Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:16]([OH:19])[C:17]#[CH:18]>C(Cl)Cl>[OH:19][CH2:16][C:17]#[C:18][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C#CCO
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC)c(C#CCO)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
500 mg of dimethyl 5-bromodicarboxylate (from Example 3) and 121 mg of propargyl alcohol are dissolved in methylene chloride in a flask flushed with argon, and 840 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 25 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 30 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation and chromatography on silica gel, 260 mg of a white solid remain.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Br[C:26]1[CH:31]=[N:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2cnc(C3CC3)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-bromo-5-cyclopropyl-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.46 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([NH2:10])[C:8]#[CH:9].CN(C1C=CC=CN=1)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[C:3]([NH:10][CH2:7][C:8]#[CH:9])=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C#CCN
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C#CCNC(=O)N(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dimethyl carbamylchloride (0.84 mL, 9.1 mmol) was added to a stirred solution of propargylamine (0.62 mL, 9.1 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (5 mL) at room temperature. The resulting suspension was stirred at ambient temperature for approximately 15 h. The reaction mixture was diluted with ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (i-5), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[Cl:38][C:39]1[S:43][C:42]([S:44](Cl)(=[O:46])=[O:45])=[CH:41][CH:40]=1.O>ClCCl>[Cl:38][C:39]1[S:43][C:42]([S:44]([O:30][C:27]2[CH:26]=[CH:25][C:24]([N:10]3[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:15])[N:13]=[C:9]3[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:29][CH:28]=2)(=[O:46])=[O:45])=[CH:41][CH:40]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)c2ccc(Cl)s2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.16 ml, 1.12 mmol) in dichloromethane (2.5 ml) were cooled to −78° C. 5-Chlorothiophen-2-sulfonyl chloride (244 mg, 1.12 mmol) in dichloromethane (2.5 ml) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (84 mg, 60%) as a solid.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[NH:20][CH:19]=1)=O)=O)C1C=CC=CC=1.C(Cl)Cl.CO.[OH-].[NH4+]>>[CH2:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH3:9])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(c1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12

Procedure:
(R)-3 -(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-dibenzylamino-1H-indole was used. Column chromatography using solution with methylene chloride/methanol/ammonium hydroxide [9:1:0.1] afforded the title compound as a pale green foam: 1H NMR (CDCl3) δ7.82 (br s, NH), 7.35-7.19 (m, 10H), 7.20 (d, J=8.6 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.85 (dd, J=2.3 and 8.7 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 4.65 (s, 4H), 3.25-3.02 (m, 2H), 2.52 (dd, J=9.5 and 13.9 Hz, 1H), 2.39-2.15 (m, 2H), 2.30 (s, 3H), 1.85-1.40 (m, 4H); 13C NMR (CDCl3) δ143.2, 139.7, 130.5, 128.5, 128.2, 127.3, 126.8, 122.9, 112.5, 112.2, 111.8, 103.4, 67.0, 57.4, 56.4, 40.6, 31.4, 29.7, 21.9. HRMS: calculated for C28H31N3 409.2520. Found 409.2475.
