Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:15](O)=[O:16])=[O:12])=[CH:9][CH:8]=1.[NH2:33][CH2:34][CH2:35][OH:36]>>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=2)[C:15]([NH:33][CH2:34][CH2:35][OH:36])=[O:16])=[O:12])=[CH:30][CH:31]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCC2CC2(F)F)cc1
Reactant: NCCO
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCC2CC2(F)F)cc1
Yield: 63.1 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-({4-[(2,2-difluorocyclopropyl)methoxy]benzoyl}amino)-3-[4-(trifluoromethoxy)phenyl]propanoic acid (352 mg, 0.766 mmol) prepared in Example 40 (40c) and 2-aminoethanol (55 μL, 0.919 mmol) to give 243 mg of the title compound (white powder, yield: 63%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[N+](=[CH2:15])=[N-]>C(OCC)C>[CH3:15][O:11][C:10]([CH:7]1[CH2:8][CH2:9][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6]1)=[O:12]
Reactant: CCCC[C@H]1CCC(C(=O)O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCC[C@H]1CCC(C(=O)OC)C1

Procedure:
A mixture of 84 mg of (1RS,3S)-3-butylcyclopentanecarboxylic acid (prepared in Reference Example 14) and 1.0 ml of a 1M solution of diazomethane in diethyl ether was stirred with cooling. The mixture was concentrated under ambient pressure to give 72 mg of the title compound having the following physical characteristic.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15]([OH:24])=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: Oc1nc2ccccc2cc1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reaction time: 3 h

Procedure:
5.70 g (18.0 mmol) 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinolin-2-ol were placed in 200 mL methanol. 1.00 g palladium on charcoal (10%) were added and the reaction mixture was hydrogenated for 3 h at 50° C. under a hydrogen atmosphere. The catalyst was removed by suction filtering and the mother liquor was concentrated to dryness by rotary evaporation. The residue was triturated with diethyl ether and the undissolved solid was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[C:20](OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[C:3]2[C:10](=[O:19])[C:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:20][O:9][C:4]=2[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc(O)cc1)c1c(O)cc(O)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(Cl)c12
Temperature: 140 °C
Reaction time: 70 h

Procedure:
A solution consisting of 1-(2-chloro-4,6-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (50 mg), acetic anhydride (1.2 mL) and sodium acetate (44 mg) was prepared. The solution was heated at 140° C. for 50 min, cooled to room temperature and stirred for 70 h. The soution was quenched with saturated sodium bicarbonate (10 mL), water (1 mL) and methanol (10 mL). After stirring for 3 h the solution was acidified to pH 5 with saturated potassium diphosphate and extracted with ethyl acetate (3×15 mL). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting yellow oil was diluted with toluene and dehydrated for 1.5 h using a Dean-Starke trap. Chromatography using reverse phase preperative HPLC provided the title compound (18 mg). 1H NMR (DMSO-d6): 11.07 (s br, 1H), 9.46 (s br, 1H), 7.03 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=2.4 Hz), 6.79 (s, 1H), 6.78 (d, 2H, J=8.7 Hz), 2.18 (s, 3H); MS: 303 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Br)ccc1N
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of 2-amino-5-bromobenzonitrile (1 g, 5.1 mmol) in 20 mL of DCM, DIPEA (27.9 mmol, 5.5 eq.) was added followed by thiophene-2-carbonyl chloride (25.4 mmol, 5.0 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% EtOAc in hexane eluant) to afford 120 mg of N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide. MS (EI) for C12H7BrN2OS: 307 (M+H). Step 2: N-[4-Bromo-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a mixture of the nitrile N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide (120 mg, 0.4 mmol), sodium azide (0.5 mmol, 1.3 eq.), and triethylamine hydrochloride (0.5 mmol, 1.3 eq.) in a sealed tube, 1 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 10° C. overnight. The mixture was cooled to room temperature, diluted with another 5 mL of toluene, transferred to a separatory funnel and washed 3×10 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 18 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.99-7.95 (m, 21), 7.82 (dd, 1H), 7.33 (t, 1H). MS (EI) for C12H8BrN5OS: 350 (M+H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH3:12].[C:13]1([S:23](Cl)(=[O:25])=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:25])=[O:24])[CH3:12]
Reactant: CCc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: CCc1c(C(F)(F)F)noc1NS(=O)(=O)c1cccc2ccccc12
Yield: 70 %

Procedure:
N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonamide was prepared, as described in Example 90, from 5-amino-4-ethyl-3-trifluoromethylisoxazole and 1-naphthalenesulfonyl chloride in 70% yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 135°-137° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:25][C:24]=1[C:32]([F:33])([F:35])[F:34]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Product: COc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 70 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-(methyloxy)-3-(trifluoromethyl)benzoyl chloride. MS (ESI): m/z 467 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1>[C:42]([O:46][C:47](=[O:48])[NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51]([NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:52])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2.52 g, 6.62 mmol), benzylamine (0.723 ml, 6.62 mmol) and N,N-diisopropylethylamine (1.153 ml, 6.62 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound tk91) (1.95 g, 6.30 mmol) in tetrahydrofuran (20 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)-tert-butyl(1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk92) (2.357 g, 5.91 mmol, 94%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>C(O)C.[Pd]>[CH3:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(N)c1C
Yield: 98 %

