Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5](OC)=O.O1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:10]1[C:4]2[C:5](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CBr
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
Procedure 2 is illustrated with the conversion of diol (S)-28 to diester (S)-29. To a solution of optically pure (S)-28 (5.8 g., 10.5 mmol) in 250 ml. of tetrahydrofuran was added sodium hydride as a 50% suspension in oil (2.4 g., 50 mmol), and the mixture was stirred at 25° for 2 hr. Methyl bromoacetate (7.6 g., 50 mmol) was added to the above suspension, and the mixture was heated to reflux for 6.5 hours. The reaction mixture was cooled, filtered, and the filter cake was washed with tetrahydrofuran. The combined filtrate was evaporated to an oil that was chromatographed on 150 g. of silica gel. Elution of the column with 1.4 l. of dichloromethane gave non-naphthalene containing products (pmr). Elution with 3.5 l. of 2% methanol-ether gave (S)-29. The eluate was evaporated to give 3.2 g. (44%) of a glass, which was dried at 165° under 0.07 mm for 1 hour, [α]54625 -25.7° (C 1.0, (CH2)4O). The 70 ev mass spectrum of the material gave a parent ion at m/e 692. A 100 MHz pmr spectrum in CDCl3 gave the following signals: δ 7.7-8.05 (m, ArH, 4H), 7.0-7.5 (m, ArH, 6H), 5.0 (s, ArCH2O, 4H), 4.35 (s, OCH2CO2, 4H), 3.80 (s, OCH3, 6H), 2.8-3.8 (m, OCH2CH2O, 2OH). Table I records the analysis. ##STR93##
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cccc2nccn12
Agent: Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc2nccn12

Procedure:
Using 2.55 g (12 mmol) of 5-(3-hydroxypropyl)imidazo-[1,2-a]pyridine hydrochloride, 3.90 ml (28 mmol) of triethylamine and 1.08 ml (14 mmol) of methanesulfonyl chloride, the same procedure as in Reference Example 8 was followed, to yield 5-(3-methanesulfonyloxypropyl)imidazo-[1,2-a]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH:24][CH3:25].Cl>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[N:24]([CH3:25])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which it was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:25][NH:24][C:22]([C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:20][N:19]=1)=[O:23]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80° C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35° C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NM (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA′BB′ quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](I)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45].C([O-])([O-])=O.[K+].[K+].C(#N)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.O>[F:38][C:39]1[CH:40]=[C:41]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:2]=4[F:1])[CH:8]=3)[NH:13][CH:14]=2)[CH:42]=[CH:43][C:44]=1[F:45]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Reactant: OB(O)c1ccc(F)c(F)c1
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: [K+]
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4ccc(F)c(F)c4)c3c2)c1F
Temperature: 160 °C
Yield: 44.2 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.025 g, 0.038 mmol), 3,4-difluorophenylboronic acid (0.0090 g, 0.057 mmol), K2CO3 (0.026 g, 0.19 mmol), and Pd(PPh3)4 (0.0022 g, 0.0019 mmol) were taken up in 4:1 acetonitrile (“ACN”)/water (1.5 mL) and degassed with argon for 10 minutes. The reaction mixture was heated to 160° C. for 10 minutes under microwave irradiation. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. DCM was added to the oil, and a solid precipitated out, which was collected by filtration giving N-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (8.5 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 10.97 (s, 1H), 9.80 (br s, 1H), 8.66 (br s, 1H), 8.52 (br s, 1H), 7.99 (br s, 1H), 7.69-7.75 (m, 1H), 7.51-7.59 (m, 3H), 7.25-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=505.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[C:18]([CH2:21]O)[N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:23]([NH2:25])=[O:24])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[C:18]([CH2:21][S:31]([CH3:30])(=[O:33])=[O:32])[N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:23]([NH2:25])=[O:24])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccccc1COc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CS(C)(=O)=O)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 49 (step 1), 210 mg of 3-[(2-ethylbenzyl)oxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 112 mg of methanesulfonyl chloride, and 104 mg of triethylamine in 5 ml DMF give 3-[(2-ethylbenzyl)oxy]-5-{6-[(methylsulfonyl)methyl]-1H-imidazo[4,5-c]pyridin-1-yl}thiophene-2-carboxamid as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=O.[CH3:18][NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2)(=[O:22])=[O:21].N1CCCCC1>C(O)C>[CH3:18][NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:15]\[C:7]1[NH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:6]=1[CH2:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])(=[O:22])=[O:21]
