Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26](B6OC(C)(C)C(C)(C)O6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[OH2:38]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:18][N:19]([C:23]5[N:24]=[CH:25][C:26]([OH:38])=[CH:27][N:28]=5)[CH2:20][CH2:21][O:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: O
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(B6OC(C)(C)C(C)(C)O6)cn5)CCO4)c3n2)cn1
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(O)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrimidin-2-yl)morpholine 109 mg (0.22 mmol) was dissolved in THF 3 ml and distilled water 3 ml, and NaBO3 65 mg (0.651 mmol) was added. The mixture was stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was extracted with MC and water, and the organic layer was dried over Na2SO4. Prep LC with 4% MeOH/MC gave a product 54 mg (63%).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CN(C=O)C.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2](/[CH:31]=[CH:30]/[C:29]([O:33][CH3:34])=[O:32])=[CH:3][CH:4]=3)=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (125 g, 373 mmol) and Pd(PPh3)2Cl2 (13.09 g, 18.64 mmol) in DMF (2500 mL) and diisopropyl ethylamine (326 mL, 1864 mmol) at room temperature was added (subsurface) methyl acrylate (845 mL, 9322 mmol) over 3-4 hours. As the addition started, the reaction was heated at 120° C. for 13 hours. Methyl acrylate (150 mL, 1654.8 mmol) was added (subsurface). The reaction was heated at 120° C. for 1 hour. The mixture was cooled to RT. Excess methyl acrylate and diisopropyl ethylamine were remove in vacuo. The resulting mixture was filtered through celite pad and the cake was washed with EtOAc (2000 mL). The resulting mixture was washed with water (2×), dried with anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 5% to 500/(EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (81 g, 238 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=1.46 (s, 3 H), 3.73 (s, 3 H), 6.28 (d, J=16.17 Hz, 1 H), 6.59 (s, 1 H), 6.90 (dd, J=8.59, 2.02 Hz, 1 H), 7.00 (d, J=8.59 Hz, 2 H), 7.21 (d, J=2.02 Hz, 1 H), 7.37-7.48 (m, 3 H), 7.59 (d, J=16.17 Hz, 1 H), LC/MS (m/z. MH+): 341.1.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][C:18]([C:21](=[S:23])[NH2:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CO[C:28](OC)([N:30]([CH3:32])[CH3:31])[CH3:29]>>[CH3:31][N:30]([CH3:32])[C:28](=[N:22][C:21]([C:18]1[CH:19]=[N:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)=[S:23])[CH3:29]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=S)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1
Product: CC(=NC(=S)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1)N(C)C
Reaction time: 8 h

Procedure:
A mixture of intermediate 4 (0.013 mol) and 1,1-dimethoxy-N,N-dimethyl-ethanamine (0.021 mol) was allowed to stand overnight and then used without further purification, yielding N-[1-(dimethylamino)ethylidene]-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-3-pyridinecarbothioamide (intermediate 5).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[N:34]=[C:35]([NH:38]N)[S:36][CH:37]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:38]([C:35]4[S:36][CH:37]=[C:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[O:26][CH3:25])[N:34]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: COc1ccccc1-c1csc(NN)n1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: COc1ccccc1-c1csc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)n1
Yield: 21 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and [4-(2-methoxy-phenyl)-thiazol-2-yl]-hydrazine according to the method described for Example 91 in 21% yield. MS: M=506.2.13 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:42])[N:13]2[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:41].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:42])[N:13]2[C:34]1[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)CC3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCc2c(-c3ccccc3Cl)cc(OC3CCNC3)cc2N1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 3-([5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]oxy}pyrrolidine-1-carboxylate (0.051 g) in 6 mL of CH2Cl2 was added 1 mL of TFA and the mixture was stirred for 1 h at rt. The reaction mixture was purified by preparative thin layer chromatography eluting with 10% ethanol/dichloromethane to give the product. Mass spectrum m/z (ESI) 487.15 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.CN([CH:19]=[O:20])C1C=CC=CC=1>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH:19]=[O:20]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CN(C=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc(F)cc(F)c1

