Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:24])=[O:23])=[C:18]([CH3:34])[CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:35][C:36]([CH3:43])([CH3:42])[C:37](=O)[CH2:38][C:39]#[N:40].Cl>C(O)C>[NH2:40][C:39]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)(=[O:24])=[O:23])=[C:18]([CH3:34])[CH:17]=2)[N:14]=[C:37]([C:36]([CH3:43])([CH3:42])[CH3:35])[CH:38]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1cc(NN=C(c2ccccc2)c2ccccc2)ccc1S(=O)(=O)NCCN1CCOCC1
Agent: Cl
Solvent: CCO
Product: Cc1cc(-n2nc(C(C)(C)C)cc2N)ccc1S(=O)(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 4-(N′-benzhydrylidene-hydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)-benzene sulfonamide (1.00 g, 2.09 mmol) and 4,4-dimethyl-3-oxopentanenitrile (392 mg, 3.13 mmol, 1.5 eq) in anhydrous ethanol (10.5 mL, 0.2 M) was added p-toluenebenzene sulfonic acid (402 mg, 4.18 mmol, 2.0 eq), and the reaction mixture was stirred at reflux under nitrogen. After 18 h, concentrated HCl (2 mL) was added and the reaction mixture was stirred at reflux under nitrogen for an additional 4 h. The reaction mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between EtOAc (500 mL) and aqueous saturated NaHCO3 solution (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (70% to 90% EtOAc/hexane) to give 799 mg (91%) of the desired product. 1H-NMR (DMSO-d6) δ 7.85 (d, J=8.4 Hz, 1H), 7.61 to 7.55 (m, 3H), 5.40 (s, 1H), 5.38 (broad s, 2H), 3.46 (t, J=4.5 Hz, 4H), 2.88 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 2.27 to 2.18 (m, 6H), 1.20 (s, 9H); MS LC-MS [M+H]+=422, RT=1.95 min.
Reaction SMILES: [Cl-].[C:2]1([N+:8]2[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[Cl-:14].[C:2]1([N+:8]2[C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1Cl
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Nc1cn[n+](-c2ccccc2)c(Nc2ccccc2)c1Cl
Temperature: 10 °C
Yield: 84.6 %

Procedure:
30 parts of 1-phenyl-4-amino-5,6-dichloropyridazinium chloride in 150 parts of water is stirred with 18 parts of aniline for 10 minutes at 50°C. The solution has 50 parts of concentrated hydrochloric acid added to it and is cooled to 10°C. 30.5 parts (84.6% of theory) of 1-phenyl-4-amino-5-chloro-6-anilinopyridazinium chloride is obtained; C16H14N4Cl2, melting point (with decomposition) 130°C after having been recrystallized from water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([OH:22])=O)=[CH:4][CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:27][CH2:24][CH2:25][N:26]2[C:20](=[O:22])[C:11]2[N:10]([CH:14]=[C:13]([C:15]([N:16]([CH3:17])[CH3:18])=[O:19])[CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1cc(C(=O)O)n(CC(=O)c2ccc(Cl)cc2)c1
Reactant: NCCN
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2n(c1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Yield: 26.8 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylic acid (90 mg, 0.27 mmol) in 1,4-dioxane (10 mL) was added ethane-1,2-diamine (0.1 mL, 1.5 mmol). The reaction mixture was heated at reflux 4 h (monitored by LCMS). The reaction mixture was then concentrated in vacuo to give an oil that was purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-20% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-N,N-dimethyl-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carboxamide as a light brown solid (26 mg, yield 27%) 1H NMR (400 MHz, d6-acetone): δ 2.75-2.84 (m, 1H), 2.95-3.21 (m, 6H), 3.33 (ddd, 1H, J 11.2, 7.7, 3.3 Hz), 3.49 (ddd, 1H, J 11.0, 7.7, 3.2 Hz), 3.72 (dt, 1H, J 11.0, 8.0 Hz), 4.41 (d, 1H, J 12.6 Hz), 4.75 (d, 1H, J 12.6 Hz), 7.01 (d, 1H, J 1.6 Hz), 7.13 (d, 1H, J 1.6 Hz), 7.26-7.35 (m, 4H). Used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 107.2 %

