Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)[C:7]=1[CH3:29])=[O:5])[CH3:2].[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][OH:30])=[CH:33][CH:34]=2)=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)[C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(I)c(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(CO)cc2)c(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C
Temperature: 110 °C

Procedure:
To a mixture of Example 96 (33 mg, 0.060 mmol), 4-(hydroxymethyl)phenylboronic acid (12 mg, 0.080 mmol), palladium acetate (2.2 mg, 0.010 mmol) suspended in ethanol (0.50 mL) was added 1 M aqueous Cs2CO3 (0.080 mL, 0.080 mmol), and heated in a microwave (Personal Chemistry: Emrys Creator) at 110° C. for 15 minutes. The mixture was diluted with Et2O (2 mL), stirred thoroughly, filtered through diatomaceous earth with Et2O rinse. The filtrate was washed with 1 M pH 7 potassium phosphate buffer, dried (Na2SO4), filtered and concentrated under reduced pressure and the residue chromatographed on an Alltech silica column (average pore size 60 Å, particle size 50 μM) (30→10% hexanes/Et2O) to provide a white foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.81 (d, 2H), 7.49 (d, 2H), 7.48 (bs, 2H), 7.14 (d, 2H), 7.14 (d, 2H), 7.06 (d, 2H), 6.95 (d, 2H), 5.10 (t, 1H), 4.45 (d, 2H), 4.02 (q, 2H), 2.32 (s, 3H), 1.0 (t, 3H); MS (ESI) m/z m/z 525/527.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and isobutylamine (0.372 mL, 3.71 mmol) the title compound was obtained as an off-white foam (90 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.61-7.78 (m, 1H), 7.26-7.42 (m, 3H), 7.14-7.27 (m, 3H), 6.04-6.22 (m, 1H), 2.89-3.07 (m, 2H), 1.72-1.85 (m, 1H), 1.37 (s, 9H), 0.82 (d, J=6.4 Hz, 6H). MS (ESI): 576.2 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:63](O)(=[O:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CN(C=O)C.O>[C:63]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)(=[O:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 72 %

Procedure:
DIPEA (77.35 mg, 0.60 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (70 mg, 0.16 mmol) in DMF (2 mL). HOBT (19.8 mg, 0.14 mmol) and EDCI.HCl (63.74 mg, 0.33 mmol) were then added. After 2 minutes benzoic acid (16.35 mg, 0.13 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was precipitated and filtered to afford 40 mg (67.2% yield) of biphenyl-4-carboxylicacid {2-[4-benzoyl-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 92.6%, 1H NMR Values: (CDCl3) δ 7.9 (d, 2H), 7.7 (d, 2H), 7.6 (d, 2H), 7.5-7.4 (m, 8H), 7.3 (s, 1H), 4.4 (s, 2H), 3.8 (s, 4H), 3.6 (s, 4H).
Reaction SMILES: [CH3:1][Si:2]([CH3:37])([O:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[O:3][Si:4]([CH3:31])([CH3:30])[O:5][Si:6]([CH3:29])([CH3:28])[O:7][Si:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([CH2:26][OH:27])[OH:25])([CH3:10])[CH3:9].C[SiH](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C>>[OH:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][Si:8]([CH3:10])([CH3:9])[O:7][Si:6]([CH3:28])([CH3:29])[O:5][Si:4]([CH3:30])([CH2:31][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([OH:25])[CH2:26][OH:27])[O:3][Si:2]([CH3:1])([CH3:37])[O:32][Si:33]([CH3:34])([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCCCCCCCCOCC(O)CO
Agent: C[SiH](C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C
Product: C[Si](C)(C)O[Si](C)(C)O[Si](C)(CCCCCCCCCCCOCC(O)CO)O[Si](C)(C)O[Si](C)(C)CCCCCCCCCCCOCC(O)CO
Yield: 48 %

