Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[Cl:14][CH2:15][CH2:16][C:17]([C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C(CCCl)c1ccc2[nH]c3ccccc3c2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a 90 ml solution of 5.0 g of carbazole and 4.2 g of 3-chloropropionyl chloride in nitromethane, 4.8 g of aluminum chloride was added portionwise, followed by stirring at 45° C. for 1 hour. The reaction mixture was poured over 100 ml of ice water, and the organic layer was separated and then washed by sequential additions of a 50 ml saturated aqueous sodium hydrogen carbonate solution and 50 ml of distilled water. After the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off to yield a crystalline residue. The residue was collected by filtration and dried under reduced pressure to yield 4.8 g of the title compound as a light red crystal having a melting point of 148° to 151° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:12][CH:11]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C(=O)Nc2ccc3ccc(OC)nc3n2)cc1
Temperature: 4 °C
Yield: 67.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-ethoxybenzoic acid (8 g), N,N'-carbonyldiimidazole (7.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (5.6 g). The product produced by precipitation in water (9.4 g; m.p. 74° C.) is dissolved in boiling acetonitrile (94 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 30° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-4-ethoxybenzamide (7 g) is produced, m.p. 145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[C:11]([CH:12]=1)=[N:10][C:9](=O)[N:8]1[NH:14][CH:15]=[N:16][C:7]=21.O(Cl)[Cl:20].CN(C)C1C=CC=CC=1>>[Cl:20][C:9]1[N:8]2[N:14]=[CH:15][N:16]=[C:7]2[C:6]2[CH:5]=[C:4]([O:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:12][C:11]=2[N:10]=1
Reactant: COc1cc2nc(=O)n3[nH]cnc3c2cc1OC
Reactant: ClOCl
Solvent: CN(C)c1ccccc1
Product: COc1cc2nc(Cl)n3ncnc3c2cc1OC

Procedure:
300 mg of 8,9-Dimethoxy-1,2,4-triazolo-[1,5-c]quinazoline-5-one is refluxed with 5 ml Phospherous oxychloride and a catalytic amount of N,N-dimethylamline for 18 hours. The reaction mixture is then evaporated in vacuo to dryness; the residue taken up in methylene chloride and the methylene chloride layer extracted several times with cold sodium bicarbonate solution, with water, dried and then avaporated in vacuo to dryness. The residue is crystallized from methylene chloride/diethyl ether to give 5-chloro-8,9-dimethoxy-1,2,4-triazolo-[1,5-c]-quinazoline, m.p. 258°-260°.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:12]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[C:10]([I:12])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CC(C)(C)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of commercially available 4-tert-butylaniline (2.00 g, 13.4 mmol) in MeOH (10 mL) was added to a mixture of silver sulfate (4.17 g, 13.4 mmol) and iodine (3.39 g, 13.4 mmol) in MeOH (30 mL). The mixture was stirred at room temperature for 4 h. The mixture was filtered. The filtrate was concentrated. The title compound was obtained after flash chromatography using EtOAc:hexane/2:8 as the eluant. 1H NMR (CDCl3, 500 MHz): B7.65 (d, J=2. Hz, 1H), 7.20 (dd, J=8.5, 2.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 1.30 (s, 9H).
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]3[CH:19]=[C:20]([CH2:31][C:32]([OH:34])=[O:33])[CH:21]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23]=3[OH:24])[NH:15]2)=[CH:11][C:10]=1[C:35](=[NH:38])[NH:36]O>C(O)(=O)C.[Pd]>[C:35]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[Cl:8])[NH:15][C:14]([C:18]1[CH:19]=[C:20]([CH2:31][C:32]([OH:34])=[O:33])[CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]=1[OH:24])=[CH:13]2)(=[NH:36])[NH2:38]
Reactant: N=C(NO)c1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N=C(N)c1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl
Reaction time: 1.5 h

Procedure:
Acetic anhydride (1.1 eq, 0.77 ml, in 7 ml of AcOH) was added drop wise to a stirring solution of 3 g of 18 in 34 ml of acetic acid at ambient temperature under N2 over several minutes. HPLC 15 minutes thereafter indicated formation of a hydrophobic product. A catalytic amount of Pd/C (10% w/w) was added to the reaction mixture and teh reaction vessel then was charged with H2 (atm.). The reaction mixture was agitated for about 1.5 h. The agitated reaction mixture was passed through a celite pad (rinsed with ACOH). The filtrate was diluted with ethyl acetate to yield a precipitate. The colid was isolated and dried in vacuo to yield 2.05 g of the crude amdidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCC2)c(C(=O)O)c1

