Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[C:23]1([CH3:35])[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:33]=[C:32]([NH2:34])[O:31][N:30]=2)[CH:24]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:1]1([CH2:10][C:11]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:25]3[CH:24]=[C:23]([CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH:33]=2)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cn1cnc2ccccc21
Reactant: Cc1cccc(-c2cc(N)on2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(-c2cc(NC(=O)Cn3cnc4ccccc43)on2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.1 %

Procedure:
(1H-Benzimidazol-1-yl)acetic acid (50 mg, 0.28 mmol) (Example 1B) suspended in dichloromethane (5 mL) and diisopropylethylamine (0.19 mL, 1.12 mmol) and stirred for 1 h at room temperature until a clear solution was observed. 3-m-Tolyl-isoxazol-5-yl amine (53 mg, 0.28 mmol) and bromotripyrrolidinophosphonium hexaflurophosphate (PyBroP) (130 mg, 0.28 mmol) were then added and stirred for 24 h at room temperature. Sodium carbonate was then added and the mixture passed through a hydrophobic frit. The organic layer was collected and evaporated to dryness. The residue was then purified by preparative HPLC affording title compound 1 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (3H, s), 5.07 (2H, s), 6.50 (1H, s), 7.17-7.24 (3H, m), 7.33 (1H, t, J=7.6 Hz), 7.52 (2H, t, J=8.6 Hz), 7.57 (1H, s), 7.65 (1H, d, J=7.2 Hz), 8.18 (1H, s). MS (ES) m/z: 333.1 [M+H].
Reaction SMILES: [CH2:1]([C@@H:3]([C@@H:9]([OH:11])[CH3:10])[C:4](OCC)=[O:5])[CH3:2].[NH3:12]>C(O)C>[CH2:1]([C@@H:3]([C@@H:9]([OH:11])[CH3:10])[C:4]([NH2:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](CC)[C@H](C)O
Reactant: N
Solvent: CCO
Product: CC[C@H](C(N)=O)[C@H](C)O
Yield: 85.5 %

Procedure:
(2S,3S)-Ethyl 2 ethyl-3-hydroxybutyrate (1 gram) is dissolved in 5 ml of absolute ethanol followed by the addition of 0.5 gram of gaseous ammonia. The solution is kept in a stoppered flask, and the progress of the reaction is followed by thin layer chromatography. After the reaction is judged complete, the ethanol is evaporated and the resulting residue redissolved in ethyl acetate. Ammonia is removed by extraction with 1% HCl, and the ethyl acetate solution is dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (2S,3S)-2 ethyl-3-hydroxybutyramide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][F:17])[NH:14][C:13](=[S:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:25]([C:22]2[CH:21]=[CH:20][C:19]([Br:18])=[CH:24][N:23]=2)=[O:26])=[CH:3][C:4]=1[C:9]1([CH2:16][F:17])[CH2:10][O:11][CH2:12][C:13](=[S:15])[NH:14]1
Reactant: Nc1cnc(Cl)c(C2(CF)COCC(=S)N2)c1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(Cl)c(C2(CF)COCC(=S)N2)c1)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-amino-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholine-3-thione (33 mg, 0.12 mmol), 5-bromo-pyridine-2-carboxylic acid (36 mg, 0.18 mmol) and HOAt (29 mg, 0.215 mmol) in DMF (0.4 ml) was cooled to 0° C. and DIPEA (0.042 ml, 0.24 mmol) and EDC (34 mg, 0.18 mmol) were added, the reaction mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature over night. At 0° C. aq. 1M KHCO3 was added and the mixture extracted with toluene. The combined organic layers were washed with water, dried with Na2SO4 and evaporated. The residue was taken up in DCM/MeOH 65/35 from which the product started to crystallize. Filtration, rinsing of the crystallized material with DCM and drying provide the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc2[nH]ccc12
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Clc1cccc2c1ccn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 16.9 g of 4-chloro-1H-indole, 170 ml of benzene, 85 ml of aqueous 50% sodium hydroxide solution, 1.89 g of n-tetrabutyl ammonium hydrogen sulfate and 16.6 ml of benzyl chloride was heated at 60° C. with strong stirring for 4 hours and was then cooled to room temperature. The decanted organic phase was washed with water, dried and evaporated to dryness. The 30.2 g of residue were chromatographed over silica gel and were eluted with cyclohexane to obtain 22.8 g of 4-chloro-1-benzyl-1H-indole melting at 58°-60° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C@H:6]([NH:15]CCN(C(OC(C)(C)C)=O)CCCC1C=CC2CCCNC=2N=1)[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1)[CH3:2].Cl.CO>CCOC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C@@H:6]([C:7]1[CH:12]=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:15])[CH3:2]