Procedure:
The 3,5-difluorobenzaledehyde used as a starting compound can be prepared as follows: 3,5-difluorophenylmagnesiumbromide can be prepared as described by A. Roe and W. F. Little: J.Org.Chem. 20 (1955) 1577. A solution of 3,5-difluorophenylmagnesiumbromide in diethylether is added dropwise to a solution of N-methylformanilide in tetrahydrofuran. By working up this reaction mixture, 3,5-difluorobenzaldehyde is obtained. b55 =86°-88° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][NH:15]S(C(C)(C)C)=O.Cl.O1CCOCC1>CO>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][NH2:15]
Reactant: CC(C)(C)S(=O)NCc1ccc2oc3ccccc3c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ccc2oc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of N-(dibenzo[b,d]furan-2-ylmethyl)-2-methylpropane-2-sulfinamide (2.280 g; 7.55 mmol) in MeOH (24 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (4.0 ml; 16.00 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was concentrated to dryness under reduced pressure. DCM, water, and Na2CO3 (5.50 g) were added, and the organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording dibenzo[b,d]furan-2-ylmethanamine as a yellow solid. LC-MS (conditions A): tR=0.51 min.; no ionisation.
Reaction SMILES: CC1C=CC(N[N:9]=[C:10]2[C:15]3=[N:16][C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[C:23](=[O:24])[N:14]3[CH:13]([CH3:25])[CH2:12][CH2:11]2)=CC=1>O>[CH3:25][CH:13]1[N:14]2[C:15](=[N:16][C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[C:23]2=[O:24])[C:10]2[NH:9][C:19]3[C:20]([C:11]=2[CH2:12]1)=[CH:21][C:22]([CH3:23])=[CH:17][CH:18]=3
Reactant: Cc1ccc(NN=C2CCC(C)n3c2nc2c(c3=O)CCCC2)cc1
Solvent: O
Product: Cc1ccc2[nH]c3c(c2c1)CC(C)n1c-3nc2c(c1=O)CCCC2
Temperature: 180 °C
Yield: 84.3 %

Procedure:
1 g of 6-(4-Methyl-phenylhydrazono)-9-methyl-1,2,3,4,6,7,8,9-octahydro-pyrido[2,1-b]quinazoline-11-one is added to 10 g of polyphosphoric acid heated to 180° C. and the reaction mixture is heated for 40 minutes at this temperature. After cooling the mixture is diluted with 60 ml of water. A yellowish-white crystalline precipitate is obtained which is filtered and washed with water. After drying the obtained solid is dissolved in chloroform and the undissolved part is filtered off. The solution is treated with active charcoal and evaporated. The obtained yellowish-white oil is crystallized from ethyl acetate. 0.4 g of 7,10-dimethyl-5-oxo-1,2,3,4,7,8-hexahydro-5H,13H-indolo[2',3';3,4]pyrido[2,1-b]quinazoline are obtained melting at 220° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:33]([OH:36])[C:34]#[CH:35]>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:35]#[C:34][CH2:33][OH:36])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: C#CCO
Product: CCCCCCc1cccc(-c2nc(C#CCO)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 12, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with prop-2-yn-1-ol to give the title compound as light brown oil. MS: 477.3 (MH+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@H:10]1[CH3:26])(C(C)(C)C)(C)C.C1COCC1.Cl.C(=O)([O-])O.[Na+]>CO>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@@H:10]([CH3:26])[C@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-chlorobenzonitrile (65.7 mg) in a mixed solvent of THF (6 mL) and methanol (6 mL) was added 6 mol/L hydrochloric acid (4.0 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[S:13][CH3:12]
Reactant: CSc1ccccc1N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CSc1ccccc1Nc1cc(F)ccc1[N+](=O)[O-]