Procedure:
Undecamethylpentasiloxanylundecylglyceryl ether (F) was obtained in a 48% yield in the same manner as Example 4. At this time, since 1,5-dihydrodecamethylpentasiloxane was included in a raw material of undecamethylpentasiloxane, 1,5-bis[11-(2,3-dihydroxypropoxy)undecyl]decamethylpentasiloxane (G) was obtained at the same time. The obtained compound (G) was isolated and refined by a silica gel column. The structures of the obtained products were confirmed by an analysis using IR and NMR spectra. The result of the analysis of the compounds was as follows. ##STR23##
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:11]([OH:13])=O)[N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:37]([O:39][C:40](=[O:59])[C@H:41]([CH3:58])[CH2:42][C@H:43]([NH2:57])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)[CH3:38].C(N(CC)CC)C>CN(C=O)C.O>[C:48]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:47]=[CH:46][C:45]([CH2:44][C@@H:43]([NH:57][C:11]([C:4]2[N:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=2)=[O:13])[CH2:42][C@H:41]([C:40]([O:39][CH2:37][CH3:38])=[O:59])[CH3:58])=[CH:50][CH:49]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(=O)O)nc(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)O)nc(O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-hydroxypyrimidine-4,6-dicarboxylic acid (71 mg, 0.39 mmol) in DMF (10 mL) is added HOBT (59 mg, 0.39 mmol) and EDCl (74 mg, 0.39 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 1) (120 mg, 0.35 mmol) and triethylamine (0.15 ml, 1.16 mmol) are added. After stirring the mixture at room temperature for five hours, water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to elute the title compound. HPLC retention time 1.32 minutes (condition C); MS 478.3 (M+H); 1H NMR (400 MHz, DMSO-d6): δ ppm 1.05-1.07 (d, J=7.07 Hz, 3H), 1.09-1.12 (t, J=7.07 Hz, 3H), 1.72-1.79 (m, 1H), 1.81-1.89 (m, 1H), 2.44-2.49 (m, 1H), 2.77-2.82 (m, 1H), 2.89-2.95 (m, 1H), 3.95-4.01 (q, J=7.07 Hz, 2H), 4.16-4.26 (m, 1H), 7.26-7.28 (m, 2H), 7.31-7.35 (m, 1H), 7.41-7.45 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 8.73-8.76 (d, J=9.35 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][Cl:23])[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Product: ClCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of 2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethanol (2.90 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloro-2-(4-chloromethyl-2-pyridyloxymethyl)imidazo[1,2-a]pyridine (2.63 g, yield 85%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 118–119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16](C(OC(C)(C)C)=O)[NH:17]C(OC(C)(C)C)=O)[CH:13]=[C:12]([N+:32]([O-:34])=[O:33])[CH:11]=1.O1CCOCC1.Cl>O>[NH:16]([C:14]1[CH:13]=[C:12]([N+:32]([O-:34])=[O:33])[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=1)[NH2:17]
Reactant: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(NN)n1
Reaction time: 14 h

Procedure:
A mixture of the title compound from Example 19 Step B (2.0 g, 2.2 mmol), 23 mL 1,4-dioxane and concentrated HCl (2 mL) was stirred for 14 h. Concentrated HCl (8 mL) was added dropwise. After 1 h, concentrated HCl (4 mL) was added dropwise. After 4 h, the reaction mixture was diluted with water and concentrated to a solid form. The solid was further washed by ether twice to give the crude title compound which was used without further purification: LCMS m/z 275.5 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)[CH2:33][CH3:34]>>[CH:11]1([CH2:10][CH2:9][C:8]([N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=3[CH:29]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:43]#[C:42][C:39]3[CH:40]=[CH:41][C:36]([O:35][CH2:32][CH2:33][CH3:34])=[CH:37][CH:38]=3)=[CH:31][CH:30]=2)=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#Cc1ccc(OCCC)cc1
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Product: CCCOc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 4-(propoxy)-phenylacetylene as a beige powder (59%). M+ (ESI): 566.2. HPLC, Rt: 6.17 min (Purity: 97.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(C)cccc4C)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(C)cccc4C)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2,6-dimethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:24]([O-])=O)=[C:10]([NH:13][C:14](=O)[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28])([CH3:3])[CH3:2]>[Ni]>[CH:1]([CH:4]1[C:12]2[CH:11]=[C:10]3[NH:13][C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:24][C:9]3=[CH:8][C:7]=2[N:6]([CH3:27])[C:5]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C)C(=O)C3C(C)C)cc1
Agent: [Ni]
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C(C)C)C(=O)N4C)cc1
Temperature: 100 °C

