Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[C:36]([O:38][CH3:39])=[O:37].[CH3:46][C:47](=[CH2:50])[CH2:48]O.Cl>O1CCCC1.O>[CH3:48][C:47](=[CH2:46])[CH2:50][O:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: C=C(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)COc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Triphenyl phosphine (7.87 g, 30 mmol) was dissolved in 80 mL of tetrahydrofuran followed by the addition of diethyl azodicarboxylate (5.23 g, 30 mmol) in a dry ice bath. The reaction mixture was stirred 30 minutes, added dropwise with a solution of methyl 3-hydroxy-4-nitro-benzoate 1b (2.96 g, 15 mmol) in tetrahydrofuran, and stirred 10 minutes followed by the addition of 2-methyl-allyl alcohol (1.41 g, 19.50 mmol), then stirred for another 1 hour. The resulting mixture was heated to room temperature and stirred for 12 hours. The resulting mixture was added with 10 mL of water, added dropwise with 1 M hydrochloric acid to adjust pH to 2 to 3 and extracted with ethyl acetate (50 mL×3). The combined organic phase was added dropwise with 1 M sodium hydroxide solution to adjust pH to 9 to 10, extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 3-(2-methylallyloxy)-4-nitro-benzoate 4a (3 g, yield: 79.6%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.[N+:15]([NH:18][C:19]([NH:21][CH2:22][CH2:23][NH2:24])=[NH:20])([O-:17])=[O:16].[N:25]12CCCN=C1CCCCC2.O>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:25][NH:20][C:19]([NH:21][CH2:22][CH2:23][NH2:24])=[N:18][N+:15]([O-:17])=[O:16])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: N=C(NCCN)N[N+](=O)[O-]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NNC(=N[N+](=O)[O-])NCCN
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of 4-amino-5-chloro-2-methoxy benzoic acid (0.6 g) and N,N'-carbonyldiimidazole (0.49 g) in anhydrous dimethylformamide (DMF) (15 ml) was stirred at room temperature for 30 minutes, then a solution of N-nitro-N'-aminoethylguanidine hydrochloride (0.55 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF was added. The mixture was stirred for 4 hours at 50° C., then was cooled, poured into water and extracted with methylene chloride. The organic layer was washed with sodium carbonate solution and dried. After cooling, the title compound was collected as a solid, M.p. 226°-227° C. (dec.)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:27][C:28]([N:30]([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)[CH3:31])=[O:29])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH:17]([CH3:19])[CH3:18])=[O:12])[CH:8]=1)#[N:2].[ClH:42].O1CCOCC1.C(OCC)C>ClCCl>[ClH:42].[ClH:42].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:27][C:28]([N:30]([N:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40]2)[CH3:31])=[O:29])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[CH3:19])=[O:12])[CH:8]=1)#[N:2]
Reactant: Cc1ccc(C#N)cc1N(CC(=O)NCCN(C(=O)OC(C)(C)C)C(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(C#N)cc1N(CC(=O)NCCNC(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
The compound (2.81 g, 4.99 mmol) obtained in step B was dissolved in dichloromethane (15 ml), 4N hydrochloric acid-dioxane solution (15 ml, 60 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hr. Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (2.60 g, yield 97%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:11]([O:13][C@@H:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(C(=O)O)c2ccsc2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
