Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]1[CH2:32][CH:31]3[N:16]([C:17](=[O:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:15]1)=[N:8][C:7]([N:38]1[CH:42]=[CH:41][CH:40]=[N:39]1)=[CH:6]2.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]1[CH2:32][CH:31]3[N:16]([C:17](=[O:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:84][S:85]([CH:88]5[CH2:90][CH2:89]5)(=[O:87])=[O:86])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:15]1)=[N:8][C:7]([N:38]1[CH:42]=[CH:41][CH:40]=[N:39]1)=[CH:6]2
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)nc(-n3cccn3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title compound was prepared from 18-[6-methoxy-3-(pyrazol-1-yl)isoquinolin-1-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (33) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=677 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][Br:11])[C:3]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)ccc(Br)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(Cl)c1CBr
Yield: 98.9 %

Procedure:
3-Bromo-2-chloro-6-fluoro-toluene (8.0 g), N-bromosuccinimide (NBS) (6.42 g) and a catalytic amount of benzoyl peroxide in carbon tetrachloride (40 ml) were heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool and then filtered. The filtrate was concentrated to give a colourless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluorobenzene as an off-white solid (10.7 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl.N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:2]1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-tetrahydrofuran-3-ol (25.4 g) in dichloromethane (250 mL) and pyridine (60 mL) is added at 0° C. N,N-dimethylaminopyridine (DMAP; 1 g) and p-toluene-sulfonylchloride (73 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0→95:5) to give the title compound. Yield: 59.5 g; Mass spectrum (ESI+): m/z=243 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]#[C:10][C:11]1[N:12]=[C:13]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]2=[N:15][CH:16]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O.[Cu](I)I>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[C:11]([CH:16]=[N:15][C:14]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[CH:18]=[CH:19][C:13]=32)=[CH:10][CH:9]=1
Reactant: CC1CCCCN1CC#Cc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Agent: I[Cu]I
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CCCCN1c1ccc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 130 °C
Reaction time: 3 h
Yield: 19.5 %

