Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:28][CH2:27]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: COCC1CCNCC1
Product: COCC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 4-(methoxymethyl)piperidine to give 224. MS: (ESI+)=425.1
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=[CH:8]1.O>C1COCC1>[N:7]1([C:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CCOC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)C=C(n1ccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a suspension of LiAlH4 (202 mg) in dry THF (2.4 ml) a solution of 1,2-dihydro-3-(1-imidazolyl)-6-ethoxycarbonyl-naphthalene (2.8 g) in dry THF (22 ml) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was refluxed for 1 day and then stirred overnight at room temperature. H2O (40 ml) was added and the precipitate formed filtered off. The filtrate was concentrated, extracted with CHCl3, dried (Na2SO4) and evaporated under vacuum to give 1,2-dihydro-3-(1-imidazolyl)-6-hydroxymethyl-naphthalene (2 g), m.p. 88°-91° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[N:7]=[C:6]2[CH3:22].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=1)[N:7]=[C:6]2[CH3:22]
Reactant: COc1ccc2nc(-c3ccc(C(=O)O)cc3)nc(C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(=O)O)cc2)nc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 4-(6-methoxy-4-methylquinazolin-2-yl)benzoic acid (180 mg, 0.612 mmol) in anhydrous DCM (10 mL) was added BBr3 (0.29 mL, 3.05 mmol, d=2.64 g/mL) dropwise at 0° C. The resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched with H2O (30 mL), then extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was washed with MeOH (10 mL) to give Compound V-2 (130 mg, yield 76%). 1H NMR (DMSO-d6 400 MHz): δ 13.06 (brs, 1H), 10.46 (brs, 1H), 8.60 (d, J=8.4 Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.95 (d, J=9.2 Hz, 1H), 7.56 (dd, J=8.8, 2.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 2.90 (s, 3H). MS (ESI): m/z 280.9 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([NH:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O.O1CCOCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1NCCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
Methyl 6-(benzenesulphonylmethyl)-2-[2-(t-butoxycarbonylamino)-ethylamino]-3-(furan-3-yl)benzoate (Intermediate 122, 0.115 g) was added to a solution of lithium hydroxide monohydrate (0.168 g) in water (1 ml) and dioxane (3 ml) and the mixture was heated at 100° C. for 1 hour. The reaction was cooled to room temperature, diluted with water and washed with diethyl ether. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM:MeOH:AcOH:water (350:20:3:2) to give 6-(benzenesulphonylmethyl)-2-[2-(tert-butoxycarbonylamino)-ethylamino]-3-(furan-3-yl)benzoic acid (0.1 g) as a pale yellow gum.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].C([NH2:18])CCCCC.C1CCN2C(=NCCC2)CC1>>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:18])[C:2]1=[O:3]
Reactant: CCCCCCN
Reactant: O=c1ccc2ccccc2o1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cc2ccccc2oc1=O
Reaction time: 240 h

Procedure:
Coumarin (0.3775 g, 2.583 mmol), 2.0 equimolar of n-hexylamine (0.5324 g, 5.261 mmol) and 0.1 equimolar of DBU (0.0418 g, 0.275 mmol) were added and mixed in bulk. The mixture was reacted in an oven and kept at 50° C. for 10 days. The resultant crude mixture was separated by preparative Thin Layer Chromatography (TLC) (eluent: ethylacetate/n-hexane=1/4 (vol./vol.)) to give corresponding coumarin monoamine (1:2) adduct (0.8287 g, 2.378 mmol, yield=92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: NCCC1CCN(c2ccc(Br)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCCC1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed according to the method described in Example 1 (step 1.5.). Starting with 4.52 g (15.90 mmol) of 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-ethylamine, prepared in step 10.2., 1.89 g (17.49 mmol) of ethyl chloroformate, 5.13 g (39.76 mmol) of N,N-diisopropylethylamine and 0.19 g (1.59 mmol) of N,N-dimethylaminopyridine, and after purifying on a column of silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 3.87 g of expected product are obtained in the form of a powder.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)#[N:2].ClCC(OC(=O)CCl)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>ClC(Cl)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[C:28]([O:33][CH3:34])[CH:29]=1)=[O:15])#[N:2]
Reactant: COc1ccccc1OC
Reactant: N#CCCCCCCCCCCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)CCCCCCCCCCC#N)cc1OC
Temperature: 75 °C
Reaction time: 6 h
Yield: 85.7 %