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN(C)C)CCCC3)C(=O)N2
Yield: 70 %

Procedure:
3-(3-Dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (71 mg, 0.3 mmol), 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) and piperidine (0.03 ml) in 1 ml of ethanol was stirred at 60° C. for over night. The mixture was cooled and the solids collected by vacuum filtration and washed with ethanol to give (93 mg, 70% yield) of 3-[1-[3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.COCCOC>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.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:21]=[CH:22][CH:23]=[CH:24]4)[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Reactant: OB(O)c1ccc2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc4ncccc4c3)nc(OC)n2)cc1
Yield: 71 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (150 mg, 0.51 mmol, Intermediate (8) prepared as described in Example 2 step 1), quinoline-6-boronic acid [176 mg, 1.02 mmol, Intermediate (22)], Cs2CO3 (590 mg, 1.81 mmol) tetrakis(triphenylphosphine)palladium (0) (59 mg, 0.051 mmol), ethylene glycol dimethyl ether (4 mL) and water (1 mL) is placed in a microwave tube, sealed and evacuated and flushed with argon three times and irradiated in a microwave oven at 140° C. for 10 minutes. The reaction mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residual solid is subjected to flash column chromatography on silica gel eluting with a mixture of EtOAc and heptane. The material is recrystallized from MeOH to afford [2-(4-methoxy-phenyl)-ethyl]-(2-methoxy-6-quinolin-6-yl-pyrimidin-4-yl)-amine [140 mg, 71%, Example 10(a)] LCMS: RT=5.97 minutes, MS: 387 (M+H). IC50=0.6 nM
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(=O)C>[N:17]1([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Solvent: CC(=O)O
Product: c1ccc2c(c1)N=C(N1CCCCC1)c1cscc1N2

Procedure:
A solution of 0.7 g. of 10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine in 5 ml. of piperidine is treated with a drop of glacial acetic acid and heated under reflux for 4 days. Excess piperidine is removed under reduce pressure and the oily residue is warmed with dilute acetic acid and filtered. The filtrate is cooled and made alkaline with concentrated ammonium hydroxide to give a yellow solid. Recrystallization from acetone-petroleum ether (30°-60°C.) gives yellow crystals, m.p. 157°-159°C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH:36]4[CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: NC1CC1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: CN(C)C=O
Product: N#Cc1c(NC2CC2)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 50 mg (0.09 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.013 ml (0.19 mmol) of cyclopropanamine were stirred in 1.3 ml of DMF overnight. The crude product was purified directly by preparative HPLC (acetonitrile/water). The collected product fractions were once more dissolved in 2 ml of DMF, 0.013 ml (0.19 mmol) of cyclopropanamine was added and the mixture was stirred at RT overnight. The crude product was then once more purified by preparative HPLC (acetonitrile/water). This gave 20 mg (39% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:4]=1[CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(OCC)C>[Br:22][CH2:21][C:17]1[C:4]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[C:8]3[C:9]([NH:11][C:12](=[O:13])[C:7]=23)=[O:10])=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1Cc1cccc2c1C(=O)NC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: COc1cccc(CBr)c1Cc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of (2-methoxy-6-methylbenzyl)phthalimide (0.286 g, 1.02 mmol) in CC4 (25 mL) was added recrystallized N-bromosuccinimide (0.177 g, 0.99 mmol) followed by benzoyl peroxide (28 mg, 0.11 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (25 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (3:1 hexanes-EtOAc) provided 0.31 g (86%) of (6-(bromomethyl)-2-methoxybenzyl)phthalimide as a white solid. 