Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[O:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:32])=[O:33])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 72.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)piperidine-1-carboxylate (intermediate 13) (150 mg, 0.222 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (106 mg, 0.334 mmol) using Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) and sodium carbonate (59 mg, 0.557 mmol) in toluene/ethanol/water (4/1/1 ml) to afford 120 mg (71.8% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=750.4 (M+1).
Reaction SMILES: [Li].[O:2]([CH2:5][CH3:6])CC.IC.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2(C(O)=O)[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2([C:5](=[O:2])[CH3:6])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)=[CH:14][CH:15]=1
Reactant: CCOCC
Reactant: Cc1ccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1
Agent: [Li]
Solvent: O
Solvent: CI
Product: CC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
To a stirred solution of 17.4 parts of lithium in 140 parts of dry 1,1'-oxybisethane is added dropwise a small amount of a solution of 193.7 parts of iodomethane in 210 parts of dry 1,1'-oxybisethane. After the reaction is started by heating, there are added 420 parts of dry 1,1'-oxybisethane. The remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 45 minutes. Then there are added portionwise (quickly) 41.8 parts of 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid (exothermic reaction: reflux temperature is maintained). Upon completion, stirring at reflux is continued for one hour. The reaction mixture is cooled in an ice-bath and decomposed by the dropwise addition of 1000 parts of water. The organic layer is separated and discarded. The aqueous phase is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from 2,2'oxybispropane, yielding 26 parts (62.4%) of 1-{4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinyl}ethanone; mp. 133.7° C.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=1.O>C(O)(=O)C.CCOC(C)=O>[Br:1][C:16]1[NH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3]
Reactant: BrBr
Reactant: O=C(O)c1cc(CCc2ccccc2Br)c[nH]1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(CCc2ccccc2Br)c(Br)[nH]1
Yield: 44.6 %

Procedure:
Bromine (0.021 mL, 0.414 mmol) was added dropwise over 5 minutes to a stirring solution of 65 (0.1014 g, 0.345 mmol) in acetic acid (1.1 mL). When the reaction was judged complete by HPLC (20 min), H2O was added, and the solid that precipitated was filtered off and washed with H2O. The light purple solid that was obtained was dissolved in EtOAc, washed with Na2SO3 and H2O, then dried with Na2SO4, filtered, and concentrated. The product was purified by preparative reverse phase HPLC with 40:60 H2O:CH3CN (w/0.05% TFA); 20 mL/min.; λ=214 nM. 0.0574 g (44.6%) of 173 was obtained as a fluffy pale pink solid. 1H (CD3OD, 400 MHz): δ 7.50 (1H, d, J=7.8 Hz), 7.24-7.00 (3H, m), 6.68 (1H, s), 2.92 (2H, t, J=˜7.8 Hz), 2.67 (2H, t, J=˜7.8 Hz) ppm. Partial 13C (CD3OD, 100 MHz): δ 163.25, 141.86, 133.73, 131.85, 128.89, 128.54, 125.26, 124.68, 117.16, 105.89, 37.91, 27.62 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 37.91, 27.62; CH carbons: 133.73, 131.85, 128.89, 128.54, 117.16 ppm. HPLC: 10.473 min.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:10]=[N:11][C:12](F)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:10]=[N:11][C:12]([O:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)nc2)oc2cc(N)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N)c(Br)cc12
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N-methylbenzofuran-3-carboxamide (500 mg, 1.41 mmol) and 4-fluorophenol (460 mg, 5.21 mmol) in DMF/THF (1 mL/7 mL) was added K2CO3 (260 mg, 5.62 mmol) under N2. The mixture was heated at 90° C. for 8 h. The reaction mixture was concentrated in vacuo and it was extracted with EtOAc. It was washed with H2O, brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EA=4:1) to give the product of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran-3-carboxamide (380 mg, yield: 61%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (d, J=2.4 Hz, 1H), 8.23˜8.25 (m, 1H), 7.74 (s, 1H), 7.02˜7.09 (m, 4H), 6.91 (d, J=8.8 Hz, 1H), 8.85 (d, J=4.8 Hz, 1H), 5.76 (s, 1H), 4.20 (s, 2H), 2.95 (d, J=5.2 Hz, 3H). (M+H)+: 456/458.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:50])[C:39]=2[CH:40]=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:43]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]4)[C:42]3=[O:50])[C:39]=2[CH:40]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc(F)c(F)cc43)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, tert-butyl 4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (ddd, J=9.0, 7.6, 1.5 Hz, 1H), 7.16-7.06 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=10.3, 6.3 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 3.74-3.56 (m, 2H), 2.69 (t, J=12.4 Hz, 2H), 2.07-1.96 (m, 1H), 1.68-1.63 (m, 2H), 1.45 (s, 9H), 1.32-1.26 (m, 2H); MS (ES+) m/z 493.3 (M+23).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([NH:10][C:11]1[N:12]=[C:13](C2N=CNN=2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]>O1CCOCC1>[C:7]([NH:10][C:11]1[N:12]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCNCC4)c3n2)cc1OC
Yield: 78.8 %