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 100 ml pyrrolidine. A cooling bath was applied as necessary during the addition. After the addition was complete, the reaction was heated on a steam bath for three hours, cooled, poured into ice water and made acidic with concentrated HCl until precipitation of product was complete. Recrystallization from ethanol gave 19.4 grams 5-nitro-2-(1-pyrrolidinyl)benzoic acid. m.p. = 224°-266° C dec. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-(1-pyrrolidinyl)benzoic acid. m.p. = 205°-208° C dec.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=2.C(OC1C=C2C(=CC=1)NC(C)=C2/C=[CH:31]/[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33])C>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1/[CH:11]=[CH:31]/[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33])=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=2
Reactant: CCCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: CCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Product: CCCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Yield: 69 %

Procedure:
2-Methyl-5-propoxyindole-3-carboxaldehyde 409b (200 mg, 0.920 mmol) was reacted in a similar manner to that for 402a to yield a bright yellow powder (204 mg, 69%): mp 228-229° C. TLC Rf 0.40 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.88 (s, 1H), 8.81-8.80 (m, 2H), 8.08-8.06 (d, 1H, J=15.3 Hz), 7.93-7.92 (m, 2H), 7.41 (d, 1H, J=2.22 Hz), 7.34-7.31 (d, 1H, J=15.24 Hz), 7.30-7.29 (d, 1H, J=8.64 Hz), 6.85-6.83 (dd, 1H, J1=8.64 Hz, J2=2.28 Hz), 4.04-4.02 (t, 2H, 6.54 Hz), 2.56 (s, 3H), 1.80-1.74 (sex, 2H, J=6.66 Hz), 1.03-1.01 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, d6-DMSO) δ 188.2, 154.6, 150.6, 145.75, 145.18, 139.6, 131.0, 126.6, 121.4, 112.90, 112.25, 111.4, 109.3, 104.4, 69.6, 22.3, 12.2, 10.6. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.00; H, 6.23; N, 8.69.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]=1[O:9][CH3:10].[Br:20][C:21]1[CH:22]=[C:23]([C:34](O)=[O:35])[C:24]2[C:25]([CH3:33])=[CH:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28]=2[CH:29]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]([C:34]([NH:1][CH2:2][C:3]2[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:7][C:8]=2[O:9][CH3:10])=[O:35])[C:24]2[C:25]([CH3:33])=[CH:26][N:27]([CH:30]([CH3:31])[CH3:32])[C:28]=2[CH:29]=1
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.40 g, 1.496 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.44 g, 1.486 mmol), and HOAt (0.21 g, 1.543 mmol) in DMF (25 mL) was added EDC free base (0.25 g, 1.610 mmol). The reaction was stirred at RT overnight then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 30% EtOAc in hexanes) to give the product tert-butyl (5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.81 g, 1.485 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.42 (s, 1H), 8.41 (t, J=4.8 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 6.99 (d, J=1.8 Hz, 1H), 4.40 (d, J=5.1 Hz, 2H), 3.81 (s, 3H), 2.35 (s, 3H), 2.10 (d, J=1.0 Hz, 3H), 1.47 (s, 9H), 1.38 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 545.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: Cc1ccc(C=O)c(C)c1
Product: Cc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C)c1