Reactant: CCOC(=O)C[C@H](NCCN(CCCc1ccc2c(n1)NCCC2)C(=O)OC(C)(C)C)c1ccc(OC)nc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)c1ccc(OC)nc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of the ester 7-6 (14.1 g, 26 mmol) in EtOAc (350 mL) cooled to -20° C. was treated with HCl (gas) for 10 minutes then stoppered and stirred at 0° C. for 1.5 hr. The volatiles were removed in vacuo, the residue taken up in 150 mL of water and treated with solid K2CO3 to pH~10. This solution was extracted with EtOAc (3×150 mL), washed with brine, dried (Na2SO4) and concentrated to give an oil. Column chromatography (silica gel; 5% MeOH in CHCl3) gave the β-alanine 7-5; further elution with 5% MeOH in CHCl3 saturated with NH3 gave 7-7 as a viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (3H, t), 1.8-1.95 (4H, m), 2.5-2.8 (12H, m), 3.39 (2H, m), 3.92 (3H, s), 4.09 (2H, q), 5.01 (1H, bs), 6.34 (1H, d), 6.72 (1H, d), 7.06 (1H, d), 7.59 (1H, dd), 8.07 (1H, d).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([C@H:12]([CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[N+:10]=[N-:11]>C1(C)C=CC=CC=1>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C@:13]([OH:20])([C@H:12]([N:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=[N:10]1)[CH3:29])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: C[C@@H](N=[N+]=[N-])[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C#Cc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H](n1cc(-c2ccccc2)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 130 °C

Procedure:
A mixture of toluene (80 ml), phenylacetylene (6.7 ml) and (2R,3R)-3-azido-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (2 g) was heated for 8 hours at 130° C. After cooling, toluene was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel 50 g, eluent: ethyl acetate) to give Compound 58 (0.85 g) as a colorless powder.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5](=[O:31])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].CC(C)([O-])C.[K+].[N:38]1([CH2:43][C:44](=O)[CH2:45][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[CH:42]=[CH:41][N:40]=[CH:39]1>O1CCCC1>[N:38]1([CH2:43][C:44]([CH2:45][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:31])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: COc1ccc(CCCC(=O)Cn2ccnc2)cc1
Reactant: CCOC(=O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC=C(CCCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 1 h

Procedure:
A stirred suspension containing (7-ethoxy-7-oxoheptyl) triphenylphosphonium bromide (12 g, 0.024 mol) in dry tetrahydrofuran (40 ml) at room temperature under a nitrogen atmosphere was treated with potassium t-butoxide (2.70 g, 0.024 mol). The resulting orange mixture was stirred for 1 hour, treated with a solution of 1-(1H-imidazol-1-yl)-5-(4-methoxyphenyl)-2-pentanone (5.0 g, 0.019 mol) in dry tetrahydrofuran (20 ml) and then stirred for an additional 14 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (300 ml), washed with water (3×150 ml) and extracted into hydrochloric acid (4×150 ml of 5M). The acid extracts were combined, washed with ethyl acetate, basified using sodium carbonate, and extracted with ethyl acetate (4×250 ml). The organic extracts were combined, washed with water then brine, dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel, 40% ethyl acetate in hexane to 100% ethyl acetate) to yield an isomeric mixture of E- and Z-ethyl 8-[(1H-imidazol-1-yl)methyl]-11-(4-methoxyphenyl)-7-undecenoate as a pale-yellow oil having the following structural characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=5)[C:29]#[N:30])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.CC1(C)C(C)(C)OB([C:53]2[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH:54]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:29]([C:28]1[CH:31]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@@H:10]4[CH2:9][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:53]6[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH:54]=6)=[CH:7][N:6]=5)[CH2:13][CH2:12][O:11]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[CH:26][C:27]=1[F:32])#[N:30]
Reactant: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N3CCO[C@H](Cn4nnc5ncc(-c6ccc(F)c(C#N)c6)nc54)C3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
In a pressure tube reactor, ((S)-5-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-2-fluorobenzonitrile 100 mg (0.20 mmol) was added, and potassium carbonate 83 mg (0.60 mmol) was added. Pd(dppf)2Cl2 8 mg (0.01 mmol) was further added, followed by 1,4-dioxane 3 ml, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate 74 mg (0.24 mmol), and H2O 0.5 ml. The mixture was stirred at room temperature for 10 minutes under nitrogen gas, and then stirred at 80° C. for 2 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Column chromatography using 50% ethylacetate/hexane gave (S)-tert-butyl 4-(2-(2-((6-(3-cyano-4-fluorophenyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate 104 mg (0.17 mmol) with a yield of 87%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10]>O>[CH3:6][C:7]1[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cl)c(C)c1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
