Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([O:47][CH3:48])([CH3:46])[CH3:45])[C:39](=[O:49])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([O:47][CH3:48])([CH3:46])[CH3:45])[C:39](=[O:49])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(C)(C)Cn1ccc(Br)cc1=O
Product: COC(C)(C)Cn1ccc(-c2ccc(C(C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetra methyl-1,3,2-d ioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75 Method 1. Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([CH3:28])[CH:16]=1.C(N(CC)CC)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:48]1([CH2:51][C:52](O)=[O:53])[CH2:50][CH2:49]1>CN(C)C=O>[CH:48]1([CH2:51][C:52]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][N:8]=4)=[CH:16][C:17]=3[CH3:28])[CH2:23][CH2:24]2)=[O:53])[CH2:50][CH2:49]1
Reactant: COc1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2c1
Reactant: O=C(O)CC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(Nc3ccc(OC4CCN(C(=O)CC5CC5)CC4)c(C)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a suspension of (6-Methoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (108mg, 0.251 mmol) in N,N-dimethylformamide (1.0 mL) was added triethylamine (143 μL, 1.03 mmol) and the preformed acyl imidazolide (0.343 mmol). The acyl imidazolide is prepared by mixing CDI (56 mg, 0.343 mmol), DMF (1 mL) and cyclopropylacetic acid (34 mg, 0.343 mmol) and stirring for one hour at ambient temperature. After addition of the acyl imidzolide, the reaction was stirred at room temperature overnight. The reaction was then filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 71.4 mg of 2-Cyclopropyl-1-{4-[4-(6-methoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-ethanone was isolated. 1H NMR (300 MHz DMSO d6), δ 9.505 (s, 1H), 8.435 (s, 1H) 7.904 (d, J=9.0, 2.7 Hz, 1H), 7.708 (d, J=9.0 Hz, 1H), 7.552 (dd, J=2.7 Hz, 1H), 7.576-7.511 (m, 2H), 7.480 (dd, J=9.0, 2.7 Hz, 1H), 7.062 (d, J=9.0 Hz, 1H), 4.647-4.600 (m, 1H), 3.951 (s, 3H), 3.951-3.730 (m, 1H), (m, 1H), 3.729-3.645 (m, 1H), 3.442-3.369 (m, 3H), 2.300 (d, J=6.9 Hz, 2H), 2.223 (s, 1H), 1.985-1.882 (m, 2H), 1.692-1.576 (m, 2H) 0.980 (m, 1H), 0.499-0.439 (m, 2H), 0.162-0.113 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2([C:26]#[N:27])[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)=[O:8].[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:26]([C:16]1([C:13]2[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:28]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[CH:3]=[N:4][CH:5]=3)=[CH:15][CH:14]=2)[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1)#[N:27]
Reactant: N#CC1(c2ccc(NC(=O)c3cncc(Br)c3)cn2)CCC2(CC1)OCCO2
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#CC1(c2ccc(NC(=O)c3cncc(-c4ccc(F)cc4)c3)cn2)CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A solution of 5-bromo-N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]nicotinamide (213 mg), 4-fluorophenylboronic acid (63 mg), bis(triphenylphosphine)palladium (II) dichloride (100 mg) and sodium carbonate (636 mg) in a mixture of toluene (5 ml), ethanol (1 ml) and water (1 ml) was stirred at 100° C. for six hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography to give the titled compound (31 mg).
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[CH3:11][SiH:12]([N:14](Cl)[C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13]>C1COCC1>[CH3:11][SiH:12]([N:14]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13]
Reactant: c1ccc2[cH-]ccc2c1
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[SiH](C)N(C1C=Cc2ccccc21)C(C)(C)C
Reaction time: 6.5 h
Yield: 73.6 %

Procedure:
Lithium indenide (1.73 g, 0.014 moles) in THF (50 mL) was added drop wise to a solution of dimethylsilyl(t-butylamino)chloride (3.53 g, 0.021 moles) in THF (75 mL). This mixture was allowed to stir for 6.5 hrs. And the volatile materials were removed. The residue was extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as an oil (2.53 g, 74.3% yield).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][NH:29][CH:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:40]([CH:45]=O)[CH2:41][C:42]([OH:44])=[O:43].CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[C:23]([O:22][C:20]([C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:27][CH2:28][N:29]([CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)[CH2:45][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=CCCC(=O)O
Reactant: CC(C)(C)OC(=O)[C@H](CCNC1CCCc2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CCN(CCCC(=O)O)C1CCCc2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl (2S)-2-[[(9H-9-fluorenylmethoxy)carbonyl]amino]-4-(1,2,3,4-tetrahydro-1-naphthylamino)butanoate (16 mg,0.030 mmol) in MeOH (0.5 ml) were added succinic semialdehyde (15 wt. % solution in water, 48 μl, 0.077 mmol), HOAc (2 μl, 0.035 mmol) and NaBH3CN (2.3 mg, 0.074 mmol), and the mixture was stirred at RT for 6 h. After adding water, the mixture was extracted with chloroform, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford 4-[[(3S)-3-(tert-butoxycarbonyl)-3-[[(9H-9-fluorenylmethoxy)carbonyl]amino]propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (18 mg, 98%): MS(ES+) m/e 613 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.98 (br, 1H), 7.76 (d, J=7.3 Hz, 2H), 7.61 (m, 3H), 7.40 (t, J=7.3 Hz, 2H), 7.31 (m, 2H), 7.15 (m, 2H), 7.06 (d, J7.6 =Hz, 1H), 5.64 (br, 1H), 4.36 (m, 2H), 4.22 (m, 3H), 2.75-2.17 (m, 8H), 2.10-1.65 (m, 8H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.5 g, 9.6 mmol), 2-chloro-5-aminomethylpyridine (2.7 g, 19 mmol), acetonitrile (10 mL), and N,N-diisopropylethylamine (3.4 mL, 19 mmol) was subjected to microwave irradiation at 180° C. for 2 h. After standing at rt overnight, the precipitated solids were collected by filtration and washed with cold acetonitrile (5 mL×2), and dried to yield a yellow powder (2.8 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].[CH3:12][C:13]1[C:22]2[C:17](=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=2Cl)[N:16]=[CH:15][CH:14]=1.C(O)(=O)CCC(O)=O.NCCCC(NC1C=C(OC)C(OC2C=CC=C(C(F)(F)F)C=2)=C2C=1N=CC=C2C)C>C(OCCO)C.O>[CH3:25][O:24][C:20]1[C:21]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:22]2[C:17](=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH3:12]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Cl
Reactant: COc1ccc(O)cc1
Agent: COc1cc(NC(C)CCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: O=C(O)CCC(=O)O
Agent: [K+]
Solvent: CCOCCO
Solvent: O
Product: COc1ccc(Oc2c(OC)cc([N+](=O)[O-])c3nccc(C)c23)cc1
Yield: 68 %

Procedure:
A solution of 4-methoxyphenol (5.76 g, 46.5 mmol) and KOH (2.61 g, 46.6 mmol) in 2-ethoxyethanol (90 mL) was heated with removal of water until the pot temperature reached 130° after which time 4-methyl-5-chloro-6-methoxy-8-nitroquinoline, prepared as in Example 1 (9 g, 35.7 mmol), was added. The reaction mixture was heated at reflux (130°) for 2 hours and cooled at 5° for 18 hours. Filtration afforded the title compound (8.25 g, 68%), mp 158°-60°.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[NH:37][NH2:38]>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:38]1
Reactant: NNc1ccnc2ccc(Cl)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccc(Cl)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (6-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=484.1 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:5].[OH:13][C:14]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:14]=2[OH:13])[CH2:7][CH2:8][S:9][CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(N)CCSCC1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2cccc(C)c2O)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of HCl salt of 4-amino-tetrahydro-thiopyran-4-carboxylic acid methyl ester (529 mg, 2.5 mmol), 2-hydroxy-3-methyl-benzoic acid (380 mg, 2.5 mmol), HATU (1.14 g, 3.0 mmol) in anhydrous DMF (20 mL) is added DIPEA (1.66 mL, 10 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 10-80% EtOAc in heptane) to give a pure product (27) as white solid (102 mg, 13%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F.[H+].[F-].[K+].[Cl-].[NH4+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:42]3[CH:43]=[N:44][C:39]([F:38])=[CH:40][CH:41]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 19.8 %

Procedure:
A solution of the above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene (200 mg), 6-fluoropyridine-3-boronic acid 58 (117 mg), tri-tert-butylphosphine.tetrafluoroboric acid adduct (24 mg), potassium fluoride (80 mg) and tris(dibenzylideneacetone)dipalladium (0) (27 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 2 days under argon atmosphere. Added thereto was a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-70:30) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (44 mg) as colorless crystals. APCI-Mass m/Z 631 (M+NH4).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[C:22]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>>[C:1]1([CH2:7][CH2:8][C:9]([O:12][C:13]2[C:22]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)CCc1ccccc1

Procedure:
This compound was prepared in three steps according to the method described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 3-phenylpropionyl chloride was used instead of 2-furancarbonyl chloride and methyl 2-hydroxy-3-propionylbenzoate was used instead of the ethyl homolog, yielding methyl 2-(3-phenylpropionyloxy)-3-propionylbenzoate. This compound was used without purification for the second step. The title compound melted at 107.5°-109° C. after crystallization from ethanol.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]C)([F:4])[F:3].Br.C(O)(=O)C>O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([F:4])[F:3]
Reactant: COc1ccccc1SC(F)(F)F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccccc1SC(F)(F)F
Yield: 46 %

