Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:39])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CSc1ccc(C)c(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(C)c(C)c1
Temperature: -78 °C
Yield: 21 %

Procedure:
Into a solution of methyl 5-(3,4-dimethylphenylthio)-4-(N,N-dipentylcarbamoyl)pentanoate (0.55 g) in dry dichloromethane (10 ml) were added portions of m-chloroperbenzoic acid (70%, 0.31 g) with stirring at -78° C. After stirring at -78° C. for 3 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with benzene/ethyl acetate (2:1) to give 0.12 g of methyl 5-(3,4-dimethylphenylsulfinyl)-4-(N,N-dipentylcarbamoyl)pentanoate (diastereomer A) in a early fraction and 0.36 g of diastereomer B in a later fraction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1.C([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:33][C:31]4[CH:30]=[CH:29][C:28]([O:35][CH3:36])=[C:27]([CH:32]=4)[C:26]([OH:37])=[O:25])[CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3ccsc3)c2c1
Product: COc1ccc(CN2CCC(c3cn(Cc4ccsc4)c4cc(F)ccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.12 g (0.34 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 0.11 g (0.44 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. The crude mixture was purified by HPLC-MS using a C-18 column.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH:57]=[CH:56][N:55]=[CH:54]1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][N:53]2[CH:57]=[CH:56][N:55]=[CH:54]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: c1c[nH]cn1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3ccnc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (k) the (3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with imidazol and sodium hydride in N,N-dimethylformamide to yield the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-imidazol-1-yl-propoxy)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 783 (M+H)+.
Reaction SMILES: [Br-:1].[Br-].[CH2:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH:4]=[CH2:5].[O-]CC.[Na+]>C(O)C>[O:12]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:3][CH:4]1[CH2:5][Br:1]
Reactant: [Br-]
Reactant: C=CCc1ccccc1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: BrCC1Cc2ccccc2O1
Yield: 79.7 %

Procedure:
A solution of bromine (90 g) in carbon disulphide (100 ml) was added dropwise to a well stirred solution of O-acetyl-2-allylphenol (100 g) in carbon disulphide (300 ml) at -10° C. over 1 hour. The solution was evaporated to dryness in vacuo, to afford O-acetyl-2-allylphenol dibromide which was immediately dissolved in dry ethanol (300 ml) containing 10 ml of a saturated ethanolic-hydrogen chloride solution. The solution was heated under gentle reflux for 2 hours, and then evaporated to dryness in vacuo. The residue was triturated with n-pentane, and the solid 2-allylphenol dibromide (135 g) was collected and washed twice with portions of n-pentane. The product is pure enough for further reaction. 2-Allylphenol dibromide (135 g) in dry ethanol (300 ml) was treated with a solution of sodium ethoxide (38 g) in ethanol (100 ml) with cooling and stirring, keeping the temperature of the reaction between 30° and 35° C. After addition, the reaction was stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue was partioned between n-pentane and water. The n-pentane fraction was washed with 2% sodium hydroxide solution, water, and dried (Na2SO4). Evaporation to dryness in vacuo afforded crude (2,3-dihydro-2-benzofuranyl)-methyl bromide (90 g), which distilled at 110°-118° C./0.5 mm to afford product (78 g) of slightly higher purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[Cl:28][C:29]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:30]=1[NH:31][C:23]([C:15]1[C:16]2[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=2[C:11]2[NH:10][C:9]([NH:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:27])=[N:13][C:12]=2[CH:14]=1)=[O:25]
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Cc1ccc(N)c(Cl)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(Cl)cncc4Cl)[nH]c3c3c2OC(C)(C)C3)c(Cl)c1
Yield: 23.7 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2-chloro-4-methylaniline (0.052 g, 0.361 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.030 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 2.26 (s, 3H), 3.08 (s, 2H), 7.16 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.36 (s, 1H), 8.43 (s, 2H), 8.46 (s, 1H), 10.09 (s, 1H), 10.99 (br s, 1H), 11.52 (br s, 1H); MS [M+H]+: 517.97.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[F:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(F)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(F)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 57 %

Procedure:
The product of step B was coupled with sodium benzenesulfinate using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) provided tert-butyl 6-fluoro-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (141 mg, 57%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.97-7.94 (m, 2H), 7.88 (br s, 1H), 7.61-7.47 (m, 4H), 4.57 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.89 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[O:30])[CH:4]=1)[C:11]([OH:13])=[O:12])([CH3:18])[CH3:19]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Product: COc1ccc(NC(=O)OCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.Cl.[CH3:12][NH:13][CH:14]1[C:19]2=[C:20]([CH3:27])[C:21]3[C:26]([N:18]2[CH2:17][CH2:16][CH2:15]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>O1CCCC1>[CH3:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]2[CH2:17][CH2:16][CH2:15][CH:14]([N:13]([CH3:12])[CH:1]=[O:3])[C:19]=12
Reactant: CNC1CCCn2c1c(C)c1ccccc12
Reactant: O=CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Formic acid (7 mL) and acetic anhydride (14 mL) were mixed and heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-N,10-dimethylpyrido[1,2-a]indol-9-amine hydrochloride (7.49 g, 35 mmol) in tetrahydrofuran (40 mL) was added, and the mixture was stirred at room temperature overnight. The resultant solution was poured onto ice, and products were extracted with ether. The combined extracts were washed with 5% hydrochloric acid, 5% bicarbonate, and water. After drying (MgSO4) and filtration, the solvent was removed, and the residual oil was rapidly filtered through a silica gel column packed in chloroform/methanol 50:1. The title formamide was obtained as a yellowish oil 6.3 g (74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])C=O.C(Cl)(=O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCO>[Br:10][C:9]1[CH:8]=[CH:7][C:4]([CH:15]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(Br)c(F)c1
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCOC(OCC)c1ccc(Br)c(F)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-fluoro-4-bromobenzaldehyde (20.0 g, 98.5 mmol) in dry EtOH (120 mL) was added acetyl chloride (2.04 mL, 29.6 mmol) followed by the addition of triethyl orthoformate (6.55 mL, 39.4 mmol) and the contents were heated to 70° C. for 3 h. The contents were cooled to room temperature and shifted to a rotary evaporator and subjected to reduced pressure (280 mm Hg) with bath temperature 65° C. for 45 min. The pressure was further lowered to remove all the solvent. To this mixture, fresh Ethanol (60 mL), acetyl chloride (1.5 mL), triethyl orthoformate (5.0 mL) and heated to 70° C. for 2 h. The solvent was removed under the reduced pressure and diluted with EtOAc (200 mL), washed with saturated sodium bicarbonate (3×100 mL), brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue purified by silica gel column (basified with 5% Et3N, eluent: EtOAc/hexanes, 1/20) to afford 1-bromo-4-(diethoxymethyl)-2-fluorobenzene as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (t, J=8.1 Hz, 1H), 7.36-7.33 (m, 2H), 5.54 (s, 1H), 3.63-3.52 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Methyl 4-[N-(3-phenyl-1H-indazole-5-yl)carbamoyl]benzoate (92 mg, 0.247 mmol) was added to a solution of lithium hydroxide (10 mg, 1.23 mmol) in tetrahydrofuran (5 mL) and water (5 mL). The solution was allowed to stir at room temperature for 3 hours. The solution was acidified using a 5% HCl solution. The resulting white precipitate was filtered and dried to provide the title compound (62 mg, 70% yield). 1H NMR (DMSO-d6) δ 13.22 (br s, 1H), 10.48 (s, 1H), 8.55 (s, 1H), 8.06 (s, 4H), 7.92 (d, 2H), 7.75 (d, 1H), 7.55 (m, 3H), 7.38 (m, 1H); ES-MS (m/z) 358 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NCc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.100 g, 0.267 mmol), ethanol (2.0 mL) and then benzylamine (0.350 mL, 3.21 mmol) via syringe at once. The sealed contents were irradiated at 140° C. for 3 hr. The contents were transferred to a heat block and heated at 135° C. for 16 hr., and then at 145° C. for an additional 12 h. After cooling to room temperature, the contents were diluted with CH2Cl2 and pre-absorbed onto silica gel. The crude product was purified by silica gel chromatography (dry loaded, eluent; gradient of 5-80% DCM and chloroform containing 10% 2M Ammonia (in methanol)). The isolated solid was triturated with MTBE, filtered, and washed with additional MTBE. The collected solid