Procedure:
Using 2,4-dimethylbenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 135. 1H NMR(CDCl3) δ: 9.55 (broad s, 1H), 9.35 (broad s, 1H), 7.18 (d, 1H, J=7.7 Hz), 7.01-6.95 (m, 2H), 6.64 (s, 1H), 6.51 (s, 1H), 4.57 (ABq, 2H), 4.25-4.20 (m, 1H), 4.20 (s, 2H), 3.67 (app t, 1H), 3.50-3.10 (m, 6H), 2.70-2.50 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.23-2.10 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:16])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])([O-:3])=[O:2]
Reactant: OCCCCCCCCBr
Reactant: O=[N+]([O-])c1cc(O)ccc1-c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCCCCCCCO)ccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
3-Nitro-4-phenylphenol (860 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by addition of 8-bromo-1-octanol (1.86 g, 6.0 mmol). After stirring at 50° C. for 5 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 8-(3-nitro-4-phenylphenoxy)octan-1-ol (1.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19](Cl)[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,6-dichloro-4-trifluoromethyl-pyridine. The title compound was obtained as a yellowish solid (Yield=30%). MS ISP (m/e): 383.1 (39) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.67 (d, 1H), 7.39 (d, 1H), 7.23 (d, 1H), 7.11 (s, 1H), 6.99 (s, 1H), 6.965-6.85 (m, 3H), 3.87 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([CH:14]=1)[OH:13]>O1CCOCC1>[CH:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([OH:13])[CH:14]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: Nc1cc(O)cc(O)c1
Reactant: CC(C)N=C=O
Solvent: C1COCCO1
Product: CC(C)NC(=O)Nc1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
52 ml (0.53 mole) of isopropyl isocyanate are added dropwise over a period of 20 minutes to a solution of 62.5 g (0.5 mole) of 5-aminoresorcinol in 1000 ml of dioxan, the internal temperature rising to 35° C. The whole is subsequently stirred for 5 hours at room temperature and then 1000 ml of petroleum ether are added whereupon the title compound is precipitated in the form of fine crystals.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][CH2:8][CH2:9]O.OS(O)(=O)=O.O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:9][CH2:8][Cl:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: OCCCl
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)C(=O)OCCCl
Temperature: 25 °C
Yield: 60 %