Procedure:
Piperazine (430 mg, 5 mmole) was added to a stirred suspension of 2-acetamido-6-(3,4-dimethoxyphenyl)-4-(1,2,4-triazolyl)pyrido[3,2-d]pyrimidine (977 mg, 2.5 mmole) in dioxane (70 ml). The reaction mixture was refluxed for 16 hours. The precipitate was filtered off and washed with a small amount of dioxane. The filtrate was evaporated to dryness and the residue washed with diethyl ether. Both fractions (the precipitate and the washed filtrate) were combined, resulting in the pure title compound (805 mg, yield 79%) which was characterized by its mass spectrum as follows: MS (m/z): 409 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 717.3 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[OH:20].Br[CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH:4]1[C:3]2[C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=3[O:20][CH2:25][CH2:24][CH2:23][CH2:22][O:1][C:2]=2[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=1
Reactant: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2O)c(O)c1
Reactant: BrCCCCBr
Product: CC(=O)c1ccc2c(c1)OCCCCOc1cc(C(C)=O)ccc1-2

Procedure:
was synthesized from 1,1′-(2,2′-dihydroxy-[1,1′-biphenyl]-4,4′-diyl)-diethanone and 1,4-dibromobutane by following an analogous procedure described in Step 1, Example 1. m/z 325.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>C(Cl)(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 4-methoxybenzene-1-sulfonyl chloride (2.4 g, 12 mmol) in CHCl3 (20 mL) was added methanamine (5 mL, 40 mmol) in EtOH. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The resulting solid was washed with H2O (5 mL), ether, and air-dried to give 4-methoxy-N-methylbenzenesulfonamide (1.12 g, 48% yield) as a white solid. MS (ESI positive ion) m/z: 202 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([N:13]=[CH:14][CH2:15][CH3:16])[CH:5]=1.C(O)(=O)C.[H][H]>CN1C(=O)CCC1.O.C(O)C>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][CH2:14][CH2:15][CH3:16])[CH:5]=1
Reactant: CCC=Nn1cc(C)c2ccccc21
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCNn1cc(C)c2ccccc21
Temperature: 30 °C
Yield: 96 %

Procedure:
In a 800 L vessel, prepare a solution of 3.0 kg (74.4 mol) sodium borohydride and 26.8 kg (124 mol, 86% purity) 3-methyl-N-(propylidene)-1H-indol-1-amine in 108 kg NMP. Prepare a solution of 4.5 kg (74.4 mol) glacial acetic acid in 27 kg NMP. Add the acetic acid solution over a period of about 30 nm at 30° C. to the sodium borohydride solution. Immediately hydrogen is evolved. Stir the reaction mixture at 30° C. until completion of the reaction (˜1 h). Add 6.3 kg ethanol to the reaction mixture, foaming occurs immediately. The reaction mixture is then worked-up by adding additional 80 L water cautiously. Attention is taken during the addition of water such that foaming is controlled, slow addition of water is recommended especially in the beginning to avoid uncontrolled foaming. Care is taken to ensure no or only minimal foaming occurs while the first 1–2 L of water is added. The reaction mixture is allowed to stand over night. Extract the water phase three times with 45 kg n-heptane and wash the combined organic phases with 66 L water. Evaporate the combined organic phases to dryness. This results in 22.4 kg 3-methyl-N-propyl-1H-indol-1-amine (yield 90%, 94% purity) as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])/[C:10](=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)/[CH2:11][CH3:12])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].B(Br)(Br)Br>C(Cl)Cl>[OH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)/[CH:13]=[C:10](\[CH2:11][CH3:12])/[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]([F:26])([F:24])[F:25])[CH:4]=1)=[O:22]
Reactant: CC/C(=C\c1cccc(OC)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC/C(=C\c1cccc(O)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of (2E)-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-methoxybenzylidene)butanamide (216 mg, 0.54 mmol) in DCM (15 mL) was cooled to 0° C. under an atmosphere of argon. To this solution was added BBr3 (1M in DCM, 1.18 mL). The cooling bath was removed and the reaction mixture was allowed to warm to rt. After stirring for 2 h, the reaction was quenched by the addition of water. The mixture was extracted with EtOAc and the combined organic solutions were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was triturated with DCM and filtered to give the desired phenol (189 mg). 1H NMR (400 MHz, d4-MeOH): δ 8.19 (d, 1H), 7.91-7.87 (dd, 1H), 7.55 (d, 1H), 7.24-7.16 (m, 2H), 6.87-6.85 (m, 2H), 6.77-6.74 (dd, 1H), 2.63 (q, 2H), and 1.14 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30][CH2:31]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30][CH2:31][N:17]1[C:16](=[O:19])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]2=[N:18]1
Reactant: OCCc1c(F)cccc1F
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CCc2c(F)cccc2F)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Reaction time: 5 h
Yield: 52.5 %

