Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2c(c1)CCO2
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc2c1OCC2
Temperature: 0 °C
Reaction time: 44 h
Yield: 40.5 %

Procedure:
To a stirred and cooled mixture of 32 nil of sulfuric acid and 14 ml of water there were added 17 g of 2,3-dihydro-5-chlorobenzofuran, while keeping the temperature at 25° C. After cooling to 0° C., there were added dropwise 14 ml of nitric acid. Stirring and cooling at 0° C. was continued for 44 hours. The reaction mixture was diluted with water (temp. <10° C.) and stirred for 15 min. The precipitate was filtered off, washed with water and recrystallized from a mixture of ethyl acetate and hexane (30:70), yielding 8.9 g (40.5%) of 5-chloro-2,3-dihydro-7-nitrobenzofuran (interm. 3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])O[C:9](=[O:10])[C:2]=12.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[OH:16][CH2:15][CH2:14][CH2:13][N:12]1[C:7](=[O:11])[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NCCCO
Solvent: ClC(Cl)Cl
Product: O=C1c2cccnc2C(=O)N1CCCO
Temperature: 155 °C
Yield: 70.1 %

Procedure:
To a suspension of 4.0 g (27 mmol) furo[3,4-b]pyridine-5,7-dione in 10 ml chloroform a solution of 2.03 g (27 mmol) of 3-aminopropanol in 7 ml chloroform was added and the mixture was heated to reflux for 30 minutes. Now the solvent was slowly evaporated and the mixture was gradually heated to 150-160° C. while the vacuum was maintained. After two hours the mixture was cooled to room temperature and the brownish crude product was purified by flash chromatography (silica gel, ethyl acetate/MeOH 15:1) to afford 3.9 g (70%) of the desired product as a white powder. 1H-NMR (CDCl3): 1.89-1.95 (m, 2H), 2.25 (s, br, 1H), 3.64-3.68 (m, 2H), 3.90-3.96 (m, 2H), 7.60-7.66 (m, 1H), 8.14-8.20 (m, 1H), 8.93-8.99 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][N:11]2[CH2:12][C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=O)(C)(C)C.[ClH:25]>>[ClH:25].[ClH:25].[F:21][C:19]([F:20])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][N:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2Cc3c(cccc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Product: FC(F)(F)c1cccc2c1CN1CCNC[C@@H]21
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole (37 mg, 0.11 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 15 min, the solution was concentrated, diluted with water, and lypholized to give (R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole bis hydrochloric acid salt (33 mg, 99%) as an off white solid.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C(N(CC)C1C=CC=CC=1)C.B.[Cl:34][C:35]1[CH:36]=[C:37]([C:42](=[O:45])[CH2:43][CH3:44])[CH:38]=[CH:39][C:40]=1[Cl:41].Cl>CO.CC(OC)(C)C>[Cl:34][C:35]1[CH:36]=[C:37]([C@@H:42]([OH:45])[CH2:43][CH3:44])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Solvent: CO
Product: CC[C@H](O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A 250 mL round-bottom flask was charged with MTBE (35 mL), a solution of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (2.51 mL, 2.51 mmol) and borane diethylaniline (4.45 mL, 25.1 mmol) at RT then heated to 40° C. A MTBE (20 mL) solution of 156 (6.00 g, 25.1 mmol) was added dropwise and the reaction was stirred at 40° C. for 3 h. The reaction was cooled to RT and MeOH (5 mL) was then added slowly, followed by 1M HCl and the reaction was stirred for 18 h. The water was removed and the remaining organic phase dried (Na2SO4), filtered and concentrated to get a light gray oil. The crude product was purified by SiO2 chromatography (SNAP 100) eluting with EtOAc/hexane (1:3) to afford 3.45 g (66%) of (S)-1-(3,4-dichlorophenyl)propan-1-ol (158) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13]([C:18]1[CH:30]=[C:29]([C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])[CH:28]=[CH:27][C:19]=1[O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])([CH2:16][CH3:17])([CH3:15])[CH3:14]>C(OCC)(=O)C>[C:13]([C:18]1[CH:30]=[C:29]([C:31]([CH2:34][CH3:35])([CH3:32])[CH3:33])[CH:28]=[CH:27][C:19]=1[O:20][CH:21]([CH2:25][CH3:26])[C:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])=[O:23])([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1O

Procedure:
In 100 ml of ethyl acetate was dissolved 25 g (133×10-3 mole) of 2-amino-4-chloro-5-nitrophenol. To the solution was added 50 g of 2-(2,4-di-t-amylphenoxy)butanoic acid chloride at room temperature, and then the mixture was refluxed under heating for 2 hours. After the reaction, a solvent was evaporated under reduced pressure and the residue was recrystallized from hexane to obtain products. Yield: 61 g.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>O>[F:1][C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCC2
Temperature: 150 °C
Yield: 27.6 %