Reaction SMILES: C(S([NH:7][CH:8]([C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][OH:13])[CH3:9])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH:8]([C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][OH:13])[CH3:9]
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(Cl)cc1CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)c1ccc(Cl)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(1-tert-butylsulfinamidylethyl)-5-chlorobenzyl alcohol from the previous step (isomer 1, 0.410 g, 1.42 mmol) in MeOH (5 mL) at ambient temperature was added 4M HCl in dioxane (0.71 mL, 2.8 mmol). The resulting solution was stirred at ambient temperature for 0.5 h, then concentrated in vacuo. The residue was partitioned between EtOAc and water basicified to pH=8 with saturated NaHCO3 solution. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure. 2-(1-aminoethyl)-5-chlorobenzyl alcohol was obtained as a pink oil that crystallized on sitting (0.2 g; HPLC RT=2.06 min, method A; 1H NMR, 400 MHz, CDCl3, 7.3 ppm (s, 1H), 7.28 ppm (d, 1H), 7.22 ppm (d, 1H), 4.73 ppm (d, 1H), 4.45 ppm (d, 1H), 4.3 ppm (m, 1H), 1.52 ppm (d, 3H).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Linoleoyl chloride (25.0 g, 83.6 mmol) was added, dropwise, to a cooled (0° C.) solution of Meldrum's acid (1) (13.3 g, 92.0 mol) and pyridine (14.8 mL, 184 mmol) in CH2Cl2 (180 mL) and the solution was allowed to warm (rt, 16 h). The reaction mixture was washed with an equal volume of HCl (5%, aq., 2×), dried (Na2SO4), filtered and concentrated. The residue was dissolved in dry methanol (200 mL) and heated at reflux (6 h). The solution was cooled (rt), concentrated and the crude oil was purified by flash chromatography (4% EtOAc-hexanes) to yield (11Z,14Z)-methyl 3-oxoicosa-11,14-dienoate (2) (24.5 g, 87%) as a pale yellow oil. Rf 0.38 (10% EtOAc-hexanes). FW 336.51, C21H36O3.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1)OCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)N(Cc2ccccc2)c2ccc(Cl)cc2)cc1)OCC

Procedure:
To a solution of 0.50 g of 4-diethoxyphosphinylmethyl-N-(4-chlorophenyl)benzamide in 10 ml of dry THF was added in portions 0.07 g of sodium hydride (60%, in oil) under ice-cooling with stirring. After stirring for 30 minutes under ice cooling, a solution of 0.23 g of benzyl bromide in 2 ml of dry THF was added. After stirring for 5 hours at room temperature, 30 ml of water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1) to give 4-diethoxyphosphinylmethyl-N-benzyl-N-(4-chlorophenyl)benzamide. It was recrystallized from benzene-n-hexane to give 0.40 g of colorless columnar crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1>>[Cl:19][C:20]1[N:21]=[C:22]([NH2:27])[N:23]=[C:24]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:25]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1

Procedure:
Analogously to example 8, the title compound is synthesized from 266 mg (1.09 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) and 179 mg (1.09 mmol) of 4,6-dichloro-2-pyrimidineamine.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=O)=[C:4]([NH:11][C:12](=[O:17])[C:13](F)(F)F)[C:3]=1[CH3:18].[CH3:19]CN(C(C)C)C(C)C.NC1C(C)=C(Br)SC=1C(OC)=O.[C:40]([O:46][C:47]([C:49](F)(F)F)=O)(C(F)(F)F)=[O:41]>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]2[C:7]([OH:9])=[C:13]([C:40]([O:46][CH2:47][CH3:49])=[O:41])[C:12](=[O:17])[N:11]([CH3:19])[C:4]=2[C:3]=1[CH3:18]
Reactant: COC(=O)c1sc(Br)c(C)c1NC(=O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: COC(=O)c1sc(Br)c(C)c1N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2sc(Br)c(C)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 5-bromo-4-methyl-3-(2,2,2-trifluoroacetamido)thiophene-2-carboxylate. At 0° C., DIEA (4.32 mL, 24.8 mmol) was added dropwise to a solution of methyl 3-amino-5-bromo-4-methylthiophene-2-carboxylate (6.20 g, 24.8 mmol) in DCM (100 mL), followed by dropwise addition of TFAA (3.45 mL, 24.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with CHCl3, washed with water, dried over MgSO4, and evaporated. The crude product was purified by flash chromatography using EtOAc/hexanes to give the title compound. MS (ESI) m/z: Calculated; 346.1: Observed; 345.9. 1H NMR (300 MHz, CDCl3) δ ppm 9.62 (1H, br. s.), 3.89 (3H, s), 2.15 (3H, m).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[CH2:18]([N:20]([CH2:23]C)[CH2:21][CH3:22])C.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30]C=CC=1>C1C=CC=CC=1>[CH3:23][N:20]([CH3:18])[C@H:21]1[CH2:22][CH2:30][CH2:31][C@H:26]1[C:25]([OH:32])=[O:8]
