Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=3)[CH:17]=2)[N:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56]O)[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:27]=[CH:26][C:25]([O:28][CH2:56][CH2:55][N:52]4[CH2:53][CH2:54][O:49][CH2:50][CH2:51]4)=[CH:24][N:23]=3)[CH:17]=2)[N:10]=1
Reactant: OCCN1CCOCC1
Reactant: O=C(Cc1cccc(-c2ncc(O)cn2)c1)N1CCC(c2cc(Cl)ccc2Cl)=N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1)N1CCC(c2cc(Cl)ccc2Cl)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6.2 A suspension of 108 mg (0.253 mmol) of 1-[3-(2,5-dichlorophenyl)-4,5-dihydropyrazol-1-yl]-2-[3-(5-hydroxypyrimidin-2-yl)phenyl]ethanone, 100 mg (0.38 mmol) of triphenylphosphine and 64.4 μl of 2-morpholinoethanol in 0.5 ml of THF is cooled in an ice bath, and 74 μl (0.38 mmol) of diisopropyl azodicarboxylate are slowly added dropwise. The reaction mixture is stirred at room temperature for 16 hours. The mixture is evaporated and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 1-[3-(2,5-dichlorophenyl)-4,5-dihydropyrazol-1-yl]-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]phenyl}-ethanone (“A8”) as colourless crystals; ESI 540;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>[Cu]I.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>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dibromopyridine (1.0 eq, 5.0 g, 20.9 mmol) in TEA (100 ml) under an inert atmosphere of nitrogen is added copper(I) iodide (0.1 eq, 406 mg, 2.09 mmol) and PdCl2(PPh3)2 (0.1 eq, 1.5 g, 2.09 mmol). Trimethylsilylacetylene (1.2 eq, 3.6 ml, 25 mmol) is added and the resulting mixture is stirred at room temperature for 2 h. The solvent is removed in vacuo and the residue is partitioned between water and DCM. The organic portion is separated and washed with sat. aqueous NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (hexane/DCM) yields the title compound; [M+H]+=254/256.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[NH2:12])[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[C:24]([Cl:29])[N:23]=1>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[NH:12][C:26]2[N:25]=[C:24]([Cl:29])[N:23]=[C:22]([Cl:21])[N:27]=2)[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Solvent: O
Product: O=S(=O)(O)c1cc(O)c2c(Nc3nc(Cl)nc(Cl)n3)cc(S(=O)(=O)O)cc2c1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
An ice cold neutral solution of 1-hydroxy-8-aminonaphthalene-3,6-disulphonic acid (31.9 parts) in water (120 parts) was added, with stirring, to a freshly prepared suspension of 2,4,6-trichloro-s-triazine (18.5 parts) in ice and water (140 parts). The mixture was stirred for 3 hours at 0 to 5° C. to give a solution of 1-hydroxy-8-(2,4-dichloro-s-triazin-6-ylamino-)naphthalene-3,6-disulphonic acid (solution 1).
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1)C.[C:10]1([C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16](=[O:21])[C:17](=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]2)[C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC1=NCCCC1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: CC(=O)C(C(=O)c1ccccc1)=C1CCCCN1
Reaction time: 32 h

Procedure:
12.7 g (0.1 mole) of 2-ethoxy-3,4,5,6-tetrahydropyridine and 24.4 g (0.15 mole) of 1-phenyl-1,3-butanedione are mixed and heated together in a nitrogen atmosphere, with stirring, for 32 hours in an oil bath at 100°. The reaction mixture is cooled, and subsequently chromatographed on silica gel with an ethyl acetate/hexane mixture as the eluant. The main fractions are combined and crystallised from ether to obtain 1-phenyl-2-(2-piperidinylidene)-1,3-butanedione in the form of yellow crystals, m.p. 80-81°.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=O)[C:39]([F:42])([F:41])[F:40])[CH:33]=3)[N:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CO.N1C=CC=CC=1>[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[N:2][OH:3])[C:39]([F:40])([F:41])[F:42])[CH:33]=3)[N:15]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Temperature: 60 °C
Yield: 100.1 %

