Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C>C(OCC)C.Cl.O1CCOCC1>[Cl-:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][NH3+:15]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2ccccc2c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]CCOc1ccc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a cooled (0° C.) single necked flask containing a solution of tert-butyl {2-[(1-chloronaphthalen-2-yl)oxy]ethyl}carbamate in 4 mL of ethyl ether, 5 mL of 4 M HCl solution in dioxane were added. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduce pressure to afford 2-[(1-chloronaphthalen-2-yl)oxy]ethanaminium chloride as a white solid (92% yield) which was pure by TLC and NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A round-bottom flask was charged with (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (11.7 g, 34.58 mmol) in ethanol (350 mL). Some heating was required in order to dissolve all of the starting material in ethanol. A full spatula scoop of 10% palladium on carbon was added into the reaction flask. The reaction mixture was stirred under hydrogen gas at atmospheric pressure overnight at room temperature. After this time, it appeared that approximately 750 mL hydrogen gas had been consumed, and TLC (1:3 ethyl acetate, hexanes) indicated that the starting material had been consumed. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated to afford 7.91 g (92%) of (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester, which was used in the next step without further purification. MS (ES−) cald. for C14H13FO3 [(M−H)−] 247, obsd. 247.1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:9])=[O:8].C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[OH:28][C:27]([CH3:29])([CH3:26])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccccc2C)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(C(C)(C)O)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under inert gas, 0.95 g of N-(2,4-dimethoxybenzyl)-C-o-tolylmethanesulfonamide was initially charged in 20 ml of THF, and then, at a temperature of −78° C., 4.06 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 1.22 ml of acetone were added. After stirring for 10 minutes, the reaction solution was admixed with 2 ml of trifluoroacetic acid and allowed to warm up to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 1.5 ml of trifluoroacetic acid were added. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated by rotary evaporation and the residue was taken up in a mixture of water and dichloromethane. The solid which precipitates out was filtered off with suction and discarded. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. Since the product was also present in the aqueous phase of the filtrate, this was extracted twice with 50 ml of ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. Both residues were purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation (516 mg). This gave the product with a molecular weight of 243.3 g/mol (C11H17NO3S).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:30])[CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:31]([O:30][CH:10]([CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(C)C(COCc1ccccc1)OC(C)=O
Yield: 95.7 %

Procedure:
In chloroform, 4.33 g of 1-benzyloxy-3-hexadecyloxy-2-butanol, 26.34 g of acetic anhydride and 10.42 g of triethylamine were heated under reflux for 17 hours. The reaction mixture was treated in a conventional manner and purified by silica gel column chromatography to give 4.56 g of 2-acetyloxy-1-benzyloxy-3-hexadecyloxybutane.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[OH:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3O)CC2)c(OC)nc1C
Yield: 59 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>ClCCl.O>[Cl:8][CH2:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of aniline (40 g, 0.429 mol) in dichloromethane (500 mL) cooled at 0° C., was added 3-chloropropanoyl chloride (49.1 mL, 0.515 mol) drop wise with constant stirring. Reaction mass was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (4×500 mL). The combined organic layer was washed with saturated sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.58-7.56 (d, J=8 Hz, 2H), 7.30-7.26 (t, J=8 Hz, 2H), 7.05-7.01 (t, J=7.6 Hz, 1H), 3.88-3.85 (t, J=6.4 Hz, 2H), 2.82-2.81 (t, J=6.0 Hz, 2H). MS (M+1): 184.1.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[NH3:31]>>[NH2:31][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:3]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: N
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 24 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine with ammonia followed by purification on a silica gel column using ethyl acetate/toluene =8.2 as eluant.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=CC=[CH:45][CH:44]=1>C(O)CCC>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:48]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH2:43][CH2:44][CH3:45]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.0 gram of p-toluenesulfonic acid monohydrate in 10 ml of n-butyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 3 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 50 ml of ethyl ether and 50 ml of petroleum ether were added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine-n-butyl ester di(p-toluenesulfonate) in 95% yield; mp. 160°-164° C.
