Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.[Br:14]N1C(=O)CCC1=O>C(O)(=O)C>[Br:14][C:4]1[C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(Cl)c(C)cc1O
Solvent: CC(=O)O
Product: CCC(=O)c1cc(Cl)c(C)c(Br)c1O
Temperature: 65 °C

Procedure:
The 1-(5-chloro-2-hydroxy-4-methylphenyl)propan-1-one (1.6 g, 8.0 mmol) was dissolved in acetic acid (20.0 mL) and N-bromosuccinimide (1.7 g, 9.7 mmol) was added. The reaction was warmed in an oil bath to 65° C. and monitored by LC/MS. After heating for 3 h the reaction was complete. This was allowed to cool to room temperature and was concentrated in vacuo. The residue was diluted with EtOAc and washed with water (twice), brine, dried over magnesium sulfate and concentrated to give 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)propan-1-one as an amber oil. This oil was dissolved in DMF (10.0 mL) and potassium carbonate (3.3 g, 24 mmol) and methyl iodide (0.75 mL, 12 mmol) were added. The reaction was stirred at 65° C. for 18 hours. The reaction was complete, and the reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one as an oil (1.8 g, 81%). LCMS calculated for C11H13BrClO2 (M+H)+: m/z=290.9, 292.9. found: 290.8, 292.9.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20]C(C)(C)C)=[O:19])[CH:12]=[CH:13][CH:14]=1>>[OH:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:25][C:17]=2[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1cccc(O)c1

Procedure:
Trifluoroacetic acid 5.0 mL solution of the obtained tert-butyl 2-((3-hydroxyphenyl)amino)-4-phenylbenzoate was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, hexane and diisopropyl ether were added to obtained residue, solid matter was filtrated to give 2-((3-hydroxyphenyl)amino)-4-phenylbenzoic acid 15 mg of yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11](C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)[CH2:10]1.Cl[C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])=[C:60]([NH:79][CH2:80][CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[N:59]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:82]1([CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:80][NH:79][C:60]2[N:59]=[C:58]([N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:3]([NH:8][C@@H:9]4[CH2:13][CH2:12][NH:11][CH2:10]4)=[O:5])[CH2:10]3)[N:66]=[C:65]3[C:61]=2[N:62]=[CH:63][N:64]3[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate Example 1 (Step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with 1,3-di(R)-pyrrolidin-3-yl-urea (Intermediate B).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:3]1=[O:14].[OH:15][C@@H:16]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH:36]=1)[CH2:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO>[OH:15][C@@H:16]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH:36]=1)[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:3]2=[O:14])[CH2:20][CH2:19]1
Reactant: N[C@@H]1CCN(c2ccc(Cl)cc2)C1=O
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCC(=O)CC3)ccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCC(N[C@@H]4CCN(c5ccc(Cl)cc5)C4=O)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one as prepared in Example 14 (0.08 g) in EtOH (3 ml) was added 1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one as prepared in Example 13 (0.15 g, 0.53 mmol) and sodium triacetoxyborohydride (0.112 g, 0.53 mmol). The reaction was stirred at room temperature for 48 hours. The solvent was removed and the residue purified using preparative TLC (10:1 DCM:MeOH) to yield (3R)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)-1-(4-chlorophenyl)pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:9]=2[O:8][C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2oc1=O
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C1C(=O)Oc2ccc(Cl)cc2C1c1ccccc1
Yield: 50.6 %

Procedure:
To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester (4.4 g) in ethanol (300 ml) was added platinum oxide (0.30 g), followed by stirring at room temperature in a hydrogen atmosphere (3 to 4 atm) for 3 hours. After the catalyst was filtered off, the filtrate was distilled to remove the solvent, followed by treatment of the residue with isopropyl ether, to yield 6-chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (2.24 g).
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][NH:13][CH2:14][CH3:15]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:13]([CH2:14][CH3:15])[CH3:12])[N:11]=[C:5]2[CH:6]=1
Reactant: CCNC
Reactant: Brc1ccn2nc(Br)nc2c1
Solvent: CCO
Product: CCN(C)c1nc2cc(Br)ccn2n1
Yield: 59.6 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.61 mmol) and N-methylethanamine (4.00 ml, 46.6 mmol) in ethanol (4 ml) was heated for 4 hours to 120° C. in a high pressure vessel. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 10-30% as eluent affording (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl-methyl-amine (549 mg, 59.6%) as a white solid. mp: 109-111° C., MS: m/z=255/257 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: ClCCCCBr
Product: Cc1ccc(OCCCCCl)cc1C

Procedure:
Prepared by Procedure U and Scheme AK using 3,4-dimethylphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:21][OH:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[N:21][OH:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1Cl
Reactant: NO
Product: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1Cl
Yield: 41 %