Procedure:
(rac)-7-Isopropyl-2-(4-methoxy-phenyl)-5-methyl-5,7-dihydro-1H-imidazo [4,5-f]indol-6-one is prepared from (rac)-N-(3-Isopropyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methoxy-benzamide (443 mg) by hydrogenation at 70° C. as described in Example 1b) using Raney-nickel (70 mg). The catalyst is filtered off and the filtrate heated at 100° C. for 1 h. After a typical aqueous work-up the crude material is purified by flash chromatography on silica gel eluting with light petroleum/EtOAc (3:1) to give the desired compound (311 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[C:7]=1[OH:14])=[O:25]
Reactant: O=C=Nc1ccccc1Br
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 61.3 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (88 mg, 62%). EI-MS (m/z) 446.2, 448.3, 450.3 (M−).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+].Cl>C(COC)OC>[NH2:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1c([N+](=O)[O-])ccc2c1CCCC2
Temperature: 0 °C
Yield: 94.8 %

Procedure:
1-(Acetylamino)-2-nitro-5,6,7,8-tetrahydronaphtalene (2.5 g; 10.7 mmol) was suspended in a mixture of dimethoxyethane (30 ml) and aqueous sodium hydroxide (32 ml, 1 M). The mixture was heated to reflux for 2 hours. After cooling two volumes of ice-water was added, and the mixture was neutralised by addition of hydrochloric acid (32 ml, 1 M). The product was filtered off, washed with water and air-dried to yield 1-amino-2-nitro-5,6,7,8-tetrahydronaphtalene (1.95 g, 95%). This product (1.92 g; 10.0 mmol) was dissolved in ethanol and hydrogenated at ambient pressure using Pd (5% on activated carbon) as the catalyst. When the hydrogen uptake had ceased, the mixture was filtered through celite and the filtrate was evaporated to dryness to leave 1,2-diamino-5,6,7,8-tetrahydronaphtalene (1.55 g, 96%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:6][C:5]=2[N:4]([CH3:19])[C:3]=1I>C(O)(=O)C.O.[Zn]>[I:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[N:6][C:5]=2[N:4]([CH3:19])[CH:3]=1
Reactant: Cn1c(I)c(I)c2c(=O)[nH]c(NC(=O)C(C)(C)C)nc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(I)c2c(=O)[nH]c(NC(=O)C(C)(C)C)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a suspension of N-(5,6-diiodo-7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide (941 mg, 1.88 mmol) in acetic acid (9 ml) and water (2 ml) was added zinc powder (246 mg, 3.76 mmol), and the mixture was stirred at room temperature for 1 day. After addition of zinc (123 mg, 1.88 mmol), the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with water and stirred at 0° C. for 2 hours. The resulting crystals were collected by filtration, washed with water and dissolved in tetrahydrofuran. The solution was filtrated, and the filtrate was concentrated in vacuo. The residue was washed with diiopropyl ether to give 545 mg (78%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH2:28])(=[S:27])[CH2:25][CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:28]=[C:24]([CH2:25][CH3:26])[S:27][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCC(N)=S
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Product: CCOC(=O)c1c[nH]c2c1-c1nc(CC)sc1CC2