Reaction SMILES: ClC1C=CC2OC3C=CC=CC=3CN(C(O)=O)C=2C=1.CC(C)(OC([N:26]([CH2:51][C:52]1[O:53][CH:54]=[CH:55][CH:56]=1)[CH2:27][CH2:28][C:29]([NH:31][NH:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:36]1=2)=[O:34])=[O:30])=O)C>>[O:53]1[CH:54]=[CH:55][CH:56]=[C:52]1[CH2:51][NH:26][CH2:27][CH2:28][C:29]([NH:31][NH:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:36]1=2)=[O:34])=[O:30]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1ccco1
Agent: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCNCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)amino]-1-oxopropyl]hydrazide (25) was prepared in the same manner as 8-chlorodibenz-[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-[(2-thienylmethyl)amino]propylhydrazide, monohydrochloride (18), as described above in Example 18, on a 0.37 mmol scale from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-furanylmethyl)amino]-1-oxopropyl]hydrazide (24), prepared as described above in Example 24, to yield 0.14 g (78%) of product. Analysis calculated for C22H21N4O4Cl.HCl.0.25 H2O (M.W. 481.86): C, 54.84; H, 4.71; N, 11.63. Found: C, 54.56; H, 4.60; N, 11.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:32]([O:31][C:29]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (160 mg, 0.381 mmol) was dissolved in DCM (20 ml), and DMAP (0.056 g, 0.539 mmol) was added followed by benzyl chloroformate (0.077 ml, 0.539 mmol). The reaction mixture was stirred at RT for 6 hours. Additional benzyl chloroformate (0.077 ml, 0.539 mmol) was added, and stirring was continued at RT overnight. The reaction mixture was diluted with DCM and washed with aqueous saturated NH4Cl solution (20 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The crude was purified by chromatography on silica gel cartridge (DCM:ethyl acetate=8:2) to give 0.120 g of desired compound. A further purification by trituration with ethanol (10 mL) was required to afford (S)-4-(2-(benzyloxycarbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide as a white amorphous solid (0.101 g, 0.182 mmol, 47.9% yield, MS/ESI+554.01 [MH]+, [αD]=−6.9, c=0.68, DCM).
Reaction SMILES: [Li]CCCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:33]#N.C1C[O:45]CC1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:33]([C:32]2[CH:31]=[C:30]([O:29][CH3:28])[C:37]([O:38][CH3:39])=[C:36]([O:40][CH3:41])[CH:35]=2)=[O:45])=[N:25][CH:26]=1
Reactant: COc1cc(C#N)cc(OC)c1OC
Reactant: C1CCOC1
Reactant: COc1ccc(C)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1ccc(CC(=O)c2cc(OC)c(OC)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
n-BuLi in hexane (1.6 M, 7.6 mL, 11.9 mmol) was added dropwise to a solution of diisopropylamine (1.089 g, 10.9 mmol) in THF (25 mL) at −60 to −70° C. under N2. The mixture was stirred for 10 min. A solution of 5-methoxy-2-methyl-pyridine (1.274 g, 10.35 mmol) in THF (5 mL) was added dropwise to the above mixture. Stirring was continued for another 10 min and 3,4,5-trimethoxybenzonitrile (1.88 g, 9.74 mmol) in THF (5 mL) was added at −70° C. The mixture was stirred at −78° C. for 1 h and then allowed to warm to room temperature. Stirring was continued for another 2 h and the reaction mixture was poured into an ice-cold aqueous NH4Cl solution. The organic layer was separated and the aqueous phase was extracted with ether. The combined organic layers were extracted with a dilute HCl solution. The aqueous layer was washed with ether, neutralized with 10% aqueous NaOH, and extracted with ether. The organic layer was washed with water and dried. The residue was purified by chromatography eluting with CH2Cl2 to give 2-(5-methoxypyridin-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanone (2.31 g, 75.0%).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:12][C@H:13]([C:18]([N:20]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].C([BH3-])#N.[Na+]>>[CH2:8]([O:7][C:5]([C@@H:4]([NH:12][C@H:13]([C:18]([N:20]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])[CH2:3][CH:2]([CH3:11])[CH3:1])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(=O)CC(C)C
Reactant: CC[C@H](C)[C@H](N)C(=O)N(CC(=O)O)c1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)[C@H](CC(C)C)N[C@H](C(=O)N(CC(=O)O)c1cccnc1)[C@@H](C)CC

Procedure:
Ethyl 4-methyl-2-oxopentanoate and L-isoleucyl-N-(3-pyridyl)-glycine were condensed in the presence of sodium cyanoborohydride to yield N-[1-(S)-ethoxycarbonyl-3-methylbutyl]-L-isoleucyl-N-(3-pyridyl)glycine.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([F:19])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C1COCC1.C1C(=O)N([Br:47])C(=O)C1>C(Cl)Cl.O>[Br:47][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([F:19])=[N:8]2)=[O:18]
