Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.[NH2:20][C:21]1[N:26]=[C:25]2[CH2:27][C:28]3([CH2:38][C:24]2=[CH:23][CH:22]=1)[C:36]1[C:31](=[N:32][CH:33]=[CH:34][CH:35]=1)[NH:30][C:29]3=[O:37].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:37]=[C:29]1[NH:30][C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:36]2[C:28]21[CH2:27][C:25]1=[N:26][C:21]([NH:20][C:8](=[O:10])[CH2:7][N:6]3[C:5]4[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=4[N:3]([C:15]4[S:16][CH:17]=[CH:18][N:19]=4)[C:2]3=[O:1])=[CH:22][CH:23]=[C:24]1[CH2:38]2
Reactant: O=C(O)Cn1c(=O)n(-c2nccs2)c2ccccc21
Reactant: Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n(-c2nccs2)c2ccccc21)Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (62 mg, 0.23 mmol, described in Intermediate 33), (±)-2-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 5), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26]1[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:29]4[CH:30]=[N:31][C:26]([C:25]([F:34])([F:24])[F:33])=[CH:27][CH:28]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C(F)(F)F)nc4)ncnc32)CC1
Yield: 21.5 %

Procedure:
4-[4-(6-Trifluoromethyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 22%) was prepared using the procedure described for the preparation of Example 96, by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 6-trifluoromethyl-pyridin-3-ol (Matrix Scientific, Columbia, S.C., USA; 31 mg, 0.19 mmol) in the presence of potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL). Mass spectrum (ES) MH+=465. HRMS Calcd. for C21H24F3N6O3 (MH+): 465.1857. Found: 465.1857.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[NH2:54]>C(O)(=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([N:54]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]
Reactant: COc1ccc(N)cc1OC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1OC
Yield: 59 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (52 mg, 0.22 mmol), triethyl orthoformate (0.45 ml), 3,4-dimethoxyaniline (62.8 mg, 0.41 mmol), and acetic acid (0.06 ml) were used to give 48 mg (0.13 mmol, 59% yield) of the title compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:23])[C:12]([CH3:22])([S:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([SH:14]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C:12]([CH3:13])([CH3:22])[C:11]([NH:10][C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[O:9][N:8]=1)=[O:23])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(SCC1CCCNC1)C(=O)Nc1cc(C(C)(C)C)on1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)[SH](CC1CCCNC1)C(C)(C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
A solution of 175 mg (0.52 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(piperidin-3-ylmethylsulfanyl)-propionamide 0.18 mL (1.04 mmol) of N,N-diisopropylethylamine and acetic anhydride (1.5 mL) were heated for 0.5 h to 100° C. within a microwave (CEM discover). The solvent was removed under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford 183 mg of 2-(1-acetyl-piperidin-3-ylmethylsulfanyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-:15].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([OH:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(CC(C)C)C(=O)OC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(O)(CC(C)C)C(=O)O
Reaction time: 24 h
Yield: 73.6 %

Procedure:
Air was bubbled for 1 hour at room temperature through a suspension of 0.5 g (3 mmol) dimethyl-(2-methylpropyl)malonate and 1.73 g (5 mmol) cesium carbonate in 7 ml dimethylformamide. Stirring was continued at room temperature for 24 hours. 25 ml water was added and the mixture was extracted with diethylether. Acidification with aqueous 1 N hydrochloric acid to pH=1 and extraction with ethylacetate yielded 0.42 g (83%) (R/S)-2-hydroxy-2-isobutyl-malonic acid monomethyl ester, MS (m/e): 189.4 (M−H)−.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([Cl:54])[N:53]=1)[C:48](O)=[O:49].Cl.CNOC>CN(C=O)C>[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([Cl:54])[N:53]=1)[C:48]([N:9]([O:8][CH3:4])[CH3:10])=[O:49]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
HATU (1.97 g, 5.20 mmol), HOAT (707 mg, 5.20 mmol) and DIEA (1.77 ml, 10.5 mmol) were added to 2,6-dichloroisonicotinic acid (1 g, 5.20 mmol) in anhydrous DMF (5 ml). The mixture was stirred for 5 minutes, then N-methyl methoxylamine hydrochloride (507 mg, 5.20 mmol) was added in one portion followed by DIEA (800 μl, 5.2 mmol). The reaction was stirred for 30 minutes, then the crude product was partitioned between EtOAc (50 ml) and water (50 ml) and the organic level washed with water (3×50 ml). The organic phase was dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc:n-hexanes (2:3) to afford the title compound (1.12 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[C:33]([F:42])=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[C:33]([F:42])=[C:34]([S:38]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-chloro-2-fluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 570.8 ([M+H]+)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].I[CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)[CH2:32][CH3:33]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 29.2 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g), 60% sodium hydride in oil (0.30 g), dimethylformamide (25 ml), and 1-iodopropane (0.60 g), the title compound (0.32 g) was obtained as a crystalline solid, m.p. 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH3:29])=[C:24]([OH:27])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39]Br)([CH3:33])([CH3:32])[CH3:31]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:28][CH3:29])[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:2]([Cl:1])[CH:3]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1OCCCNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
CsOH monohydrate (0.452 g, 2.69 mmol) was added to a mixture of 4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ol (1 g, 2.45 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (0.64 g, 2.69 mmol), tetrabutylammonium iodide (5 mg) and 4 Å molecular sieves (2 g) in DMF (10 mL) at room temp. Stir for 3 hours. The reaction mixture was then filtered through celite and washed with EtOAc (30 mL). The organic solution was washed with water (20 mL) and concentrated. FLC (10:1 EtOAc:Hexanes) provided desired product (1.02 g, 73.7%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:22]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:33][OH:34])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:20]=[C:8]([O:9][C:10]2[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5R)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulfonyl)pyrazine (496 mg, 0.82 mmol) synthesized in Example (101c) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 0.82 mL, 0.82 mmol) was added, followed by stirring for 2 hours under nitrogen atmosphere. To the reaction solution, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (133 mg, yield 35%) as a white solid.
Reaction SMILES: C(O)(=O)C.OO.S(=O)(=O)(O)O.[C:12]([O:15][OH:16])(=[O:14])[CH3:13].CC(C)=O.N.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]1([NH:35]N=C(C)C)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)=NN=C(C)C>CO>[C:12]([O:15][OH:16])(=[O:14])[CH3:13].[N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CC(C)=NNc1ccccc1
Agent: CC(=O)OO
Agent: CC(C)=NN=C(C)C
Agent: N
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: c1ccc(N=Nc2ccccc2)cc1
Yield: 80.5 %