1H NMR (CDCl3) δ 3.78 (s, 3H), 4.90 (s, 2H), 5.00 (s, 2H), 6.83 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=7.2 Hz), 7.25 (dd, 1H, J=7.2, 8.4 Hz), 7.67–7.69 (m, 2H), 7.78–7.81 (m, 2H). ES-MS m/z 382 (M+Na), 384 (M+Na).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][N:6]([C:8](=[O:16])[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1.[CH3:25][NH2:26]>C(Cl)Cl.CO>[CH3:24][C:2]1([CH3:1])[CH2:7][N:6]([C:8](=[O:16])[CH:9]([NH:26][CH3:25])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: CN
Reactant: CCOC(=O)C=CC(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC(NC)C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 36.6 %

Procedure:
In 3 ml of methylene chloride was dissolved 0.5 g of ethyl 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-4-oxo-2-butenoate followed by addition of 0.116 g of methylamine in methanol. The mixture was stirred at room temperature for 4 days, at the end of which time the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were washed with ethanol-hexane to give 0.2 g of ethyl 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-3-methylamino-4-oxobutanoate.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2Cl)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: CC(C)(O)CNc1cc(Cl)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 103a from N-(4-trifluoromethoxy-phenyl)-2-chloro-4-(2-hydroxy-2-methyl-propylamino)-5-nitro-benzoic acid amide (300 mg, 0.67 mmol), morpholine (233 μL, 2.7 mmol), DIPEA (1.1 mL, 6.7 mmol) and MeCN (3 mL) in a microwave oven at 150° C. (45 min). Yield: 324 mg. HPLC Rt=1.58 min (method H). MS m/z: 499 [M+H]+.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (119 mg, 94 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (122 mg, 99%) which was obtained as a white solid. MS: m/e=410.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:15][C@@:14]2([CH2:16][O:17][CH3:18])[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:19](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:15][C@@:14]2([CH2:16][O:17][CH3:18])[CH2:13][N:12]([CH3:19])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC[C@]12CNCC[C@@]1(c1ccc(Cl)c(Cl)c1)C2
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC[C@]12CN(C)CC[C@@]1(c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane (E2a, 25 mg) was dissolved in methanol (1 mL); acetic acid (0.015 mL) was added followed by sodium triacetoxyborohydride (27.8 mg) and formaldehyde 37% in water (0.06 mL). The reaction mixture was stirred at room temperature overnight. Volatiles were then evaporated and the residue partitioned between DCM (20 mL) and aqueous sat NaHCO3 (20 mL) solution, dried and concentrated. Purification by chromatography (NH column) eluting with a gradient 0-100% ethyl acetate-cyclohexane afforded the title compound (16 mg).
Reaction SMILES: [N+:1]([O-:16])([O:3][C@@H:4]([C@H:6]([O:12][N+:13]([O-:15])=[O:14])[CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH3:5])=[O:2].[CH2:17]([O:19][C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:23]2[C:62]([C:66]([O:68][C:69]([CH3:84])([O:71][C:72](OC3C=CC([N+]([O-])=O)=CC=3)=[O:73])[CH3:70])=[O:67])=[CH:63][CH:64]=[CH:65][C:22]=2[N:21]=1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42]([C:43]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:23]2[C:62]([C:66]([O:68][C:69]([O:71][C:72]([O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C@@H:6]([O:12][N+:13]([O-:15])=[O:14])[C@H:4]([O:3][N+:1]([O-:16])=[O:2])[CH3:5])=[O:73])([CH3:84])[CH3:70])=[O:67])=[CH:63][CH:64]=[CH:65][C:22]=2[N:21]=1)[CH3:18]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(CCO)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,3R)-6-hydroxy-4-methylhexane-2,3-diyl dinitrate (Intermediate 2, 0.78 g, 3.26 mmol) was added to a stirred solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (Intermediate 4, 1.96 g, 2.17 mmol) in CH2Cl2 (20 mL). The solution was stirred at room temperature overnight. The solution was diluted with CH2Cl2 (20 mL) washed with a solution of NaH2PO4 5% (2×20 mL) and brine. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, TLC method, n-Hexane/EtOAc 6:4, Rf:0.45) affording the title compound that was used without any further purification.