Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>CS(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][N:16]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.12 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.78 g, 4.12 mmol). The product was isolated as an orange granular solid. Yield 0.61 g (34%). mp 225°-230° C. FDMS m/e=432 (M+ of free base). α[D]589 =+1.98 (c=1.01 , dimethylsulfoxide).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22]C([Mg]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH:7]2[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CN(C)C(c1ccc(Cl)cc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (22.43 g, 100 mmol) in abs. ether (100 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of 4-chlorophenylmagnesium bromide in ether (200 ml, 200 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:11]=[C:10]([F:12])[C:7]([CH2:8][OH:9])=[C:6]([F:13])[CH:5]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[C:6]([F:13])=[CH:5][C:4]([Br:3])=[CH:11][C:10]=1[F:12])(=[O:23])=[O:22]
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,6-difluorobenzyl alcohol (1.00 g, 4.48 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (0.81 mL, 5.79 mmol) followed by DMAP (55 mg, 0.45 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,6-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,6-difluorobenzene as a yellow oil. LC-MS-conditions 01: tR=1.00 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH2:37][C:38]5[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][CH:39]=5)=[O:36])=[CH:31][CH:30]=4)=[O:27])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:47]1([CH:50]=O)[CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:50][CH:47]4[CH2:49][CH2:48]4)[CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH2:37][C:38]5[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][CH:39]=5)=[O:36])=[CH:33][CH:34]=4)=[O:27])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (−)-8-(4-(2-butoxyethoxy)phenyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (120 mg) in 1,2-dichloroethane (10 ml), cyclopropanecarboxaldehyde (65.6 mg) and sodium triacetoxyborohydride (119 mg) were added. The mixture was stirred at room temperature for overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, and dried over MgSO4. The volatile materials were removed in vacuo and the residue was purified by column chromatography (basic silicagel, ethyl acetate) to give (−)-8-(4-(2-butoxyethoxy)phenyl)-1-(cyclopropylmethyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (55 mg) (compound 57) as a yellow amorphous.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:22][O:23][C:24]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[C:25]=1[NH2:26]>S(Cl)(Cl)=O.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([NH:26][C:25]2[C:27]([O:33][CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:24]=2[O:23][CH3:22])=[O:14])=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)Nc1c(OC)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1.54 g (5 mmole) of the title compound of Example 3 in 20 ml of thionyl chloride was refluxed for 3 hours and then concentrated to dryness in vacuo. 523 mg (1.6 mmole) of the resulting acid chloride was dissolved in 20 ml methylene chloride and to the solution was added 292 mg (1.6. mmole) 2,4,6-trimethoxyaniline and 195 mg (1.6 mmole) 4-dimethylaminopyridine. The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was partitioned between 60 ml ethyl acetate and 20 ml 1N aqueous hydrochloric acid solution. The ethyl acetate layer was washed with 50 ml water and 50 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 100 g silica gel, eluting with 1:1 hexane/ethyl acetate to yield 370 mg (49% yield) of the title compound as a whitish solid.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([CH2:75][C:76]2[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=2)[CH:79]=O)[CH2:71][CH2:70]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:78]3[CH:81]=[CH:82][CH:83]=[C:76]([CH2:75][N:72]4[CH2:73][CH2:74][N:69]([CH3:68])[CH2:70][CH2:71]4)[CH:77]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN1CCN(Cc2cccc(C=O)c2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4cccc(CN5CCN(C)CC5)c4)nc23)CC1
Reaction time: 6 h
