Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH:3]=[CH2:4].[Sn](Cl)(Cl)(Cl)[Cl:16]>O>[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:16])[C:7]=1[NH2:12])[CH:3]=[CH2:4]
Reactant: C=CCNc1ccncc1[N+](=O)[O-]
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: C=CCNc1ccnc(Cl)c1N
Temperature: 90 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
35% Hydrochloric acid (55 mL) was added to allyl(3-nitropyridin-4-yl) amine (3.02 g) and this was heated to 90° C. Tin chloride (19.1 g) was added, and this was reacted at 90° C. for 30 minutes. The reaction solution was cooled on iced water, and 250 mL of iced water was added. The reaction solution was concentrated under reduced pressure, and then a saturated solution of ammonia-methanol (250 mL) was added, and this was stirred for 20 hours. Ethyl acetate (750 mL) was then added, and this was filtered through celite, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted by ethyl acetate-hexane (1:1) gave the title compound (2.88 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Product: Fc1cccc(C(F)(F)F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-fluoro-6-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 166.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:24]([O:26][CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:24]([O:26][CH2:27][CH2:28][NH2:29])=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc([N+](=O)[O-])c1

Procedure:
Prepared by a method analogous to that of Example 1(b) from 10.0 g (18.2 mmol) of 1,4-dihydro-2,6-dimethyl-3-(2-methoxyethoxy)carbonyl-4-(3-nitrophenyl)-5-(2-phthalimidoethoxy)carbonyl-pyridine and 2.65 ml (54.6 mmol) of hydrazine hydrate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18](=[S:20])[NH2:19]>>[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: Cc1ccncc1C(N)=S
Product: Cc1ccncc1-c1nc(-c2ccncc2)cs1
Yield: 24 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(pyridin-4-yl)ethanone hydrobromate (460 mg) and 4-methylpyridine-3-thiocarboxamide (248 mg), the title compound (99 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][CH2:18]C)(=[O:16])[CH2:14][SH:15].C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[S:15][C:14]=1[C:13]([O:17][CH3:18])=[O:16]
Reactant: CCOC(=O)CS
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1sc2ccc([N+](=O)[O-])cc2c1N
Yield: 54 %

Procedure:
2-Chloro-5-nitrobenzonitrile (25.0 g, 136.9 mmol), commercially available, was treated with 1 equivalent ethyl thioglycolate and 1 equivalent K2CO3 in ethanol by the procedure described in Example 41A to yield the title compound (19.68 g, 54%). m.p. 208°-210° C. 1H NMR(300MHz, DMSO) δ9.23 (d, 1H), 8.29 (d, 1H), 8.11 (dd, 1H), 7.45 (br s, 2H), 4.29 (q, 2H), 1.31 (t, 3H). MS (DCI/NH3) m/e 284 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([C:14]#[C:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[N:8]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC(CC)CC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C(CC)CC
Temperature: 68 °C
Yield: 94.2 %

Procedure:
To a solution of [2-Chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine (326 mg, 1 mmol) in THF (2 mL) is added a solution of 1M TBAF in THF (5 mL, 5 mmol) at ambient temperature. The reaction mixture is heated at 68° C. for 2 hours. After cooling down, the mixture is concentrated in vacuo. The crude product is purified by column chromatography (SiO2, EtOAc:Heptane=5:95 to 40:60) to give 307 mg of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (289 mg; 60% suspension in paraffin oil) in THF (10 ml) was treated under an argon atmosphere at RT dropwise with a solution of 1,2,3-triazole (500 mg) in THF (10 ml). The mixture was stirred at RT for 1 hour and was then treated at 0° C. dropwise with (2-(chloromethoxy)ethyl)trimethylsilane (1.21 g). Stirring was continued for 2 h. The reaction was quenched with water (10 ml), the layers were separated and the aqueous layer once extracted with AcOEt (15 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo to give the title compound as a crude product that was used without further purification. Colorless liquid (1.5 g). MS (m/e): 198.204 (M-H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:14]=1)=[O:12])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[Cl:46].O>O1CCCC1>[Cl:46][C:37]1[CH:38]=[C:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:40]=[CH:41][C:36]=1[CH2:35][O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([Si:22]([CH:23]([CH3:24])[CH3:25])([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:14]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOc1c(O)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(OCc2ccc(S(C)(=O)=O)cc2Cl)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (665, 40 mg, 0.064 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (3.32 mg, 0.083 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 40 minutes, then 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (21.72 mg, 0.077 mmol) was added to the reaction mixture. It was stirred at room temperature overnight. The mixture was then poured into water and was extracted with ethyl acetate. The organic layer was collected and washed with brine, dried over magnesium sulfate. After removal of the solvent, a crude compound as light yellow oil was obtained (666, 84 mg).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:15]2[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1c(Cl)cccc1Cl
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 288 mg 2-(2,6-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 533 mg colorless viscous oil (95%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: CS(=O)(=O)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(C)(=O)=O
Yield: 74.1 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.17 mmol) was reacted with methanesulfonyl chloride (172 μL, 2.17 mmol) to provide 720 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide as a yellow powder, m.p. 109-110° C. Analysis: Calculated for C22H33N5O3S: % C, 59.04; % H, 7.43; % N, 15.65; Found: % C, 58.78; % H, 7.38; % N, 15.48.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][C:4]=1[Cl:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[S:7][C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[C:4]([Cl:9])[N:5]=1
Reactant: Clc1nc(Cl)c(CBr)s1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2sc(Cl)nc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 5-(bromomethyl)-2,4-dichloro-1,3-thiazole, 6-methyl-2-sulfanylpyrimidin-4-ol (500 mg, 3.5 mmol), and triethylamine (2.5 mL, 18.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (778 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.46 (s, 2H), 6.09 (s (br), 1H); M+ 310.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]2([F:29])[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2([F:29])[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC1(F)CNCCC1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
To a solution of t-butyl 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate (5.2 g, 12.9 mmol) in MeOH (100 mL) was added 4 M HCl/dioxane (32.2 mL, 130 mmol) and the reaction mixture was stirred at rt for 5 h. The mixture was then evaporated under reduced pressure, and the residue was diluted with a saturated sodium bicarbonate solution and extracted with 200 mL of ethyl acetate. The layers were separated and the organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to preparative HPLC (method C) to afford 2.5 grams (63%) of racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine. LCMS (method F) RT 2.044 min, m/z 304 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.31-7.48 (m, 5H) 7.21 (d, J=8.53 Hz, 2H) 6.98 (d, J=9.04 Hz, 2H) 5.10 (s, 2H) 3.05-3.20 (m, 2H) 2.98 (d, J=13.05 Hz, 1H) 2.74-2.87 (m, 1H) 2.60 (t, J=11.55 Hz, 1H) 1.88-2.00 (m, 4H) 1.72 (d, J=13.05 Hz, 1H), 19F NMR (377 MHz, DMSO-d6) δ-102.276, -102.900, -115.135, -115.759.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:29][CH2:30][O:31][C:32]([CH2:34]Br)=[O:33].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:30]([O:31][C:32](=[O:33])[CH2:34][N:16]1[CH2:17][C@@H:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[C@:12]2([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[O:14])[CH2:15]1)[CH3:29]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1C[C@@H](c2ccc(C#N)cc2)[C@]2(C1)C(=O)N(c1cc(Cl)cc(Cl)c1)C(=O)N2C
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of Example 15 (100 mg, 0.24 mmol), ethyl bromo acetate (29 μl, 0.26 mmol) and K2CO3 (36.6 mg, 0.26 mmol) in toluene (2 ml) was heated to 100° C. for 5 h. After cooling to room temperature, the precipitate (unreacted starting material) was removed by filtration. The filtrate was concentrated and purified by chromatography over silica gel (eluent: DCM then acetone) to yield the above-titled compound as an oil (47.2 mg). 1H NMR (CDCl3): 7.63 (2H, d, J=8.3 Hz), 7.25–7.30 (3H, m), 6.68 (2H, d, J=1.5 Hz), 4.23 (2H, q, J=7.1 Hz), 3.89 (1H, dd, J1=11.7 Hz, J2=6.3 Hz), 3.55–3.65 (2H, m), 3.3–3.5 (3H, m), 3.26 (3H, s), 3.05 (1H, d, J=10.8 Hz), 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45]1(Br)[CH2:47][CH2:46]1>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:3]1([O:8][C:9]2[C:17]3[N:16]=[C:15]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:47][CH2:45][CH2:46]1
Reactant: BrC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OC4CCCC4)cccc32)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Cyclopropyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product in 50% yield.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20]COC)[C:5]=1[O:24][CH3:25].Cl>CO>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:24][CH3:25]
Reactant: COCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Agent: Cl
Solvent: CO
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Temperature: 50 °C
Yield: 90.9 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)phenyl) isobenzofuran-1(3H)-one (1 g, 2.73 mmol) in methanol (75 mL) was added concentrated hydrochloride (5 mL) and the reaction mixture was heated to 50° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The obtained residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (800 mg, 91%).