Procedure:
To a flask containing (+/−)-2-[3-(2-methyl-piperidin-1-yl)-prop-1-ynyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (185 mg, 0.48 mmol) was added copper iodide (37 mg, 0.19 mmol), and DBU (0.34 mL, 2.28 mmol) in dry dimethyl acetamide (1 mL). The mixture was vacuum degassed and heated to 130° C. and stirred for 3 hours. The mixture was cooled to ambient and quenched via the addition of water (30 ml) and ethyl acetate (30 ml).The material was shaken in a reparatory funnel, and the ethyl acetate phase was collected. The aqueous phases were back extracted with ethyl acetate (2×25 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC using 25% ethyl acetate in hexanes as eluant. The product band was collected to provide 36 mg of (+/−)-8-(2-methyl-piperidin-1-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacene as a brown-black oil. Note that starting material (90 mg) was also recovered. This material was subjected to the identical reaction conditions as above (but over-night heating), to provide an extra 12 mg of product. MS (M+H)+=385.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)[C@@H](N)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(−)-2-amino-3-methyl-1-butanol (57 □l, 0.515 mmol) and diisopropylethylamine (90 □l, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.S(Cl)(Cl)=O.[CH3:36]O>>[CH3:36][O:30][C:29]([CH:25]1[CH2:26][C:27](=[O:28])[N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])=[CH:22][CH:21]=2)[CH2:24]1)=[O:31]
Reactant: CO
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CC(=O)N(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-{4-[4-(2,4-Dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (1.54 g) described in Example 333 was dissolved in methanol (10 mL), thionyl chloride (0.29 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture, and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.39 g).
Reaction SMILES: [C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1C=CC=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:13][CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])=[O:27])=[CH:24][CH:23]=1
Reactant: CC(N)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1ccc(Cl)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 23.6 grams (0.138 mole) of α-naphthylethylamine and 20.2 grams (0.20 mole) triethylamine in 150ml of dry benzene, there is added dropwise a solution of 24.8 grams (0.142 mole) of p-chlorobenzoyl chloride in 150 ml of benzene. After stirring overnight at room temperature the salts are filtered off and the filtrate is concentrated in vacuo. The resultant residue is crystallized from methylene chloride/hexane to give N-(p-chlorobenzoyl)-α-naphthylethylamine, m.p. 117°-118° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([B:22]([OH:23])[OH:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)cc1C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cc1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.), stirred solution of 3-isopropyl-4-methoxybromobenzene (2.5 g) was added n-butyllithium (4.8 mL of a 2.5 M solution in hexanes) dropwise. After 30 min, triisopropylborate (5 mL) was added and the reaction solution was allowed to warm to RT and then stirred for 18 h. The reaction solution was concentrated in vacuo, saturated aqueous sodium bicarbonate was added and the resulting mixture was stirred for 30 min. The reaction was extracted with ethyl acetate. The organic layer was washed with water then brine, dried over sodium sulfate, and concentrated in vacuo to afford a solid, which was triturated with hexanes to afford the title compound as colorless plates (1.1 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[C:20]1([CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH:28]4[CH2:36][C:37](O)=[O:38])[CH2:32]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]1([CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH:28]4[CH2:36][C:37]([N:12]2[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]2)=[O:38])[CH2:32]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC(C2)C(c2ccccc2)C1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)C(c3ccccc3)C1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Triethylamine 1.00 ml was added in a methylene chloride 30 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 815 mg, and stirred at 0° C. for 30 min. 4-phenyl-2-adamantyl acetic acid 774 mg and WSC 1.65 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 16.5 hours. The reaction mixture was washed with 1N hydrochloric acid and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-phenyl-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 229 mg and refluxed under heating for I hour. The reaction mixture was cooled, then added water and 2.5N sodium hydroxide thereto, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of flash column chromatography (Merck, silica gel 60: 230-400 mesh, chloroform) to obtain the product. Yield: 878 mg (Yield 78%)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example 18 using rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 460.0 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([CH2:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]1)([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2ccccc2)C1
Yield: 91.5 %

Procedure:
(R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 (5.26 g, 17.28 mmol) in 20 mL of dry THF was added slowly to 34.5 mL of 1.0 M borane in THF while stirring in an ice bath. The mixture was refluxed for 2 hours, then cooled in an ice bath, and quenched with 20 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH 10. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford (R)-N-(1-Boc-piperidin-3-ylmethyl)-aniline 28 as a colorless oil (4.59 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[F:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:26][CH2:25][C:24]1[C:19]([C:16]2[CH:17]=[N:18][C:13]([F:12])=[CH:14][CH:15]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)=[S:11]
Reactant: NCc1cccnc1-c1ccc(F)nc1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: Fc1ccc(-c2ncccc2CNC(=S)Nc2cccc(Cl)c2Cl)cn1
Yield: 72 %

Procedure:
The title compound was synthesized by general procedure 1 using 2,3-dichlorophenylisothiocyanate and C-(6′-fluoro-[2,3]bipyridinyl-3-yl)-methylamine (Example 192F) to give 0.974 g (72%) of 1-(2,3-dichloro-phenyl)-3-(6′-fluoro-[2,3]bipyridinyl-3-ylmethyl)-thiourea as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 4.74 (d, J=4.1 Hz, 2H), 7.31 (dd, J=2.5, J=8.2 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.49 (dd, J=4.7 Hz, J=7.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.87 (dd, J=1.5 Hz, J=7.9 Hz, 1H), 8.17 (dt, J=2.5 Hz, J=8.2 Hz, 1H), 8.39 (bs, 1H), 8.41 (d, J=2.5 Hz, 1H) 8.60 (dd, J=1.6 Hz, J=4.7 Hz, 1H), 9.49 (bs, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm; 5%-100% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min), then 100% acetonitrile isocratic 2 minutes, Rt 10.30 min. (94.3%); MS: M+H+ 407.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>[Pd].CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1C#CCCO
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCCO
Temperature: 70 °C
Reaction time: 16 h