A mixture of 2-(4-methoxyphenylamino)-2-(thiophen-3-yl)acetic acid (I56) (544 mg, 2.01 mmol), (R)-quinuclidin-3-ol (614 mg, 4.83 mmol), DCC (511 mg, 2.47 mmol), and HOBT (380 mg, 2.48 mmol) in dry THF (160 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between EtOAc and 2M NaHCO3. The organic phase was further washed with 2M NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (DCM/MeOH=95/5 to 7/3) to obtain (R)-quinuclidin-3-yl 2-(4-methoxyphenylamino)-2-(thiophen-3-yl)acetate (40 mg, 5% yield).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([CH2:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)(O)=[O:7]>CN(C=O)C>[Cl:3][C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C:9]=1[CH:6]=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)COc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: O=Cc1oc2ccccc2c1Cl
Temperature: 25 °C
Yield: 25.6 %

Procedure:
To a cooled solution of phosphorus oxychloride (19 mL, 209 mmol) in DMF (40 mL) is slowly added 2-carboxymethoxybenzoic acid (6.84 g, 35 mmol) in portions. The mixture is warmed to room temperature for 30 min and then heated to 90° C. overnight. The mixture is cooled to room temperature and poured carefully into ice water, extracted with ethyl acetate (3×50 mL), dried with sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, hexanes/ethyl acetate, 4:1) gave title compound (1.62 g, 26%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.82-7.88 (m, 2H), 7.69-7.73 (m, 1H), 5.51-7.56 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(N)nc4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (627 g, 2.0 mmol) and commercially available 2-amino-5-bromopyridine (450 mg, 2.6 mmol) according to general procedure II. Obtained as a yellow solid (93 mg, 12%). MS (ISP) 406.2 [(M+H)+]; mp 162° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:33]([N:40]1[CH2:44][CH2:43][C@@H:42]([NH2:45])[CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CC#N>[CH2:33]([N:40]1[CH2:44][CH2:43][C@@H:42]([NH:45][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH2:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-Trifluoromethyl-benzoylamino)acetic acid (4.2 g, 17 mmol) and NMM (2.8 mL, 25.5 mmol) in dry THF (30 mL) at −10 to −15° C. under N2, was slowly added isobutylchloroformate (2.4 mL, 17.85 mmol) via syringe. The reaction mixture gradually became pink. 15 min later, a solution of (3R)-1-benzylpyrrolidin-3-amine (3.0 g, 17 mmol) in THF (15 mL) was dropwise added to the above mixed anhydride over 20 min, maintaining reaction temperature <−10° C. The reaction mixture became a dark red color. 1 h later, the reaction mixture was allowed to warm to rt, and quenched with water (25 mL), extracted with EtOAc×3, dried, filtered and concentrated to give an orange solid. MeCN was added and concentrated to remove EtOAc. Then MeCN (15-20 mL) was added to afford a slurry, which was chilled in ice bath and stirred for 30 min. After filtration, the solid product was rinsed with cold MeCN (10-15 mL) until the filtrate was colorless After dried under high vacuum overnight, a pale yellow solid product: 5.0 g (73%) was afforded. MS (M+H+)=406.2; 1H NMR (CDCl3) δ 8.16 (s, 1H), 8.00 (dd, 1H), 7.78 (dd, 1H), 7.57 (m, 1H), 7.25 (m, 6H), 7.06 (m, 1H), 6.39 (m, 1H), 4.48 (m, 1H), 4.04 (d, 2H), 3.62 (d, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.57 (m, 1H), 2.36 (m, 2H).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:31]=[CH:30][C:23]([O:24][CH:25]2[CH2:29][CH2:28][NH:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][CH:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:33])[F:32])=[CH:31][CH:30]=2)[CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 42 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A6) and 3-(4-trifluoromethyl-phenoxy)-pyrrolidine (Example 25(b)). The crude material was purified by chromatography (methanol/dichloromethane) to yield the title compound as a light brown solid (yield 42%). MS (m/e): 488.1 (M+H+, 100%).