Procedure:
1-(3-Chloro-4-methoxyphenyl) -2-[4-(methylthio)phenyl]-ethan-1-one oxime was prepared in 41% yield from the reaction of 1-(3 chloro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one from Step 4 with hydroxylamine by the method outlined in Example 1, Step 1: 1H NMR (CDCl3 /300 MHz) δ 7.69 (d, J=2.22 Hz, 1H), 7.47 (dd, J=8.66, 2.22 Hz, 1H), 7.21-7.16 (m, 4H), 6.86 (d, J=8.66 Hz, 1H), 4.11 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[I:18][C:8]1[C:7]([NH2:10])=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2c(c1)OCC2
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1cc2c(cc1I)CCO2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,3-dihydrobenzofuran-6-amine (S6-1; 95 mg, 0.7 mmol) in acetonitrile (3 mL) cooled in an ice-bath was added NIS (158 mg, 0.7 mmol). After stirring at 0° C. for 20 min, the mixture was condensed and purified by flash chromatography (hexane:EtOAc, 90:10 to 20:80) to yield S7-1 (180 mg, 98%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 6.26 (s, 1H), 4.53 (t, J=8.5 Hz, 2H), 3.09 (t, J=8.4 Hz, 2H); MS (ESI) m/z 261.9 [M+H]+.
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[C:8]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=3[N:23]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:8]3[C:7]([Cl:6])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[N:23][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Solvent: CCC#N
Product: N#Cc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Temperature: 85 °C
Yield: 56 %

Procedure:
Trimethylsilyl bromide (1 mL) was added to a solution of 3-chloro-2-(4-chlorothiazolo[5,4-c]pyridine-2-yl)-benzonitrile (0.364 g, 1.18 mmol) in propionitrile (15 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 85° C. for 2 hours and then the volatiles were removed under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% methanol in DCM to afford the title compound as a pale brown solid (230 mg, 56% yield). LCMS (Method D): RT=3.70 min, m/z: 337 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][NH:23][CH3:24]>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([N:23]([CH3:24])[CH3:22])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CNC
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Product: CC(C(=O)N(C)C)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 97.2 %

Procedure:
Following the procedure of Example 6 but starting with 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (10 g.) and dimethylamine (4.5 g.), 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)-N,N-dimethylpropionamide (10 g.) is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: CSc1nccc(I)n1
Reactant: Nc1ccc2[nH]c(-c3ccc(F)cc3)nc2n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KN(TMS)2 (688 mg 3.65 mmol) in toluene (3.5 ml) is added at 0° C. to a solution of 2-(4-fluorophenyl)-5-aminoimidazo[4,5-b]pyridine (684 mg 3 mmol) in DMF (10 ml). After stirring 1 h at room temperature, 2-methylthio4-iodopyrimidine (832 mg 3.3 mmol) in toluene (3.3 ml) is added dropwise and heated for 18 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 60/40) and renders the title compound as a yellow foam (300 mg 27%)
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[N:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.CCN(C(C)C)C(C)C.[NH:27]1[C:31]([CH2:32][C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)=[N:30][N:29]=[N:28]1>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]4[NH:30][N:29]=[N:28][N:27]=4)[CH:34]=3)[N:12]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Clc1ncnc(-n2c(Cl)nc3ccccc32)n1
Reactant: Nc1cccc(Cc2nnn[nH]2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2ccccc2n1-c1ncnc(Nc2cccc(Cc3nnn[nH]3)c2)n1
Temperature: 67.5 °C

