Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C=O)C>[Br:11][C:6]1[CH:7]=[C:8]([CH2:9][O:10][CH2:15][CH3:16])[C:3]([NH2:2])=[N:4][CH:5]=1
Reactant: CCI
Reactant: Nc1ncc(Br)cc1CO
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (2-amino-5-bromo-pyridin-3-yl)-methanol hydrobromide (Apollo, Cheshire, UK, 3.52 mmol) in DMF (15 ml) cooled with an ice-bath was treated with 55% NaH in oil (7.4 mmol) and the RM was stirred for 5 min at 0° C. and 30 min at rt, then was added iodoethane (3.87 mmol) and the RM was stirred for 1 h 15 min at rt. The RM was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a light yellow oil. (HPLC: tR 2.07 min (Method A); M+H=231, 233 MS-ES)
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[O:19][CH3:20].CON(C)[C:24](=[O:40])[CH:25]([O:38][CH3:39])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([C:10]2[N:11]=[C:12]([C:24](=[O:40])[CH:25]([O:38][CH3:39])[C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)[O:13][C:14]=2[C:15]([F:16])([F:17])[F:18])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ncoc2C(F)(F)F)cc(OC)c1Br
Product: COc1cc(-c2nc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)oc2C(F)(F)F)cc(OC)c1Br

Procedure:
1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 4-(4-bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazole (prepared from 4-bromo-3,5-dimethoxybenzaldehyde according to Heterocycles, 1992, 34, 1047) and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (20-40% EtOAc-hexanes) gave the product as a yellow solid (0.032 g, 14% yield). MS: m/z 585.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CC(C)OCCN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 86.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 2-(2-bromoethoxy)propane (200 mg, 0.252 mmol) gave 7-cyclopentyl-2-{5-[4-(2-isopropoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (103 mg, 86%). MS (ESI) m/z 521.3 (M+H)|
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Product: COCCOc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1
Yield: 18.8 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (138 mg, 0.5 mmol) and 4-chloro-6-(2-methoxyethoxy)quinazoline from Example 40A Step 5 (119 mg, 0.5 mmol) using the procedure of Example 16C. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (45 mg, 0.094 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.62 (s, 1H), 7.94 (d, 1H), 7.74-7.64 (m, 3H), 7.60 (s, 1H), 7.42 (t, 1H), 7.27 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 4.37-4.31 (m, 2H), 3.78-3.71 (m, 2H), 3.34 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]([C:10]#[C:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:34][Si](C)(C)C(C)(C)C(C)C)[CH2:25][CH2:26]2)=[CH:21][CH:20]=3)[CH2:17][CH:16]=1)[CH3:14])([CH3:9])[CH3:8])(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:8][C:7]([OH:6])([C:10]#[C:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([OH:34])[CH2:25][CH2:26]2)=[CH:21][CH:20]=3)[CH2:17][CH:16]=1)[CH3:14])[CH3:9]
Reactant: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)CC#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]32)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CC#CC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
To a solution of 114 g (131 mmol) crude [[(3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]cholesta-5,7,16-trien-23-yn-3-yl]oxy]dimethyl(1,1,2-trimethylpropyl)silane in 500 mL of THF was added 200 g (765 mmol) tetrabutylammonium fluoride hydrate with the aid of 500 mL of THF. After stirring at room temperature for 18 hr., the mixture was diluted with 500 mL of ethyl acetate and 500 mL of 10% aqueous ammonium chloride. The aqueous layer was extracted twice with 500 mL each of ethyl acetate. The combined organic layers were washed with 500 mL of 10% aqueous ammonium chloride, 500 mL of water, and 500 mL of brine. The organic layer was dried over MgSO4 and concentrated to a total weight of 525 g. The resulting suspension was stirred at room temperature for 2 hr and then stored in a freezer overnight. The solid was filtered, washed with cold ethyl acetate, and air-dried for 2 hr to give 27.8 g of crude (3β)-cholesta-5,7,16-trien-23-yne-3,25-diol. This was suspended in 270 mL of methanol and the mixture was refluxed for 10 min. Then, 55 mL waster was added dropwise over 10 min. The suspension was stirred at 60° C. for 1 h, and stored in a refrigerator overnight. The precipitate was filtered, washed with cold 100 mL 50% aqueous methanol, and dried in a vacuum oven at 45° C. to give 25.4 g (49.1% over four steps) of (3β)-cholesta-5,7,16-trien-23-yne-3,25-diol as white crystals: mp 185°-192° C. Anal. Calcd. for C27H38O2 : C, 82.18; H, 9.71. Found: C, 81.93; H, 9.74.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH3:12])[C:3]=1[Cl:13].Cl.NC1C2CCCCC=2C(C#N)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:12])[C:3]=1[Cl:13]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cc1c(N)ccc(Br)c1Cl
Yield: 83 %

