Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)=[C:14]([O:16][CH2:17][CH:18]=[CH2:19])[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.O1CCCC1>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)=[C:14]([O:16][CH2:17][CH2:18][CH3:19])[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C=CCOc1nc(-c2c(C)nn3ccccc23)sc1-c1nnc[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1nc(-c2c(C)nn3ccccc23)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
To a solution of 2-methyl-3-[4-(prop-2-en-1-yloxy)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridine (70 mg, 0.55 mmol) produced in Example 27 in ethanol (15 mL)-tetrahydrofuran (15 mL) was added 10% palladium/carbon (73 mg), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere (1 atm). Palladium/carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (43 mg, 61%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Under ice-cooling, 8.42 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 3.0 g of hydrazine monohydrate and 60 ml of tetrahydrofuran were mixed, and the mixture was stirred at room temperature for 3 hours. A deposited precipitate was collected by filtration, and washed successively with tetrahydrofuran and methyl t-butyl ether to obtain 4.85 g of 3-bromo-N-[4,6-dibromo-2-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]12[CH:23]([N:24]3[CH2:27][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:25]3)[CH:19]([CH2:20][NH:21][CH2:22]1)[CH2:18][O:17][CH2:16]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:20][CH:19]2[CH:23]([N:24]3[CH2:25][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][NH:39][C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:27]3)[CH:15]([CH2:16][O:17][CH2:18]2)[CH2:22]1)=[O:6]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5C6CNCC5COC6)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2C3COCC2CN(C(=O)c2ccnc(C(F)(F)F)c2F)C3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a mixture of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (50.0 mg, 0.239 mmol) and {1-(3-oxa-7-azabicyclo[3.3.1]non-9-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (128 mg, 0.239 mmol) in DMF (2 mL) were added triethylamine (0.100 mL, 0.717 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (127 mg, 0.287 mmol). The mixture was stirred at room temperature for 2 hours. Direct purification with prep-LCMS (pH=10) afforded 50 mg (30% yield) of the desired product. LCMS found: 696.3 (M+1)+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([CH3:16])[CH2:5][NH:4]1)[CH3:2].C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([CH3:16])[CH2:5][N:4]1[CH3:19])[CH3:2]
Reactant: CC[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (2R,5R)-5-ethyl-2-methyl-1-(phenylmethyl)piperazine (prepared according to procedures in J. Med. Chem. 2006, 49, 716-726, utilizing Boc-D-2-aminobutyric acid in place of N-Boc-L-alanine) (902 mg, 4.13 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (0.435 mL, 37% water solution, 5.78 mmol) followed by sodium triacetoxyborohydride (1050 mg, 4.96 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield (2R,5R)-2-ethyl-1,5-dimethyl-4-(phenylmethyl)piperazine (875 mg, 91%). LCMS: (M+H)+: 233.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:25]([CH3:26])[C:24](=[O:27])[CH2:23][C@@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:28]=1)[C:6]([OH:8])=O.C(N(C(C)C)C(C)C)C.[NH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:25]([CH3:26])[C:24](=[O:27])[CH2:23][C@@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:28]=1)[C:6]([NH:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N1CCC[C@@H]1CC(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N1CCC[C@@H]1CC(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-methoxy-4-((R)-6-methyl-5-oxo-2,3,3a,4,5,6-hexahydro-1H-6,8,10,10b-tetraaza-benzo[e]azulen-9-ylamino)-benzoic acid (I-102a), 0.32 mL (0.0018 mole) of ethyldiisopropylamine and 0.082 g (0.00072 mole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.31 g (0.00072 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 3 hours, then diluted with saturated sodium carbonate. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (100:0-60:40) gave 0.060 g of 3-methoxy-4-((R)-6-methyl-5-oxo-2,3,3a,4,5,6-hexahydro-1H-6,8,10,10b-tetraaza-benzo[e]azulen-9-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-102).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[NH:16][C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[N:16]([CH3:36])[C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2cc(F)ccc21
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1c(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)cc1=O
Reaction time: 0.25 h