Procedure:
Hydroxylamine hydrochloride (0.08 g, 1.2 mmol) was added to methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (compound of Example 33) (0.285 g, 0.515 mmol) in MeOH (4.00 mL) and pyridine (0.666 mL) to give a yellow solution. After heating at 60° C. 5 days, the mixture was concentrated to dryness and the residue was dissolved into DCM (75 mL) and MeOH (15 mL) and this solution was washed with sat. NaHCO3 (20 mL). The aqueous layer was extracted two time with a mixture of CH2Cl2 (50 mL) and MeOH (10 mL) and the combined organic layers were dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (293 mg, 100% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H) 1.44-1.56 (m, 4H) 1.76-1.87 (m, 2H) 2.23-2.44 (m, 6H) 3.57-3.67 (m, 2H) 3.88 (s, 3H) 4.04-4.12 (m, 2H) 7.25-7.33 (m, 1H) 7.34-7.46 (m, 2H) 7.50 (m, J=7.6, 4.1 Hz, 1H) 7.55 (d, J=7.4 Hz, 1H) 7.81 (dd, J=8.2, 1.2 Hz, 1H) 7.99 (d, J=1.2 Hz, 1H) 8.36 (d, J=8.2 Hz, 1H) 12.07 (d, J=3.5 Hz, 1H); MS m/z 569.2 (M+H)+; HPLC >95%, RT=1.88 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=O.[Cl:13][C:14]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N=C=NC(C)C)(C)C>ClC(Cl)C>[Cl:13][C:14]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:9](=[O:11])[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:12]
Reactant: CC(C(=O)O)c1ccccc1Cl
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC(Cl)Cl
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Reaction time: 16 h
Yield: 37 %

Procedure:
A solution of 2-(2-chlorophenyl)propionic acid (350 mg, 1.9 mmole) and 2-chloro-3-trifluoromethylbenzylamine (398 mg, 1.9 mmole) in 5 mL of dichloroethane was treated with diisopropylcarbodiimide (0.3 mL, 1.9 mmole) and the reaction was stirred for 16 hours. The solvent was removed, and the residue taken up in Et2O. The Et2O was washed with H2O, 0.1N HCl, and aqueous Na2CO3, dried and the solvent removed. Recrystallization from a mixture of CH2Cl2 and hexane gave the titled compound, 265 mg (37% yield). MS (ESI) 376 (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([NH2:19])=[O:18])[CH2:12]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([NH2:19])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCC1CCCN(C(N)=O)C1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: NCCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.8 %

Procedure:
3-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (392.7 mg, 1.45 mmoles) (prepared as described in Preparative Example 242, Step A above) was dissolved in methanol (7.5 mL) and 10% conc. sulfuric acid in 1,4-dioxane (19.5 mL) was added. The mixture was stirred at 25° C. for 1.25 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the diluted with methanol and BioRad AG1-X8 resin (OH−form) was added until the dryness and chromatographed on a silica gel column (30×2.5 cm) using 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-aminoethyl)piperidine-1-carboxamide (233 mg, 94%): FABMS: m/z 172.1 (MH+); HRFABMS: m/z 172.1444(MH+). Calcd for C8H18N3O requires: m/z 172.1450; δH (CDCl3+3% CD3OD) 1.14 (1H, m, CH2), 1.40 (2H, m, CH2), 1.49 (1H, m, CH), 1.58 (1H, m, CH2), 1.69 (1H, m, CH2), 1.85 (1H, m, CH2), 2.55 (1H, m, CH2), 2.67 (5H, m, CH2/NH2), 2.76 (1H, bm, CH2), 2.84 (1H, m, CH2) and 3.82 ppm (2H, m, CONH2); δc (CDCl3+3% CD3OD) CH2: 24.8, 30.9, 36.6, 38.9, 44.9, 50.0; CH: 33.4.
Reaction SMILES: C1(S([O-])(=O)=O)C=CC=CC=1.[C:11](#[N:13])[CH3:12].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>C(OCC)(=O)C>[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH:17][CH2:12][C:11]#[N:13]
Reactant: Cc1cccc(C)c1N
Reactant: CC#N
Agent: O=S(=O)([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NCC#N