Reaction SMILES: [OH:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1.[CH3:34][C:35]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>CN(C=O)C>[OH:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:48]1[CH2:49][CH2:50][N:45]([C:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[C:35]([CH3:34])[CH:44]=2)[CH2:46][CH2:47]1)=[O:7]
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: CC(O)/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(C(=O)/C=C/C(C)O)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4-Hydroxypent-2-enoic acid (67 mg, 0.52 mmol) was dissolved in anhydrous DMF (2.5 ml), DCC (107.5, 0.52 mmol) and HOAt (106.7 mg, 0.79 mmol) were added and the mixture was stirred at room temperature for 15 minutes. 2-Methyl-4-piperazin-1-yl-quinoline (118.2 mg, 0.52 mmol) was added and stirring was continued for 90 minutes. The mixture was evaporated to dryness, taken up in a mixture of acetonitrile and methanol and filtered. The filtrate was evaporated to dryness again and purified by preparative HPLC (gradient of water containing 0.1% TFA and acetonitrile). 110 mg were obtained (0.33 mmol, 65%). MS (ES): m/z=326.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol; see Example 48) in dioxane (5 mL) was reacted with piperazine (9 mmol) following the general procedure H to afford 4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-yl-benzamide. The product was dissolved in dry THF (6 mL) and was treated with BOC anhydride (3.6 mmol) and stirred for 4-6 h. The solvent was removed to dryness, and the residue obtained was suspended in ether (50 mL) with stirring. The solid formed was collected by filtration, washed with ether and dried in vacuo to afford 4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[NH:22])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]=2[O:2]1.C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]2[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=[C:10]2[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc3c(c2)OCO3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc3c(c2)OCO3)cc1
Yield: 46.7 %

Procedure:
To a mixture of 3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (2.32 g, 7.3 mmol) and sodium bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture to reflux for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.1 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl)-1,3-benzodioxole (1.46 g, 47%) as a white solid: mp 200–202° C. Anal. Calc'd. for C18H15N2SO5F3.0.25 PhCH3: C, 52.55; H, 3.80; N, 6.21. Found: C, 52.73; H, 3.78; N, 6.01.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.[N:18]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:22]2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:44]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][C:49](CN)=[C:48]([N+:54]([O-:56])=[O:55])[CH:47]=2)[CH:42]=[CH:41][N:40]=1>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:38][C:39]2[CH:44]=[C:43]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH:18][CH3:22])=[C:48]([N+:54]([O-:56])=[O:55])[CH:47]=3)[CH:42]=[CH:41][N:40]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN1CCC(C(=O)O)CC1
Reactant: NCc1ccc(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNc1ccc(Oc2ccnc(NC(=O)C3CCN(C)CC3)c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 1-methylpiperidine-4-carboxylic acid (1 eq) in N,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP (2 eq) and the mixture was stirred at ambient temperature until homogeneous. To it was added [4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and the resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the resulting 1-methyl-N-(4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridin-2-yl)piperidine-4-carboxamide was purified by silica gel chromatography. MS: MH+=386.2.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].Cl.[CH3:13][NH:14][CH3:15].[CH2:16]=O.Cl>C(O)C>[CH3:13][N:14]([CH3:15])[CH2:1][CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CC(CN(C)C)C(=O)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
In a 500 ml round bottomed flask equipped with a reflux condensor was mixed 84 g of 4-chloropropiophenone (0.50 mole), 50 g of dimethylamine hydrochloride (0.61 mole), 20 g of paraformaldehyde (0.67 mole), 50 ml of ethanol, and 10 ml of concentrated aqueous hydrochloric acid. The mixture was refluxed for 18 hours, cooled and partitioned between ethyl ether and water. The ether layer was discarded and the aqueous layer was basified with sodium hydroxide and the resulting mixture extracted twice with fresh ethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 105 g of 3-dimethylamino-2-methyl-4'-chloropropiophenone, an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH:10]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH2:11].[Cl:17]CCl>>[Cl:17][CH:10]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH2:11][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ClCCl
Reactant: C=CS(=O)(=O)CC
Reactant: ClSc1ccc(Cl)cc1
Product: CCS(=O)(=O)C(Cl)CSc1ccc(Cl)cc1

Procedure:
Five grams of 4-chlorophenylsulfenyl chloride was refluxed with 3.3 g ethyl vinyl sulfone for 3 hours in 20 ml of dichloromethane. The stripped product showed 3 spots by thin layer chromatography and was purified by chromatography over silica gel. The purified product eluted with dichloromethane and solidified after stripping to a white solid, 6.4 g, m.p. 60°-62° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10](O)[CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Cl:22][CH:10]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)c1cc(C(C)(C)C)on1
Solvent: c1ccncc1
Solvent: O
Product: CC(Cl)c1cc(C(C)(C)C)on1
Reaction time: 5 h

Procedure:
1.18 g of 1-(5-t-butyl-isoxazol-3-yl)ethanol was dissolved in 2 ml of pyridine, and 1.36 of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.60 g of 3-(1-chloroethyl)-5-t-butylisoxazole.
