Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].Cl>O.CCOCC>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1Cl
Reactant: Clc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccccc1Cl

Procedure:
To 12.7 g. (0.52 moles) of magnesium turnings in 200 ml. of anhydrous ether is added 10.0 g. (0.052 moles) of p-bromochlorobenzene, and the mixture is warmed to reflux. When the Grignard reaction begins, the heat is removed and 80.0 g. (0.47 moles) of additional p-bromochlorobenzene in 80 ml. of ether is added dropwise as the refluxing continues. When the addition is completed, the reaction is heated at reflux for 2 hours, cooled, and 73.4 g. (0.52 moles) of o-chlorobenzaldehyde are slowly added. The reaction is refluxed for 2 hours, cooled and poured into iced water. The resulting mixture is made acidic with hydrochloric acid, and the organic phase is separated. The aqueous layer is extracted with ether, and the extract is added to the organic phase. This solution is washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oily solid. The material is crystallized from petroleum ether to give 109.4 g. (83%) of the product, mp 68°-70°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.176 mmol) and isobutylamine (2 mL) the title compound was obtained as a yellow powder (90 mg, 0.149 mmol, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.86 (d, J=5.3 Hz, 1H), 7.67 (t, J=6.1 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.21-7.31 (m, 4H), 7.14 (bs, 1H), 5.62 (bs, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.45 (t, J=4.8 Hz, 4H), 3.02 (bs, 2H), 1.78-1.86 (m, 1H), 0.87 (d, J=6.6 Hz, 6H). MS (ESI): 603 [M−H]−.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([Cl:15])[CH:2]=1.C([Li])CCC.[Cl:21][CH2:22][CH2:23][CH2:24]I>O1CCCC1>[Cl:21][CH2:22][CH2:23][CH2:24][CH:7]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:6]1[CH:1]=[CH:2][C:3]([Cl:15])=[CH:4][CH:5]=1
Reactant: Clc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: ClCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 4,4′-dichlorodiphenylmethane (4.37 g, 18.4 mmol) (Blackwell, J. et all, J. Chem. Soc., 1961, 1405) in dry tetrahydrofuran (50 ml) was treated at 0° C. with butyllithium (12.1 ml of 1.6 M, 19.36 mmol) added dropwise over 15 min. After 15 min, the red solution was then added dropwise to a cold (−78° C.) solution of 1-chloro-3-iodopropane (15.0 g, 73.4 mmol) in dry tetrahydrofuran (120 ml). After 20 min at −78° C., the reaction mixture was quenched by the addition of saturated ammonium chloride (100 ml) and diluted with toluene. The organic phase was washed with brine and dried. The oil obtained after evaporation of the solvent was purified on silica gel (elution hexane-toluene 85:15) and distilled under vacuum to give 2.54 g (44%) of the title material as a clear oil: bp 110-130° C./1.5 torr (air bath temperature).
Reaction SMILES: [Cl-].[CH:2]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[N+:33]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)([O-:35])=[O:34]>O1CCCC1.C(Cl)Cl>[CH:2]1([C:6]2[S:7][CH:8]=[C:9](/[CH:11]=[CH:39]/[C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: c1ccc([P+](Cc2csc(C3CCC3)n2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(/C=C/c2csc(C3CCC3)n2)c1
Yield: 70.4 %

Procedure:
A slurry of 1.8 g of [(2-cyclobutyl-4-thiazolyl)methyl] triphenylphosphonium chloride, in 80 ml of tetrahydrofuran was sealed under a positive argon atmosphere and the mixture cooled with an ice bath. Sodium hydride (0.2 g; 50% oil dispersion) was added and stirring and cooling continued for 30 min afterwhich 0.6 g of 3-nitrobenzaldehyde was added. The cooling bath was removed and the mixture was stirred at room temperature for 1 hr. The mixture was then filtered, condensed in vacuo and the residual materials taken up in 100 ml of methylene chloride. This solution was then washed with water, dried (MgSO4) and condensed in vacuo to yield 0.8 g of (E)-2-cyclobutyl-4-[2-(3-nitrophenyl)ethenyl]thiazole; m.p. 112°-115° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26]Cl)[CH:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C-:32]#[N:33].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:32]#[N:33])[CH:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [C-]#N
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) in ethanol (0.8 mL) and water (0.4 mL) were added NaCN (22 mg, 0.45 mmol) and KI (cat) at room temperature. The reaction mixture was stirred for 30 min at 110° C. in the microwave before being purified by column chromatography on silica gel (5-15% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[NH:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[NH:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)[S:8][C:7]=4[C:6]=3[CH:28]=2)[CH:31]=[N:30]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(-c4cn[nH]c4)ccc2OCC3)c(F)c1