Procedure:
A mixture of 4.69 g of 2-methoxyphenyl trifluoromethyl sulfide, obtained according to Example 3, 20 ml of 48% strength by weight aqueous hydrobromic acid, and 20 ml of 96% strength by weight acetic acid was boiled under reflux for 24 hours. The completion of the reaction was then checked by gas chromatography. After cooling, the reaction mixture was poured into water. The organic phase was separated off and the aqueous phase was extracted with dichloromethane. The extract was combined with the organic phase. Drying over magnesium sulfate, concentration, and vacuum distillation gave 2.01 g (46% of theory) of 2-hydroxyphenyl trifluoromethyl sulfide (boiling point 65-66° C. at 26 mbar, melting point 35-37° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Product: COc1ccc(-c2cc(Oc3ccc(Cl)cc3Cl)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.495 mmol) and 2,4-dichlorophenol were reacted as starting materials at 150° C. for 15 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (195.5 mg, 93.9%). Melting point: 152.2-152.8° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH3:27])[CH2:11][CH2:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:9][CH:10]([CH3:27])[CH2:11][CH2:12][N:13]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:15]=[N:14]1
Reactant: Cc1ccc(Br)cc1
Reactant: CC(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnn(CCC(C)C)c2)cc1
Reaction time: 0.17 h
Yield: 158.2 %

Procedure:
To a solution of p-bromotoluene (0.66 g, 3.86 mmol) in tetrahydrofuran (20 ml) was added a solution of 1-(3-methylbutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.41 g, 1.55 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (40 mg, 0.077 mmol) and water (40 μl) and the mixture refluxed under nitrogen for 43 h. Water (50 ml) was added to the reaction mixture and stirring continued at RT for 10 min followed by extraction with ether (2×50 ml). The ether extract was then dried (MgSO4) and evaporated to give a brown oil (0.56 g) that solidified on standing. Purification by column chromatography (silica gel, 100% chloroform) afforded 1-(3-methylbutyl)-4-(4-methylphenyl)-1H-pyrazole (13) as a waxy pale yellow solid (0.216 g, 53%). 1H nmr (CDCl3, 300 MHz) 0.97, d (6.3 Hz), 2×Me; 1.62, m, H3″; 1.80, dt (7.3 Hz), H2″; 2.35, s, 4′-Me; 4.16, t (7.5 Hz), H1″; 7.16, d (8.1 Hz), H3′,5′; 7.37, d (8.1 Hz), H2′,6′; 7.59, s, H3 or H5; 7.74, s, H5 or H3. ESI (+ve) MS m/z 229 (M+H, 100%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].Cl.[CH3:30]OC1C=C(C2C(CC)(C)C(=O)N(C3CCNCC3)N=2)C=CC=1OC.ClCC(OC(=O)CCl)=O>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH2:18][CH3:30])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for A1 using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B9) and chloroacetic anhydride as starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C=O)C>[CH2:18]([N:7]1[C:8]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[C:5]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:6]1=2)[CH3:19]
Reactant: O=C1NCCc2[nH]c3ccc(F)cc3c21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(F)ccc31)C(=O)NCC2
Yield: 21.2 %

Procedure:
8-Fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (I-59f: 500 mg, 2.44 mmol) in DMF (200 mL) was reacted with 60% NaH (196 mg, 8.16 mmol) and ethyl iodide (456 mg, 2.92 mmol) to afford the crude product. The reaction mass was quenched with chilled water and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 120 mg of the product (21.2% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:32])[C:18]([NH:20][CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:32])[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NCC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A suspension of benzyl N-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}glycinate (Example 86, 350 mg, 0.80 mmol) and palladium hydroxide (20% on carbon, wetted with ca. 50% water, 30 mg) in ethyl acetate (25 mL) was stirred under hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide N-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}glycine (0.273 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][C@@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][C@@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(O[C@@H]2CCOC2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1O[C@@H]1CCOC1
Temperature: 80 °C
Yield: 78.4 %

Procedure:
To (R)-methyl 3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate (0.95 g, 3.8 mmol) were added dioxane (10 mL) and NaOH (10 mL, 1 M) and the mixture was heated at 80° C. for 0.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in water and was washed with EtOAc (×3). The aqueous layer was acidified and a solid was formed. The aqueous layer (with the solid) was washed with EtOAc (×3). The combined organics were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield (R)-3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoic acid (0.71 g, 79%) as a white solid. ESI-MS m/z calc. 238.1, found 239.3 (M+1)+; Retention time: 1.21 minutes (4 min run). 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 7.54 (dd, J=8.3, 1.4 Hz, 1H), 7.46 (d, J=1.3 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.13-5.02 (m, 1H), 4.04-3.62 (m, 7H), 2.40-2.12 (m, 1H), 2.10-1.86 (m, 1H).