Procedure:
A mixture of 12.5 g (51.4 mmol) of N-(4-fluorophenethyl)benzamide and polyphosphoric acid (150 ml) was heated at 150° C. for 5 days. Then the hot solution was poured into water and the reaction was quenched by the addition of NaHCO3. It was extracted with DCM (3×300 ml). The combined organic phases were washed with brine (300 ml), dried over Na2SO4, filtered and concentrated to small volume under vacuum. 3.2 g of the crude product 7-fluoro-1-phenyl-3,4-dihydroisoquinoline were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+].[F:42][C:43]([F:54])([F:53])[C:44]1[C:45]2[CH2:52][CH2:51][O:50][CH2:49][C:46]=2[NH:47][N:48]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:53][C:43]([F:42])([F:54])[C:44]1[C:45]2[CH2:52][CH2:51][O:50][CH2:49][C:46]=2[N:47]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[CH:7]=2)[N:48]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: FC(F)(F)c1n[nH]c2c1CCOC2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-n1nc(C(F)(F)F)c2c1COCC2
Temperature: 150 °C
Reaction time: 18 h
Yield: 5.5 %

Procedure:
5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 150 mg, 0.282 mmol) copper (1+) iodide (59.1 mg, 0.310 mmol), N,N-dimethylglycine (32.0 mg, 0.310 mmol) and K2CO3 (86 mg, 0.620 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (2 ml) to give a light blue solution with a white precipitate. To this mixture, 3-(trifluoromethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole (P38, 179 mg, 0.931 mmol) was added. After 18 h shaking at 150° C., the reaction mixture was diluted with EtOAc (5 ml) and the organic phase was washed with water (4×10 ml), then brine (5 ml), dried over Na2SO4, then filtered and the solvent evaporated. The obtained crude was passed through an SCX cartridge and eluted with 2M solution of ammonia in MeOH. The obtained mixture was iteratively purified (two times) by preparative LC-MS. The obtained fraction was passed through an SCX cartridge and eluted with 2M solution of ammonia. Obtained 8.8 mg of the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[N:19]1.N1C2C=CC=C(N)C=2C=N1>>[CH3:17][N:18]1[C:26]2[C:21](=[C:22]([NH:27][C:2]([NH:1][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)=[O:3])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19]1
Reactant: O=C=NCc1ccc(N2CCCCC2)cc1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.43 (s, 1H), 8.37 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H), 7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1H), 4.40 (d, 2H), 3.99 (s, 3H), 3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m, 2H); MS (ESI) (M+H)+ 364.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(4-Fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(4-fluorophenyl)-6-trifluoromethyl-pyrimidine (example E.103) (0.24 g, 0.68 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.21 g, 0.82 mmol) according to the general procedure VI. Obtained as a light brown solid (0.38 g), which was subsequently deprotected.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][C:4](OCC)=[O:5].[CH3:15][NH:16][C:17]([NH2:19])=[S:18].C1CCN2C(=NCCC2)CC1.CS(O)(=O)=O>O>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:5])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CNC(N)=S
Agent: CS(=O)(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cn1c(S)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A solution of ethyl 3-oxo-3-(4-pyridyl)propionate (29.0 g, 150 mmol), N-methyl thiourea (40.6 g, 450 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (22.4 ml, 150 mmol) was refluxed for 4 hours and the solution of methanesulfonic acid (14.4 g, 150 mmol) in water (50 ml) was added after cooling by ice-water. The precipitate was washed with water, filtered and dried to give the title compound (23.7 g, 72%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([SH:20])[S:18][CH:19]=2)=[CH:11][CH:10]=1.[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22].O>CN(C=O)C>[C:21]([O:25][C:26](=[O:29])[CH2:27][S:20][C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Sc1nc(-c2ccc(Cl)cc2)cs1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CSc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
888.7 mg (8.78 mmol) of triethylamine were added dropwise with caution to a solution of 1000 mg (4.39 mmol) of 4-(4-chloro-phenyl)-thiazole-2-thiol and 856.5 mg (4.39 mmol) of bromoacetic acid tert-butyl ester in 15 ml of DMF. The reaction mixture was stirred at room temperature for 1.5 h. Then water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated. Yield: 1.44 g.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]2[NH2:19])([O-:9])=[O:8]>N1C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]2[NH:19][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])([O-:9])=[O:8]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Reaction time: 12 h

