Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]([C:20]2[S:30][C:29]3[N:31]4[C:22](=[CH:23][N:24]=[C:25]4[CH:26]=[CH:27][CH:28]=3)[CH:21]=2)=[O:19])[CH2:12][CH2:11]1.C(N(CC)CC)C.[I-].[Na+]>C(O)C.O>[S:6]1[CH:7]=[C:3]([CH2:2][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]([C:20]3[S:30][C:29]4[N:31]5[C:22](=[CH:23][N:24]=[C:25]5[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)=[O:19])[CH2:12][CH2:11]2)[N:4]=[CH:5]1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: ClCc1cscn1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(Cc2cscn2)CC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 90 °C
Yield: 36.5 %

Procedure:
To a solution of 255 mg (1.5 mM) of 4-chloromethylthiazole, 387 mg (1 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride, and 697 ml (5 mM) of triethylamine in ethanol (10 ml) was added 225 mg (1.5 mM) of sodium iodide at room temperature and the mixture was refluxed on an oil bath at 90° C. overnight. To this reaction mixture was added water and the reaction product was extracted into ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over Na2SO4. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The fractions eluting with ethyl acetate/ethanol/triethylamine (20/20/1) were pooled to provide the title compound as red oil (150 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCCC1.[Cl:24][CH2:25][CH:26]1[O:28][CH2:27]1>>[Cl:24][CH2:25][CH:26]([OH:28])[CH2:27][O:17][C:15]1[CH:14]=[CH:13][C:11]2[CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][O:9][C:10]=2[CH:16]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Solvent: C1CCNCC1
Product: OC(CCl)COc1ccc2c(c1)OCC(c1ccccc1)C2

Procedure:
11.3 g 3-phenyl-7-hydroxy-3,4-dihydro-2H-1-benzopyrane, 0.1 cm3 piperidine and 22 cm3 1-chloro-2,3-epoxypropane were stirred at 90° C. for 9 hours. The solution was evaporated under reduced pressure, then twice 60-60 cm3 of benzene were distilled off from the residue, it was dissolved in 50 cm3 of tetrahydrofurane and into the solution hydrochloric gas was introduced for 5 minutes. The solution was evaporated after an hour's standing, and the residue was crystallized from aceton. 10 g 1-chloro-3-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-propanol (m.p. 74°-76° C.) was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH3:15][S:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])[CH:21]=3)[C:17]([S:16][CH3:15])=[CH:18]2)=[N:12][CH:13]=1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Potassium tert-butoxide (9.75 g, 86.95 mmol, 1.5 eq) and 5-bromo-2-chloropyrimidine (11.21 g, 57.97 mmol, 1.0 eq) were added to (3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (16.0 g, 57.97 mmol, 1.0 eq) in DMF (100 mL). The mixture was stirred at 120° C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a pad of celite. The filtrate was washed with water (2×100 mL) and brine (50 mL), and dried over sodium sulphate. The solvents were distilled off and the residue was purified by silica gel column chromatography [100-200 mesh; ethyl acetate/petrolether=1:1]. Yield: 8.0 g (32% over two steps).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].[CH:23](N(CC)C(C)C)([CH3:25])[CH3:24].C(Br)C=C>C(Cl)Cl>[CH2:25]([N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[C:3]2=[O:22])=[CH:8][CH:9]=1)(=[O:14])=[O:15])[CH:23]=[CH2:24]
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.6 %

Procedure:
Synthesised according to general procedure 67. To a stirring suspension of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 0.59 mmol) in CH2Cl2 (0.50 mL), under N2, at 0° C., was added N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) followed by allylbromide (51 uL, 0.59 mmol). The mixture was stirred at ambient temperature for 19 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (220 mg, 0.57 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H), 2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:17](=[O:23])[N:18]([CH2:21]C)CC)=[C:9]([CH:16]=1)CNC(=O)OC)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:16]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:17](=[O:23])[NH:18][CH2:21]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CNC2=O
Temperature: 110 °C
Yield: 56.2 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 103b (858 mg, 2.68 mmol), tetrahydrofuran (5 mL), methanol (5 mL) and 2 M aqueous lithium hydroxide (5 mL). The vial was loaded in a Biotage microwave and heated at 110° C. for 2.5 h. After this time, the solution was neutralized with 2 M hydrochloric acid to pH 7 and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 50% ethyl acetate to 100% ethyl acetate/hexanes) to afford a 56% yield (285 mg) of 103c as an off-white solid: mp=132-134° C.; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H, J=7.8 Hz), 7.52 (m, 2H), 6.71 (br s, 1H), 4.44 (s, 2H), 1.37 (s, 9H), MS (ESI+) m/z 190.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH2:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 1,3-dihydro-1-methyl-3(R)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].[K].[O-]CCCC.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:3]1[C:4]([Br:10])=[C:5]([Br:9])[C:6]([C:7]#[N:8])=[C:2]1[Br:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: BrCc1ccccc1
Agent: CCCC[O-]
Agent: [K]
Solvent: C1CCOC1
Product: N#Cc1c(Br)c(Br)n(Cc2ccccc2)c1Br
Reaction time: 8 h

