Example 1 was dissolved in tetrahydrofuran (10 ml) and ethyl alcohol (10 ml), and 4N sodium hydroxide (10 ml) was added. The mixture was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 6N hydrochloric acid and the precipitated crystals were collected by filtration to give the title compound (0.9 g, yield 96%).
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][CH2:15][C:16]2([F:20])[F:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:25]([O:24][C:22]([NH:21][C@@:13]12[CH2:14][CH2:15][C:16]([F:20])([F:19])[C@@H:17]1[CH2:18][NH:11][CH2:12]2)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@]12CCC(F)(F)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]12CCC(F)(F)[C@@H]1CNC2
Yield: 102.5 %

Procedure:
[(1S,5R)-1-tert-Butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3,3,0]octan-3-yl]carboxylic acid benzyl ester (65.0 mg, 0.16 mmol) was dissolved in methanol (10 mL). 10% palladium-carbon (50% wet) (20 mg) was added, and the mixture was stirred in a hydrogen atmosphere for one hour. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to give 43 mg of the title compound as a colorless solid.
Reaction SMILES: [S:1]([Cl:3])Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11].N1C=CC=CC=1>C(Cl)Cl>[Cl:3][S:1][N:12]([C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=1)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14]
Reactant: ClSCl
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)N(SCl)c1ccc(Cl)c(Cl)c1

Procedure:
A 5.7-g (0.055 mol) sample of sulfur dichloride was added dropwise to a mixture of 11.7 g. (0.05 mol) of N-(3,4-dichlorophenyl)-N',N'-dimethyl urea and 4.7 g (0.06 mol) pyridine in 50 ml methylene chloride cooled in an ice bath. After the completion of the addition, the pyridine hydrochloride was filtered. Hexane was added to precipitate additional pyridine hydrochloride, which was removed by filtration. Evaporation of the resulting filtrate gave the product as a clear yellow oil. The NMR spectrum showed an N',N'-dimethyl singlet at 3.0 ppm (relative to tetramethylsilane). Elemental analysis showed: %S, calc. 10.7, found 10.7; %Cl, calc. 35.6, found 35.4; %C, calc. 36.1, found 36.4; %H, calc. 3.0, found 3.2; %N, calc. 9.3, found 8.7.
Reaction SMILES: [NH2:1][C:2]1[S:6]C(C2C=CC(F)=C(C=2)C#N)=[N:4][N:3]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22](O)=O)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:6][C:2]([NH2:1])=[N:3][N:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: N#Cc1cc(-c2nnc(N)s2)ccc1F
Product: CCOc1ccc(-c2nnc(N)s2)cc1OCC

Procedure:
5-(3,4-Diethoxyphenyl)-1,3,4-thiadiazol-2-amine TDZ INT-2 was synthesized in a similar manner as 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 using 3,4-diethoxybenzoic acid. LCMS-ESI (m/z) calculated for C12H15N3O2S: 265.3; found 266.1. [M+H]+, tR=2.58 min. 1H NMR (400 MHz, DMSO) δ 7.45-7.31 (m, 1H), 7.23 (dd, J=8.3, 2.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 4.31-3.94 (m, 4H), 3.4 (s, 2H), 1.42 (qd, J=6.8, 3.3 Hz, 6H).