Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Yield: 82.5 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole), 2.17 g (0.01 mole) of 3,4,5-trimethoxybenzyl chloride, 0.51 g (0.005 mole) of triethylamine, and 1.4 g (0.01 mole) of potassium carbonate were mixed with 20 ml of toluene, and the resulting mixture was heated at the refluxing temperature for 2 hours. The reaction liquid was left to cool, washed by shaking with water, and then the organic liquid layer was concentrated under reduced pressure to obtain 3.8 g (82.5% yield) of oily 1-(3,3-diphenylpropyl)-4-(3,4,5-trimethoxybenzyl)piperazine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.Cl.[CH3:49][Si:50]([CH3:77])([CH3:76])[CH2:51][CH2:52][O:53][CH2:54][N:55]1[C:59]2[N:60]=[CH:61][N:62]=[C:63]([C:64]3[CH:65]=[N:66][N:67]([C:69]4([CH2:73][C:74]#[N:75])[CH2:72][NH:71][CH2:70]4)[CH:68]=3)[C:58]=2[CH:57]=[CH:56]1.Br[C:79]1[CH:90]=[CH:89][C:82]([C:83]([NH:85][CH:86]([CH3:88])[CH3:87])=[O:84])=[CH:81][C:80]=1[F:91].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:74]([CH2:73][C:69]1([N:67]2[CH:68]=[C:64]([C:63]3[C:58]4[CH:57]=[CH:56][N:55]([CH2:54][O:53][CH2:52][CH2:51][Si:50]([CH3:76])([CH3:49])[CH3:77])[C:59]=4[N:60]=[CH:61][N:62]=3)[CH:65]=[N:66]2)[CH2:70][N:71]([C:79]2[CH:90]=[CH:89][C:82]([C:83]([NH:85][CH:86]([CH3:88])[CH3:87])=[O:84])=[CH:81][C:80]=2[F:91])[CH2:72]1)#[N:75]
Reactant: CC(C)NC(=O)c1ccc(Br)c(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)c(F)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.32 g, 0.52 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.50 g, 5.18 mmol) (see WO 2009/114512), 4-bromo-3-fluoro-N-isopropylbenzamide (1.6 g, 6.2 mmol), and cesium carbonate (5.1 g, 16 mmol) in toluene (120 mL) under N2, followed by palladium acetate (0.12 g, 0.52 mmol). The reaction mixture was stirred at 120° C. for 5 hours. After the reaction mixture was cooled to room temperature, the organic layer was separated from the solid. The solid was dissolved in water (50 mL), extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-40%) to afford the desired product (2.20 g, 72.1%. LCMS (M+H)+: m/z=589.3.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:13][N:14]([C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]([CH3:33])[N:20]=1)[S:15]([CH3:18])(=[O:17])=[O:16].CN(C)C=O.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][N:14]([C:19]1[C:23]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)=[CH:22][N:21]([CH3:33])[N:20]=1)[S:15]([CH3:18])(=[O:16])=[O:17]
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CN(c1nn(C)cc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-c3cn(C)nc3N(C)S(C)(=O)=O)n2n1
Temperature: 95 °C
Yield: 38.1 %