Reactant: OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CN(C)[C@H]1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of diphenyl phosphoryl azide (44.3 g., 0.16 mole) in 50 ml. benzene was added in 15 minutes to a solution of the part B amino acid (25.3 g., 0.16 mole) in 750 ml. benzene. After 15 minutes, triethyl amine (16.2 g., 0.16 mole) was added over 5 minutes. The solution was stirred for 30 minutes, then refluxed for 30 minutes. Benzyl alcohol (51.8 g., 0.48 mole) was added and the mixture refluxed overnight. The solution was extracted with 10% HCl. The aqueous layer was washed with ether, made basic with 40% NaOH, and extracted with ether. The ether layer was washed with water and saturated salt solution, dried (MgSO4), and evaporated to a brown oil (7.9 g.). The nmr (CDCl3) of the crude product was reasonable for a benzyl carbamate. The benzyl N-[2-(dimethylamino)cyclopentyl]carbamate material was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([N:32]2[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]2)=[O:27])=[CH:4][N:3]=1
Reactant: O=C1CNCCN1
Reactant: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ncc(/C=C/C(=O)N2CCNC(=O)C2)c2scc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of Example 11B (0.09 g, 0.23 mmol), 2-piperazinone (0.069 g, 0.69 mmol), HOBT (0.095 g, 0.7 mmol), N-methylmorpholine (0.22 mL, 0.92 mmol), and EDCI (0.136 g, 0.71 mmol) in DMF (1 mL) was stirred at room temperature overnight, treated with water (20 mL), and filtered. The filter cake was dried to provide 110 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 3.20-3.36 (br m, 2H), 3.71-3.91 (br m, 2H), 4.03-4.35 (m, 2H), 5.94 (br s, 2H), 6.92-7.15 (br m, 1H), 7.11-7.16 (m, 4H), 7.21 (t, J=7.3 Hz, 1H), 7.42-7.52 (m, 4H), 7.63 (s, 1H), 7.71 (d, J=14.9 Hz, 1H), 8.13 (br s, 1H), 8.33 (s, 1H); MS (ESI(−)) m/e 469.3 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CN(C)CCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN(C)C)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N,N-dimethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.05-8.01 (m, 3 H), 7.88-7.86 (d, J=8.8 Hz, 1 H), 7.70-7.68 (d, J=1.2 Hz, 1 H), 7.56-7.52 (m, 2 H), 6.05 (s, 1 H), 5.41 (s, 2 H), 4.56 (s, 2 H), 3.96-3.93 (dd, J=6.0, 6.4 Hz, 2 H), 3.75-3.73 (q, J=4.4 Hz, 2 H), 3.43-3.40 (q, J=6.0 Hz, 2 H), 3.01 (s, 3 H), 2.45 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1N.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1)(=[O:15])[CH3:14].[N:26]1C=CC=CC=1>>[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:8][C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=3[N:26]=2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: c1ccncc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(C(=O)O)c1N
Product: COc1ccc2nc(-c3ccc(OC(C)=O)cc3)oc(=O)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
16.7 gm (0.1 mol) of 3-methoxy-anthranilic acid were dissolved in 100 ml of pyridine, and the solution was mixed, while cooling and stirring, with 23.8 gm (0.1 mol+20%) of 4-acetoxy-benzoyl chloride. After 2 hours the reaction was finished, and the reaction mixture was poured into ice water. The precipitate thus obtained was suction-filtered off, dried and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[NH2:5].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[O:30][C:31]([CH3:34])=[N:32][N:33]=3)[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[O:30][C:31]([CH3:34])=[N:32][N:33]=4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: Nc1ccc(OCc2ccccc2F)c(Cl)c1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5F)c(Cl)c4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 3-chloro4-(2-fluoro-benzyloxy)aniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.64(1H,bs), 9.40(1H,s), 8.97(1H,s), 8.58(1H,d), 8.11(1H,d), 7.94(1H,d), 7.71(1H,dd), 7.63(1H,dd), 7.45(2H,m), 7.30(2H,m), 5.31 (2H,s), 2.68(3H,s); m/z (M+1+) 462.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH2:31][CH2:32]O)=[CH:23]1.[Br-]>C1CCCCC1.C(#N)C.O>[Br:1][CH2:32][CH2:31][C:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:22][CH:23]=1