Procedure:
46.6 g (0.023 M) of methyl 2-(4-hydroxybut-1-ynyl)benzoate and 5 g of wet 10% palladium-on-charcoal are added to 900 ml of methanol in a 2000 ml stainless-steel autoclave. The reaction medium is then stirred under hydrogen pressure (10 bar) at 70° C. for 16 hours.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6](=[O:13])[CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][CH:10]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1.O>[CH3:3][O:4][C:5]1[C:6](=[O:13])[CH:7]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([CH3:11])([CH3:12])[CH2:9][CH:10]=1
Reactant: COC1=CCC(C)(C)CC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)C1C(=O)C(OC)=CCC1(C)C
Reaction time: 0.25 h
Yield: 2084.3 %

Procedure:
60% sodium hydride in mineral oil (2.41 g, 60.3 mmol) was suspended in anhydrous tetrahydrofuran (60 mL) under argon atmosphere and treated with a solution of 2-methoxy-5,5-dimethyl-cyclohex-2-enone (6.20 g, 40:2 mmol) in anhydrous tetrahydrofuran (50 mL). After 15 minutes, a solution of diethyl oxalate (8.17 mL, 60.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added and the mixture was refluxed for 1 hour. The slurry was diluted with water (800 mL), acidified with 1 N HCl (50 mL) and extracted with ethyl acetate (500 mL×2). The organic layers were collected, washed with brine, dried on Na2SO4 and evaporated to dryness to obtain the crude title compound (10.60 g) as an orange oil, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:13][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
To a mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (100 mg, 0.386 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 118 mg, 0.386 mmol) in acetonitrile (2 mL) at room temperature was added Hunig's Base (0.081 mL, 0.463 mmol). The reaction mixture was stirred at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford a light yellow oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate/hexane (0-70%) to give tert-butyl 1-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (175 mg, 0.332 mmol, 86% yield) as a white, crystalline solid. The compound had an HPLC retention time=3.34 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=527.13. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H), 3.26-3.33 (m, 3H), 3.54-3.59 (m, 2H), 3.70 (s, 2H), 7.46 (d, J=8.28 Hz, 2H), 7.56-7.62 (m, 2H), 7.63-7.68 (m, 1H), 7.78 (d, J=7.28 Hz, 2H), and 8.16 (d, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]([F:40])([F:39])[C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2ccc(C(F)(F)F)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid to afford an off-white solid. UPLC-MS (condition 1) tR=2.77 min, m/z=513.0 [M+H]+, m/z=511.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.15-3.27 (m, 2H) 3.35-3.46 (m, 1H) 4.16-4.26 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.00 (d, J=8.07 Hz, 1H) 8.06-8.14 (m, 2H) 8.80 (d, J=2.20 Hz, 1H) 8.85 (d, J=1.71 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[N:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[N:35]=[C:31]([CH3:30])[S:32][CH:33]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)cs1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5csc(C)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(2-methyl-1,3-thiazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B35), HBTU (167 mg), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography for three consecutive times (amino phase silica gel, eluent: EtOAc) to yield the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2sc(Nc3ccc(Br)cc3)nc2c1
Agent: Br
Product: Oc1ccc2sc(Nc3ccc(Br)cc3)nc2c1
Reaction time: 0.1 h

Procedure:
The mixture of (4-bromophenyl)(5-methoxybenzothiazol-2-yl)amine and hydrobromic acid (48%) was subjected to the microwave at 150° C. for 6 mins to yield the desired product. MS: MH+=321
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH3:19])[N:8]([CH:23]([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)c(C)c1
Yield: 36 %

Procedure:
Prepared according to Example 101 from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 2-iodopropane (0.07 mL, 0.7 mmol) to give the title compound (0.059 g) as a white solid.