Procedure:
To a stirred mixture of 1.00 g (3.04 mmol) of 2,4,5-tribromopyrrole-3-carbonitrile and 0.68 g (6.1 mmo1) of potassium ! -butoxide in 30 mL of dry THF under a nitrogen atmosphere is added 1.10 mL of benzyl bromide. The mixture is heated to reflux and stirred overnight. After dilution with 100 mL of water and 150 mL of ethyl acetate, the organic mixture is separated and washed with salt solution, dried over magnesium sulfate, and concentrated in vacuo to leave 2.34 g of orange oil. The oil is triturated under a mixture of 5:1 hexane/ether to give a white solid collected by filtrations 0.81 g, mp 100°-103° C. The filtrate yields a second crop; 0.11 g, mp 100°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+]>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CC1(c2ccc(F)c(Cl)c2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: NCC1(c2ccc(F)c(Cl)c2)CCCCC1

Procedure:
The title compound was prepared from 1-(3-chloro-4-fluorophenyl)cyclohexanecarbonitrile. A solution of the crude product in MTBE was basicified at 0° C. with KOH, extracted with MTBE and evaporated. The residue was diluted in DCM, filtered through an aminopropyl column and evaporated to give the primary amine (64.1 mg, 25%) as an oil. LCMS Rt=7.62 min, m/z=242 (M+1). 1H NMR (CDCl3, δ) 7.34 (dd, J=2.4, 7.1 Hz, 1H), 7.19 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.11 (t, J=8.7 Hz, 1H), 2.68 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79 (bs, 2H). 13C NMR (CDCl3, δ, mult): 157.4(0), 154.9(0), 142.2(0), 129.5(0), 127.0(0), 126.9(1), 120.8(1), 120.6(1), 116.3(1), 116.1(1), 54.5(2), 43.3(0), 33.7(2), 26.5(2), 22.0(2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.CC(C)=[O:29].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:11]([C:9]1[O:10][C:6]2[C:5]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:4]([F:26])[CH:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)([OH:29])=[O:12]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C(=O)O)oc23)c1=O
Yield: 76.9 %

Procedure:
1.5 g (3.84 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 20 ml of acetone, and a Jones' reagent was dropwise added thereto at 5° C. until the orange color no longer disappeared. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 76.9%) of the desired product as white crystals. Melting point: 267-268° C. (decomposed).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-chloro-5-trifluoromethyl-benzoic acid (57.8 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 63 mg (42.1% yield) of biphenyl-4-carboxylicacid {2-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 97.5%, 1H NMR: (DMSO) δ 8.7 (s, 1H), 8.0-7.9 (t, 3H), 7.9-7.7 (m, 6H), 7.54-7.38 (m, 3H), 4.2 (dd, 2H), 3.8-3.6 (m, 4H), 3.6-3.4 (m, 2H), 3.2 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:12]2[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.CN(C)CCN>O1CCOCC1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:19]=[C:12]2[C:13](=[O:18])[N:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:15][CH2:16][CH2:17][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCCn2nc(OCc3ccccc3)cc21
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)CCN
Solvent: C1COCCO1
Product: O=C1c2cc(OCc3ccccc3)nn2CCCN1c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Copper (I) iodide (0.02 g, 0.1 mmol) was added to a stirred suspension of 2-(benzyloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (0.5 g, 1.94 mmol), 4-iodofluorobenzene (0.63 g, 2.8 mmol) and N,N-dimethylethylenediamine (0.034 g, 0.38 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 110° C. for 16 hours and then the solvent was evaporated in vacuo. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by preparative-HPLC (Gemini 250 Å×20 mm, gradient ACN in water from 41% to 71% with 0.05% NH4OH in water) to yield 2-(benzyloxy)-5-(4-fluorophenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (0.42 g, 62% yield). C20H18FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (quin, J=6.6 Hz, 2H), 3.80 (t, J=6.3 Hz, 2H), 4.43 (t, J=6.9 Hz, 2H), 5.20 (s, 2H), 6.27 (s, 1H), 7.07-7.17 (m, 2H), 7.27-7.42 (m, 5H), 7.42-7.48 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(Cl)[Cl:21].Cl>O1CCOCC1>[ClH:21].[CH:1]1([CH2:4][NH:5][C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[CH2:2][CH2:3]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CC[C@H](NCC2CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (cyclopropylmethyl)(trans-4-hydroxycyclohexyl)carbamate (0.857 g, 3.2 mmol) in a solution of methylene chloride (6 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (3 mL) was stirred at r.t. 2 hours. Concentration yielded 0.658 g of trans-4-[(cyclopropylmethyl)amino]cyclohexanol hydrochloride (100%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCCCOc2ccccc2)cc1