Procedure:
Lactic acid (74 mL of an 85% aqueous solution, 0.84 mol) and freshly distilled 2-chloroethanol (670 mL, 10.0 mol) were refluxed with 400 mL of toluene and 0.4 mL of conc. H2SO4 until one equivalent of H2O was collected in a Dean-Stark trap. The reaction mixture was cooled to room temperature, diluted with ethyl ether, and washed with a NaHCO3 /NaCl solution. The organic phase was dried with MgSO4, solvent was removed under reduced pressure, and the residue was distilled at 10 mm Hg. A fraction recovered at 95°-100° C./10 mm Hg was redistilled to give 2-chloroethyl lactate as a clear colorless liquid (76.7 g, 60%): b.p. 95° C./10 mm Hg; 1H NMR δ1.46 (d, 3H, J=6.9 Hz), δ2.95 (bs, 1H), δ3.72 (t, 2H, J=5.6 Hz), δ4.35 (q, 1H, J=6.9 Hz), δ4.44 (m, 2H); 13C NMR 20.4, 41.2, 64.8, 66.8, 175.2 ppm; HRMS calcd for C4H5ClO3Tms (M-CH3) 209.0401, obsd 209.0392.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[Cl:38]>CN(C=O)C>[Cl:38][C:32]1[C:33]([Cl:37])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:4]1[C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:6]=2[N:7]=[C:3]1[CH:2]([F:1])[F:22]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A mixture of of methyl 2-(difluoromethyl)-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 68 (1000 mg, 3.2 mmol), K2CO3 (884 mg, 6.4 mmol) and 1-(bromomethyl)-2,3-dichlorobenzene (926 mg, 3.8 mmol) in DMF (30 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into water (100 mL) and filtered, the filter cake was collected and purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (1.4 g, 93%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 3.16 (s, 4H), 3.74 (s, 4H), 3.92 (s, 3H), 5.77 (s, 2H), 6.21 (d, 1H, J=7.5 Hz), 7.20-7.58 (m, 5H); LC-MS: m/e=470 [M+1]+
Reaction SMILES: [CH:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[O:21][CH2:20][CH2:19][O:18]3)[C:12]2=[O:32])[C@H:7]([CH2:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:6]1)([CH3:3])[CH3:2].C=O.[C:45]([BH3-])#N.[Na+]>CO.CCOC(C)=O>[CH:1]([N:4]([CH3:45])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=4)[O:21][CH2:20][CH2:19][O:18]3)[C:12]2=[O:32])[C@H:7]([CH2:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)N[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Compound 39i-b (103 mg, 168 μmol) and 37% formaldehyde (50 μL, 1.8 mmol) were dissolved in MeOH (2 mL) and stirred for 3 h at room temperature. Sodium cyanoborohydride (16 mg, 252 μmol) was added and the mixture was stirred for 2 h. The reaction was diluted with EtOAc (400 mL), washed with saturated NaHCO3 (3×150 mL) and brine (100 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by CombiFlash chromatography (silica, 0–10% CH2Cl2/MeOH) and then lyophilized from CH3CN/H2O to give title compound (77 mg, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.90–7.82 (m, 2H), 7.71 (s, 1H), 7.68–7.42 (m, 6H), 4.15–3.92 (m, 3H), 3.80–3.00 (m, 7H), 2.71–2.10 (m, 9H), 1.93–1.40 (m, 9H), 1.17–0.95 (m, 6H); 19F NMR (282 MHz, CDCl3) δ −62.9; ESI MS m/z 623 [C32H41F3N2O5S+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:11][OH:12]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:12][CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCCC1
Reactant: CO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCCCN1C(C)=O
Yield: 90.3 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 23.2 g of N-acetylhexahydroazepine and 57.7 g of methanol in the presence of 0.26 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of N-acetylhexahydroazepine the current is switched off. The calculated mean cell voltage is 40.8 volts. Work-up of the electrolysis solution gives 25.4 g of 1-acetyl-2-methoxyhexahydroazepine (boiling point 53° C./0.06 mbar; nD25 =1.4775), which corresponds to a product yield of 90.1% and a current efficiency of 71.5%.
Reaction SMILES: [CH:1]1([C:4]([CH:26]2[CH2:28][CH2:27]2)([C:6]2[S:7][C:8]([C:11]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)=[CH:9][N:10]=2)[OH:5])[CH2:3][CH2:2]1.C(O)(=O)C>C(OCC)(=O)C.[Pd]>[NH2:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)([CH:26]3[CH2:28][CH2:27]3)[OH:5])=[N:10][CH:9]=2)[CH:12]=[C:13]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(-c2cnc(C(O)(C3CC3)C3CC3)s2)cc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cnc(C(O)(C3CC3)C3CC3)s2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of the product of Step 4 (239 mg, 0.595 mmol) in ethyl acetate (5.4 mL)/acetic acid (0.54 mL) was added Pd/C (10 wt %, 60 mg, 0.056 mmol) and the reaction flask was purged with N2 and then H2. The reaction was stirred for 4 hr at room temperature under H2 (balloon; 25 mg of Pd/C were added after 2 h to complete the reaction) and then filtered through a microfilter (Glass Acrodisc 25 mm) and was washed with dichloromethane. The filtrate was concentrated, stripped with toluene (3×) and then dried under vacuum overnight to provide 221 mg (0.595 mmol, quant. yield) of {5-[3-amino-5-(morpholin-4-yl)phenyl]-1,3-thiazol-2-yl}(dicyclopropyl)methanol as a fluffy solid of sufficient purity to be used directly. MS APCI: [M+H]+ m/z 372.1.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)=[CH:16][CH:15]=3)=[CH2:13])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Agent: Cl
Product: C=C(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Yield: 50 %

Procedure:
In the same manner as in 1-2 of Example 1 except for using the thus obtained 1,1-bis(4-pyrrolidinylphenyl)ethane instead of 1,1-bis(4-dimethylaminophenyl)ethane and using hydrochloric acid instead of nitric acid in 1-2 of Example 1, 1,1-bis(4-pyrrolidinylphenyl)ethylene (m.p. 211° C.) was obtained in a yield of about 50%.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[S:18])SC)([OH:3])=[O:2].[N-:19]=[N+:20]=[N-:21].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]([SH:18])=[N:21][N:20]=[N:19]1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCCCCCCCCC(=O)O
Agent: [Na+]
Product: O=C(O)CCCCCCCCCCn1nnnc1S

Procedure:
Methyl 10-carboxydecyldithiocarbamate (28 g., 0.096 mol.) was reacted with 6.5 g. (0.1 mol.) of sodium azide according to the procedure described in Example 7. Acidification upon work-up gave 1-(10-carboxydecyl)tetrazole-5-thiol as a white precipitate, m.p. 95°-98°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[S:40](Cl)(=[O:42])=[O:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:40]([C:36]3[S:35][CH:39]=[CH:38][CH:37]=3)(=[O:42])=[O:41])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 103 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with thiophene-2-sulfonylchloride to give 95 mg 4-tert.-butyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=5.60 min, [M+1]+=633.60, [M−1]−=631.70.