Procedure:
5-(9-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole was treated with 4-pyrazoleboronic acid pinacol ester using standard Suzuki condition to yield 400. NMR: (CDCl3): 3.15 (2H, t), 4.31 (2H, t), 6.82 (1H, s), 7.01 (1H, d), 7.08-7.18 (2H, m), 7.31 (1H, d), 7.51-7.55 (1H, m), 7.72 (1H, s), 7.90 (2H, s, br.), 8.18 (1H, s). MS. ESI+ 489 (MH++MeCN)
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([C:31]1[N:39]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(Cc1ccccc1)=NO
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 46 mg (44% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:2].I[CH3:35]>>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:35])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)cc(C(F)(F)F)c1
Product: CCOC(=O)C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 213, Step 5, using the following starting materials: {2′-[(acetyl-ethyl-amino)-methyl]-5,4′-bis-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester and iodomethane.
Reaction SMILES: [CH2:1](O)[CH:2]([OH:5])[CH:3]=[O:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.[Pd]>[CH2:7]([NH:14][CH2:1][CH:2]([OH:5])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: O=CC(O)CO
Agent: [Pd]
Solvent: CO
Product: OCC(O)CNCc1ccccc1
Yield: 53.7 %

Procedure:
In yet a further method, N-benzyl-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2-hydroxypropylamine was formed in the following manner. D,L-Glyceraldehyde (5.0 g) was added to benzylamine (18.19 g) in methanol (90 ml) and the mixture was hydrogenated at 344 kPa (50 p.s.i.) over 5% palladium on carbon (1.0 g) for 31/2 hours. The mixture was filtered, evaporated under reduced pressure and subjected to column chromatography on silica (eluant dichloromethane:methanol saturated with ammonia 9:1) to give as an oil 3-benzylamino-1,2-propanediol (5.4 g). Part of this (4.9 g) and benzaldehyde (10 ml) were heated to 150° C. for 30 minutes. Volatiles including water were collected by distillation. The mixture was then cooled, benzaldehyde distilled off at low pressure, and the desired product 2-phenyl-3-benzyl-5-hydroxymethyloxazolidine (2.7 g) distilled at 190° C. (0.2 mm Hg). To this oil (2.69 g) in pyridine (4 ml) was added in portions toluene-p-sulphonyl chloride (1.90 g) at 5° C. The mixture was stirred at room temperature for 2 hours, treated with potassium carbonate (1.65 g) in water (7.5 ml), extracted into dichloromethane (3×10 ml) and evaporated under reduced pressure to give an oil. This oil dissolved in dimethylformamide (5 ml) was added in portions, to a solution of the anion of 4-[2-(cyclopropylmethoxy)ethyl]phenol (1.9 g) (prepared in situ using sodium hydride (0.5 g)) in dimethylformamide (5 ml) at 5° C. The mixture was heated for 6 hours to 60°-70° C., cooled, poured on to ice (30 g), extracted into diethyl ether (3×30 ml) and evaporated under reduced pressure to give an oil. This was slurried under water (30 ml), concentrated hydrochloric acid (6 ml) was added, stirred for 30 minutes and ether (30 ml) added. The resultant solid (1.1 g) was filtered off, slurried with ether, filtered and separated between dichloromethane and dilute sodium hydroxide. The dichloromethane layer was dried, filtered and evaporated to give an oil which crystallised on standing to afford N-benzyl-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2-hydroxypropylamine (0.8 g), identical with an authentic sample by chromatography and a nuclear magnetic resonance spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(c1cccc(C#N)c1)[Si](C)(C)C
Yield: 96.8 %

Procedure:
About 5.87 g of 3-aminobenzonitrile, 11.57 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.41 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 12 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 3-[bis(trimethylsilyl)amino]benzonitrile (3-BTMSABZN) as a brown oil (12.62 g, 97% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (multiplet, 1H, aromatic proton), 6.81 (multiplet, 1H, aromatic proton), 6.67 (multiplet, 1H, aromatic proton), 6.59 (multiplet, 1H, aromatic proton), −0.10 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:32][CH:31]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(N3CCN(Cc4ccc(Cl)cc4)CC3)ccc2N1
Reaction time: 4 h
Yield: 32.5 %