Procedure:
The title compound was prepared (0.70 g, 83% yield) from 22A in a manner similar to that described in Experiment 2D.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:4]1)[CH3:2].[CH3:36][CH:37]([CH3:41])[C:38](Cl)=[O:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:30]=[CH:31][C:32]([NH:33][C:38](=[O:39])[CH:37]([CH3:41])[CH3:36])=[CH:34][CH:35]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(NC(=O)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To a cloudy orange mixture of 4-(1-ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)aniline (280 mg, 0.61 mmol) in dry CH2Cl2 (6 mL) was added TEA (253 uL, 1.82 mmol), DMAP (4 mg, 0.03 mmol) and 2-methylpropanoyl chloride (77 uL, 0.73 mmol). The reaction was stirred for 15 min at room temperature, quenched with water and diluted with CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 followed by 1% MeOH in CH2Cl2 and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by Gilson reverse phase HPLC (MeCN/H2O with 0.1% TFA). The clean fractions were neutralized with aqueous NaHCO3, extracted with three portions of CH2Cl2 followed by 1% MeOH in CH2Cl2, dried (Na2SO4), filtered and concentrated under reduced pressure to give 139 mg (43%) of the title product as a yellow solid. ESMS [M+H]+: 533.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CO[N:25]=[C:26]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:27]Br.CC(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>CC(C)=O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[N:25]=[C:2]3[CH:3]=[C:4]([CH:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)=[O:14])[CH2:9][CH2:8]4)[CH:5]=[CH:6][N:1]3[CH:27]=2)=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccncc2)CC1
Reactant: CON=C(CBr)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2ccn3cc(-c4ccc(F)cc4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 500 mL round bottom flask was charged with crude pyridine 33 (8.20 g, 27.7 mmol), acetone (300 mL), and O-methyloxime 30 (6.8 g, 27.7 mmol), and the reaction mixture was allowed to stir at room temperature for 12 hours, after which thin-layer chromatography testing suggested that pyridinyl salt formation was complete. The reaction was then concentrated under reduced pressure in a 500 mL round bottom flask, and charged with methanol (200 mL), additional pyridinyl salt prepared previously (600 mg), and potassium tert-butoxide (3.90 g, 34.6 mmol). The resulting mixture was heated to 65° C. for 4 hours. The reaction mixture was then poured into 400 mL of an aqueous solution saturated with NaHCO3 and extracted with 3×250 mL of methylene chloride. The organic fractions were pooled, dried over Na2SO4, filtered, concentrated under reduced pressure, then dissolved in a minimum volume of CH2Cl2, then loaded onto 3×40 g Isco RediSep normal phase silica cartridges, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, and 1% concentrated ammonium hydroxide. Fractions containing the desired product were pooled and concentrated under reduced pressure; fractions containing impure product were pooled, concentrated under reduced pressure, then dissolved in a minimum volume of CH2Cl2, and loaded onto 2×40 g Isco RediSep normal phase silica cartridges, and purified on an Isco OptiX10 CombiFlash instrument using a gradient which started at 100% heptane and ended at 100% ethyl acetate. This process was repeated once on the remaining impure product. Yield of 34: 3.10 g (26%). 1H NMR (500 MHz, CDCl3) δ 1.50 (m, 2H), 1.76 (m, 2H), 2.55 (m, 1H), 2.77 (bs, 2H), 4.45 (bs, 2H), 5.04 (s, 2H), 6.48 (d, J=5.3 Hz, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.24 (m, 6H), 7.57 (s, 1H), 7.76 (m, 2H), 7.86 (d, J=7.1 Hz, 1H). MS (ESI+) 430.2.
Reaction SMILES: [CH:1]1([N:4]([CH:6]2[C:15]3[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=3)[C:9]([CH3:20])([CH3:19])[CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:52])[C:24]([C:27]1[CH:32]=[CH:31][C:30](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:21][O:22][C:23](=[O:52])[C:24]([C:27]1[CH:28]=[CH:29][C:30]([C:18]#[C:17][C:12]2[C:13]([CH3:16])=[CH:14][C:15]3[CH:6]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])[CH2:7][CH2:8][C:9]([CH3:20])([CH3:19])[C:10]=3[CH:11]=2)=[CH:31][CH:32]=1)([CH3:26])[CH3:25]
Reactant: C#Cc1cc2c(cc1C)C(N(C)C1CC1)CCC2(C)C
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc3c(cc2C)C(N(C)C2CC2)CCC3(C)C)cc1

Procedure:
Following General Procedure B and using cyclopropyl-(6-ethynyl-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amine (Intermediate 174, 0.1 g, 0.29 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.09 g, 0.29 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained (0.035 g, 26%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)N4CCOCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 150 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 3 mL of dioxane and 36.9 mg of morpholine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 74 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)morpholine-4-carboxamide are obtained in the form of a yellow wax, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=[O:5].C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:6][C:4](=[O:5])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: COC(OC)C(C)=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COC(OC)C(=O)C=CN(C)C
Reaction time: 16 h

Procedure:
1,1-dimethoxyacetone (pyruvic aldehyde dimethyl acetal, Aldrich Chemical Co.) (3 cm3) was added dropwise with stirring to tert-butoxy-bis(dimethylamino)methane (Fluka Chemie AG) (5 cm3) and stirring continued at ambient temperature for 16 hours. The low-boiling impurities were removed by evaporation under reduced pressure. This left an orange oil (5.82 g) (1H NMR (CDCl3): δ2.88(3H,br s); 3.10(3H,br s); 3.40(6H,s); 4.58(1H,s); 5.34(1H,d); 7.76(1H,d)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2F)=[CH:4][CH:3]=1.[F:23][CH:24]([F:27])[CH2:25][OH:26].CC([O-])(C)C.[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[O:26][CH2:25][CH:24]([F:27])[F:23])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]

Procedure:
The subtitle compound is prepared from N-(4-bromophenyl)-2-fluoro-4-methylamino-5-nitro-benzamide, 2,2-difluoroethanol and KOtBu in analogy to example 1e.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:18]1([C:22]([C:24]2[CH:25]=[C:26]([Cl:31])[C:27](Cl)=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[CH:25]=[C:26]([Cl:31])[C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)OC)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (240 mg, 0.1 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (278 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was poured into water (30 mL) and acidified with 1N hydrochloric acid before being extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (as evidenced by LCMS data only m/z 435 (M+H)+) as a brownish oil (550 mg). The crude methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (434 mg, 1 mmol) was dissolved in THF (15 mL) and methanol (5 mL) then 1N aqueous Lithium hydroxide solution (2 mL) added followed by the dropwise addition of water until a clear solution obtained. The mixture was stirred was stirred for 4 hours at RT and the organics removed by evaporation. The aqueous solution was filtered, extracted with ethyl acetate (10 mL) and the aqueous layer acidified with 2N hydrochloric acid. The acidified layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired compound as a pale oil (375 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32 (quin, 2H), 3.34 (s, 3H), 3.42-3.55 (m, 2H), 4.13-4.34 (m, 4H), 4.54 (q, 1H), 6.93 (s, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), m/z 421 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[C:39]([B-](F)(F)F)([CH3:41])=[CH2:40].[K+].CCN(CC)CC>CC(O)C.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].C(Cl)Cl>[CH2:40]=[C:39]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:26][CH2:27]3)[CH:20]=[N:19][CH:18]=1)[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: C=C(C)[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 90 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 0.855 mmol), potassium isopropenyltrifluoroborate (Frontier Scientific, Inc., Logan, Utah; 152 mg, 1.027 mmol), PdCl2(dppf)-CH2Cl2 adduct (Acros Organics, Geel, Belgium; 34.9 mg, 0.043 mmol), and Et3N (0.119 mL, 0.855 mmol) in IPA (8.0 mL) was stirred under argon at 90° C. for 1 h. Additional potassium isopropenyltrifluoroborate (76 mg, 0.513 mmol) was added to the reaction and the resulting mixture was stirred under argon at 90° C. for 1 h. The reaction was subsequently cooled to RT and concentrated onto silica gel. Chromatographic purification (ISCO, 40 g silica gel column, 0-50% EtOAc/hexanes, 15 min, 254 nm) furnished (4R)-tert-butyl 4-(6-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (411.1 mg, 0.753 mmol, 88% yield) as a white foam: MS (ESI, pos. ion) m/z: 546.3 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[I:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(N(CC)CC)C>CCOC(C)=O>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[I:21])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@@H](NC(=O)c2ccccc2I)N=C(c2ccccc2)c2ccccc21
Reaction time: 1 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, o-iodobenzoylchloride and triethylamine were mixed at room temperature and stirred 1 hour. Flash chromatography of the reaction solution on silica gel (5% Et2O in CH2Cl2) provided the title compound as a crystalline solid from EtOAc: m.p. 115°-120° C. (physical change), 173°-175° C. (melt).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:26]=[CH:25][C:24](=[O:27])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=4[NH:12][C:11]=23)=[O:20])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Cc2nc3c([nH]2)CCCC3)cc1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(C(=O)c2ccc(=O)n3c4c([nH]c23)CCCC4)cc1

Procedure:
The compound is prepared as described in example 25 with 500 mg (1.49 mmol) of 1-(4-methylphenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example IL), 160.7 mg (2.98 mmol) of sodium methylate and 125 mg (1.49 mmol) methyl propiolate.