Procedure:
In 50 ml of dichloroethane were dissolved 10.5 g (0.05 mole) of 11-cyanoundecanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 8.98 g (0.065 mole) of 1,2-dimethoxybenzene and 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 75° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 14.2 g of 4-(11-cyanoundecanoyl)-1,2-dimethoxybenzene.
Reaction SMILES: C([O:9][CH2:10][C:11]1([O:42][C@H:41]([CH2:43][O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:31]([O:32]C(=O)C2C=CC=CC=2)[C@@H:21]1[O:22]C(=O)C1C=CC=CC=1)OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:53]([Si](C)(C)C)[C:54]#[CH:55].B(F)(F)F.CCOCC>C(#N)C>[C:45]([O:44][CH2:43][C@@:41]1([O:42][C@H:11]([CH2:10][OH:9])[C@@H:21]([OH:22])[C@@H:31]1[OH:32])[CH:53]=[C:54]=[CH2:55])(=[O:52])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: C#CC[Si](C)(C)C
Reactant: O=C(OC[C@H]1OC(COC(=O)c2ccccc2)(OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: C=C=C[C@@]1(COC(=O)c2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart G, D-fructofuranose pentabenzoate 57 and propargyltrimethylsilane in acetonitrile at 0° C. are reacted with boron trifluoride etherate, giving 4,7-anhydro-4-C-[(benzoyloxy)methyl]-1,2,3-trideoxy-D-manno-octa-1,2-dienitol, tribenzoate 58, which is treated with sodium methoxide in methanol, giving 4,7-anhydro-1,2,3-trideoxy-4-C-(hydroxymethyl)-D-oluco (or D-manno)-octa-1,2-dienitol 59. Compound 59 is treated with cupric sulfate and sulfuric acid in acetone followed by sodium carbonate in pyridine, giving 4,7:41,5-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-D-manno-octa-1,2-dienitol 60 which is reacted with sodium hydride in dimethylformamide at 0° C. and then with 15 benzyl bromide and methanol, giving 4,7:41,5-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-6,8-bis-O-(phenylmethyl)-D-manno-octa-1,2-dienitol 61. Compound 61 is ozonized at -78° C. in dichloromethane containing pyridine, then treated with zinc dust and acetic acid, giving 2,5:21,3-dianhydro--2-C-[(1-hydroxy-1-methylethoxy)methyl]-4,6-bis-O-(phenylmethyl)-D-mannose 62, which is dissolved in diethyl phosphite and reacted with sodium ethoxide in ethanol, followed by sodium dihydrogen phosphate in dichloromethane, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)hydroxymethyl]-1,3-0-(1-m®thylethylidene)-4,6--bis-O-(phenylmethyl)-D-glucitol 63. Compound 63 is treated with diisopropylethylamine and 2-(trimethylsilyl)ethoxymethyl chloride in dichloromethane, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)--4,6-bis-O-(phenylmethyl)-D-glucitol 64, which is hydrogenated in methanol over palladium hydroxide on carbon, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)-[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol 65. Compound 65 is reacted with diphenyl phosphorochloridate in pyridine at 0° C., giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)-[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol, 6-(diphenyl phosphate) 66, which is reacted with bromotrimethylsilane in dichloromethane, then hydrogenated in ethanol over platinum oxide, giving 2,5-anhydro-2-C-(hydroxyphosphonomethyl)-D-glucitol, 6-(dihydrogen phosphate) 67. ##STR16##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH:17]=O)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:19][OH:20].CO.N1C=CC=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH:17]=[N:19][OH:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(O)cc2)c2occc2c1
Reactant: NO
Solvent: CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: ON=Cc1cc(-c2ccc(O)cc2)c2occc2c1
Temperature: 68 °C

Procedure:
To a 25 ml round bottom flask was added 7-(4-hydroxyphenyl)-benzofuran-5-carbaldehyde (400 mg, 1.68 mmol), hydroxylamine hydrochlorode (234 mg, 3.36 mmol), anhydrous MeOH (10.4 ml), and anhydrous pyridine (0.272 ml, 3.36 mmol). The reaction was then heated to 68° C. and the reaction was brought to reflux for 1 h. The reaction was then cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 410 mg (96%) product as a yellow solid. The crude material was pure by 1H NMR (−4% cis isomer was detected) and LC-MS (one peak): mp 192–194° C. 1H NMR (300 MHz, DMSO-d6): δ 6.92 (2H, d, J=8.6 Hz), 7.05 (1H, d, J=2.2 Hz), 7.69–7.72 (3H, m), 7.79 (1H, d, J=1.4 Hz), 8.09 (1H, d, J=1.1 Hz), 8.27 (1H, s), 9.74 (1H, s), 11.14 (1H, s); MS (ESI) m/z 254 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.O.[CH:51]([C:53]1[CH:63]=[CH:62][C:56]([CH:57]=[CH:58][C:59]([OH:61])=[O:60])=[CH:55][CH:54]=1)=O>CO.[Pd]>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:51]([C:53]4[CH:63]=[CH:62][C:56](/[CH:57]=[CH:58]/[C:59]([OH:61])=[O:60])=[CH:55][CH:54]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Agent: [Pd]
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Yield: 91 %