Procedure:
To a mixture of 1.0 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.11 g of potassium carbonate and 20 ml of DMF was added 780 mg of 4-chlorobenzyl chloride and the mixture was stirred at 70°-80° C. for 4 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from chloroform-methanol gave 500 mg of 6-[4-(4-chlorobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 190°-191.5° C., colorless needles.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@H:7]([CH2:10]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C=O)C>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@@H:7]([CH2:10][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(Cl)c(Cl)cc3O2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2cc(Cl)c(Cl)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:3]1=[O:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>O1CCCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:3]2=[O:27])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 1-{[(3-amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 193°-194° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=O)(C)(C)C.[CH2:17]([CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])[CH3:18].Cl>CC(O)=O>[CH2:23]([C:19]1[C:20]([CH3:21])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[CH2:9][NH:8][CH2:15][C:14]3=2)[C:17]=1[CH3:18])[CH3:24]
Reactant: CCC(C(C)=O)C(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Agent: Cl
Solvent: CC(=O)O
Product: CCc1c(C)nc2c3c(nn2c1C)CNC3
Temperature: 25 °C
Reaction time: 32 h
Yield: 77.6 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (0.6 g; 2.68 mmol; 1 eq.) and 3-ethyl-2,4-pentanedione (0.36 mL; 2.68 mmol; 1 eq.) in AcOH (8 mL) was stirred at room temperature for 32 hours. Aq. 32% HCl (1.05 mL; 10.7 mmol; 4 eq.) was added and the resulting mixture stirred for a further 16 hours. After concentration in vacuo, the residue was triturated in MTBE and the precipitate filtered off and dried. The solid was taken up in ethyl acetate and washed with 1M aq. NaOH (2×), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (450 mg, 94%) as a beige solid. 1H NMR (DMSO-d6) δ 4.05-4.00 (m, 4H), 2.73-2.63 (m, 5H), 2.51 (s, 3H), 1.12 (t, J=7.4 Hz, 3H). UPLC/MS: (MS+) 217.3 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C)C=O>[F:20][CH:16]([F:21])[O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2cc(OC(F)F)cnc12
Temperature: 100 °C
Yield: 15.8 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (CAS25369-37-3) (500 mg, 2.63 mmol) in dimethylformamide (5 ml) was treated with sodium chlorodifluoroacetate (481 mg, 3.15 mmol). The mixture was heated to 100° C. overnight under a nitrogen atmosphere. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=9:1 to 8:1 as the eluent yielding 100 mg (16%) of the 3-difluoromethoxy-8-nitro-quinoline as a yellow solid; (calculated) C10H6F2N2O3 [240.2]; (found) [M+H]+=241.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH2:24])=[N:20][CH:21]=1>>[CH3:12][N:7]1[C:6]2[CH:13]=[C:2]([NH:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:26])([F:14])[F:25])=[CH:21][N:20]=3)[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: CN1C(=O)COc2ccc(Br)cc21
Product: CN1C(=O)COc2ccc(NCCc3ccc(C(F)(F)F)cn3)cc21

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound 4-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-4H-benzo[1,4]oxazin-3-one (MS m/e: 352.2 [M+H]+) was prepared from 6-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH2:22]1COCC1.C[Mg]Br.Cl>C(OCC)(=O)C.O>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:22])[CH:12]=[C:13]([S:15]([F:19])([F:18])([F:20])([F:17])[F:16])[CH:14]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (980 mg) was dissolved in abs. THF (50 ml), and methylmagnesium bromide solution (2.1 ml; 3M solution in diethyl ether) was added dropwise while stirring at 0° C. After the addition had ended, the ice bath was removed and the mixture was stirred at RT for 1 h. To complete the reaction, more methylmagnesium bromide solution (0.3 ml) was added and the mixture was stirred for a further 2 h. After storing overnight in a refrigerator, the reaction mixture was admixed with 1 N hydrochloric acid while cooling. Addition of water and ethyl acetate was followed by extraction twice more with ethyl acetate, and the combined organic phases were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means of chromatography on silica gel (100/0 to 50/50 n-heptane/ethyl acetate within 30 min). The product-containing fractions were combined, the solvent was removed and the residue was dried under high vacuum. 650 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[CH2:8][OH:9]
Reactant: O=[N+]([O-])c1cc(Br)ccc1CO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1CO
Temperature: 75 °C
Yield: 95 %

Procedure:
A mixture of (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 7.97 mmol), iron powder (2.23 g, 39.9 mmol), ammonium chloride (213 mg, 3.99 mmol), ethanol (20 mL), and water (10 mL) was heated at 75° C. for 1 h, then after cooling filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to produce (2-amino-4-bromo-phenyl)-methanol (1.53 g, 90%). Off-white solid, MS (EI)=201.0 (M+).