Reactant: OCCc1coc2ccccc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CC#N
Solvent: O
Product: BrCCc1coc2ccccc12
Reaction time: 12 h

Procedure:
Triphenylphosphane dibromide (5.52 g, 14.41 mmol) was suspended in abs. acetonitrile (15 ml) under argon, the suspension was brought to 19° C. in a water batch and 2-(benzofuran-3-yl)ethanol (2.11 g, 13.1 mmol), dissolved in abs. acetonitrile (7 ml) was added in the course of 15 min. During the addition the temperature of the reaction mixture was kept between 19 and 21° C. The mixture was then left to stand for 12 h without further cooling. The triphenylphosphane which had precipitated out during this period of time was removed from the reaction mixture by filtration. The filtrate obtained was concentrated. For complete removal of the phosphane, the residue obtained was taken up in cyclohexane (20 ml) and the mixture was filtered over a layer of silica gel (15 g) about 3 cm thick. The silica gel was washed with cyclohexane (5×20 ml). The solution obtained in t his way, which contains the desired bromide in a pure form, was concentrated on a rotary evaporator. This was isolated in a yield of 2.47 g (87%) as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:22][CH2:21]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:29])[CH2:24][CH2:25]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6]
Reactant: O=C(O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: CN1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(-c4ccccc4)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 0.035 g (0.078 mmol) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.044 g (0.39 mmol) of 1-methyl homopiperazine, 0.032 g (0.10 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.032 mL (0.23 mmol) of triethylamine in N,N-dimethylformamide (2 mL) are stirred overnight at room temperature. The mixture is concentrated under reduced pressure and the residue is diluted with water which causes a solid to precipitate from solution. The colorless solid is collected by filtration, washed with water and dried to provide 0.032 g (75%) of 3-chloro-N-(2-{4-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]piperidin-1-yl}-5-phenylpyridin-3-yl)benzamide (124) as a colorless solid. [M+H]+=546.3.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C)=O)[CH2:4]1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: COC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1

Procedure:
A mixture of methyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (110 grams) and n-butylamine (370 grams) was heated to reflux and stirred. After completion of the reaction, the reaction mixture was distilled under reduced pressure. Water (500 ml) was added to the obtained residue followed by sodium bicarbonate and washed it with petroleum ether. The reaction mixture was extracted into methylene chloride. The solvent from the reaction mixture was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])[CH2:2][CH3:3].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1>>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)C(O)c1ccc(OCCCBr)cc1
Reactant: CCCc1cc(Oc2cnccn2)ccc1O
Product: CCCc1cc(Oc2cnccn2)ccc1OCCCOc1ccc(C(O)C(=O)OCC)cc1

Procedure:
The title compound was prepared according to the method described in Example 22, Step C using 2-propyl-4-pyrazinyloxyphenol (19.0 g, 62.0 mmol) and ethyl 4-(3-bromopropoxy)mandelate (19.5 g, 58.9 mnol) (as prepared in Example 22, Step C) as the starting materials.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1(Br)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([NH:4][CH2:3][CH2:2][OH:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrC1CCCCCCC1
Reactant: NCCO
Product: OCCNC1CCCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.