Procedure:
Into a 1-Neck round-bottom flask, 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.580 g, 2.38 mmol), N-Methyl-N-[1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-3-yl]-methanesulfonamide (1.50 g, 4.75 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.274 g, 0.238 mmol), N,N-Dimethylformamide (10 mL, 100 mmol), 1,4-Dioxane (20 mL, 200 mmol), and 1.50 M of Sodium carbonate in Water (9.50 mL, 14.2 mmol) were added. The reaction mixture was heated at 95° C. overnight. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a solid. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded N-Methyl-N-[1-methyl-4-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-3-yl]-methanesulfonamide as a yellow solid (0.32 g, 38%) 1256f. Into a 8-dram vial, Methylene chloride (10 mL, 200 mmol), N-Methyl-N-[1-methyl-4-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-3-yl]-methanesulfonamide (0.250 g, 0.709 mmol), and m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.175 g, 0.709 mmol) were added. The reaction mixture was stirred at room temperature for one hour. Sat. NaHCo3 and DCM was added. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to afford a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16]O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:32]([CH2:16][C:14]1[CH:13]=[N:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:15]=1)=[N+:33]=[N-:34]
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)cn2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(-n2cc(CN=[N+]=[N-])cn2)cc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of [1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-methanol (1.80 g, 7.12 mmol, 1.00 equiv) and diphenylphosphoryl azide (2.35 g, 8.54 mmol, 1.2 equiv) in THF (15 mL) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 g, 8.54 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 4-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (1.90 g, 97%). LCMS: (MH)+=278.0 (1.45 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2OCC1
Reactant: O=[N+]([O-])O
Solvent: O
Product: COC(=O)C1=Cc2cc(Cl)cc([N+](=O)[O-])c2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 2,3-dihydro-7-chloro-1-benzoxepin-4-carboxylate (1.0 g) was added to nitric acid (4.5 ml, d=1.42) under ice-cooling and the mixture was stirred at ambient temperature for 2 hours. The mixture was poured into water and the isolated precipitate was collected by filtration to give methyl 2,3-dihydro-7-chloro-9-nitro-1-benzoxepin-4-carboxylate (1.04 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[C:29][Si](C)(C)C)=[CH:24][C:23]=2[F:34])=[C:4]([CH:12]=[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:23]([F:34])[CH:24]=1)#[CH:29]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(COCCO)c(F)c2F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(COCCO)c(F)c2F)c(F)c1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a solution of the resultant 3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide (37.6 mg) in tetrahydrofuran (anhydrous, 1.0 ml) was added tetra-n-butylammonium fluoride (1 M solution in THF, 113 μL, 113 μmol) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. 0.1 N Hydrochloric acid was added to the resultant residue, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with 0.1 N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Presep Silica Gel Type S (Wako Pure Chemical Industries), 10 g, CH2Cl2/MeOH (10:1 to 5:1)) to give 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide (21.9 mg, 68%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:16]([S:29][CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[N:4]=1.C(O)(=[O:33])C.OO>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:16]([S:29]([CH3:30])=[O:33])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: CC(=O)O
Reactant: COc1cc(OC)nc(OC(C(=O)O)C(SC)(c2ccccc2)c2ccccc2)n1
Agent: OO
Solvent: O
Product: COc1cc(OC)nc(OC(C(=O)O)C(c2ccccc2)(c2ccccc2)S(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g (2.9 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylthio-3,3-diphenylpropionic acid were introduced into 15 ml of glacial acetic acid at 0° C. and 294 μl of 30% strength H2O2 were added dropwise. The mixture was stirred at room temperature overnight, poured into water, extracted with CH2Cl2 and washed with sodium thiosulfate solution and brine. After drying, 1 g of substance was isolated as a white foam.
Reaction SMILES: C(OC(=O)[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([CH:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)(C)(C)C.Br[C:44]1[S:48][C:47]([C:49]([NH2:51])=[O:50])=[N:46][CH:45]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:36]1([C:33]2[CH:34]=[CH:35][C:30]([NH:7][C:8]3[C:9]4[N:10]([CH:27]=[CH:28][N:29]=4)[C:11]([C:44]4[S:48][C:47]([C:49]([NH2:51])=[O:50])=[N:46][CH:45]=4)=[CH:12][N:13]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: NC(=O)c1ncc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: NC(=O)c1ncc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)s1

Procedure:
In the same way as described for Compound 212, step 3, using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.25 g, 0.365 mmol), 5-bromo-thiazole-2-carboxylic acid amide (60.5 mg, 0.29 mmol) and Pd(PPh3)4 (63.3 mg, 0.055 mmol) in DMF. Purification by silica gel column chromatography eluting with 99:1 and 95:5 DCM:MeOH affords the title compound as a free base (27.4 mg, 49%).
Reaction SMILES: N#N.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=1)(=[O:5])[CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1>[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15]([Cl:29])=[O:16])[N:14]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1cccc(Cc2nc(C(=O)O)co2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(Cc2nc(C(=O)Cl)co2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(3-acetyl-benzyl)-oxazole-4-carboxylic acid (314 mg, 1.28 mmol) in toluene (12.8 mL) was treated with a drop of DMF followed by oxalyl chloride (0.14 mL, 1.54 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(3-acetyl-benzyl)-oxazole-4-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@H](O)c2ccccc2)C1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: COCO[C@H]1CCN([C@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 49 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol and methyl 4-methylaminobenzoate in 49% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]2[C:13]([CH:19]=[CH:18][CH2:17][O:16]2)=[CH:14][CH:15]=1)=[O:4]
Reactant: C#CCOc1cccc(NC(=O)C(C)(C)C)c1C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Yield: 75.7 %

Procedure:
A solution of methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (Intermediate 13, 4.74 g) and [bis(trifluoromethanesulfonyl)imidate]-(triphenylphosphine)gold (2:1) toluene adduct (0.060 g) in toluene (70 mL) was heated to 85° C., under an atmosphere of nitrogen for 3 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20% to give methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (3.59 g) as a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH3:13][C:14]([CH3:34])([CH3:33])[C@@H:15]([C:17]([N:19]1[CH2:24][C@@H:23]2[CH2:25][C@H:20]1[CH2:21][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[NH2:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:16][C@H:15]([C:17]([N:19]1[CH2:24][C@@H:23]2[CH2:25][C@H:20]1[CH2:21][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[C:14]([CH3:34])([CH3:33])[CH3:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 1H-indole-2-carboxylic acid (14.6 g, 91 mmol) in CH2Cl2 (300 mL) was added 1,1-dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (28.1 g, 91 mmol), EDC (20.9 g, 109 mmol), HOBt (2.45 g, 18 mmol), and NMM (25.2 g, 249 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with sat. NaHCO3 (150 mL), 1N HCl (150 mL), sat. NaHCO3 (150 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by column chromatography (petroleum ether/ethyl acetate, 2:1). Concentration of the desired fractions afforded the title compound (40.5 g) as a yellow solid. LCMS (m/z): 455.3 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[O:19]=[C:7]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C1CSCCN1
Product: CCCCCCCCCCCC(=O)N1CCSCC1