Reaction SMILES: COC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=C(N)C=1.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([O:33][C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:37]3)=[C:31]([N+:51]([O-])=O)[CH:30]=1>>[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([O:33][C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:37]3)=[C:31]([NH2:51])[CH:30]=1
Reactant: COc1ccc(Oc2ccc3c(c2)CC(c2ccccc2)C3)c([N+](=O)[O-])c1
Agent: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1
Product: COc1ccc(Oc2ccc3c(c2)CC(c2ccccc2)C3)c(N)c1

Procedure:
5-Methoxy-2-(2-phenylindan-5-yloxy)phenylamine was prepared as described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine in Example 3(b) using 200 mg of 5-(4-methoxy-2-nitrophenoxy)-2-phenylindane. 1H-NMR (400 MHz, d6-DMSO): 7.33-7.27 (m, 4H), 7.23-7.18 (m, 2H), 6.82 (d, 1H, J 8.4 Hz), 6.81 (s, 1H), 6.77 (dd, 1H, J 2.3, 8.4 Hz), 6.69 (d, 1H, J 2.3 Hz), 6.48 (bd, 1H, J 6.4 Hz), 3.71 (s, 3H), 3.66 (k, 1H, J 8.3 Hz), 3.24 (dd, 2H, J 8.3, 15.6 Hz), 2.93 (m, 2H). (M)+=331 (100%)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.ClCCCl.O=[C:39]1[CH2:42][CH:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:39]4[CH2:40][CH:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:42]4)[CH2:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (8.00 g, 15.2 mmol) in 1,2-Dichloroethane (119.5 mL, 1517 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (2.58 g, 15.2 mmol) and Acetic acid (0.86 mL, 15 mmol) dropwise followed by Sodium triacetoxyborohydride (3.86 g, 18.2 mmol) and the mixture was stirred at RT for 19 h. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 150 mL sat NaHCO3. The aqueous phase was washed with 70 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a tan glass that produced a sticky foam when placed under high vac. The crude material was purified by flash chromatography (SiO2 eluting with 3-4% 7N NH3 in CH3OH/CH2Cl2) to yield a light yellow viscous oil that producted a sticky foam under high vacuum (5.03 g). MS 608.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 81.7 %

Procedure:
9.6 g of N-benzyloxycarbonyl-DL-isoleucine, 3.7 g of triethylamine, 150 ml of chloroform, 3.9 of ethyl chlorocarbonate and 3.7 g of 2-amino-1,3,4-thiadiazole were subjected to a reaction similar to that in Example 1(i) to obtain 10.3 g (yield: 82%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 145°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:13][N:12]=[C:8]2[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: NN
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To 1-(5-bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol.) was added anhydrous hydrazine (240 mL, 7.65 mol.). The reaction mixture was heated under reflux for 10 hours. The reaction mixture was allowed to cool to room temperature and was stirred for 16 hours. The reaction mixture was added to ice (1.4 L). The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered and the white solid product was washed with water. The white solid was dried in a vacuum oven to afford the desired 5-bromo-3-methyl-1H-indazole 104 (86.1 g, 0.408 mol.) which was used without further purification.