Procedure:
The title compound was prepared from 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil by the method of J. Perutmattam, Syn. Commun. 1989, 19:3367-3370. 1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was freshly prepared by shaking a mixture of 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c), 5.00 g) in methanol (250 ml)-water (25 ml) with 10% palladium on carbon (0.50 g) under hydrogen at 344.7 kPa (50 psi) on a Parr shaker for 2 h. The catalyst was filtered off (Celite™) and the colorless filtrate was concentrated to 25 ml. 4-Formylcinnamic acid (Aldrich, 2.53 g, 14.35 mmol) was added to this solution of 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil and the resulting yellow mixture was concentrated and the residual yellow solid dried by evaporation of several portions of absolute ethanol. The resulting yellow powder (Schiff base intermediate) was stirred in dimethoxyethane (115 ml) with iodine (4.0 g) at 60° C. (oil bath) for 20 h. A saturated aqueous solution of sodium thiosulfate was added to the warm reaction mixture until complete decolorization of iodine resulted. The pale yellow precipitate was filtered off, washed with water, and dried at 67 Pa (0.5 Torr) to give (E)-4-[1,3 -bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid as a pale yellow powder (6.73 g, 91%), m.p. >300° C. Such samples were further purified by dissolving them in 1N aqueous sodium hydroxide, filtering the resulting hazy solution through Celite™, and acidifying the clear filtrate with hydrochloric acid. The resulting precipitate was filtered and washed with water to give title compound as a pale yellow powder, m.p. >300° C.; 1H-NMR (DMSO-d6) δ: 13.80 and 12.40 (both br m, 1 each, CO2H and NH), 8.12 (d, J=8.3 Hz, 2, 2 phenyl CH), 7.84 (d, J=8.4 Hz, 2, 2 phenyl CH), 7.64 (d, J=16.0 Hz, 1, CH=), 6.64 (d, J=16.0 Hz, 1, CH=), 3.93 (d, J=7.0 Hz, 2, CH2N), 3.79 (d, J=6.8 Hz, 2, CH2N), 2.0-1.4 and 1.3-0.85 (both br m, 22 total, 2 cyclohexyl).
Reaction SMILES: Br[CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH-].[NH4+:18]>>[NH2:18][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2
Reactant: [NH4+]
Agent: [OH-]
Product: NC(C(=O)O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
α-Bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is then dissolved in ammonium hydroxide, preferably 30% ammonium hydroxide and the reaction mixture is heated preferably to 65° C. The reaction mixture is then concentrated to a solid. EtOH is then added and the reaction is again concentrated to yield a racemic mixture comprising (<aS)-<a-amino-3-hydroxytricyclo[3.3.1.1 3,7]decane-1-acetic acid (Formula V). See also Example 19 herein.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[K+].[CH3:35][C:36]1[O:40][C:39]([C:41]([O-:43])=O)=[N:38][N:37]=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][C@@H:61]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C@H:62]([NH2:64])[CH3:63])=[CH:57][CH:58]=3)[CH:53]=[N:52]2)=[CH:47][CH:46]=1>CN(C=O)C.ClCCl>[F:44][C:45]1[CH:46]=[CH:47][C:48]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][C@H:61]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C@@H:62]([NH:64][C:41]([C:39]4[O:40][C:36]([CH3:35])=[N:37][N:38]=4)=[O:43])[CH3:63])=[CH:57][CH:58]=3)[CH:53]=[N:52]2)=[CH:49][CH:50]=1
Reactant: Cc1nnc(C(=O)[O-])o1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2ccccc2)o1
Reaction time: 0.33 h