Yield: 27.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.12 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.37 mmol, 0.37 mL) and 3-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.14 mmol, 29 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (19 mg, 27%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.37 (d, J=6.7 Hz, 3H, CHCH3), 2.17 (s, br, 4H, piperazine N(CH2)2), 2.37-2.48 (m, br, 4H, piperazine N(CH2)2), 2.55-2.58 (m, br, 4H, piperazine N(CH2)2), 2.64-2.67 (m, br, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2Ar), 3.60 (q, J=6.5 Hz, 1H, CHCH3), 3.68 (s, br, 4H, piperazine N(CH2)2), 7.41 (d, J=5.9 Hz, 2H, pyridine H-3 & H-5), 7.43 (d, J=7.7 Hz, 1H, phenyl H-6), 7.50 (t, J=7.7 Hz, 1H, phenyl H-5), 8.06 (d, J=7.7 Hz, 1H, phenyl H-4), 8.14 (s, br, 1H, phenyl H-2), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.56 (d, J=5.9 Hz, 1H, pyridine H-2 & H-6), 13.52 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][N:2]1[CH2:13][C:5]2[CH:6]=[CH:7][C:8]3[C:12]([C:4]=2[CH2:3]1)=[N:11][CH2:10][N:9]=3.C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23](I)[CH:24]=[CH:25][CH:26]=1>CN1CCCC1=O.[Cu]>[Br:20][C:21]1[CH:26]=[C:25]([N:9]2[C:8]3[CH:7]=[CH:6][C:5]4[CH2:13][N:2]([CH3:1])[CH2:3][C:4]=4[C:12]=3[NH:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CN1Cc2ccc3c(c2C1)=NCN=3
Reactant: Brc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1Cc2ccc3c(c2C1)NCN3c1cccc(Br)c1

Procedure:
A mixture of 6,8-dihydro-7-methyl-2H-pyrrolo[3,4-e]benzimidazole (0.25 g), K2CO3 (0.26 g), 3-bromo-1-iodobenzene (0.8 g) and Copper powder (15-20 mg) was heated in N-methyl-2-pyrrolidone (5 ml) at 180° C. for 3 hours. The mixture was then partitioned between EtOAc and water. The organic phase was dried over Na2SO4 and evaporated. The oily residue was purified on SiO2 with EtOAc as the eluent. 1H--NMR (500MHz,CDCl3) ppm: 2.8(s,3H), 4.2(s,2H), 4.45(s,2H), 7.2-7.7(m,6H aromatic) 8.1 (s, 1H imidazole).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][CH:33]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3c2)cn1

Procedure:
The title compound was prepared in the same manner as described for example 76 from 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (300 mg, 0.696 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (183 mg, 0.835 mmol). The title compound was collected as 75 mg (24%); 1H NMR (DMSO-d6, 400 MHz): 1.45 (d, J=6.4 Hz, 3H), 2.11 (s, 3H), 2.24 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 4.36-4.38 (m, 2H), 5.03-5.09 (m, 1H), 5.87 (s, 1H), 7.36 (s, 1H), 7.38 (s, 1H), 8.01 (s, 1H), 8.11 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 8.89 (s, 1H), 11.48 (s, 1H); LCMS (ES+) m/z: 444.21.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[O:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][C:76]2[CH:83]=[CH:82][C:79]([CH:80]=O)=[CH:78][CH:77]=2)[CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:80]([C:79]3[CH:78]=[CH:77][C:76]([O:75][CH2:74][CH2:73][N:70]4[CH2:69][CH2:68][O:67][CH2:72][CH2:71]4)=[CH:83][CH:82]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 18.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(2-morpholinoethoxy)benzaldehyde (1.2 eq, 0.091 mmol, 22 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (8 mg, 19%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (t, J=4.0 Hz, 4H, piperazine N(CH2)2), 2.72 (t, J=5.7 Hz, 2H, PhOCH2CH2), 3.30 (hidden by DMSO water peak, 4H, morpholine N(CH2)2), 3.59 (t, J=4.6 Hz, 4H, morpholine O(CH2)2), 3.61 (s, 2H, NCH2), 3.65 (s, br, 4H, piperazine N(CH2)2), 4.17 (q, J=5.8 Hz, PhOCH2CH2), 7.10 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (ddd, J=7.6, 4.8, 0.4 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.8 Hz, pyridine H-4), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.7 Hz, 1H, pyridine H-2), 13.39 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Mg].CO[CH:4]([O:12]C)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.O>C1COCC1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ni](Cl)Cl>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: Brc1nccs1
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60° C. A solution of 82.6 g (357 mmol) of 4-bromo-benzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is then added dropwise thereto in the course of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise in the course of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromo-thiazole and 5.39 g (9.95 mmol) of 1,3-bis(diphenylphosphino)propane-nickel(II) chloride (Aldrich; Milwaukee/USA) in 1.68 liters of THF. The reaction mixture is stirred at RT for 12 hours; a further 5.39 g of 1,3bis(diphenylphosphino)-propane-nickel(II) chloride are added and stirring is continued for a further 7 hours. 840 ml of water are added, stirring is carried out for 10 min, the THF is evaporated off in a rotary evaporator and the residue is stirred in 1.0 liter of diethyl ether and 340 ml of 2N HCl for 1.5 hours. The aqueous phase is separated off and extracted twice with ethyl acetate. The organic phases are washed twice with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Chromatography (SiO2; hexane/ethyl acetate=4:1) and digestion in hexane yield 4-(thiazol-2-yl)-benzaldehyde; TLC: Rf=0.21 (hexane/ethyl acetate=3:1); m.p. 91-92° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=O)[CH2:12][CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO>[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:17][NH:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1nc[nH]n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc[nH]n2)cc1OC1CCCC1