Procedure:
A solution of 158.5 g (0.804 mol) of benzenesulphonate-acetonitrile in 200 ml of ethyl acetate is run dropwise into a solution of 193.6 g (1.608 mols) of 2,6-dimethyl-aniline in 400 ml of ethyl acetate. The mixture is heated under reflux for 3 hours, cooled and the excess aniline benzenesulphonate is filtered off. The filtrate is evaporated to dryness. The residue is taken up in ether. Insoluble material is again filtered off and discarded. The ether is evaporated to dryness. The residue is taken up in a mixture of petroleum ether/benzene (3:4 v/v). The crystals which form are filtered off.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]2[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]2)[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]3[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]3)=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2COCC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2COCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.03 g) in 2-propanol (20 mL) were added 1,5-anhydro-2,4-dideoxy-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]-threo-pentitol (980 mg) and piperidinium acetate (448 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (260 mg). Absolute configuration undetermined.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])OC2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:41][NH:42][CH3:43]>ClCCl.O1CCCC1>[Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])[N:42]([CH3:43])[CH3:41])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate (from step 1) (0.350 g, 0.570 mmol) dissolved in dichloromethane (6.0 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydorfuran (0.427 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.226 g, 63.3%). 1H NMR (400 MHz, DMF-d6) δ 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d, J=7.45 Hz, 1H), 6.88 (app t, J=5.84 Hz, 1H), 6.68 (s, 1H), 5.45 (s, 2H), 5.42 (s, 1H), 4.35 (d, J=5.84 Hz, 1H), 2.92 (s, 6H), 2.44 (s, 3H). ES-HRMS m/z 520.1065 (M+H C24H24BrF2N3O3 requires 520.1042).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:8]2.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(CNc2ccc3c(CN)cccc3n2)o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CNc2ccc3c(CNC(=O)c4ccc(F)cc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a cooled (ice bath) and stirred solution of (5-aminomethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (95 mg, 0.355 mmol) and triethyl amine (39.6 mg, 0.39 mmol) in THF (2 ml) was added 4-fluorobenzoyl chloride (62 mg, 0.39 mmol) and the mixture was allowed to stir at room temperature for 16 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as off-white solid (67 mg, 48%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:23][O:24]CC2C=CC=CC=2)[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.CN(C=O)C.[Pd]>[CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)CC1CCCC1
Reaction time: 60 h
Yield: 99.9 %