Procedure:
2-(4-Chloro-phenyl)-cyclohexanone (51 mg, 0.24 mmol) was dissolved in chloroform (1 mL). To this solution bromine (41.0 mg, 0.26 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (74 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([NH:22][N:23]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCN(CC=C)c1ccccc1C=O
Reactant: NNc1ccccc1
Solvent: CO
Product: C=CCN(CC=C)c1ccccc1C=NNc1ccccc1

Procedure:
To 1 mole of N,N-diallylaminobenzaldehyde in methanol, was added 1.2 moles of phenylhydrazine. The mixture was heated under reflux for about 2 hours to yield diallylaminobenzaldehyde N-phenylhydrazone (melting point: 63.5°-65.0° C.). Into a mixture of 5 cc of 5N sodium hydroxide solution and 20 cc of dimethyl sulfoxide, were added 5.0 g of said hydrazone and 4.8 g of allyl bromide. The mixture was stirred for 2 hours at room temperature. After completion of the reaction, 50 cc of water and ethyl acetate were added to the reaction mixture to extract the organic layer. The extract was freed from the ethyl acetate by distillation and the residue was recrystallized from 150 cc of alcohol to yield 3.8 g of pale yellowish white crystals melting at 38.5°-40.0° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:18]=1)(=O)C.[OH-].[Na+].Cl>C(O)C.O>[C:15]([N:14]1[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:18][C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc2c(c1)CCCCN2C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCCCc2cc(O)ccc21
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
7-Acetoxy-1-acetyl-2,3,4,5-tetrahydro-1H-benzazepine (D23, 3.88 g, 16 mmol) was stirred in ethanol (40 ml) as NaOH (1.26 g, 32 mmol) was added in water (5 ml). After stirring for 30 min, the mixture was diluted with water (500 ml), and acidified with 5M HCl. The tan precipitate was filtered off and dried, yielding 2.02 g (63%) of the title compound. A further 0.80 g (25%) of this material was isolated by dichloromethane extraction of the filtrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:48]=[N+]=[N-])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CCC3)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1

Procedure:
In analogy to the procedure described in example 10(c), the (3R,4R)-3-[1-(2-azido-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reduced with sodium borohydride in presence of nickel(II) chloride hexahydrate to yield the (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 660 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[C@@H:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:19]=1.[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:20][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=3[C:7](=[O:18])[N:8]3[CH2:17][CH2:16][CH2:15][C@H:9]3[C:10]=12
Reactant: O=C1c2cc(Cl)ccc2-n2cncc2[C@@H]2CCCN12
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
3 g (11 mmol) of (S)-7-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of dimethylformamide are stirred at 90° for 30 minutes with 1.60 g of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. By chromatography on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained (S)-1,7-dichloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 209°-210°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[F:10][C:11]1[C:16]([CH2:17]Br)=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=1[F:22].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[F:10][C:11]1[C:16]([CH2:17][O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=1[F:22]
Reactant: Cc1cccc(C)c1O
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1OCc1c(F)c(F)c(F)c(F)c1F
Yield: 96 %