Procedure:
A crude peracetic acid solution was prepared by mixing 17.3 g glacial acetic acid (0.29 mole), 7.2 g of a hydrogen peroxide solution having 68% by weight of H2O2 (0.145 mole of H2O2), and 0.7 g concentrated sulphuric acid, and reacting the mixture for several hours at ambient temperature. A solution was obtained which contained 0.10 mole peracetic acid and 0.033 mole uncoverted hydrogen peroxide, and which was introduced into 200 ml of methanol at 0° C. Within the space of half an hour 34.8 g acetone (0.6 mole), 12.2 g of an ammonia solution having 28% by weight NH3 (0.2 mole), and 18.6 g aniline (0.2 mole) were added, after which the mixture was determined by gas phase chromatography to contain 4.6 g of acetone phenylhydrazone (0.031 mole, which was 31% of the theoretical yield compared to the peracid), 1 g of acetone azine (0.009 mole, which was 9% of the theoretical yield), and 0.025 mole of azobenzene.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:3]=1.[Li]C(C)(C)C.[F:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>C1COCC1.CCCCC>[F:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(C(O)c3cccc(F)c3)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
To a solution of toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared as exemplified in method 6) in THF (2 mL) at −90° C. under nitrogen atmosphere was added a solution of tBuLi in pentane (1.7 M, 90 uL) dropwise. After stirring for 5 min, 3-fluoro-benzaldehyde (40 uL, 0.38 mmol) was added and the reaction mixture was slowly warmed up to 10° C. over 2 h, then quenched with a saturated solution of ammonium chloride and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 26 mg of toluene-4-sulfonic acid 3-[3-[(3-fluorophenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester. The material was dissolved in dichloromethane (0.3 mL) under nitrogen atmosphere. Triethylsilane (24 uL, 0.149 mmol) was added, followed by boron trifluoride etherate (7 μL, 0.149 mmol) dropwise. After stirring for 15 h, the reaction was quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane three times. The extracts were combined and concentrated under vacuum. The crude was treated with 2 mL of EtOH and 2 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 70° C. for 1 h. The mixture was acidified to pH 4 with 1 N aqueous HCl, and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(3-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a beige solid (8 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.11 (s, 3H), 6.74 (dd, J=2.5, 8.5 Hz, 1H), 6.97 (dt, J=2.0, 8.5 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.13 (d, J=10.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.30 (q, J=8.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.56 (broad s, 1H), 11.6 (s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:20][CH:21]=[CH2:22])[CH2:8][CH2:7][N:6]1[C:9]([C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[S:14][CH:15]=1)=[O:10])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7][N:6]1[C:9]([C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[S:14][CH:15]=1)=[O:10])=[O:4]
Reactant: C=CCC1(C(=O)OC)CCN1C(=O)c1csc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CCCC1(C(=O)OC)CCN1C(=O)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 2-allyl-1-(benzo[b]thiophene-3-carbonyl)-azetidine-2-carboxylic acid methyl ester Intermediate 197 (1 eq.) in MeOH was added Pd/C (0.2 eq.), the flask was evacuated and backfilled with H2. The reaction was stirred for 15 h at 20° C. under atmospheric pressure. The crude was filtered through a pad of celite and washed with EtOH and EtOAc. The filtrate was concentrated under reduced pressure to afford 1-(benzo[b]thiophene-3-carbonyl)-2-propyl-azetidine-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27]([C:28](Cl)=[O:29])=[C:26]([CH3:31])[O:25][N:24]=2)=[C:19]([Cl:32])[CH:18]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.CC#N>[CH3:13][O:14][C:15](=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27]([C:28](=[O:29])[NH:7][CH2:6][CH2:5][O:4][C:3]3[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])=[C:26]([CH3:31])[O:25][N:24]=2)=[C:19]([Cl:32])[CH:18]=1
Reactant: COC(=O)Cc1ccc(-c2noc(C)c2C(=O)Cl)c(Cl)c1
Reactant: NCCOc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(-c2noc(C)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(2,4-Dichloro-phenoxy)-ethylamine 29 (17 mg, 0.08 mmol) in toluene (2 mL) is cooled to 0° C. A solution of intermediate 26 (0.08 mmol) and triethylamine (23 μL, 0.16 mmol) in MeCN (1 mL) is added and the solution is warmed to room temperature. After stirring at room temperature for 1 h the mixture is poured into H2O and extracted three times with EtOAc. The organic layers are combined, dried (MgSO4), filtered, and concentrated to afford crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethylcarbamoyl]-5-methyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 30.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[C@@H:11]([C:8]1[N:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH2:29]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc3ncc([C@@H](C)c4cc5cnn(C)c5cc4F)n3n2)CC1

