Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1.Cl([O-])(=O)(=O)=O.[Li+].ClCCl>C(#N)C>[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(F)cc3)CC1)O2
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (1.0 g, 3.32 mmol) in acetonitrile (12.0 mL) was added (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.614 g, 3.65 mmol) followed by lithium perchlorate (0.388 g, 3.65 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and dichloromethane (100 mL) added to it. The reaction was then washed with water (100 mL). The organic layer was separated, washed with water, dried with sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO2, 80% EtOAc in dichloromethane to 100% EtOAc) to give the desired product as a purple solid (0.73 g, 45%). M.p.=174-175° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=1.6, 7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.66 (dt, J=1.6, 7.6 Hz, 1H), 7.5 (dt, J=1.6, 7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.9-6.84 (m, 2H), 4.18-4.1 (m, 1H), 4.0-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.96 (s, 2H), 2.86-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.6-2.5 (m, 2H), 2.2-2.12 (m, 2H), 1.98-1.82 (m, 2H); LCMS: 470 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=30.54
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:9])[CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]([CH3:10])[C:4](=[O:9])[CH:3]=1
Reactant: Oc1cc(Br)cc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(Cl)cc(Br)cc1=O
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 4-bromo-6-chloropyridin-2-ol (1.0 equiv.) in DMF (0.16 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.2 equiv.) at room temperature. The solution was stirred for 2 hours, then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate two more times, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and heptanes (0-50% ethyl acetate). The pure fractions were concentrated to yield 4-bromo-6-chloro-1-methylpyridin-2(1H)-one in 38% yield. LCMS (m/z) (M+H)=221.9/223.9, Rt=0.64 min.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[S:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2cn[nH]c(=S)c2c1

Procedure:
13.9 g of 7-nitro-1(2H)-phthalazinone and 16.3 g of Lawesson reagent in 170 ml of acetonitrile are heated under reflux for 45 minutes. The reaction mixture is filtered while hot. The filtrate is cooled in an ice-bath and the crystals obtained are removed by filtration under suction. After drying in vacuo and recrystallization there is obtained 7-nitro-1(2H)-phthalazinethione as yellow crystals of m.p. 233°-234° (methanol/acetonitrile).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C)c1
Yield: 72.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (442 mg) described in Preparation Example 37 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (571 mg) was obtained.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[CH:18]=2)[CH2:12]1.O=S(Cl)[Cl:37]>C(Cl)(Cl)Cl>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[C:18]=2[Cl:37])[CH2:12]1
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(Cl)c(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O

Procedure:
Compound 4 (40 mg, 0.1 mmol) in CHCl3 (2 mL) was treated with SOCl2 (200 μL) at 100° C. for 30 min, concentrated, and then purified by LC-MS to give the title compound 7. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.73 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 5.32-5.42 (m, 2H), 3.43 (s, 3H), 3.33-3.40 (m, 2H), 3.17 (m, 2H), 2.87 (s, 1H), 2.08 (m, 1H), 1.70 (m, 1H), 1.32-1.43 (m, 2H). MS (ES) [m+H] calc'd for C18H21ClN5O2, 374.1. found, 374.1.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1(OC)C=CC=CC=1.C.[H][H]>[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: COc1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1 Part of nitroanthraquinone with a content of 97.0 percent of 1-nitroanthraquinone, 9 parts of anisole and 0.005 parts of catalyst (10 percent Pd on active charcoal) are heated to 130° in an autoclave with a capacity of 20 parts by volume and equipped with a rotary agitator. While heating, rinsing with nitrogen is effected and, on reaching the reaction temperature, hydrogen is passed through to provide a total pressure of 6.0 kp per cm2, at which the agitator is activated and hydrogenation effected until an amount of hydrogen corresponding to 264 parts by volume is taken up. The hydrogen is now followed by nitrogen and the catalyst separated, the filtrate cooled down to room temperature, when 1-aminoanthraquinone is formed in easily filtrable crystals. The crystallization product is separated, washed with a small quantity of cold benzene and dried at 100° and 20 mm of Hg. 0.83 Parts of a product containing 98.0 percent of 1-aminoanthraquinone are obtained, which corresponds to a yield of 95.1 percent of the theory. By concentrating the mother liquor, a further 0.05 parts of a product containing 71 percent of 1-aminoanthraquinone is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: COc1ccc(N)c(CO)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN2CCOCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-morpholine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and morpholine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride) 3280 cm-1NH2 ; 3410 cm-1NH2 ; 2830 cm-1OCH3 ; 2800 cm-1N-alkyl; 1500 cm-1C=C; 1600 cm -1 C=C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CC(C)(C)CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)(C)CNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2,2-dimethylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 347 (M+, 2), 332 (20), 292 (30), 290 (78), 100 (bp), 70 (16).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25]Br)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([NH2:38])(=S)[CH2:35][CH3:36].C1COCC1>C(O)C>[NH2:38]/[C:34](/[CH2:35][CH3:36])=[CH:25]\[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:27]
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: CCC(N)=S
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
A mixture of 6-bromo-3-(2-bromoacetyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (300 mg), thiopropionamide (70 mg), THF (3 ml) and ethanol (3 ml) was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-hexane:ethyl acetate=1:2) and recrystallized (ethyl acetate-hexane) to give the title compound (100 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([NH:23][C:24](=O)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH2:16]([N:23]1[C:11](=[O:13])[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:24]1[C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4)cc(OC)c1OC
Temperature: 0 °C
Yield: 68 %