Procedure:
0.58 cm3 of butyryl chloride is added to 1 g of 5-nitro-1H-indazole-3-amine, prepared as described in, SU 742430 (CA: 94 :65676) in 25 cm3 of pyridine, and cooled to about 5° C. The reaction medium is allowed to return to about 19° C. over 12 hours. The insoluble material present is filtered off and the filtrate is then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 480 mg of N-[5-nitro-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.C([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=O)C>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:29]5[CH2:33][CH2:32][NH:31][C:30]5=[O:34])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCNC3=O)cn2)CC1
Yield: 51.3 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 1-acetylimidazolidin-2-one (72 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (78 mg) was obtained.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41]O)[CH:35]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:41][CH2:40][C:36]1[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: OCCc1cccnc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(F)ccc2n1CCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A solution of 0.365 g (1.44 mmol) of 1,1′-(azodicarbonyl)dipiperidine in 10 ml of tetrahydrofuran is added dropwise to a solution of 0.2 g (0.97 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.178 g (1.45 mmol) of 2-(pyrid-3-yl)ethanol and 0.36 ml (1.44 mmol) of tributylphosphine in 30 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature and then concentrated under reduced pressure and taken up in 50 ml of cyclohexane. The suspension is then filtered and the filtrate is chromatographed on a column of silica (eluent: dichloromethane/methanol). 0.125 g of the expected product is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([O:20][C:21](=O)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:24]=2)C=CC=CC=1>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:21](=[O:20])[NH:22][C:23]2[CH:24]=[C:25]([S:29]([NH2:30])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CO
Product: NS(=O)(=O)c1cccc(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)c1
Temperature: 80 °C

Procedure:
A solution of (R)—N-benzyl-3-aminopyrrolidine (14.9 g, 0.084 mol) in methanol (100 mL) is added to a suspension of (3-sulfamoyl-phenyl)-carbamic acid phenyl ester (25 g, 0.084 mol). The resulting pale orange solution is stirred at mild reflux (DrySyn @ 80° C.) for two hours, then allowed to cool to room temperature, before the volatile components are removed under reduced pressure. The orange syrup is purified by flash column chromatography (silica; DCM/methanol 10:1) to give a beige foamed solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16](CC4C=CC(OC)=CC=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:29])[CH:9]=1)[C:5]#[N:6]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:29])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Temperature: 75 °C

Procedure:
3-chloro-5-{[5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}benzonitrile (0.0097 g, 0.023 mmol) was dissolved in TFA (2 mL) and heated at 75° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was subjected to automated silica gel chromatography eluting with 0-25% ethyl acetate in hexanes to give the title product. LRMS (M+1)=304.8
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:21])C=1>C(OCC)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:12])[N+:11]=1[O-:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: CCCCOc1cccc(C)[n+]1[O-]
Yield: 51.5 %

Procedure:
To a solution of 19.0 g (0.12 mol) of 6-butoxy-α-picoline dissolved in 250 ml of diethyl ether was portionwise added 23.8 g (0.14 mol) of m-chloroperbenzoic acid under ice-cooling. After standing under ice-cooling for one hour, the mixture was further left to stand at room temperature for several days. The reaction mixture was extracted with water and then adjusted to pH=11 with an addition of sodium carbonate. After extraction with chloroform, the extract was concentrated under a reduced pressure to give 11.2 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]=[C:7]([C:17](O)=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]=[C:7]([CH2:17][OH:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2c(Br)cccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCC1=Cc2ccccc2Oc2c(Br)cccc21
Yield: 99 %

Procedure:
Preparation analogous to Example 12f) from 6-bromo-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 99% crude, brown oil; TLC (silica gel; hexane/ethyl acetate=7:3; UV): Rf =0.07; 1H-NMR (CDCl3, 200 MHz): 3.54 (s, 2H); 6.70-7.49 (m, 8H).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1>C(=O)=O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]=[N:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10]
Reactant: Cc1ccccc1N=C=O
Agent: O=C=O
Product: Cc1ccccc1N=C=Nc1ccccc1C
Yield: 93.2 %

Procedure:
133 g of o-tolylisocyanate and 5 g of solid, insoluble catalyst from Example 2a were heated to 140° C. with stirring. After evolution of 12.1 liters of carbon dioxide, which took place within 2 hours, the catalyst was suction filtered and the filtrate was distilled. 103.5 g of di-o-tolyl-carbodiimide, b.p. 130°-132° C./0.1 Torr were obtained (94% of the theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1cccnc1CO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(-c2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:51]=[CH:50][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[NH:43][CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:48][CH2:49][CH:44]([NH:43][C:35]3[N:34]([CH2:33][C:32]4[CH:50]=[CH:51][C:29]([F:28])=[CH:30][CH:31]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:45][CH2:46]2)([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: CS(=O)(=O)OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1N(Cc2ccccc2)CCC1(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1
Reaction time: 12 h

Procedure:
Combine 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.99 g, 2.57 mmol), (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.80 g, 2.57 mmol), and N,N-diisopropylethylamine (0.73 g, 5.65 mmol) in acetonitrile (37 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and water. Separate the layers and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give a residue. Partition the residue between dichloromethane and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.22 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).