Reactant: CC(=O)c1cccc2nc(F)c(NC(C)(C)C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(C(=O)CBr)cccc2nc1F
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A solution of 1-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)ethanone (343b) (113 mg, 0.43 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (149 μL, 0.65 mmol), and TEA (181 μL, 1.29 mmol) in DCM (4.3 mL) was stirred at 0° C. for 30 min when silyl enol ether was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give an oil. To a solution of the resulting oil in water (0.13 mL) and THF (4.3 mL) at RT was added NBS (92 mg, 0.52 mmol) and stirred for 1 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-15% EtOAc in hexanes to give 2-bromo-1-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)ethanone (343c) (85 mg, 0.25 mmol, 58% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 9H) 4.94 (s, 2H) 5.41 (br. s., 1H) 7.44 (t, J=7.82 Hz, 1H) 7.87 (dd, J=8.02, 1.57 Hz, 1H) 7.92 (dd, J=7.43, 1.37 Hz, 1H). 19F NMR (377 MHz, CDCl3) δ ppm −79.69 (s, 1F). MS (ESI, pos. ion) m/z: 340.2/342.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH2:13][O:12][C:9]=3[CH:10]=2)[C:5](=[O:16])[NH:4][N:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH2:13][O:12][C:9]=3[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:18][CH2:19][CH2:20][Cl:21])[N:3]=1
Reactant: Cc1n[nH]c(=O)c2cc3c(cc12)OCCO3
Reactant: ClCCCBr
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nn(CCCCl)c(=O)c2cc3c(cc12)OCCO3

Procedure:
1-[4-Methyl-6,7-ethylenedioxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 4-methyl-6,7-ethylenedioxy-1(2H)-phthalazinone with 1-bromo-3-chloro-propane in dimethylformamide. Rf -value (chloroform/methanol = 19/1) : 0.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:30])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(NCc4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A vial was charged with 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.250 g, 0.582 mmol), benzaldehyde (59.2 μL, 0.582 mmol), and 4 Å MS (0.25 g). DCE was added (1.9 mL) and the reaction mixture was stirred at room temperature for 18 h. Sodium triacetoxyborohydride (0.308 g, 1.46 mmol) was added and the reaction mixture was stirred for a further 24 h. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and was then extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (2-40% EtOAc/hexanes) to yield the titled compound (0.273 g, 90% yield). MS (ESI/Cl): mass calcd. for C27H33N5O4Si, 519.2; m/z found, 520.2 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)[C:19](=[O:35])[C:20]([C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH:31]([CH3:33])[CH2:30][C:29]=3[CH:34]=2)=[C:21]([CH2:23][CH3:24])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[NH:3][C:4](=[O:7])[O:5][N:50]=3)=[CH:41][CH:42]=2)[C:19](=[O:35])[C:20]([C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH:31]([CH3:33])[CH2:30][C:29]=3[CH:34]=2)=[C:21]([CH2:23][CH3:24])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(CC)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(CC)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-4-ethyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.46 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.45 g, 88%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[OH:20]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:20][C@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]2[O:13][CH3:12])[CH:7]=1
Reactant: CO[C@H]1CCCC[C@@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to III.1 from 926 μl 2,4-difluor-nitrobenzene and 1 g (1S,2S)-2-methoxycyclohexanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[NH:15][N:14]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:18]([C:16]1[NH:15][N:14]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[N:17]=1)[CH2:19][CH3:20]
Reactant: CCCc1nc(C2Cc3ccccc3N2C(C)=O)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1nc(C2Cc3ccccc3N2)n[nH]1

Procedure:
A solution of the compound 91 (0.42 g) in ethanol (25 ml) was treated with an aqueous NaOH solution (3 M, 25 mL) and the reaction mix was refluxed for 24 hours. The reaction was cooled, diluted with ethyl acetate, and treated with cold distilled water. The layers were separated and the aqueous fraction was extracted 5 times with ethyl acetate and the combined organic fractions were dried, concentrated and purified by preparatory column chromatography yielding 2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole.