Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1.Cl.[O:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54]Cl)[CH2:49][CH2:48]1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:54][CH2:53][N:50]3[CH2:51][CH2:52][O:47][CH2:48][CH2:49]3)[C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:9][CH:10]=1
Reactant: ClCCN1CCOCC1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Agent: Cl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN3CCOCC3)c3ccccc23)cc1
Yield: 89 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using Compound 1 (2.0 g, 3.19 mmol) obtained in Example 1 and 2-morpholinoethylchloride hydrochloride (600 mg, 3.19 mmol) to give 2.1 g (yield: 89%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[N:29]([CH3:36])[C:30]([CH2:33][O:34][CH3:35])=[N:31][CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[N:29]([CH3:36])[C:30]([CH2:33][O:34][CH3:35])=[N:31][CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COCc1ncc(C(=O)Oc2ccccc2)n1C
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COCc1ncc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)n1C

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester, the title compound was obtained as white crystals 48% yield). MS: m/e=418(M+H+), mp 242-245° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH:14]=[CH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]>C(OCC)(=O)C.[Pd]>[CH2:14]([C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])[CH3:15]
Reactant: C=Cc1c(C(=O)NC)[nH]c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)NC)[nH]c2ccccc12
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A mixture of N-methyl-3-vinyl-1H-indole-2-carboxamide (1.1 g, 5.4 mmol) and 10% Pd/C (55 mg) in ethyl acetate (150 mL) was stirred for 3 h under an atmosphere of hydrogen. The mixture was filtered through celite and evaporated to afford the title compound (970 mg 90%). 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.80 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.17 (t, J=6.8 Hz, 1H), 7.04 (t, J=6.0 Hz, 1H), 3.01 (q, J=7.4 Hz, 2H), 2.81 (d, J=4.6 Hz, 3H), 1.17 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([CH:17]3[CH2:19][CH2:18]3)[C:13]=2[C:14](O)=[O:15])=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10]([CH3:20])=[N:11][N:12]([CH:17]4[CH2:18][CH2:19]4)[C:13]=3[C:14](=[O:15])[N:21]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)cc2)c2c(C)nn(C3CC3)c2C(=O)O)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a stirred solution of 4-((4-chlorophenyl)((4-methoxybenzyl)amino)methyl)-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylic acid (Step 23.7) (2.30 g, 4.59 mmol) in CH2Cl2 (30 mL) under Ar was added 1-chloro-N,N,2-trimethyl-1-propenylamine (0.846 mL, 6.43 mmol) at 0° C. The reaction mixture was stirred for 1 hr at rt, quenched with a saturated aqueous solution of NaHCO3 (75 mL), and extracted with CH2Cl2 (2×100 mL) The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (100 mL), dried (Na2SO4) and evaporated. The crude material was purified by silica gel column chromatography (Hex/EtOAc 5-30%) to afford the title product (1.82 g, 4.24 mmol, 92% yield) as a yellow oil. tR: 5.76 min (HPLC 1); tR: 1.27 min (LC-MS 2); ESI-MS: 408 [M+H]+ (LC-MS 2); Rf=0.66 (hexane/EtOAc 1:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C1(CN)CCCCC1.[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:43])=[CH:45][CH:46]=1
Reactant: NCc1cccs1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1cccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-thiophenemethylamine to replace cyclohexanemethylamine, and 4[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(thiophen-2-ylmethyl)benzamide was obtained (48%) as a colorless solid: mp 167-168° C.; 1H NMR (300 MHz, CDCl3) δ7.81-7.73 (m, 2H), 7.43-7.37 (m, 2H), 7.27-7.16 (m, 3H), 7.07-7.00 (m, 2H), 6.99-6.95 (m, 1H), 6.75-6.70 (m, 1H), 6.48-6.40 (m, 3H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.83-4.78 (m, 2H), 4.59-4.50 (m, 2H), 3.09-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 166.5, 161.9, 161.3, 141.7, 140.6, 139.4, 133.7, 132.6, 128.7, 127.7, 127.5, 126.9, 126.2, 125.3, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 38.8, 29.0; MS (ES+) m/z 509.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:23]>C(OCC)(=O)C>[NH2:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[CH2:15][NH:14][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:1])[F:13])[CH:4]=1)=[S:11]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: Cc1cccc(N)c1CN
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1CNC(=S)Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
3-(Trifluoromethyl)phenyl isothiocyanate (224 mg, 1.10 mmol) was added to a solution of 2-aminomethyl-3-methyl-phenylamine (150 mg, 1.10 mmol) in ethyl acetate (3 ml); the reaction mixture was shaken at 80° C. overnight in a screw-cap vial. For workup, more ethyl acetate was added, the mixture was washed with water and brine, and dried (Na2SO4). After evaporation of the solvent under reduced pressure, the title compound (50 mg, 13%) was obtained by purification of the residue (silica gel, heptan/ethyl acetate=100:0-80:20).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[Br:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:15]([CH3:16])[CH3:14])[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: CNC
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1Br
Temperature: 70 °C
Reaction time: 11 h
Yield: 70 %