Yield: 22.7 %

Procedure:
To a stirred solution of 3-amino-1,2,4-triazole (1.5 g, 0.018 mol), 7.5 ml of 1N HCl, and 50 ml of methanol was added 3-cyclopentyloxy-4-methoxybenzaldehyde (3.3 g, 0.015 mol) and sodium cyanoborohydride (0.945 g, 0.015 mol). A precipitate formed slowly and after 20 hours the precipitate was filtered and recrystallized from methanol (135 ml) to give 1.0 g (0.0034 mol, 23%) of the title compound, mp 203-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][S:7]O)=[CH:4][CH:3]=1.O1CCCC1.[CH2:16]([O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20])[CH3:17]>C(N(CC)CC)C>[C:19]([NH:21][C:22](=[S:23])[S:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)([O:18][CH2:16][CH3:17])=[O:20]
Reactant: CCOC(=O)N=C=S
Reactant: OSCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)SCc1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
A mixture of 158.6 g of p-chlorobenzylthio alcohol, 800 ml of tetrahydrofuran, 5 ml of triethylamine and 131.6 g of ethoxycarbonyl isothiocyanate was refluxed for 21/2 hours and was then concentrated to dryness. The residue was washed with petroleum ether to obtain 233 g of p-chlorobenzyl N-carbethoxy-dithiocarbamate melting at 80° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(F)cc2)CC1
Yield: 50.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-fluorophenyl)-1-hexanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 1.0 g of 4-amino-5-chloro-N-((1-(6-(4-fluorophenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][C:7]=1[Cl:8].[CH:14](O)=[O:15]>C(OC(=O)C)(=O)C>[Cl:8][C:7]1[C:2]([NH:1][CH:14]=[O:15])=[C:3]([Cl:13])[N:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[N:6]=1
Reactant: CC(=O)Nc1nc(Cl)c(N)c(Cl)n1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
N-(5-Amino-4,6-dichloropyrimidin-2-yl)acetamide (J. Org. Chem. 1975, 40, 3141) was formylated by addition of 96% formic acid (20 mL) to a solution of (0.75 g, 3.4 mmoles) dissolved in acetic anhydride (20 mL). The resulting solution was stirred at 25° C. for one hour and then evaporated to give N-(4,6-dichloro-5-formamido-2-pyrimidinyl)acetamide as tan powder (0.77 g, 91%); structure confirmed by 1H-NMR and mass spectrum. This tan powder (840 mg, 3.37 mmol), (±)-cis-4-amino-2-cyclopentene-1-methanol (940 mg, 8.2 mmol), and triethylamine (0.80 g, 8.0 mmol) were warmed in ethanol (50 mL) in an oil bath (70°-80° C.) under nitrogen for 50 minutes and evaporated to a dark oil which was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as a peach-colored solid foam (840 mg). Crystallization from methanol gave white granules (575 mg, 52%); m.p. 189°-193°; 1H-NMR (DMSO-d6) δ 10.23 (br, 1.0, NHAc), 9.3 (br, 1.0, NHCHO), 8.15 and 7.90 (both s, total 1.0, HC=O from two conformers, peaks coalesce at 60° C.), 7.42 and 7.22 (both d, J=8.3, total 1.0, CH--NH from two conformers, peaks coalesce at 60° C.), 5.9 and 5.7 (both m, 2.0, CH=CH), 5.05 (m, 1, CH--N), 4.73 (m, 1, OH) 3.39 (m, 2, CH2OH), 2.72 (m, 1, CH), 2.40 (m, 1, 1/2 CH2), 1.36 (m, 1, 1/2 CH2).
Reaction SMILES: [CH2:1]([N:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16][CH2:15]2)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:34]>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33]([N:18]2[C:19]3[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:22])=[CH:21][CH:20]=3)[CH2:15][CH2:16][CH2:17]2)=[O:34])=[CH:37][CH:38]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To 60.4 mg (0.2 mmol) Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine in 2 ml CH2Cl2 1 drop of Huenig's base and 57 mg (0.3 mmol) 4-chlorophenyl chloroformate in 1 ml CH2Cl2 were added. The solution was stirred at RT for 30 min, was concentrated and the residue was dissolved in ether and a saturated aqueous solution of NaHCO3. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1 yielded 46 mg (50%) 6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 457 (MH+, 1Cl).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].I[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[C:16]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was synthesized in analogy to example 116, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone and 4-iodobenzotrifluoride.