Procedure:
The title compound is prepared by reacting 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with thiopropionamide essentially according to the procedures described in Example 15, Step 3. 1H NMR (CDCl3) 1.33-1.42 (m, 6H), 2.80-2.90 (m, 2H), 2.98-3.10 (m, 4H), 2.37 (q, 2H), 7.24 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]1[C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])[N:13]=[C:12]([CH3:23])[C:11]=1[C:24]#[N:25]>CO>[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]1[C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])[N:13]=[C:12]([CH3:23])[C:11]=1[C:24](=[N:1][OH:2])[NH2:25]
Reactant: Cc1ccn(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Reactant: NO
Solvent: CO
Product: Cc1ccn(C)c1-c1c(C(N)=NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.3 mL, 4.8 mmol) was added to 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (10 mg, 0.032 mmol) in MeOH (0.6 mL) and the reaction was stirred at 150° C. for 20 min in the microwave reactor. The crude reaction was purified on preparative HPLC to give E8 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (4.27 mg, 39%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 344.12 (M+H), 342.24 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.11 (s, 1H), 7.17 (t, 1H, J=8.8 Hz), 6.70 (d, 1H, J=2.87 Hz), 6.67 (m, 1H), 6.61 (dd, 1H, J=2.6, 11.9 Hz), 5.83 (d, 1H, J=2.71), 3.38 (s, 3H), 2.39 (s, 3H) and 1.72 (s, 3H).
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.Cl.[OH:28][CH2:29][C@@H:30]1[CH2:34][NH:33][CH2:32][C@H:31]1[OH:35]>>[OH:35][C@H:31]1[C@H:30]([CH2:29][OH:28])[CH2:34][N:33]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:32]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Reactant: OC[C@@H]1CNC[C@H]1O
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncs2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 4 using 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1) and trans-4-(hydroxymethyl)pyrrolidin-3-ol hydrochloride to afford an off-white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=480.1 [M+H]+, m/z=478.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04-2.18 (m, 1H) 2.78 (dd, J=10.39, 3.79 Hz, 1H) 2.97 (dd, J=9.90, 5.01 Hz, 1H) 3.18 (dd, J=10.51, 5.62 Hz, 1H) 3.23-3.28 (m, 1H) 3.32-3.37 (m, 1H) 3.37-3.47 (m, 1H) 3.91-4.03 (m, 1H) 4.63 (t, J=5.14 Hz, 1H) 4.94 (d, J=4.16 Hz, 1H) 6.99 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.83-7.98 (m, 5H) 9.16 (d, J=0.73 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH2:12]([O:19][C:20]1[C:21]([CH3:30])=[C:22]2[N:27]([CH:28]=1)[N:26]=[CH:25][N:24]=[C:23]2Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(C#N)(C)=O>>[CH2:12]([O:19][C:20]1[C:21]([CH3:30])=[C:22]2[N:27]([CH:28]=1)[N:26]=[CH:25][N:24]=[C:23]2[O:1][C:2]1[CH:3]=[C:4]2[CH:5]=[C:6]([CH3:11])[NH:7][C:8]2=[N:9][CH:10]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc2cc(O)cnc2[nH]1
Reactant: Cc1c(OCc2ccccc2)cn2ncnc(Cl)c12
Agent: CC(=O)C#N
Product: Cc1cc2cc(Oc3ncnn4cc(OCc5ccccc5)c(C)c34)cnc2[nH]1

Procedure:
5-Hydroxy-2-methyl-7-azaindole was treated with of 6-benzyloxy-4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (see WO 0071129) by a method similar to the preparation of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (1H, br. s), 7.85 (1H, s), 7.83 (1H, s), 7.70 (1H, br. s), 7.41 (6H, m), 6.15 (1H, br. s), 5.12 (2H, s) 2.92 (3H, s), 2.42 (3H, s). m/z 386 (M+H)+, 427 (M++AcCN).