Procedure:
50 mg (0.11 mmol) of 4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one were placed in 0.50 mL DMSO at RT. To this were added 88 mg (0.27 mmol) caesium carbonate and the mixture was stirred for 15 min. Then a solution of 6.5 μL (0.11 mmol) methyl iodide in DMSO was added and the mixture was stirred for 2 h at RT. More methyl iodide was added (3.3 μL, 0.055 mmol) and the mixture was stirred for a further 2 h at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([N:1]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a stirred solution of (S)-(+)-2-aminobutan-1-ol (5 g, 56.18 mmol) in dry acetonitrile (100 ml) was added dry powdered potassium carbonate (31 g, 224.72 mmol) followed by benzyl bromide (19 g, 111.11 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under vaccuo and the residue was taken up in ethyl acetate (100 ml) and water (100 ml). The organic phase was washed again with water, dried (Na2SO4) and concentrated to provide the pure product as slightly yellow oil (14.5 g, 97.3%). δH (250 MHz, CDCl3) 0.98 (3 H, t, J 7.5, CHCH2CH3), 1.38-1.2 (1H, m, CHCHHCH3), 1.94-1.78 (1 H, m, CHHCH3), 2.83-2.71 (1 H, m, CHCHHCH3), 3.22 (1 H, s, b, OH), 3.65-3.4 (2 H, m, CH2OH), 3.47 (2 H, d, J 17.5, 2×CHHPh), 3.94 (2H, d, J 17.5, 2×CHHPh), 7.46-7.26 (10 H, m, 2×C6H5); δC (250 MHz, CDCl3) 139.42 (2×C), 129.1 (2×CH), 128.52 (2×CH), 127.25 (2×CH), 61.97 (CH), 60.67 (CH2), 53.23 (CH2), 17.92 (CH2), 11.83 (CH3); m/z 270.2 (M+H)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.83 h

Procedure:
To a stirred -50° C. solution of lithium diisopropylamide (100 kg of 2 M) in tetrahydrofuranheptane was added tertiary-butyl acetate (30 kg, 255 mol) followed by a rinse of 3 kg of tetrahydrofuran, and the mixture was stirred to -45° C. to -5° C. for 50 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Step A) (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran was then added to the previous mixture. The reaction mixture was stirred for 30 minutes at -5° C. to -30° C., and transferred to 240 L of 0° C. 2.8N aqueous hydrochloric acid solution. The aqueous layer was extracted with 50 kg of ethyl acetate, the aqueous layer was separated and reextracted with 36 kg of ethyl acetate, the extracts are combined, and concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate which was not isolated. A small sample was purified by column chromatography on flash silica gel eluting with 1:1 hexane:ethyl acetate.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45]OS(C)(=O)=O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:51][CH2:52][CH2:53][OH:54].[I-].[Na+]>C(#N)C.C(O)C>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][CH2:45][NH:51][CH2:52][CH2:53][OH:54])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCCOS(C)(=O)=O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCO
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: OCCNCCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(3-hydroxypropoxy)phenyl]ethyl)benzofuran (0.23 g) and triethylamine (0.1 mL) in dichloromethane (6 mL) was added methanesulfonyl chloride (0.042 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-{(4-[3-(methanesulfonyloxy)propoxy]phenyl}ethyl)benzofuran (0.25 g). The obtained 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-{4-[3-(methanesulfonyloxy)propoxy]phenyl}ethyl)benzofuran (30 mg) was dissolved in acetonitrile (0.5 mL)-ethanol (0.5 mL). To the solution were added 2-aminoethanol (0.025 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (15 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cccc(C=Cc2ccc(O)cc2)c1
Product: COc1cccc(/C=C/c2ccc(OCCCCl)cc2)c1
Yield: 91.6 %

Procedure:
The procedures of Example 1 were followed using 4-hydroxy-3'-methoxystilbene (5.0 g, 22 mmol) and 1-bromo-3-chloropropane (4.5 mL, 44 mmol) to give 6.1 g (92%) of (E)-4-chloropropoxy-3'-methoxystilbene as an amber oil. 1NMR (CDCl3): δ7.51-6.74 (m,10H), 4.11 (t,2H), 3.81 (s,3H), 3.72 (t,2H), 2.22 (m,2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].[NH3:13]>>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: N
Product: Nc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 84 %