Procedure:
To a stirred solution of HATU (630 mg, 1.66 mmol) in DMF (1 ml) was added ethyldiisopropylamine (570 μl, 3.3 mmol), followed by 5-methyl-[1,3,4]oxadiazol carboxylic acid potassium salt (138 mg, 830 μmol) and stirred for 20 min. Then (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (300 mg, 830 mmol) in DMF (1 ml) was added to the brown/red solution and the stirring was continued for 24 h at r.t. The mixture was diluted by dichloromethane and filtrated through a path of silica gel. Solvent was removed under reduced pressure, and the residue was purified by preparative TLC on silica gel (hexane/acetone 50%). Yield 82 mg (21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:17].B1C2CCCC1CCC2.C1C[O:30]CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:30])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: C1CCOC1
Reactant: C=Cc1ccc(Oc2ccc(C)c(Cl)c2)cc1
Agent: B1C2CCCC1CCC2
Product: Cc1ccc(Oc2ccc(CCO)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To the solution of 2-chloro-4-[(4-ethenylphenyl)oxy]-1-methylbenzene (2.8 g, 11.44 mmol) in dry THF (20 mL), was added 9-BBN (30 mL, 15.00 mmol) at 0° C. and stirred at room temperature overnight. Then the reaction mixture was quenched by addition of water (3 mL), followed by aq. NaOH (3M, 15 mL), and 30% H2O2 (15 mL). The reaction mixture was heated at 50° C. for 4 h. Then the THF and some water were removed under reduced pressure, and the residue was diluted with EA (30 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. Purification via flash chromatography afforded the title compound (2 g, 66.5% yield). LCMS: rt=3.51 min, [M+H+]=245
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([O:17]N3C(=O)CCC3=O)=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.[NH2:25][CH:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([CH3:39])([CH3:38])[C:36]#[N:37])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.CO>CN(C=O)C.O>[C:36]([C:35]([C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][CH:32]=1)[CH:26]([NH:25][C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=1[CH:7]=[N:6][NH:5]3)=[O:17])[CH2:27][CH2:28]2)([CH3:39])[CH3:38])#[N:37]
Reactant: CC(C)(C#N)c1ccc2c(c1)CCC2N
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2[nH]ncc12
Temperature: 25 °C
Yield: 92.7 %

Procedure:
4-(2,5-Dioxopyrrolidin-1-yl-oxycarbonylamino)-indazole-1-carboxylic acid methyl ester (3.31 g, 9.96 mmol) was added to a solution of 2-(1-aminoindan-5-yl)-2-methylpropionitrile (2.09 g, 10.5 mmol) and DIPEA (1.8 mL, 10.3 mmol) in DMF (40 mL) under nitrogen atmosphere at ambient temperature. After 1 hour the reaction solution was diluted with water (200 mL), the resulting white precipitate was filtered off, washed with water and air-dried. The wet cake was added to a solution of methanol (100 mL), water (3 mL) and TEA (2.8 mL, 20.1 mmol). The mixture was refluxed for 30 minutes, cooled the solution to room temperature, diluted with water (500 mL), collected the white precipitate by filtration, rinsed with water and air-dried. The wet cake was vacuum dried to constant weight, yielding 1-[5-(cyano-isopropyl)-indan-1-yl]-3-(1H-indazol-4-yl)-urea (3.32 g, 93%) as a white solid. MS (ESI) m/z: 360.07 [M+H]+. 1H NMR (DMSO-d6) δ: 1.69 (s, 6H), 1.87 (m, 1H), 2.47 (m, 1H), 2.89 (m, 1H), 2.98 (m, 1H), 5.19 (q, 1H), 6.73 (d, 1H), 7.08 (d, 1H), 7.22 (t, 1H), 7.39 (s, 2H), 7.44 (s, 1H), 7.66 (d, 1H), 8.04 (s, 1H), 8.59 (s, 1H), 13.00 (s, 1H). Anal Calcd for C21H21N5O.0.4H2O: C, 68.80; H, 5.99; N, 19.10. Found: C, 68.94; H, 5.72; N, 18.95.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[F:6][C:7]([F:17])([F:16])[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:5][CH2:4][CH2:3][CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]([F:6])([F:16])[F:17])=[CH:10][CH:11]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)Oc1ccc(OCCCCl)cc1
Yield: 99.9 %

Procedure:
1-Bromo-3-chloropropane (2.37 ml, 24 mmol), 4-(trifluoromethoxy)phenol (3.56 g, 20 mmol) and potassium carbonate (4.15 g, 30 mmol) were stirred in NMP (30 ml) overnight. After removing potassium carbonate by filtration, water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off, and the residue was fractionated and purified by silica gel column chromatography (hexane:ethyl acetate=89:11) to afford the title compound as a colorless oil (5.09 g, yield 99%).
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[N:1]1([CH:2]2[CH:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)(=[O:24])=[O:23])[CH:8]=3)[CH2:3]2)[CH2:34][CH2:33][CH2:32]1
Reactant: BrCCCBr
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N2CCC2)C3)c1
Reaction time: 0.33 h

Procedure:
To N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (35.4 mg, 0.083 mmol; see example 193), 1,3-dibromopropane and potassium carbonate(12.62 mg, 0.091 mmol) in water (1 mL)+1 drop acetonitrile were added. Microwave at 120° C. for 20 min. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the crude product and was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to obtain N-(2-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass. m=3.1 mg (8%)