Procedure:
The title compound was prepared analogy to Example 38 using 6-chloro-3-[(S)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate E) (50 mg, 0.153 mmol) and 1-acetylpiperazine (39.2 mg, 0.306 mmol) (tR 3.67 min (conditions 5), MH+=421, 1H-NMR in DMSO-d6: 7.93 (s, 1H); 7.81 (d, 1H); 7.52 (d, 1H); 7.50 (s, 1H); 7.47 (d, 1H); 4.75 (m, 1H); 3.95 (s, 3H); 3.42 (m, 6H); 2.00 (s, 3H); 1.70 (d, 3H)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17](Cl)(Cl)=[S:18]>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:3][C:2]=1[N:1]=[C:17]=[S:18]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(Cl)c(N=C=S)c1
Yield: 85 %

Procedure:
A mixture of 17 parts of (3-amino-4-chlorophenyl) phenylmethanone, 9.5 parts of carbonothioic dichloride and 200 parts of 1,4-dioxane is stirred and refluxed for 15 minutes. The reaction mixture is evaporated and the oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 17 parts (85%) of (4-chloro-3-isothiocyanatophenyl)phenylmethanone; mp. 96.7° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO[CH:19](OC)[CH2:20][C:21](=[O:23])[CH3:22].Cl>C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Reactant: COC(CC(C)=O)OC
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)/C=C/c1c(-c2ccccc2)n(C)c2ccccc12
Reaction time: 14 h
Yield: 88.7 %

Procedure:
2.07 g of 1-methyl-2-phenyl-1H-indole, 1.32 g of 1,1-dimethoxy-3-butanone and 12 mL of acetic acid were mixed, then, 313 mg of 35 wt % hydrochloric acid was added into the mixture at room temperature, the added mixture was stirred for about 14 hours at the same temperature to cause a reaction. At a time point about 10 minutes after starting of stirring and reaction, blue solid precipitated to render stirring difficult. Therefore, 8 mL of acetic acid was added. After completion of the reaction, 60 mL of water was added dropwise, and the precipitated crystals were filtrated. The crystals were washed with 10 vol % methanol/water, then, dried to obtain 2.44 g of trans-4-[1-methyl-2-phenyl-1H-indol-3-yl]-3-buten-2-one (blue green solid). Yield: 89%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:12].O>O1CCCC1>[CH3:12][O:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-hydroxymethylpyridine (10 g, 92 mmol) in anhydrous tetrahydrofuran (200 ml), under an atmosphere of nitrogen, was treated with sodium hydride (4 g of a 55% oil dispersion, 92 mmol) in portions. After stirring for 15 minutes iodomethane (5.7 ml, 92 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 hours. Water (20 ml) was added and the tetrahydrofuran evaporated. The residue was partitioned between water (50 ml) and dichloromethane (70 ml). The organic layer was separated, dried (sodium sulphate) then evaporated. The crude product was purified by column chromatography on silica using ethyl acetate. The title compound was obtained (11 g, 93%) as an oil, δH (250 MHz, CDCl3) 3.42 (3H, s), 4.48 (2H, s), 7.27-7.32 (1H, m), 7.66-7.71 (1H, m), 8.53-8.60 (2H, m).