Procedure:
To a stirred solution of 5.24 g (22.5 mmol) 2-Bromo-5-fluoro-benzoic acid methyl ester (Rarechemicals) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 11 h at 70° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 16a was obtained in 70% yield (4.08 g, 15.8 mmol).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Yield: 49 %

Procedure:
Prepared in 49% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the same procedure as (2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J=7.7 Hz, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.25 (s, 2H), 7.01 (d, J=11.4 Hz, 1H), 6.89 (t, J=9.5 Hz, 1H), 5.81 (br. s., 1H), 4.69 (t, J=5.3 Hz, 1H), 3.93-3.82 (m, 1H), 3.59 (t, J=11.2 Hz, 1H), 3.49-3.40 (m, 1H), 3.26 (d, J=7.0 Hz, 1H), 2.63 (d, J=9.9 Hz, 1H), 2.40 (s, 3H), 1.89-1.57 (m, 10H), 1.50 (d, J=7.7 Hz, 1H), 1.19 (s, 3H), 1.16 (s, 9H), 1.11 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 661.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([CH3:25])=[C:11]([C:23]#[N:24])[C:12](=[O:22])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Cl)[CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1.Cl[C:27]1C=CC(SC2C(C)=C(C#N)C(=O)N(C3C=CC(Cl)=CC=3)N=2)=CC=1.ClC1C=CC(SC2C(C)=C(C#N)C(=O)N(C3C=CC=CC=3Cl)N=2)=CC=1.C1(N2C(=O)C(C#N)=C(C)C=N2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([CH3:25])=[C:11]([C:23]#[N:24])[C:12](=[O:22])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:27])[CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)nn(-c2ccc(Cl)cc2)c(=O)c1C#N
Reactant: Cc1c(Sc2ccc(Cl)cc2)nn(-c2cccc(Cl)c2)c(=O)c1C#N
Agent: Cc1c(Sc2ccc(Cl)cc2)nn(-c2ccccc2Cl)c(=O)c1C#N
Agent: Cc1cnn(-c2ccccc2)c(=O)c1C#N
Product: Cc1cccc(-n2nc(Sc3ccc(Cl)cc3)c(C)c(C#N)c2=O)c1

Procedure:
6-[(4-chlorophenyl)thio]-2,3-dihydro-2-(3-chlorophenyl)5-methyl-3-oxo-4-pyridazinecarbonitrile; 6-[(4-chlorophenyl)thio]-2,3-dihydro-2-(4-chlorophenyl)5-methyl-3-oxo-4-pyridazinecarbonitrile; 6-[(4-chlorophenyl)thio]-2,3-dihydro-2-(2-chlorophenyl)5-methyl-3-oxo-4-pyridazinecarbonitrile; 6-[(4-chloropheyl)thio]-(2,3-dihydro-2-(phenyl)5-methyl-3-oxo-4-pyridazinecarbonitrile;
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Br[CH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH:36]6[CH2:39][CH2:38][CH2:37]6)[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: BrC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cnn(C5CCC5)c4)cc32)c1
Yield: 35 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and bromocyclobutane, 147 was obtained as a yellow solid (40 mg, 35%) over two steps. 1H-NMR (500 MHz, CD3OD) δ (ppm): 9.02 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.66-7.69 (m, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 4.91-4.96 (m, 1H), 3.90-3.95 (m, 4H), 3.20-3.22 (m, 2H), 3.00-3.02 (m, 2H), 2.52-2.63 (m, 4H), 2.08-2.13 (m, 2H), 1.92-1.99 (m, 2H); MS (ESI) m/z: 415 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[N:19]=[C:18](Cl)[S:17][N:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C.O.C(OCC)(=O)C>[C:1]1([CH:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:15]2[N:19]=[C:18]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH2:28][CH2:29]3)[S:17][N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1nc(C(OC2CCCCO2)c2ccccc2)ns1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(C(OC2CCCCO2)c2nsc(N3CCN(c4ccccn4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of 3-[1-phenyl-1-(tetrahydropyran-2-yloxy)methyl]-5-chloro-[1,2,4]thiadiazole (3.11 g, 10 mmol) in DMF (50 mL) was added 1-(2-pyridyl)piperazine (3.26 g, 20 mmol) dissolved in DMF (5 mL) followed by triethylamine (4.04 g, 40 mmol). The resulting mixture was stirred at room temperature for 30 min then diluted with water (150 mL) and ethyl acetate (150 mL). The organic layer was collected, washed with water (100 mL), dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent gradient of a mixture of hexane and ethyl acetate (7/3 and 1/1) afforded 1 -{3-[phenyl-(tetrahydropyran-2-yloxy) methyl]-[1,2,4]thiadiazol -5-yl}4-pyridin-2-yl-piperazine (4.31 g, 98.4%) as a colorless foam and as a mixture of diastereoisomers. 1H-NMR (CDCl3) δ8.22 (d, J=4.6 Hz, 1H, Py-H), 7.51-7.58 (m, 3H), 7.27-7.39 (m, 3H), 6.68-6.71 (m, 2H), 5.93 and 5.88 (s, 0.5H each, αH), 4.91 and 4.67 (t, J=3.2 Hz, 0.5H each, OCHO), 3.51-4.02 (m, 2H, OCH2), 3.69-3.71 (m, 4H, 2CH2), 3.63-3.64 (m, 4H, 2CH2), 1.51-1.97 (m, 6H, 3CH2).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:3])=[O:24]
Reactant: OCCCCCCCCCBr
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 9-bromononanol (2.2 g, 10 mmols) with cooling with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with hexane (40 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of potassium carbonate (40 ml). The aqueous layers were combined, then made acidic (pH=1) with 10% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.8 g (yield: 77%) of 9-bromononanoic acid was obtained as colorless needle-like crystals.
Reaction SMILES: [N+:1]1([O-])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]([NH2:11])[N:2]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]([NH2:11])[N:2]=1
Reactant: Nc1nc2ccccc2[n+]([O-])n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc2ccccc2n1