Procedure:
To a solution of 2-methyl-3-nitro anisole A1 (5.1 g; 30.33 mmol; requires ˜30 min to dissolve) in absolute ethanol (85 mL) was added 10% Pd/C catalyst (500 mg). The solution was hydrogenated under a hydrogen filled balloon at atmospheric pressure and room temperature for 19 h. The reaction mixture was filtered through a Celite pad, rinsed and evaporated to dryness to obtain 2-methyl-3-methoxyaniline A2 as a deep mauve oil (4.1 g; 29.81 mmol; 98% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[N:21]#[C:22]Br>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([C:22]#[N:21])[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C#N

Procedure:
4.00 g of cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (prepared according to the method E. Jon Jacobson et. al. J. Med. Chemistry. 1999, Vol. 42, 1123-144) in 91 mL of dichloromethane was treated with sodium bicarbonate (4.7 g) followed by addition of cyanogen bromide (7.5 mL). The reaction mixture was heated at reflux overnight, was filtered, and was purified by column chromatography (0 to 50% ethyl acetate/hexanes) to afford 3.9 g of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ ppm 1.33 (d, 6H, J=6.5 Hz), 1.44 (s, 9H), 2.54 (m, 2H), 3.09 (m, 2H), 4.09 (m, 2H); 13C NMR (CDCl3, 75 MHz) 16.70 (2C), 28.54 (3C), 53.86 (4C), 80.86, 114.10, 154.22.
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]3[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]3=[N:23][CH:22]=2)[CH:2]=1.C=O.[C:35]([BH3-])#N.[Na+]>CS(C)=O.O>[CH3:35][N:19]([C:3]1[CH:2]=[CH:1][C:6]([C:7]([NH:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[C:25]2[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]2=[N:23][CH:22]=1
Reactant: [BH3-]C#N
Reactant: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Yield: 85 %

Procedure:
Reductive alkylation of diethyl p-aminobenzoyl-L-glutamate) (VI; R=H; R1 =C2H5) with III (Y=CHO) and hydrogen in 70% acetic acid containing Raney nickel gave a 32% yield of 5-deazaaminopterin diethyl ester. Saponification of the ester groups in a mixture of dimethyl sulfoxide-water at ambient temperature gave an 87% yield of 5-deazaaminopterin (II, R=H). Methylation of the latter compound was accomplished by treatment of II (R=H) with formaldehyde and sodium cyanoborohydride in aqueous solution at pH 6.4 to give an 85% yield of 5-deazamethotrexate, (II, R=CH3). The structure of II (R=CH3) was established as described hereinafter in Example 8C by oxidation with alkaline potassium permanganate to give the previously prepared 2-amino-4(3H)oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (VIII), which indicated that methylation had occurred either on the 4- or 10-amino group. Methylation of the 4-amino group was eliminated from consideration by alkaline hydrolysis of the 4-amino group to give 5-deaza-10-methylfolic acid (I, R=CH3).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]2[CH:26]([NH2:29])[CH2:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]2[CH:26]([NH:29][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: COCCOc1cccc2c1C(N)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCOc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.04 g, 5.0 mmol) in 1-methyl-2-pyrrolidone (10 mL) with the above described rac-4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-ylamine (1.14 g, 5.5 mmol) and N-ethyldiisopropylamine (1.27 mL, 7.5 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as an orange solid (1.24 g, 65%); MS: m/e=382.3 (M+H−).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:11][P:12]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[S:13])[CH2:6][C:7]([O:9]C)=O)=O.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[O:23]1[CH2:22][CH2:21][N:20]([P:12]([CH2:11][NH:5][CH2:6][C:7]([O:31][CH:28]([CH3:30])[CH3:29])=[O:9])([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[S:13])[CH2:25][CH2:24]1
Reactant: CC(C)O
Reactant: COC(=O)CN(CP(=S)(N1CCOCC1)N1CCOCC1)C(=O)C(F)(F)F
Product: CC(C)OC(=O)CNCP(=S)(N1CCOCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
N-trifluoroacetyl-N-[bis(morpholino)phosphinothioylmethyl]glycine, methyl ester (5.35 g, 0.0123 mole) was dissolved in isopropanol and cooled to 0° C. on an ice bath. The solution was stirred and sodium tetrahydrido boron (467 mg, 0.0123 mole) was added portionwise over a ten minute period. The solution was allowed to warm to room temperature and stirred for an additional 45 minutes. The solvent was removed by evaporation under vacuum and the resulting residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was then chromatographed on silica gel employing 25% ethanol in ethyl acetate (V:V) to obtain N-[bis(morpholino)phosphinothioylmethyl]glycine, isopropyl ester (300 mg), having a refractive index ND25 =1.5205 and the following analysis: Calculated: C, 44.33; H, 7.78; N, 11.08. Found: C, 44.83; H, 7.59; N, 10.76.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α-Bromo-p-chloroacetophenone (4.64 g) in acetonitrile (50 ml) was treated with 1,2,4-triazole (1.4 g) followed by triethylamine (2 g). The mixture was stirred at room temperature for two hours and refluxed for one hour. The solvent was removed under reduced pressure and the residue was treated with water to give a yellow solid which was filtered, washed with water and dried. Crystallisation from ethanol-petroleum ether (60°-80°) gave α-1,2,4-triazol-1-yl-p-chloroacetophenone as cream coloured plates.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:18]([O:20][C:21]([C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([NH2:33])[S:25][C:24]=1[NH2:34])=[O:22])[CH3:19]>C(O)(C)C>[CH2:18]([O:20][C:21]([C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([N:33]=[CH:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:25][C:24]=1[NH2:34])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC

Procedure:
In a 50 mL round bottom flask, 30 mg of 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester was dissolved in 20 mL of isopropanol. To this solution, 5-nitro-2-thiophenecarboxaldehyde (91 mg) was added with vigorous stirring, followed by the addition of a catalytic amount of TFA. The reaction was refluxed for 30 minutes. The title compound was isolated as a dark black-purple powder (87%) by flash chromatography (SiO2). M.p.: 194°-196° C. 1H-NMR (300 MHz, [D] acetone): δ=8.21 (s, 1H), 8.00 (d, 1H, 3J=4.4 Hz), 7.74 (s, 2H), 7.50 (d, 1H, 3J=4.4 Hz), 4.37 (q, 2H, 3J=7.1 Hz), 4.22 (q, 2H, 3J=7.1 Hz), 1.40 (t, 3H, 3J=7.1 Hz), 1.27 (t, 3H, 3J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 59.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (87 mg, 0.18 mmol) obtained in Example 59, step 2 and cyclopropanesulfonamide (109 mg, 0.90 mmol), the title compound (62 mg, 59%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:45]=1[O:52][CH3:53]>>[CH3:53][O:52][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]([O:50][CH3:51])[C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1OCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4c(OC)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.067 g of 2-(3-bromopropoxy)-1,3-dimethoxybenzene are used to prepare the title compound. Rf=0.20 (2:1 EtOAc-heptane); Rt=5.83.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([F:14])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([F:14])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2CCC2)cc1F
Agent: [Pd]
Product: Nc1ccc(C2CCC2)cc1F
Yield: 72.2 %

Procedure:
A solution of 4-cyclobutyl-2-fluoro-nitrobenzene (0.5 g, 2.6 mmol) in IMS (5 mL) was degassed with argon for 2 minutes, before 10% Pd/C (0.05 g) was added, and a balloon of hydrogen affixed. The resultant mixture was stirred for 18 hours at room temperature, before being flushed with nitrogen and filtered through hyflo®. The filtrate was concentrated in vacuo to afford the title compound as an orange/red oil (0.31 g, 74%). 1H NMR (CDCl3): 6.84 (1H, d, J=12.3 Hz), 6.77 (1H, d, J=8.1 Hz), 6.70 (1H, t, J=9.1 Hz), 3.58 (2H, broad), 3.42 (1H, m), 2.28 (2H, m), 2.01 (3H, m), 1.82 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]3[C:7](=[C:8]([CH2:19][OH:20])[S:9][CH:10]=3)[C:6]=2[CH:21]=1.Cl.Cl[CH2:24][CH2:25][CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]3[C:7](=[C:8]([CH2:19][O:20][CH2:24][CH2:25][CH2:26][NH2:27])[S:9][CH:10]=3)[C:6]=2[CH:21]=1
Reactant: NCCCCl
Reactant: OCc1scc2c1-c1cc(Cl)ccc1Oc1ccccc1-2
Agent: Cl
Product: NCCCOCc1scc2c1-c1cc(Cl)ccc1Oc1ccccc1-2

Procedure:
Starting from the alcohol 14 (0.18 mmole) and 3-chloropropylamine-hydrochloride (1.8 mmoles), an oily product was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:29])[CH2:18][C@@H:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:26]3[CH:25]=[CH:24][C:23]4[C@@H:19]([CH2:18][C:17]([OH:29])=[O:16])[CH2:20][O:21][C:22]=4[CH:27]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C[C@H]1COc2cc(O)ccc21
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)C[C@H]1COc2cc(OCc3cccnc3SC3CCCC3)ccc21
Yield: 77.8 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (11 mg, 0.05 mmol) obtained in Step C of Preparation Example 8 and ((R)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (10 mg, 0.05 mmol) obtained in Preparation Example 55 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (15 mg, 89%).