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1)=[O:5].BrBr.C(=O)(O)[O-:27].[Na+]>C(Cl)Cl>[C:18]1([CH:17]2[C:15](=[O:16])[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)=[C:13]([NH2:14])[O:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(C(C#N)C(=O)Cc2ccccc2)c1
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc(C2=C(N)OC(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In this example 0.4 g of water was admixed with 6.5 g of (3-methoxycarbonylphenyl)-benzylcarbonyl-acetonitrile in about 40 ml of methylene chloride at room temperature. 1.1 ml of bromine in about 10 ml of methylene chloride was added dropwise at room temperature. After addition of the bromine, the reaction mixture was mixed with saturated aqueous sodium bicarbonate and stirred for about 1/2 hour at room temperature, resulting in a two-phase liquid mixture. The phases were separated. The aqueous phase was extracted three times with methylene chloride. The combined extracts and methylene chloride phase were washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated by evaporation affording an oily residue. The residue was triturated with a mixture of ethyl ether and petroleum ethers affording 5.0 g of the title compound as a solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[N:15]=[N:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:18][C:7]=2[N:6]=1>C(COC)OC>[C:19]1([C:17]2[N:16]=[N:15][C:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]([N:2]([CH3:3])[CH3:1])=[N:6][C:7]=3[CH:18]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNC
Reactant: Clc1nc2cc(-c3ccccc3)nnc2c2ccccc12
Solvent: COCCOC
Product: CN(C)c1nc2cc(-c3ccccc3)nnc2c2ccccc12
Yield: 53.3 %

Procedure:
Dimethylamine (6 g), 6-chloro-3-phenyl-pyridazino-[4,3-c]isoquinoline (5.83 g, 0.02 mol) and dimetoxyethane (120 ml) are heated at 120° C. for about 8 hours in a bomb. Then the reaction mixture is concentrated to dryness under reduced pressure, the residue is disaggregated with water (200 ml) and the solid recovered by filtration is dried, yielding 5.8 g of a crude product which is crystallized from acetone to give 3.2 g of the product of the title. M.p. 134°-136° C. A further crop of about 1,7 g is obtained by purifying the residue of the concentration of the mothers liquors by means of a silica gel column chromatography which uses chloroform as the eluent. Overall yield 4,9 g (81,5%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[NH:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1.I[CH3:14]>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]2[N:12]([CH3:14])[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Sodium hydride (60%, 670 mg, 16.8 mmol) was added to a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (3.00 g, 15.2 mmol) in DMF (20 mL) at 0° C., and the reaction mixture was stirred for 30 minutes. Iodomethane (1.05 mL, 16.8 mmol) was added. The reaction mixture was subsequently stirred for 30 minutes while warming to RT, diluted with EtOAc, quenched and washed with brine. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were dried over MgSO4, concentrated, and purified by silica gel chromatography (50% EtOAc/DCM) to give the title compound as a white solid (2.98 g, 93%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38 (d, 1H, J=2.0 Hz), 8.21 (d, 1H, J=2.0 Hz), 7.65 (d, 1H, J=3.5 Hz), 6.57 (d, 1H, J=3.5 Hz), 3.81 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C8H7BrN2, 211, 213; found 211, 213.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].O[N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:5][C:2](=[CH2:1])[CH2:3][O:4][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:17]
Reactant: C=C(C)CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: C=C(C)CON1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 2-methyl-2-propen-1-ol (0.856 g) triphenyl phosphine (4.67 g) and N-hydroxyphthalimide (2.90 g) in THF (90 mL), at 0° C., diisopropyl azodicarboxylate (3.51 mL) was added. After stirring for 2 hours, the solvent was evaporated and the crude product was purified by flash chromatography (SiO2, cyclohexane/EtOAc 85/15) to give 2-(2-methylallyloxy)isoindole-1,3-dione (2.13 g, 83%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.80 (4H, bs), 5.02 (2H, d), 4.54 (2H, s), 1.83 (3H, s).