4 ml of chlorosulfonic acid are added slowly to 1 g (0.067 mol) of 2,6-dimethylbenzoic acid and the reaction mixture is stirred for 1 hour at 55° C. After cooling, the mixture is poured into 100 ml of iced water. The precipitate formed is filtered off, washed with cold water and then dried in a desiccator under vacuum to give 1.22 g of the expected product in the form of a white solid (yield=73%).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])[O:3][C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1.[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH3:1][Si:2]([CH3:24])([C:20]([CH3:22])([CH3:21])[CH3:23])[O:3][C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]([OH:13])[C:6]=2[CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(O)c1ccccc1CO2
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of 5 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-one in 50 ml of methanol is cooled to 0° C. After adding 2 g of sodium borohydride and the mixture is stirred for 1 hour, 300 ml of chloroform is added and the mixture is washed with water and a saturated saline solution, followed by drying over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to silica-gel chromatography and eluted with toluene to give 4.1 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-ol (oil). Mass spectrum m/z: 342(M+).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=[O:14])[O:11][CH:12]=1)=[O:7])[CH3:4].[BH4-].[Na+].[NH4+].[Cl-]>CCO>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][OH:14])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1coc(C=O)n1
Agent: N#N
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)c1coc(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-formyl-oxazole-4-carboxylic acid ethyl ester (272 mg, 1.61 mmol) was dissolved in EtOH (5.0 mL). NaBH4 (112 mg, 2.84 mmol) was added portionwise at 0° C. and the reaction mixture stirred at 0° C. for 1 h. Sat. aq. NH4Cl was added and the mixture extracted with EA (5×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.50. LC-MS-conditions 02: tR=0.58 min; [M+H]+=172.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C[O:11][C:12]([C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=1B(O)O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=1[C:12](=[O:11])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1cc(O)ccc1B(O)O
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(O)cc12
Yield: 17.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (500 mg, 1.96 mmol) and 2-methoxycarbonyl-4-hydroxy-phenylboronic acid (765 mg, 2.75 mmol) to provide 217 (83 mg, 17% yield) as a white solid. LC-MS (M+H=247, obsd.=247).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:33][C:34](Br)([F:36])[F:35].O>CN1C(=O)N(C)CC1>[CH3:25][C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:34]([Br:33])([F:36])[F:35])=[CH:7][CH:6]=1)([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=1)[CH3:26]
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: FC(F)(Br)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)Br)cc1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of 21.6 g of 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether and 13.9 g of potassium t-butoxide in 120 ml of DMI was added dropwise to a mixture of 80 g of dibromodifluoromethane and 50 ml of DMI with stirring for 30 minutes at 50° to 60° C., and the mixture was maintained at this temperature for 3 hours. The reaction mixture was poured into water and extracted with toluene. The toluene solution was washed with dilute hydrochloric acid and water in this order, and dried. Toluene was evaporated under reduced pressure to give 29.4 g of an oily residue. The oily residue was purified by column chromatography [silica gel: 600 g; eluent: toluene/hexane (1:1)] to give 12.4 g of the desired 3-phenoxybenzyl 2-(4-difluorobromomethoxyphenyl)-2-methylpropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Br:11]Br>OS(O)(=O)=O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][NH:7]2)=[CH:3][C:2]=1[F:1]
Reactant: BrBr
Reactant: Fc1ccc2c(c1)CCN2
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Fc1cc2c(cc1Br)NCC2