Procedure:
A mixture 100 grams (0.438 mole) of 4-phenoxybutyl bromide, 59.5 grams (0.438 mole) of p-hydroxyacetophenone, and 60.4 grams (0.438 mole) of potassium carbonate in approximately 200 milliliters of dry dimethylformamide, is stirred at its reflux temperature for a period of about 4 hours. The reaction mixture is cooled, water added, and the reaction product removed by filtration. The product is washed with a solution of 2 N sodium hydroxide, washed with water, and recrystallized twice from isopropyl alcohol to yield the desired p-(4-phenoxybutoxy) acetophenone having a m.p. of 104°-6° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:11]([NH:27][C:28]([NH:30][C:31]2[C:36]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=2[CH:40]([CH3:42])[CH3:41])=[O:29])[C:10]1=[O:43])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:11]([NH:27][C:28]([NH:30][C:31]2[C:32]([CH:40]([CH3:41])[CH3:42])=[CH:33][CH:34]=[CH:35][C:36]=2[CH:37]([CH3:39])[CH3:38])=[O:29])[C:10]1=[O:43])([OH:7])=[O:5]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(=O)OC(C)(C)C)c3ncccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(=O)O)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 405.3 %

Procedure:
To a solution of N-[(1-tert-butoxycarbonylmethyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (110 mg, 0.19 mmol) in methylene chloride (20 ml) was added trifluoroacetic acid (1 ml, 13 mmol), and the mixture was stirred at room temperature for 1.5 hour. The mixture was concentrated under reduced pressure, diluted with water, and basified with 4N aqueous NaOH solution, and washed with ethyl acetate. The aqueous layer was acidified with 2N aqueous HCl solution, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound (41 mg, 0.77 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Cl[C:9]1[N:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:9]2[N:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:2]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1Oc1cccnc1

Procedure:
Pyridin-3-ol was treated with 2-chloronicotinonitrile and processed according to the method of Example 128B to provide the product. MS (ESI+) m/z 198 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Br[CH2:20][CH2:21][CH2:22][CH3:23]>C(#N)C>[C:1]([O:5][C:6]([NH:7][NH:8][CH2:20][CH2:21][CH2:22][CH3:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCNNC(=O)OC(C)(C)C
Yield: 39 %

Procedure:
To a magnetically stirred solution of tert-butylcarbazate (47.5 gram, 359 mmol) in anhydrous acetonitrile (300 ml) was successively added DIPEA (Hünig's base) (37.6 ml, 216 mmol) and 1-bromobutane (19.3 ml, 180 mmol). The resulting mixture was reacted at 60° C. for 16 hours. The resulting mixture was allowed to attain room temperature and subsequently concentrated in vacuo and further purified by Sepacore chromatography (eluant: petroleum ether 40-60/ethylacetate=4/1 (v/v)) to give N′-butylhydrazine-carboxylic acid tert-butyl ester (intermediate XIII-1) (13.2 gram, 39%) as a pale yellow oil: 1H-NMR (400 MHz, CDCl3) δ 0.91 (t, J=7, 3H), 1.30-1.49 (m, 13H), 2.81-2.87 (m, 2H), 4.00 (br s, 1H), 6.20 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:13]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Cl)nc1
Yield: 69 %

Procedure:
6-chloropyridine-3-sulfonyl chloride (4.1 g, 19.3 mmol) was stirred in ammonium hydroxide (30 mL) at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (150 mL) and any insoluble material filtered. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous phase was further extracted with EtOAc (1×15 mL). The combined EtOAc extractions were washed with H2O (1×50 mL) and saturated NaCl (1×50 mL), dried over Na2SO4, and concentrated in vacuo to give 6-chloropyridine-3-sulfonamide (2.58 g, 69%). MS (EI) m/z for C5H5Cl2N2O2S: 190.9 (MH−).
Reaction SMILES: C(O[CH2:4][CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8]1)C.[Cl:26]C([SiH3])(Cl)Cl.C(OC(C)C)(C)C>C(#N)C>[Cl:26][CH2:4][CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8]1
Reactant: [SiH3]C(Cl)(Cl)Cl
Reactant: CCOCCNn1cc(C(=O)OCC)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cn(NCCCl)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-(ethoxymethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (200 mg) in dry acetonitrile (2.0 ml) was added trichloromethylsilane (65.8 μl) under ice -cooling and the mixture was stirred for 30 minutes, and then for 10 minutes at room temperature. To the reaction mixture was added diisopropyl ether (10 ml), which was then stirred for 15 minutes at ambient temperature. The precipitate was collected by filtration and washed with diisopropyl ether and dried in vacuo over phosphorus pentaoxide to give ethyl 1-(chloromethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (145 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1F
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-methyl-benzoic acid (1.1 g, 7.13 mmol) in methanol (20 mL) add thionyl chloride (1.02 g, 8.56 mmol). Stir the resulting mixture overnight then concentrate under vacuum to give the title compound (1.2 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cncn1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (9.37 g) in tetrahydrofuran (100 ml) was added dropwise diisobutylaluminum hydride (1.5 mol/l toluene solution, 60 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr., sodium sulfate decahydrate (13.0 g) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered, and the organic layer was concentrated to give [1-(4-fluorophenyl)-1H-imidazol-5-yl]methanol (4.10 g, 53%) as crystals. Recrystallization thereof from ethyl acetate-isopropyl ether gave pale-yellow prism crystals. melting point: 96-98° C.