Procedure:
Commercially available ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b)-thiophene-3-carboxylate (6.0 g, 26.6 mmol, 100 mol-%) and N-benzyl-3,4,5-trimethoxybenzamide (10.4 g, 34.6 mmol, 130 mol-%) were dissolved in dry 1,2-dichloroethane. The reaction mixture was cooled with an ice-salt-bath and POCl3 (1.7 ml, 24.6 mmol, 130 mol-%) was added. The reaction mixture was refluxed for 24 hours. During refluxing POCl3 (340 μl) was added twice. The reaction mixture was poured into ice-water and after neutralization with sodium acetate the product was extracted into dichloromethane. The organic phases combined were washed with sodium bicarbonate sat. (3×50 ml) and dried with MgSO4. The yield after recrystallization from i-propanol was 8.3 g (yield 68%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.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>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:18]3[CH:17]=[CH:16][C:15]([S:12](=[O:13])(=[O:14])[NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][CH:19]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)NCCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)NCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 48.8 %

Procedure:
N-(2-Benzyloxyethyl)4-tributylstannylbenzenesulfonamide (0.92 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.42 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.09 g) in xylene in nitrogen atmosphere for 45 min. After cooling, the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol system). The resulting product was dissolved in ethyl acetate and extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)sulfamoyl]phenyl}isoquinoline (0.34 g) as a pale brown oil.
Reaction SMILES: N#N.[Li]CCCC.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1([CH3:18])[O:17][CH2:16][CH2:15][O:14]1.CN([CH:22]=[O:23])C>CCCCCC.C1COCC1>[CH3:18][C:13]1([C:9]2[O:8][C:12]([CH:22]=[O:23])=[CH:11][CH:10]=2)[O:14][CH2:15][CH2:16][O:17]1
Reactant: CN(C)C=O
Reactant: CC1(c2ccco2)OCCO1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(C=O)o2)OCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 166.7 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of n-BuLi (14.6 mL of a 1.6M solution in hexane, 23.35 mmol) in THF (21 mL) at −78° C. was added dropwise a solution of 2-furan-2-yl-2-methyl-[1,3]dioxolane (3.00 g, 19.46 mmol) in THF (6.0 mL). The reaction mixture was then stirred for 1 h at −78° C. before DMF (4.52 mL, 58.38 mmol) was added dropwise. The reaction mixture was stirred for 1 h at −78° C. Sat. aq. NaH4Cl (50 mL) was added and the mixture was extracted with EA (2×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 5.91 g of crude 5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-carbaldehyde as an orange oil. LC-MS-conditions 02: tR=0.75 min; [M+H]+=183.23. The crude material was dissolved, under inert atmosphere (N2) in MeOH (59.0 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.53 g, 38.92 mmol in five equal portions). The reaction mixture was stirred at rt for 45 min. The reaction mixture was poured in water (80 mL) and the aq. layer was extracted with EA (2×60 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.27. LC-MS-conditions 02: tR=0.65 min; [M+H]+=185.28.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8]
Reactant: CCNCC
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 55 °C
Yield: 67.2 %