Procedure:
Example 1 was repeated using thiomorpholine in place of morpholine with dodecanoyl chloride to obtain N-(1-oxododecyl)thiomorpholine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[C:5]([OH:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:9])=[C:13]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[O:11][C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)c1nc(Cl)ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of 1-(6-chloro-3-hydroxypyridin-2-yl)ethanone (4.89 g) synthesized above, 2-bromo-1-cyclohexylethanone (7.01 g) synthesized in Example A51(1) and N,N-dimethylformamide (50 mL) was added potassium carbonate (11.8 g), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (5.78 g, 73%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][C:10]1([CH2:21][OH:22])[O:14][C:13]2=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]2[CH2:11]1.[H-].[Na+].C(=O)=O.CC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:21][C:10]2([CH3:9])[O:14][C:13]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]3[CH2:11]2)=[N:6][CH:7]=1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Fc1ccc(Br)cn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
5-Bromo-2-fluoropyridine (91) (0.25 mL, 2.43 mmol) was added to a solution of alcohol 101 (200 mg, 1.01 mmol) in anhydrous DMF (4.5 mL) under N2 at 0° C. The resulting mixture was treated with 60% NaH (64 mg, 1.60 mmol), then quickly degassed and resealed under N2. Further 5-bromo-2-fluoropyridine (91) (0.25 mL, 2.43 mmol) was added and the mixture was stirred at room temperature for 2 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (15 mL), added to brine (40 mL) and extracted with CH2Cl2 (8×40 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-1.5% EtOAc/CH2Cl2 gave 2-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (102) (130 mg, 36%) as a cream solid: mp (CH2Cl2/hexane) 151-153° C.; 1H NMR (CDCl3) δ 8.17 (dd, J=2.5, 0.5 Hz, 1H), 7.68 (dd, J=8.8, 2.5 Hz, 1H), 7.52 (s, 1H), 6.60 (dd, J=8.7, 0.6 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.41 (d, J=10.2 Hz, 1H), 4.01 (d, J=10.2 Hz, 1H), 1.76 (s, 3H). Anal. (C12H11BrN4O4) C, H, N.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][NH:8][CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:5]=1[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[CH2:9][NH:8][CH2:7]2
Reactant: COc1cccc(CNCC(O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc2c1C(c1cccc([N+](=O)[O-])c1)CNC2
Temperature: 0 °C

Procedure:
55 G. of rac.-α-{[(3-methoxybenzyl)amino]methyl}-3-nitrobenzyl alcohol hydrochloride and 165 g. of polyphosphoric acid (84.1% P2O5) are heated to 100° for 45 minutes. After the addition of a little ice and ethyl acetate the mixture is made alkaline with sodium carbonate and extracted. The ethyl acetate extract (46 g.) is chromatographed on 3.7 kg. of silica gel. With ether-acetone-diethylamine 19:1:1 there are eluted two uniform main fractions of 7.0 g. and 22.2 g. After acidification with ethanolic hydrochloric acid, crystallization and recrystallization from methanol-ether, from the first fraction there is obtained rac.-1,2,3,4-tetrahydro-5-methoxy-4-(3-nitrophenyl)isoquinoline hydrochloride, m.p. 217°-219° and from the second rac.-1,2,3,4-tetrahydro-7-methoxy-4-(3-nitrophenyl)isoquinoline hydrochloride, m.p. 253°-255°.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:37]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.C[C:23]1[C:24]([NH2:28])=[N:25][O:26][N:27]=1>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][C:24]1[CH:23]=[N:27][O:26][N:25]=1)=[O:6]
Reactant: Cc1nonc1N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cnon1)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
239 mg (1.06 mmol) of 2-chloro-6-(trifluoromethyl)nicotinic acid and 1.6 g (2.0 mmol) of Mukaiyama reagent on polymer (1.25 mmol/g) are admixed with 15 ml of dichloromethane (abs.) and 0.31 g (3.03 mmol) of triethylamine. Then 100 mg (1.01 mmol) of 4-methyl-1,2,5-oxadiazol-3-ylamine are added. The reaction mixture is stirred at room temperature (RT) for 14 h. Subsequently, the solid is removed by means of a frit and washed with 10 ml of dichloromethane. The filtrate is concentrated and purified by chromatography using a silica gel column with heptane/ethyl acetate. Yield: 52 mg (16%).