Procedure:
A solution of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one (42.7 g, 0.1 mol) in ethanol (800 mL) and DMF (180 mL) was subjected to catalytic hydrogenation using 10% Pd/C (4 g) and a balloon of hydrogen. The reaction was 50% complete by LCMS after 24 h. The reaction was purged with nitrogen and a fresh balloon of hydrogen was introduced. After an additional 60 h, the reaction was again purged with nitrogen, was filtered, and the filtrate solvents were removed to provide (4S)-3-[(2R)-3-cyclopentyl-2-(hydroxymethyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (33.1 g, 100%). LCMS: (M+H)+: 332.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:13]=1)[CH2:9][C:10]#[CH:11]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:16][N:15]=2)=[CH:22][CH:21]=1
Reactant: C#CCCc1cc(-c2ccc(F)cc2)no1
Reactant: Brc1ccccn1
Product: Fc1ccc(-c2cc(CCC#Cc3ccccn3)on2)cc1
Yield: 25000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (40 mg, 0.26 mmol) and 5-but-3-ynyl-3-(4-fluoro-phenyl)-isoxazole (55 mg, 0.26 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to 7:3) to yield 19 mg (65 mmol, 25%) of 2-(4-(3-(4-fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine as a white solid (M.P.=83-84° C.).
Reaction SMILES: [Na].[CH:2]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl)([O-:10])=[O:9]>CO>[CH:2]1([S:7][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: SC1CCCC1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1cccc(CSC2CCCC2)c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxyde (15.5 mL, 25 wt % in methanol) was diluted with methanol (85 mL) and treated with cyclopentanethiol (7.3 mL) at room temperature for 60 minutes, cooled to −15° C., treated with 3-nitrobenzylchloride (10.0 g) in 3 portions, kept for 2 hours at −15° C., then the temperature was increased to room temperature. The reaction mixture was concentrated in vacuo, treated with diethyl ether (350 mL), washed with water (2×150 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (14.9 g) was thus obtained and used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][C:27]=3[Cl:28])[NH:24][CH:23]=[C:22]4[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([C:29]([OH:31])=[O:30])=[CH:23][NH:24]2)=[CH:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCNC4)cc3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 129.1 %

Procedure:
To a mixture of 5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (15 mg, 0.0341 mmol) in dichloromethane (2 mL) was added TFA (0.213 g, 1.87 mmol) and the resulting mixture was stirred for 45 min at room temperature. The reaction mixture was concentrated in vacuo to give 6-chloro-5-[4-(pyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid (15 mg) as an off-white solid. MS (ES+) 341.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.99 (br, 1 H), 8.92 (br, 1 H), 8.09 (d, 1 H), 7.94 (s, 1 H), 7.65 (s, 1 H), 7.43 (m, 4 H), 3.70 (m, 1 H), 3.50 (m, 4 H), 3.17 (m, 1 H), 2.04 (m, 1 H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[C:20]([SH:22])[CH:21]=1>CS(C)=O>[Br:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[NH:23][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[C:5]=1[S:22]2
Reactant: Nc1ccc(Br)cc1S
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Br)cc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (5.94 g, 30 mmole) and 5-bromo-2-aminobenzenethiol, 6 (X=Br, 5.8 g, 30 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separetely recrystallized twice from MeOH and proves to be identical. An analytical sample of 4k, (R=Br), mp 201-203° C. occurs as light orange crystals; 2.24 g (56.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[CH:18].C(NCC)C>CN(C)C=O.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:18]#[C:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: C#Cc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Temperature: 50 °C
Yield: 62 %

Procedure:
To a stirred solution of 4-chloro-2-iodo-phenylamine (500 mg, 1.97 mmol) in dimethylformamide (4 ml) was added PdCl2(PPh3)2 (7 mg, 0.02 mmol) followed by copper(I)iodide (3.7 mg, 0.02 mmol), 1-chloro-2-ethynyl-benzene (0.28 ml, 2.36 mmol) and diethylamine (1.65 ml, 15.78 mmol) under nitrogen at RT. The resulting reaction mixture was purged with nitrogen and then heated to 50° C. for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 4% EtOAc in hexane) to yield 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (320 mg, 62% yield) as an off white solid. LC-MS: 262 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=1)[C:38](Cl)=[O:39]>ClCCl>[N:16]1[C:8]2[CH2:9][C:10]3[CH:15]=[CH:14][S:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:20]=[CH:21][C:22]([NH:24][C:38](=[O:39])[C:37]4[CH:41]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=4[CH3:42])=[CH:23][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 mmol of 5-(2-chloro-4-aminobenzoyl)-6,10-dihydro-5H-pyrido[3,2-b]thieno[3,2-e]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1 mmol of 5-fluoro-2-methylbenzoyl chloride. After stirring at room temperature for 16 hours, the solution is washed with H2O, 1M NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed to give the product as a solid.