Procedure:
1,2,3-Trifluoronitrobenzene (20.2 g, 114.1 mmol, Aldrich, Milwaukee) and methanolic ammonia (150 mL of a 2.0 molar solution, Aldrich, Milwaukee) were placed in a sealed tube and were heated to 70° C. for 2 h, after which time the solvents were removed in vacuo. The remaining residue was dissolved in ethyl acetate and was extracted with water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvents were removed in vacuo to leave a yellow solid. The title compound was recrystallized from water-methanol to afford yellow needles (16.6 g, 84%); 1H NMR (DMSO-d6) δ: 7.94 (m, 1H, Ar—H), 7.56 (br s, 2H, NH2), 6.72 (m, 1H, Ar—H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:4]([Cl:10])[CH:3]=1
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
4-bromo-2-chloro-benzaldehyde (I-3a: 10.0 g, 46.0 mmol) was dissolved in methanol and treated with isoamylamine (4.78 g, 54.7 mmol). After stirring overnight at room temperature, sodium borohydride (5.2 g, 138 mmol) was added to the reaction mixture. After stirring for 1 hour at room temperature, the reaction mixture was quenched using concentrated (37%) hydrochloric acid and the volatiles were removed under reduced pressure. The residue was taken up in an aqueous 2 N sodium hydroxide solution and extracted with ethyl acetate (2 times). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title product (I-3b: 12.7 g)
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>CC(C)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]([NH2:3])=[S:1])=[N:16][CH:17]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Br)cn1
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
1.1 Ammoniumthiocyanat (76 mmol, 1.2 eq.) is dissolved in acetone (75 ml) and benzoylchloride (1 eq.) is added dropwise. 20 min after stirring at RT, the reaction is heated to reflux. 2-Amino-5-bromopyridine (71 mmol) in acetone (50 ml) is added and 30 min heated to reflux. Afterwards, the reaction solution is poured onto ice. The precipitate is filtered and washed with water/methanol (1:1). The precipitate is dissolved in 2M NaOH (120 ml) at 80° C. and stirred 10 min at 80° C. The solution is poured into an HCl solution (5%) at 0° C. The pH of the solution is adjusted to 8 with a saturated Na2CO3 solution. The resulting precipitate is filtered and washed with water. (5-Bromo-pyridine-2-yl)-thiourea (“1”) is obtained after drying in vacuo at 40° C. as a pale yellow solid in a yield of 63%. HPLC (method C): 1.43 min; LC-MS (method A): 1.062 min, 231.95 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.[Br:22]Br.O>C(O)(=O)C>[Br:22][C:15]1[NH:14][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=2[Cl:12])=[N:17][C:16]=1[C:18]([F:21])([F:19])[F:20]
Reactant: BrBr
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c[nH]2)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c(Br)[nH]2)c(Cl)c1
Yield: 70.1 %

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (0.7 g, 0.002 mol) and bromine (0.32 g, 0.1 ml, 0.002 mol) in glacial acetic acid (5 ml) was stirred and heated at reflux for 2 hours. The cooled suspension was poured into cold water (50 ) and the solid was filtered and washed with water. The solid was dissolved in glacial acetic acid (5 ml) and bromine (0.32 g, 0.1 ml, 0.002 mol) was added. The mixture was stirred and heated at reflux for 2 hours, cooled and poured into cold water (50 ml). The solid was filtered and washed thoroughly with water to give 5-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (0.6 g) as a white solid, m.p. 295° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(OC([N:18]1[C:26]2[N:21]([C:22](=[O:28])[N:23]=[C:24](Cl)[CH:25]=2)[CH2:20][C@@H:19]1[CH3:29])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:10][C:24]1[CH:25]=[C:26]2[NH:18][C@@H:19]([CH3:29])[CH2:20][N:21]2[C:22](=[O:28])[N:23]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)cc(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluorophenyl)methanol and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[CH:13]=[C:14]([OH:16])[CH:15]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.CCOCC.[ClH:32]>C(O)(=O)C>[ClH:32].[CH3:19][N:20]1[CH2:21][CH:22]=[C:23]([C:13]2[C:12]([O:17][CH3:18])=[CH:11][C:10]([CH:2]([CH3:1])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][C:14]=2[OH:16])[CH2:24][CH2:25]1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(OC)c1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCC(C)C(C)c1cc(O)c(C2=CCN(C)CC2)c(OC)c1

Procedure:
5-(1,2-Dimethylheptyl)-3-methoxyphenol (10.0 g) of Example V, and N-methyl-4-piperidone (4.45 g) were dissolved in 20 ml acetic acid and saturated with HCl gas. Ether was added and the resulting solid recrystallized from isopropyl alcohol-ether. Yield 7.32 g, m.p. 96°-97°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:4][CH2:3]1.[CH3:24][NH:25][CH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:25]([CH3:26])[CH3:24])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CNC
Solvent: CC(=O)CC(C)C
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN(C)C

Procedure:
Using 1.38 g of N-(trans-4-methylcyclohexyl)-2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetamide (Example 128), 50 ml of methylisobutylketone, and 40 ml of 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 1.08 g of N-(trans-4-methylcyclohexyl)-2-[4-(2-dimethylaminoethoxy)-3-methoxyphenyl]acetamide (a compound of the present invention) was obtained as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: COc1ccc(NNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2nc(-c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)[nH]c2=O)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-methoxyphenyl)hydrazinecarboxylate (Intermediate-55, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.018 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 3.82 (s, 3H), 4.46 (d, J=5.8 Hz, 2H), 6.12 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 7.26-7.30 (m, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H), 11.01 (br s, 1H); MS (m/z): 433.20 (M+H+).