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of 5-fluoroindoline (4.65 g, 34 mmole) in conc. H2SO4 acid (60 ml) under argon was treated with silver sulfate (5.5 g, 18 mmole) and stirred for 0.5 h, then cooled to −5° C. and treated dropwise over 15 min with bromine (5.6 g, 35 mmole). The mixture was maintained at −5° C. for 0.5 h, then allowed to warm to room temperature over 1 h, before adding cautiously to well stirred ice/water (600 ml). The mixture was filtered through Kieselguhr, then basified by addition of 40% NaOH solution and extracted with Et2O (2×300 ml). The combined extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a beige solid (6.5 g, 89%). MH+ 216/218.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:47]3[CH2:46][CH2:45][C:44]([C:40]4[CH:41]=[CH:42][CH:43]=[C:38]([O:37][CH3:36])[CH:39]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(C2(C(N)=O)CCNCC2)c1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cccc(C2(C(N)=O)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)c1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.75 g, 1.4 mmol) and 4-(3-methoxy-phenyl)-piperidine-4-carboxylic acid amide hydrochloride (0.5 g, 1.85 mmol) to give the title compound: Rf =0.43 (silica gel, 10% methanol/chloroform).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:16][C:15](=[O:17])[NH:14][C:8]1=[N:9]2.C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:14][C:15](=[O:17])[CH2:16][N:7]1[CH2:6]2
Reactant: BrBr
Reactant: COCc1cccc2c1CN1CC(=O)NC1=N2
Solvent: CC(=O)O
Solvent: O
Product: COCc1c(Br)ccc2c1CN1CC(=O)NC1=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of 1.87 g. (0.01 mole) of 6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in 40 ml. of glacial acetic acid is added dropwise at room temperature 1.60 g. (0.01 mole) of bromine. The mixture is stirred at room temperature for one hour, water (50 ml.) is added and the volume concentrated (10-15 ml.) in vacuo. Additional water (50 ml.) is added, the solution made basic with ammonium hydroxice, warmed and the insoluble material filtered under suction. The colorless solid is washed with water, dried and crystallized from 50 ml. of 5% hydrochloric acid yielding the title product as a colorless solid. Purification is effected by crystallization from methanol/ether to yield the title product.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C:14]2[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH:22](Cl)(Cl)Cl.CO>CO.O>[CH3:22][O:20][C:19]([C:17]1[O:18][C:14]([CH2:13][O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[CH:15][CH:16]=1)=[O:21]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To produce diazomethane, 1.0 g (10 mmol) N-methyl-N-nitrosourea was added portionwise with cooling to 20 ml diethyl ether to which 7 ml of 40% KOH had been added to form a lower layer, in such a way that the reaction temperature did not exceed +5° C. 30 min after the last addition the yellow organic phase was separated off and allowed to stand for 3 h over a little solid KOH. Enough of the ethereal solution of diazomethane thus obtained was added at room temperature with stirring during a period of 15 min to a solution of 500 mg (1.6 mmol) GMF carboxylic acid (formula 4, product of Example 4) in 18 ml methanol and 2 ml water for the yellow colour just to remain and no further evolution of gas to be observed. After a further 15 min stirring the reaction was complete (TLC monitoring with mobile solvent chloroform/methanol (2:1), Rf (educt)=0, Rf (product)= 0.41), whereupon the solvent was removed under vacuum and the crude product was purified by elution from a silica gel column (3×20 cm) with chloroform/methanol (2:1). Concentration of the fractions containing the product gave 440 mg (84%) of colourless syrup with [α]D20 =+113° (c=0.8, methanol), which gradually crystallised on scratching; m.p. 72° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:6]=[CH:5]2.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][N:28]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:6]=[CH:5]3)[C:27](=[O:31])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: COC(Cn1ncc2cc(Br)ccc21)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COC(Cn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21)OC
Temperature: 130 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
A suspension of 5-bromo-1-(2,2-dimethoxyethyl)-1H-indazole (4.0, 14 mmol), 4-(benzyloxy)pyridin-2(1H)-one (3.1 g, 16 mmol), K2CO3 (2.1 g, 16 mmol), 8-hydroxyquinoline (310 mg, 2.1 mmol) and CuI (3.1 g, 16 mmol) in DMSO (20 mL) was evacuated for 30 minutes under high vacuum then backfilled with nitrogen. The mixture was stirred under nitrogen at 130° C. for 20 h and then allowed to cool. The mixture was diluted with 20% MeOH/NH4OH (10:1) in CH2Cl2 (200 mL), stirred for 15 min, and then loaded onto a silica plug. The material was eluted through the plug with 20% MeOH/NH4OH (10:1) in CH2Cl2 (400 ml) and then concentrated. The residue was dissolved in CH2Cl2, washed with LiCl (4×100 mL) and brine (1×100 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (120 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 60 min at 40 mL/min) gave the title compound (4.96 g, 85%) as a light orange solid 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.56 (d, J===8.9 Hz, 1H), 7.45-7.33 (m, 6H), 7.27 (d, J===2.9 Hz, 1H), 6.12-6.04 (m, 2H), 5.05 (s, 2H), 4.76 (t, J=5.3 Hz, 1H), 4.59 (d, J=5.3 Hz, 2H), 3.37 (s, 6H).