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (3.46 mL, 31.5 mmol) and 2-(methylthio)aniline (3.88 mL, 31.5 mmol) to give 5-fluoro-N-(2-(methylthio)phenyl)-2-nitroaniline as an orange solid: 1H NMR] (400 MHz, DMSO-d6) δ ppm 9.52 (1H, s), 8.26 (1H, dd, J=9.4, 6.1 Hz), 7.34-7.45 (3H, m), 7.26-7.32 (1H, m), 6.67-6.75 (1H, m), 6.35 (1H, dd, J=11.6, 2.6 Hz), 2.43 (3H, s); LC-MS (ESI) m/z 279.0 [M+H]+ at 2.176 min; m/z 277.0 [M−H]− at 2.169 min.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[NH:4][C:3]=1[CH3:28].[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C=O)C>[C:31]([O:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[N:4]=[C:3]([CH3:28])[C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(Cl)c(C)nc(C)c1-c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-Chloro-5-(4-(4-trifluoromethoxyphenoxy)phenyl)-2,6-dimethyl pyridin-4(1H)-one (0.41 g) in dry DMF, under nitrogen, was added all at once sodium hydride (0.05 g of a 60% dispersion in mineral oil). After stirring at rt for 30 min acetyl chloride (0.14 ml) was added. The mixture was stirred at rt for a further 2 hr, poured into iced water, extracted with ether, washed with water and satd. aq. sodium bicarbonate and dried over magnesium sulphate. Evaporation gave an oil which was triturated with hexane to give the title compound (0.2 g), m.p. 78°-80°, Nmr δH (CDCl3) 7.3-7.0 (8H, m), 2.68 (3H, s), 2.35 (3H, s), 2.05 (3H, s).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].C([Li])CCC.F[C:12]1[N:17]=[CH:16][C:15]([C:18]2[C:22]([CH2:23][N:24]([CH3:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][N:20]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[N:19]=2)=[CH:14][CH:13]=1>C1COCC1>[CH:3]([N:2]([CH3:1])[C:12]1[N:17]=[CH:16][C:15]([C:18]2[C:22]([CH2:23][N:24]([CH3:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][N:20]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[N:19]=2)=[CH:14][CH:13]=1)([CH3:5])[CH3:4]
Reactant: CNC(C)C
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N(C)c1ccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cn1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of methyl(propan-2-yl)amine (150 mg, 2.05 mmol, 4.00 equiv) in anhydrous THF (3 mL) maintained under nitrogen at −30° C. was added dropwise a 2.5M solution of n-butyllithium (1 mL, 5.00 equiv) in hexanes. After stirring for 30 min at −30° C., a solution of tert-butyl N-[2-([[3-(6-fluoropyridin-3-yl)-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]-N-methylcarbamate (200 mg, 0.45 mmol, 1.00 equiv) in THF (3 mL) was added. The resulting solution was stirred at room temperature for 4 h and then quenched by the addition of water (1 mL). The mixture was extracted with 3×10 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuum. The residue was purified on a silica gel column eluted with 0-3% of methanol in dichloromethane to give 0.18 g (80%) of (R/S) tert-butyl 2-(((3-(6-(isopropyl(methyl)amino)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl(methyl)carbamate as a yellow oil. LCMS (method A, ESI): RT=1.11 min, m/z=501.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:35][CH2:34][C:21]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1.Cl.C(OCC)(=O)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:35][CH2:34][C:21]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 199.4 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (364 mg, 0.7251 mmol) in DCM (10 mL) was added a solution of HCl in ethyl acetate (20 mL, 60 mmol). The reaction was stirred overnight at rt and then concentrated in vacuo to give the title compound as a yellow solid (317 mg, 99%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine 1,1-dioxide (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product as a light yellow solid (58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[C:17]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cccc(Cl)c1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 39.1 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,3-dichlorophenylboronic acid (Lancaster; 1.29 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,3-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (775 mg, 39%) as a solid.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]([F:28])([F:27])[CH:7]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]>CO.[C].[Pd]>[NH2:24][C:20]1[CH:19]=[C:18]([NH:17][CH:7]([C:6]([F:5])([F:27])[F:28])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(Nc1cccc(N)c1)C(F)(F)F
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To 10% palladium-carbon (50 mg) and ammonium formate (135 mg), a solution of tert-butyl (3,3,3-trifluoro-2-((3-nitrophenyl)amino)propyl)carbamate (C17, 100 mg) in methanol (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((3-aminophenyl)amino)-3,3,3-trifluoropropyl)carbamate (C18, 45 mg).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:10][O:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[NH4+]>O>[C:11]1([C@@H:8]2[CH2:7][O:6][C@@H:5]([CH2:4][NH2:1])[CH2:10][O:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=NC[C@H]1CO[C@H](c2ccccc2)CO1
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CO[C@H](c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Combine trans-2-azidomethyl-5-phenyl-1,4-dioxane (319 mg, 1.46 mmol), triphenylphosphine (765 mg, 2.92 mmol), and THF (20 mL) and H2O (5 mL). Stir the reaction mixture at room temperature overnight. Add Dowex AG 50W-X8 cation exchange resin (ammonium form, 200-400 mesh, 1 g) to the reaction and stir at ambient temperature for 20 minutes. Filter and sequentially wash the resin with THF (10 mL) then H2O (10 mL). Elute by rinsing the SCX resin with NH3 in MeOH (120 mL 7N) and concentrate the filtrate under reduced pressure to provide the title compound (280 mg, 99.6%) as a colorless oil. MS (m/z): 194 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: CNCCN1CCCC1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCN1CCCC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(2-pyrrolidin-1-yl-ethyl)amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-(2-pyrrolidin-1-yl-ethyl)-amine following General Procedure B.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[C:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][C:18]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:16])=[C:13]([C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[C:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:16])=[C:13]([C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 68.4 %

Procedure:
A solution of 0.428 g (0.582 mmol) of 1,1-dimethylethyl 4-(6-benzyloxy-2-(benzyloxycarbonyl)benzoyl)-3,5-dibenzyloxybenzoate in 5 mL of distilled quinoline was heated at 200° C. under an atmosphere of nitrogen for 3 h. The mixture was then cooled, poured onto 75 mL of ether and washed three times with 2N HCl and once with brine. The organic extracts were dried over magnesium sulfate and evaporated to give 0.42 g of the crude product, which was recrystallized from isopropanol to give 0.270 g (68%) of the title compound as a tan solid, mp 151°-156° C.