Procedure:
A mixture of 2,6-dimethylphenol (5 mmol), pentafluorobenzyl bromide (1.3 g, 5 mmol), potassium carbonate (5 g), acetone (30 ml), and 18-crown-6 ether (0.1 g) were stirred under reflux for 5 hours. Work-up procedure was the same as above. Yield: 96%; m.p.: 81°-82° C.; 1H NMR, δ: 2.37 (s, 6H, CH3), 4.91 (s, 2H, CH2O), 6.96-7.16 (m, 3H, H-Ar) ppm; 13C NMR, δ: 15.7 (CH3), 59.9 (CH2O), 110.7 (C1', 2JC-F =18 Hz), 124.6 (C4), 129.0 (C3 & C5), 131.1 (C2 & C6), 137.6 (C2' & C6', JC-F =253 Hz), 141.7 (C4', JC-F =255 Hz), 145.9 (C3' & C5', JC-F =250 Hz ), 154.6 (C1) ppm.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1ccc(N2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(N2CCOCC2)cc1
Yield: 33.1 %

Procedure:
To a stirred solution of Intermediate 6 (0.26 g) in tetrahydrofuran (30 ml) was added lithium aluminium hydride (0.2 g). The reaction was stirred at room temperature for 12 h, before water (0.2 ml), aqueous sodium hydroxide (15%, 0.2 ml) and water (0.6 ml) were added. The precipitates were removed by filtration and the filtrate dried over magnesium sulphate (2 g) and the solvent removed in vacuo. The resulting oil was purified by flash chromatography (silica, eluent 1% methanol/dichloromethane) to yield the title compound as a brown solid (0.07 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[C:13]([C:15]([OH:17])=O)[NH:12][N:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[F:18][C:19]([F:28])([F:29])[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:15]([C:13]2[NH:12][N:11]=[C:10]([C:4]3[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:14]=2)=[O:17])=[CH:26][CH:27]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cc(-c2cc(F)c(F)c(F)c2)n[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(-c2cc(F)c(F)c(F)c2)n[nH]1
Temperature: 50 °C

Procedure:
To a solution of the intermediate from step D (0.1 g, 0.41 mmol) in DMF (2 mL) was added 4-trifluoromethoxy aniline (83 μL, 0.61 mmol), DIEA (215 μL, 1.23 mmol), HOAt (0.08 g, 0.61 mmol) and EDC (0.118 g, 0.61 mmol). The reaction was heated at 50° C. for 3 hours. The reaction was diluted with ethyl acetate, washed with 1N HCl , saturated NaHCO3, and saturated NaCl solutions. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate hexanes. 1H NMR (DMSO, 500 MHz): 10.34 (bs, 1H), 7.93 (d, J=5.9 Hz, 2H), 7.8 (bm, 2H), 7.44 (bs, 1H), 7.37 (bd, J=8.0 Hz, 2H). LC-MS=3.76 min; (M+H)=402.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1