Procedure:
Diethylamine hydrochloride (0.024 g) was added to a stirred mixture of N-[5-(4-cyanoberizamido)-2-methylphenyl]-4-(chloromethyl)benzamide (0.06 g), potassium carbonate (0.082 g) and acetone (5 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. Further portions of diethylamine hydrochloride and potassium carbonate (same quanities as before) were added and the mixture was heated to 55° C. for a further 4 days. The reaction mixture was evaporated and the residue was triturated with water. The solid was isolated and dried under vacuum at 55° C. to give the title compound as a solid (0.044 g); NMR Spectrum: (CDCl3) 1.06 (t, 6H), 2.28 (s, 3H), 2.53 (m, 4H), 3.63 (s, 2H), 7.2 (d, 1H), 7.5 (d, 2H), 7.74 (m, 4H), 7.81 (d, 2H), 7.97 (d, 2H), 8.15 (s, 1H), 8.27 (s, 1H); Mass Spectrum: M−H− 439.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].Cl[CH2:11][C:12]1[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=[C:16]([CH:18]([Cl:20])[Cl:19])[N:17]=1.ClCCl>CS(C)=O>[C:1]([O:4][CH2:11][C:12]1[C:13]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])=[N:14][CH:15]=[C:16]([CH:18]([Cl:19])[Cl:20])[N:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
50 ml of absolute glacial acetic acid and 35 g of potassium acetate were added to a solution of 57.7 g (0.16 mole) of 65% strength 3-chloromethyl-5-dichloromethyl-2-phthalimidopyrazine in 1,000 ml of dimethyl sulfoxide, and the mixture was then stirred for three days at room temperature. Thereafter, 1,000 ml of dichloromethane and 1,000 ml of ice-water were added to the reaction mixture, the resulting mixture was mixed thoroughly, and phase separation was effected. The aqueous phase was extracted once with 500 ml of dichloromethane and once with 250 ml of dichloromethane. The combined organic phases were washed twice with 1,000 ml of water, dried over sodium sulfate and evaporated down in a rotary evaporator. The blackish brown oil was taken up in 20 ml of methanol at the boil, and the solution was left to crystallize at room temperature. The product was then suspended in a little diethyl ether, filtered off and dried. The crystals were then recrystallized again from methanol. 30.6 g (77% of theory) of 3-acetoxymethyl-5-dichloromethyl-2-phthalimidopyrazine of melting point 117°-118° C. were obtained. 1H-NMR (270 MHz, CDCl3): δ1.9 (s, 3H), 5.3 (s, 2H), 6.9 (s, 1H), 8.1 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[N:24]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[N:24]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: Cc1cn(C)c(Br)n1
Product: Cc1cn(C)c(-c2cc(C)c(Cl)c(C)c2)n1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-1,4-dimethyl-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.82 min; Mass spectrum (ESI+): m/z=235/237 (Cl) [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:8]([CH:9]=1)[O:10][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Temperature: 70 °C

Procedure:
A flask was charged with 5-nitro-2-pentafluoroethyl-phenol (3.67 g, 14.2 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (9.71 g, 57.1 mmol), K2CO3 (7.9 g, 57.1 mmol), and acetone (20 mL). The reaction was heated at 70° C. for 3 days. The acetone evaporated from the reaction. No reaction was observed, so the organic material was recovered by extraction of water with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. This crude mixture was dissolved in DMF (20 mL), combined with K2CO3 (5.9 g, 42.1 mmol) and heated to 70° C. for 24 h. The reaction mixture was cooled to RT, taken up in EtOAc and washed with 2 N NaOH, and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The aqueous layer was acidified, extracted with EtOAc and dried with MgSO4, filtered, concentrated in vacuo and combined with the other portion. The title compound was purified by column chromatography using 0-10% MeOH in CH2Cl2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][N:13]2[C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: CC(C)N=C=O
Reactant: Fc1cc(C2NCCc3ccccc32)ccc1C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline (0.1020 g, 0.345 mmol) in 3 mL of DCM, isopropyl isocyanate (0.0400 mL, 0.407 mmol) was added. The solution was stirred for 1 h. Solvent was evaporated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) then again with 10-40% EtOAc in hexanes to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 381.1 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.48 (t, J=7.75 Hz, 1H) 7.19-7.32 (m, 2H) 7.01-7.14 (m, 2H) 6.55 (s, 1H) 4.30 (s, 1H) 3.98-4.13 (m, 1H) 3.38-3.63 (m, 2H) 2.69-2.98 (m, 2H) 1.13-1.25 (m, 6H).