Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([CH3:17])[C:11]=1[CH3:16]
Reactant: Cc1c(N)ccc(O)c1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,3-dimethylphenol hydrochloride (1.55 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.94 g (yield 65%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a stirred solution of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (20) in THF (4 ml) were added 4-chlorobenzoic acid (147 mg), N-methylmorpholine (0.27 ml) and TBTU (401 mg). The reaction mixture was heated to 50° C. and stirred for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (SiO2; gradient: EtOAc/heptane) to afford (S)-4-{2-[4-(4-chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a white solid (254 mg, 89%). MS (ISP): 478.3 ([{37Cl}M+NH4]+), 476.3 ([{35Cl}M+NH4]+), 405.4 ([{37Cl}M+H—C4H8]+), 403.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.P(Br)(Br)[Br:18].O.[OH-].[Na+]>CN(C=O)C>[Br:18][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc2nccc(OC)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2nccc(Br)c2c1
Temperature: 80 °C

Procedure:
To a solution of methyl 4-methoxy-6-quinolinecarboxylate (910 mg) in DMF (7 ml) was added phosphorus tribromide (1.57 ml) while stirring under ice-cooling. DMF (7 ml) was added and the mixture was heated at 80° C. for 3 hr. To the reaction mixture was added water (50 ml) and the reaction mixture was made weak basic with a 1N aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration and purified by silica gel column chromatography (eluent: chloroform-methanol=100/0-100/1) to give the object compound (420 mg) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]1([OH:35])[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc2c1CCCC2
Product: CC(NC(=O)c1coc(Oc2cccc3c2CCCC3)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 89.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 5,6,7,8-tetrahydro-naphthalen-1-ol (38.7 mg, 0.26 mmol) to give the title compound (57 mg, 89%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[C:13]1([CH2:19][O-:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>>[C:13]1([CH2:19][O:20][C:2]2[C:3]3[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [O-]Cc1ccccc1
Reactant: Cc1nc2c(Cl)nccn2c1C
Agent: [Na+]
Product: Cc1nc2c(OCc3ccccc3)nccn2c1C

Procedure:
For example, treating 8-chloro-2,3-dimethylimidazo[1,2-a]pyrazine with sodium phenylmethoxide yields an 8-phenylmethoxy-2,3-dimethylimidazo[1,2-a]pyrazine as shown in rection Scheme V. ##STR17##
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:2]([N:9]([CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1)[CH2:31][CH2:30][CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CCC(CNCc1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
2-(N-benzylamino)methyl-6-methoxytetralin hydrochloride (0.602 g; obtained in Reference Example 6), 3,3-diphenylpropyl iodide (0.803 g) and potassium carbonate (0.800 g) were added to DMF (20 ml). The reaction mixture was stirred at room temperature for 24 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) to obtain the entitled compound (0.335 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=C(O)C=Cc1cc(F)c(F)c(F)c1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3 h) between 3,4,5-trifluorobenzaldehyde (7.000 g; 43.724 mmol) and malonic acid (8.644 g; 83.076 mmol) gave the product 3-(3,4,5-trifluoro-phenyl)-acrylic acid as a yellow solid (8.600 g; 97%). LC-MS: tR=0.91 min.; [M+H]+: no ionisation.
Reaction SMILES: C[O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][C:4]=1[C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[CH:22][CH:21]=2.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C.O>[OH:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([C:6]2[CH:5]=[C:4]([C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH3:27])=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3](=[O:2])[NH:8][N:7]=2)=[CH:10][C:11]=1[CH3:17]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2cc(-c3[nH]c4ccccc4c3C)c(=O)[nH]n2)cc(C)c1O
Temperature: 80 °C

Procedure:
6 mg of 4-[6-Methoxy-5-(3-methyl-1H-indol-2-yl) -pyridazin-3-yl]-2,6-dimethyl-phenol is suspended in 2 ml acetonitrile and 6.5 mg of trimethylsilyl chloride and 9.96 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h. The reaction solution is diluted with water and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 3.8 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:6].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[O:6]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:36][CH2:37]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCl)c1ccc(Oc2ccccc2)cc1
Product: O=C(CCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Oc2ccccc2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-phenoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 483.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:15].C([O-])(=O)C.[Na+].[Br:21]Br>C(O)(=O)C>[Br:21][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:15])[C:3]12[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1Nc2ccccc2C12CCCCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reaction time: 0.5 h
Yield: 654.4 %

Procedure:
To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)-one (17.6 g, 9 mmol) in acetic acid (300 mL) was added sodium acetate (8.0 g, 0.1 mol) and bromine (14.6 g, 91 mmol) with stirring. After 30 minutes at room temperature, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and evaporated and the residue was triturated with hexane. The precipitate was collected, and dried in vacuo to obtain 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (16.5 g, 67%) as off-white crystals: mp 196-199° C.; 1H NMR (DMSO-d6): δ 1.62 (m, 10H), 6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2, 1.8 Hz), 10.44 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.[N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[NH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[O:12][CH2:11][CH2:10][C@H:9]2[NH:8][C:6]1[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=[C:2]([N:25]2[C:26]3[CH:27]=[N:28][CH:29]=[CH:30][C:31]=3[N:23]=[CH:24]2)[N:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: c1cc2nc[nH]c2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(-n2cnc3ccncc32)nc1N[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C

Procedure:
A solution of (R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine in acetonitrile was treated with 3H-imidazo[4,5-c]pyridine and potassium carbonate. The mixture was stirred at reflux for 6 hours, cooled to room temperature, diluted with 150 mL of EtOAc, and washed twice with 30 mL portions of water. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (1% MeOH/DCM) provided N—((R)-8-fluorochroman-4-yl)-2-(3H-imidazo[4,5-c]pyridin-3-yl)-5-nitropyrimidin-4-amine as the first eluting isomer: (1H-NMR (300 MHz, CDCl3) δ 9.8 (s, 1H), 9.4 (s, 1H), 9.2 (s, 1H), 8.9 (d, 1H), 8.6 (d, 1H), 7.8 (d, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 5.8 (q, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H).). N—((R)-8-Fluorochroman-4-yl)-2-(1H-imidazo[4,5-c]pyridin-1-yl)-5-nitropyrimidin-4-amine eluted second: (1H-NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 9.2 (s, 1H), 9.1 (s, 1H), 8.9 (d, 1H), 8.6 (d, 1H), 8.4 (d, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 5.7 (q, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H).).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.Cl.[CH3:15][C:16]1([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][N:26]([C:28]3([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]3)[CH:27]=2)[O:17]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:33]([CH2:32][C:28]1([N:26]2[CH:27]=[C:23]([B:18]3[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:35])([CH3:15])[O:17]3)[CH:24]=[N:25]2)[CH2:31][N:30]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH2:29]1)#[N:34]
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 5-chloro-N-isopropylpyrazine-2-carboxamide (200 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (325 mg, 1.00 mmol, from Example 1, step 3) and N,N-diisopropylethylamine (401 μL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.26 g, 58%). LCMS cacld. for C22H31BN7O3 (M+1)+: m/z=452.3. Found: 452.2.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH:28]1([C:31](Cl)=O)[CH2:30][CH2:29]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:31]([CH:28]4[CH2:30][CH2:29]4)[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2noc(C3CC3)n2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and cyclopropanecarbonyl chloride following a procedure analogous to that described in Example 47. LC (method 2): tR=1.20 min; Mass spectrum (ESI+): m/z=420 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1I.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.O>O1CCOCC1>[Cl:7][C:8]1[C:9]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Oc1ccc(Cl)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Cl)c(-c2cccc(F)c2)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Caesium carbonate (1.15 g, 3.53 mmol) was added to a solution of 4-chloro-3-iodophenol (300 mg, 2.14 mmol) and 3-fluorophenylboronic acid (330 mg, 1.30 mmol) in dioxane:water (22.5 mL:4.5 mL). The reaction mixture was degassed and tetrakistriphenylphosphine palladium (0) (69 mg, 0.06 mmol) was added. The reaction mixture was stirred at 70° C. for 5 hours. The cooled reaction mixture was concentrated in vacuo and the aqueous residue was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on the biotage eluting with heptane:ethyl acetate (from 98:2 to 80:20) to give the title compound (270 mg, 100%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:19])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)ccc1OC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 1.00 g (4.76 mmol) of 4-acetoxy-3-methoxybenzoic acid (Pfaltz and Bauer, Inc.) in 4 mL of anhyd CH2Cl2 (under a CaSO4 drying tube) was added 4.15 mL (47.6 mmol) of oxalyl chloride followed by 25 μL of anhyd DMF. After stirring for 4 h at room temperature, the mixture was concentrated in vacuo to afford the title compound as light yellow crystals (1.12 g, 103%). 1H-NMR (300 MHz, CDCl3) δ7.81 (dd, 1H, J=8.4, 2.1 Hz), 7.66 (d, 1H, 2.1 Hz), 7.19 (d, 1H, 8.4 Hz), 3.91 (s, 3H), and 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][OH:32])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.90 g) was dissolved in 30 ml of ethyl acetate, to which 0.69 g of methanesulfonyl chloride and 0.61 g of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (20 ml×2) and 10 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2.2 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:38](=O)[N:39]([CH2:41][CH2:42][NH2:43])C)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:43][CH2:42][CH2:41][NH:39][CH3:38])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1>CC(O)C>[CH2:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:6]2[C:7]([Cl:8])=[C:2]([Cl:1])[N:3]=[N:4][CH:5]=2)[CH2:22][CH2:23]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2cnnc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,4,5-trichloropyridazine (2.22 g, 12.08 mmol) and DIPEA (4.21 mL, 24.16 mmol) in IPA (25 mL) was added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 3.00 g, 12.08 mmol). The resulting reaction solution was stirred at rt for 5 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL), washed with water (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (1–7 (10% NH4OH in MeOH)/99–93 CH2Cl2) to give 4-[(5,6-dichloro-pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: C([C:4]([Cl:29])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:20])[CH3:19])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[OH-].[Ba+2].[OH-].CCOCC>C(O)C>[Cl:29][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH3:20])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(Cl)(Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1)C(C)=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Cl)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1

Procedure:
In 3 ml of absolute ethanol, 400 mg of ethyl 2-acetyl-2-chloro-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate is dissolved and with stirring under ice-cooling, 85 mg of barium hydroxide (dehydrated at 125° C for 8 hours under reduced pressure) is added. After 10 minutes stirring, ether is added and the insoluble material is filtered away. The ether layer is washed with water thoroughly, dried, and the evaporation of the solvent gives the oily product of ethyl 2-chloro-3-[4-(2-benzoyl-2-propyloxy)-phenyl]propionate. In IR and NMR, this product is in good agreement with the compound No. 1 in Example 7.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[CH:5]=[C:6]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:33][C@H:34]3[C@H:38]4[O:39][CH2:40][CH:41]([CH2:42][C:43]([O:45]CC)=O)[C@H:37]4[O:36][CH2:35]3)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:23]([O:33][C@H:34]3[C@H:38]4[O:39][CH2:40][CH:41]([CH2:42][C:43]([NH2:2])=[O:45])[C@H:37]4[O:36][CH2:35]3)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CC(N)=O)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 29 h

Procedure:
Concentrated ammonium hydroxide (0.15 mL) was added to a solution of ethyl 2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (41.1 mg, 0.063 mmol) in ethanol (0.5 mL). The solution was stirred for 29 hours in a 50 degree oil bath. After cooling to room temperature, additional concentrated ammonium hydroxide (0.3 mL) was added and the mixture was heated for an additional 24 hours in a 50 degree oil bath. The solvents were removed under vacuum to give the title compound. C32H37ClN4O5Si 620.22 observed m/e: 621.38 (M+H)+ (Rt 0.98/2 min)