Procedure:
According to the same method as described in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate.
Reaction SMILES: [OH:1][C@H:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]([NH:6][CH3:7])=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+].[Al]>C1(C)C=CC=CC=1>[CH3:7][NH:6][CH2:4][CH2:3][C@@H:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[OH:1]
Reactant: CNC(=O)C[C@H](O)c1cccs1
Agent: COCCO[Al+]OCCOC
Agent: [Al]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CNCC[C@H](O)c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A 200 ml capacity flask was charged with 5.00 g of (3S)-3-hydroxy-N-methyl-3-(2-thienyl)propionamide (optical purity >99.5% ee) and 26 ml of toluene. A 18.3 g portion of 75% by weight toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride was adjusted to 50% by weight by diluting with toluene and added dropwise to the reaction solution at 50° C. spending 10 minutes and stirred for 2 hours. The reaction solution was cooled down to room temperature and mixed with 30 ml of 11% sodium hydroxide aqueous solution, and then the organic layer and water layer were separated. The water layer was extracted twice with 10 ml of toluene, the organic layers were combined, and then 404 mg of L-(+)-tartaric acid and 10 ml of saturated brine were added thereto and stirred for 20 minutes. The mixed solution was separated between layers and then the organic layer was concentrated to obtain 4.27 g of a brown oily substance. When the amount of aluminum contained in this oily substance was measured by the ICP-AES determination method, it was 5 ppm or less. This oily substance was dissolved in 30 ml of toluene, mixed with 0.3 g of activated carbon and stirred for 30 minutes, and then the activated carbon was removed by filtration. The solution was concentrated, mixed with 7 ml of toluene and stirred at room temperature, and then the thus formed pale yellow crystals were collected by filtration, washed with 4 ml of toluene and dried under a reduced pressure to obtain 1.88 g of (1S)-3-methylamino-1-(2-thienyl)-1-propanol (yield 41%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 5-chloro-1-(4-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:8]=1)N.N([O-])=O.[Na+].O.[ClH:23]>[Cl-].[Na+].O.Cl[Cu]>[Cl:23][C:4]1[CH:6]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:8]=[C:2]([I:1])[CH:3]=1
Reactant: COc1ccccc1Oc1cc(N)cc(I)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Product: COc1ccccc1Oc1cc(Cl)cc(I)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
8 (3.4 g, 9.9 mmol) was suspended in concentrated HCl (17 mL) at 0° C. and stirred for 30 min. After this period, a solution of NaNO2 in H2O (0.6 g in 9.2 mL, 19 mmol) was added dropwise. Then the resulting mixture was stirred for 1 h at room temperature. This solution was added over 30 min to a solution of CuCl (16.6 g, 40 mmol) in concentrated HCl (17.0 mL) at 65° C. After addition, the mixture was heated at 80° C. for 30 minutes. The mixture was allowed to cool to room temperature before addition of brine. The solution was extracted with ethyl acetate, dried over anhydrous MgSO4, evaporated by rotary evaporation, and purified by column chromatography to give 1-chloro-3-iodo-5-(2-methoxyphenoxy)benzene (9) (1.5 g, 42%). 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=1.6 Hz, 1H), 7.23-7.15 (m, 1H), 7.13 (dd, J=2.2, 1.4 Hz, 1H), 7.06-6.94 (m, 3H), 6.83 (t, J=2.0 Hz, 1H), 3.82 (d, J=4.5 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2([CH3:22])[CH2:19][C:18]2([Cl:21])[Cl:20])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2([CH3:22])[CH2:19][C:18]2([Cl:21])[Cl:20])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC1(COc2cc(Cl)ncn2)CC1(Cl)Cl
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC2(C)CC2(Cl)Cl)ncn1
Reaction time: 0.17 h
Yield: 85 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.3 ml of a solution containing 0.07 g of 2-butyn-1-ol was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.3 ml of a solution containing 0.23 g of 4-chloro-6-(2,2-dichloro-1-methylcyclopropylmethyloxy)pyrimidine in tetrahydrofuran at 0° C., followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(2,2-dichloro-1-methylcyclopropyl)methoxypyrimidine (the present compound (32)).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.[Br:37]N1C(=O)CCC1=O>C1COCC1>[Br:37][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:3]1[CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (121 mg, 0.22 mmol)[prepared in Example 25] and N-bromosuccinimide (52 mg, 0.290 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=622 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH3:20][O:19][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:8][CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: COC(OC)c1ccc(C(=O)Cc2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(OC)c1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1

Procedure:
5 g 1-[4-(dimethoxymethyl)phenyl]-2-phenylethanone and 4.43 g N,N-dimethylformamid dimethylacetal are stirred for 18 h at 100° C. in DMF. The solvent is removed and the crude product used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[O:11])=[C:4]([F:36])[C:3]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[O:11])=[C:4]([F:36])[C:3]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c[nH]cn3)c2F)c1
Reaction time: 2.5 h
Yield: 60 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-(triphenylmethyl)-1H-imidazole-4-carboxamide (0.145 g, 0.22 mmol) was dissolved in CH2Cl2 (3 mL) and TFA (3 mL) added. The solution was stirred for 2.5 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.070 g, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.01 (br. s., 1H), 8.53 (br. s., 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.45-7.54 (m, 4H), 7.38 (t, 1H), 4.54 (d, 2H). MS: m/z 405.0 (M+1).