Procedure:
6-(4-(Trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50.0 mg, 0.169 mmol), 2-(2,6-difluorophenyl)ethanol (40.1 mg, 0.2535 mmol, 1.5 equiv.) and PPh3 (66.5 mg, 0.2535 mmol, 1.5 equiv.) were dissolved in THF (3 mL) under nitrogen atmosphere in a 50 mL round bottomed flask. This mixture was treated with diethyl azodicarboxylate (40% toluene solution, d=0.956, 0.12 mL, 0.2535 mmol, 1.5 equiv.) at room temperature. After stirring for 5 h, the mixture was directly loaded onto preparative HPLC. The HPLC purification gave compound 63 as colorless crystals (38.6 mg, 0.0887 mmol, 52.5%). LCMS (EI: 70 eV) 458 (M++Na), 436 (M++1). FTIR (ATR) 1701 (O═C).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:3]=1[NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:15]1[NH:14][C:3]2[C:4]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[N:1]=1
Reactant: CCN(CC)c1ccc(F)c(N)c1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(F)c2nc(Nc3ccc(Cl)cc3Cl)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A mixture of 1-[2-amino-6-(diethylamino)-3-fluorophenyl]-3-(2,4-dichlorophenyl)thiourea (300 mg, 0.748 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.788 mmol) and triethylamine (0.115 mL, 0.825 mmol) in tetrahydrofuran (3 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (191 mg, 0.521 mmol, 70%).
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][OH:21])[CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl.Cl>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:28](=[O:30])[CH3:29])[CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Reaction time: 2 h

Procedure:
To alcohol 25 (900 mg, 3.23 mmol) and pyridine (0.8 mL, 10 mmol) in dry CH2Cl2 (15 mL) at 0° C. was added acetyl chloride (0.3 mL, 4.2 mmol). The resulting mixture was stirred for 2 hours, the diluted with CH2Cl2 (10 mL) and 5% HCl (10 mL). The mixture was transferred to a separatory funnel and the organic layer washed with H2O and brine. The organic layer was dried (Na2SO4), solids filtered and the solvent removed in vacuo to provide the desired acetate 26 as a yellow waxy solid (1.04 g, 100%).1H NMR (CDCl3; 400 MHz): δ: 8.72 (s, 1H), 8.30 (d, 1H, J=1.7 Hz), 7.98 (m, 2H), 7.49 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 6.84 (d, 1H, J=16.0 Hz), 6.46 (m, 1H), 4.79 (dd, 2H, J=6.2 Hz, 1.2 Hz), 2.11 (s, 3H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][C@H:5]1[OH:13])=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C@H:4]([N:1]=[N+:2]=[N-:3])[C@H:5]([OH:13])[CH2:6]1)(=[O:25])=[O:24]
Reactant: [N-]=[N+]=N[C@H]1CCN(CCO)C[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)OCCN1CC[C@H](N=[N+]=[N-])[C@H](O)C1
Reaction time: 10 h

Procedure:
A solution of cis(±)4-azido-1-(2-hydroxyethyl)piperidin-3-ol (Intermediate 45) (0.4 g, 2.15 mmol) in dry dichloromethane (15 mL) and 2,6-lutidine (0.325 mL, 2.8 mmol) was treated at −20° C. dropwise with a solution of methanesulfonyl chloride (0.175 mL, 2.26 mmol) in dichloromethane (5 mL). The temperature was allowed to reach 0° C. and kept at 0° C. for 10 hours. The resulting reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was back extracted with dichloromethane (20 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was codistilled with city DMF (10 mL) without beating. This crude preparation of the mesylate was used without further purification directly for the next step.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1ccccc1Cl
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2Cl)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-chloro-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.10 (br, 1H), 7.91 (brd, 1H), 7.70 (brd, 1H), 7.53 (dd, 1H), 7.37 (t, 1H), 7.21 (t, 1H), 7.05-6.95 (2H), 6.55 (br, 1H), 3.97 (t, 2H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 354.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[N:29]=[C:30]([C:33]([OH:35])=O)[S:31][CH:32]=1)([CH3:27])[CH3:26].[O:36]1[C:41]2([CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C=O)C>[CH:25]([C:28]1[N:29]=[C:30]([C:33]([N:39]2[CH2:40][C:41]3([CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]3)[O:36][CH2:37][CH2:38]2)=[O:35])[S:31][CH:32]=1)([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1csc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.924 g) was added in one portion to a stirred solution at 0° C. of 4-isopropylthiazole-2-carboxylic acid (0.32 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step b) (0.547 g) and triethylamine (0.781 mL) in DMF (12 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.54 g.