Procedure:
To crude 2-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzimidazole was added DIEA (381 μl, 2.184 mmol) and then a solution of DMF (1 ml) and 3-(1H-tetrazol-5-ylmethyl)phenylamine (382.7 mg, 2.1845 mmol). The reaction was heated at 60-75° C. for 18 h. The reaction was cooled to RT and concentrated to a small volume. The crude was eluted on a silica gel column with a MeOH/CH2Cl2 elution gradient, giving [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3-(1H-tetrazol-5-ylmethyl)-phenyl]amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][C:30]([O:32]CC)=[O:31].O[Li].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate, isomer 2 (1.57 g, 3 mmol) in ethanol (15 mL) was added 2 M aq LiOH.H2O (15 mL, 30 mmol) at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was washed with 1 aq N HCl until pH=5-6. The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid isomer 2 (1.33 g, 90%). LC-MS Method 5 tR=1.44 min, m/z=503.1; 1H NMR (CD3OD): δ=1.19-1.48 (m, 2H), 1.48-1.62 (m, 4H), 1.65-1.95 (m, 12H), 2.20-2.66 (m, 3H), 2.70-3.12 (m, 4H), 3.50 (m, 1H), 3.70-4.08 (m, 3H), 4.89 (m, 1H), 6.90-7.15 (m, 2H), 7.40 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][NH2:14]>O1CCCC1.C(OCC)(=O)C>[CH3:13][NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
In a dry flask 3-nitrobenzoyl chloride (7.00 g, 37.7 mmol) was dissolved in tetrahydrofuran (300 mL) and methylamine (41.5 mL of a 2.0 M solution in tetrahydrofuran, 82.9 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and extracted with water three times (100 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude solid (6.38 g, 94%) was used with further purification. 1H NMR (300 MHz, CDCl3), δ: 8.84 (bs, 1H), 8.67 (m, 1H), 8.37 (dd, J=8, J′=2, 1H), 8.28 (d, J=7, 1H), 7.78 (dd, J=8, J′=7, 1H), 2.83 (m, 3H). MS (ESI), m+/z: (M+H)+=181.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:8]1[C:4]2[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:5]=2[CH2:6][S:7]1(=[O:10])=[O:9])=[O:15])[CH3:18]
Reactant: O=S1(=O)Cc2ccc(F)cc2N1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc(F)ccc2CS1(=O)=O
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of 1,3-dihydro-6-fluoro-2,1-benzisothiazole-2,2-dioxide (2.57 g) in anhydrous pyridine (8 ml) was added ethyl chloroformate (1.79 g) at 0° C. under N2 atmosphere. The mixture was stirred for 30 minutes and concentrated in vacuo. Cold hydrochloric acid was added to the precipitate (pH=6). The resulting solution was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (methylene chloride-ethyl acetate 95:5) to give 1-ethoxycarbonyl-1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (3.1 g).
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][NH2:1]
Reactant: CN1CCNCC1CCCCc1cccc2c1C(=O)NC2=O
Reactant: NN
Solvent: CO
Product: CN1CCNCC1CCCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 4-(N-methylpiperazinyl)butylphthalimide (240 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30]C)=O)(C)(C)C.Cl>C(O)C.[OH-].[Na+]>[CH3:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[C:18]1[C:19](=[O:30])[NH:20][N:21]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:23]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1c(C)c2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2ccccc12
Temperature: 150 °C
Yield: 58.1 %

Procedure:
50 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-methyl-indole-1-carboxylic acid tert-butyl ester is dissolved in 0.75 ml ethanol and 0.75 ml 1N aqueous NaOH solution. The reaction mixture is stirred at 150° C. in microwave apparatus (200 W). The solution is neutralized by addition of 1N HCl, the solvent removed under reduced pressure and the crude product purified by HPLC chromatography (RP18 column, acetonitrile/water, 0.05% HCOOH) yielding 21.1 mg 4-(3-Methyl-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](Br)=[CH:5][N:6]=[CH:7]2.[CH3:13][S-:14].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([S:14][CH3:13])=[CH:5][N:6]=[CH:7]2
Reactant: C[S-]
Reactant: Nc1cccc2cncc(Br)c12
Agent: [Na+]
Product: CSc1cncc2cccc(N)c12

Procedure:
5-Amino-4-bromoisoquinoline (prepared according to the process described by Gordon et al., J. Het. Chem,, 4, 410 (1967)) was allowed to react with sodium thiomethoxide according to the procedure of Massie, Iowa State Coll. J. Sci., 21, 41 (1946) (Ca. 41: 3044 g) to give 5-amino-4-methylthioisoquinoline. This material was coupled with 2-hexylthiodecanoic acid (prepared by the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C@H]1CC[C@H](N)CC1>>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: CO[C@H]1CC[C@H](N)CC1
Product: CO[C@H]1CC[C@H](N(CCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-4-methoxy-cyclohexylamine,
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])N.N([O-])=[O:12].[Na+]>S(=O)(=O)(O)O.O>[OH:12][CH:4]([CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CC(O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
805 mg (5.54 mmol) of 4-methylleucine (racemate) were initially charged in 11 ml of sulphuric acid (1M) and cooled to 0° C. 2.30 g (33.3 mmol) of sodium nitrite as a solution in 6.5 ml of water were then slowly added dropwise over a period of 90 min. The solution was stirred at RT for another 24 h. The mixture was carefully diluted with 10 ml of water and the aqueous phase was extracted five times with 10 ml of methyl tert-butyl ether. The combined organic phases were washed with 25 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was used for the next step without further purification. Yield: 667 mg (82% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>ClCCl>[C:24]([CH2:23][CH2:22][C:21]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:27])([OH:26])=[O:25]
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: O=C(O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.5 %

Procedure:
To a solution of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (3.0 g) in dichloromethane (50 ml) is added succinic anhydride (1.4 g) and the mixture is stirred at room temperature for 4.5 hours. The reaction mixture is evaporated under reduced pressure in order to remove the solvent therefrom, and the resulting crystal is recrystallized from ethyl acetate to give 1-[4-(3-carboxypropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.61 g) as colorless needles, m.p. 192° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:23])[CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.[CH2:37]=O>>[CH3:23][N:17]([CH:18]1[CH2:22][CH2:21][N:20]([CH3:37])[CH2:19]1)[C:14]1[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]3[N:30]=[C:29]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:27][N:26]=3)[CH:4]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N(C)C3CCNC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(N(C)C3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The product from Example 7 was methylated via reductive amination with HCHO/NaBHCN (1.5 eq) to give the title compound. Mass: (M+1), 494.