was dried in vacuum oven at 45° C. overnight to afford the final product as 0.067 g (55%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.20 (s, 3H), 4.31 (d, J=5.05 Hz, 2H), 4.56 (d, J=6.06 Hz, 2H), 4.92 (quin, J=6.69 Hz, 1H), 5.88 (s, 1H), 6.69 (s, 1H), 7.18-7.25 (m, 1H), 7.26-7.35 (m, 2H), 7.35-7.43 (m, 2H), 7.77 (t, J=5.94 Hz, 1H), 7.83 (s, 1H), 8.47 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of 7-[(R)-1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.9 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.13 (d, J=6.6 Hz, 3H), 3.96 (s, 3H), 6.33 (q, J=6.6 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.63 (d, J=9.9 Hz, 1H), 7.85 (s, 1H), 7.93 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H). MS (ES+): m/z 377.11 (100) [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl.C(OCC)C>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:16])([CH3:17])[N:9]([O:14][CH3:15])[C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:20](=[O:21])[CH2:19][Cl:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CCCCNC1CC(C)(C)N(OC)C(C)(C)C1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCN(C(=O)CCl)C1CC(C)(C)N(OC)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A solution of 48.5 g (0.200 mol) of 4-butylamino-1-methoxy-2,2,6,6-tetramethylpiperidine in 150 ml of dichloromethane is added over a one hour interval at -10° C. to a solution of 11.3 g (0.100 mol) of chloroacetyl chloride in 100 ml of dichloromethane. The reaction mixture is then stirred at ambient temperature for 1 hour. The mixture is diluted with diethyl ether (500 ml), and solids are removed by filtration. The filtrate is washed with 1N hydrochloric acid (2×75 ml) and saturated sodium bicarbonate (100 ml), then dried over magnesium sulfate and concentrated to afford 27.8 g (87% yield) of the title compound, a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCCOc1ccc(F)cc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCOc1ccc(F)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-fluorophenoxy)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (49% yield). 1H NMR (500 MHz, CDCl3) δ 8.28, 8.05, 7.74, 7.63, 7.56, 7.35, 7.03-6.92, 6.87-6.81, 4.02-3.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([S:28]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[OH:34][CH2:33][C:32]([NH:31][S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:18]([C:17]2[CH:16]=[N:15][N:11]3[C:12]([CH3:14])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29])([CH3:36])[CH3:35]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(=O)(=O)NC(C)(C)CO)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 514.5 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:37]1[S:38][C:39]2[C:44]([Cl:45])=[N:43][C:42]([CH:46]3[CH2:48][CH2:47]3)=[N:41][C:40]=2[N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:38][C:39]4[C:44]([Cl:45])=[N:43][C:42]([CH:46]5[CH2:47][CH2:48]5)=[N:41][C:40]=4[N:49]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixed solution of the compound (0.94 g) obtained in Example 783, the compound (0.48 g) obtained in Step 5 and chloroform (2.8 ml) was added N,N-diisopropylethylamine (0.30 ml) at room temperature. The mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (1.3 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[CH3:22][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:23]([C:13](=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][C:5]2=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:22])=[CH:25][CH:26]=1)#[N:29]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: CNc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=C1C(=O)Nc2ccccc21)c1ccccc1)c1ccc(C#N)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 4-methylamino-benzonitrile in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Br:20][C:21]1[N:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[Br:20][C:21]1[CH:26]=[N:25][C:24]([O:27][CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[CH:23][N:22]=1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3cnc(Br)cn3)co2)cc1
Reaction time: 1 h

Procedure:
A mixture of 4-chlormethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.345 g, 1.2 mmol), 5-bromo-pyrazin-2-ol (0.175 g, 1.0 mmol) and cesium carbonate (Cs2CO3) (0.489 g, 1.5 mmol) in DMF (4 ml) is kept at 80° C. for 1 h. After cooling ethyl acetate (40 ml) is added, the mixture is washed with sat. NH4Cl and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexane 1:9->ethyl acetate/hexane 1:2) yielding 2-bromo-5-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl-methoxy}-pyrazine as a white solid. Yield 122 mg (29%).