Procedure:
A mixture of 8.1 g (49 mmol) 1,2,4-benzotriazine-3-amine 1-oxide, 8.1 g sodium dithionite and 800 ml 70 percent ethanol is heated under reflux for 1 h. One filters hot, evaporates the filtrate, washes the residue with water and dries. There remain 7.0 g 1,2,4-benzotriazine-3-amine (98% of theory) of the m.p. 208°-210° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][C@H:18]([NH:17][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:16][CH:15]=2)[CH2:27][CH2:26]3)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Cc4ccccc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Benzylbenzoic acid (0.50 g, 2.4 mmol) was dissolved in thionyl chloride (10 mL) and heated at reflux for 20 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (100 mg, 0.46 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethylamine (90 μL, 0.65 mmol) in methylene chloride (25 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroformnethanol saturated with NH3 (100:3) as the eluent. Yield: 130 mg (62%) of the title compound as white crystals: mp 191-192° C.; [α]21D −39° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 439 (28, M+).
Reaction SMILES: CS(O[CH:6]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH:7]([CH3:10])[CH2:8][CH3:9])(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:10][CH:7]([CH2:8][CH3:9])[CH2:6][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1
Reactant: CCC(C)C(OS(C)(=O)=O)c1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCC(C)Cc1ccc(CN)cc1
Yield: 51.8 %

Procedure:
Under a nitrogen atmosphere, add a mixture of 4-(1-methanesulfonyloxy-2-methyl-butyl)-benzonitrile (1.3 g, 4.9 mmol) in diethyl ether (5 mL) to a slurry of lithium aluminum hydride (820 mg, 19.5 mmol) in diethyl ether (25 mL) at 0° C. Heat the mixture under reflux for 1 h. Cool the mixture in an ice-bath and add water (0.9 mL), 15% aqueous NaOH (0.9 mL) and water (2.8 mL). Apply the mixture to a silica gel column eluting with dichloromethane and 5:1 dichloromethane in chloroform/methanol/concentrated ammonium hydroxide (80:18:2) to provide the title compound (450 mg, 52%). MS (ES+) m/z: 178 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 475.6 (M+H)+.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>N1C=CC=CC=1>[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:3]=[CH:2][C:1]([OH:7])=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
62.4 g of malonic acid are dissolved in 100 ml of pyridine. After termination of the exothermal reaction, 99 g of 3-phenoxybenzaldehyde and 5 g of piperidine are added, the batch is refluxed for 3 hours, cooled to 25° C. and poured onto ice/concentrated hydrochloric acid in order to wash out pyridine and piperidine, while the acid precipitates in the form of crystals. After drying, 113.7 g (95% of theory) of 3-phenoxycinnamic acid, m.p. 107°-109° C., are obtained. 18 g (0.15 mol) of thionyl chloride are added to a suspension of 24 g (0.1 mol) of 3-phenoxycinnamic acid in 100 ml of toluene, and stirred for 3 hours at 30° C. After removal of the solvent in vacuo, distillation is carried out. 24.6 g (95% of theory) of 3-(2-phenoxyphenyl)-2-propenic acid chloride, b.p. 155°-158° C./0.2 mm Hg, are obtained.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][N:12]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]1([C:15]2[C:14]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][N:12]=[C:11]([C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:9])=[O:8])[N:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCCCC(=O)O
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(O)CCCCC#Cc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 3.4 %

Procedure:
88 mg (0.7 mmol) of 6-heptynoic acid, 6 mg (0.07 eq.) of copper(I) iodide and 14 mg (0.04 eq.) of bis(triphenylphosphine)palladium(II) chloride were added to a solution of 114 mg (0.5 mmol) of 2-chloro-4,5-diphenylpyrimidine in 5 ml of triethylamine, and the mixture was stirred at 50° C. for 1 hour. The residue after evaporation was purified by preparative HPLC (method A). 6 mg (3%) of the desired product were obtained.