Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[CH:10]=[CH:11][C:12]=1[CH3:13].O>N1C=CC=CC=1>[CH3:5][O:4][C:2](=[O:3])[NH:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:7]([Br:6])[CH:8]=1
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl chloroformate (0.202 ml, 2.62 mmol) was added to a solution of 3-bromo-4-methyl-phenylamine (243 mg, 1.31 mmol) in pyridine (2 ml), and the mixture was stirred at room temperature overnight. H2O was added to the reaction mixture, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane/AcOEt) to give (3-bromo-4-methyl-phenyl)-carbamic acid methyl ester (288 mg, 90%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([N+:22]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1.O.NN>[Ni].C(O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.5 gm (36.9 mmols) of 5-methyl-6-[3'-nitro-4'-benzylamino-phenyl]-4,5-dihydro-3(2H)-pyridazinone were added to a mixture of 20 ml of 99% hydrazine hydrate and 350 ml of ethanol, and then 10 gm of Raney nickel were added. After 24 hours' stirring at room temperature, the solid components were suction-filtered off, dissolved in dimethyl formamide, the catalyst was filtered off, and the filtrate was evaporated. The crystalline residue thus obtained was digested with ethanol, washed with ether and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][C:57]2[CH:61]=[C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])[O:59][N:58]=2)=[O:55])=[CH:49][CH:48]=1.O>CN(C=O)C>[C:62]([C:60]1[O:59][N:58]=[C:57]([NH:56][C:54](=[O:55])[NH:53][C:50]2[CH:49]=[CH:48][C:47]([NH:46][C:21]([C:17]3[CH:16]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)[CH:20]=[CH:19][N:18]=3)=[O:22])=[CH:52][CH:51]=2)[CH:61]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
4-(1-(tert-Butoxycarbonyl)piperidin-4-yloxy)picolinic acid from Step 2 (188 mg, 0.58 mmol) was stirred in 3 mL of DMF. TBTU (244 mg, 0.76 mmol) was added, followed by TEA (82 μL, 0.058 mmol). After 10 min, 1-(4-aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (Ref: Milanov, Zdravko V. et al. WO2005/48948 A2, 2005 Jun. 2) (160 mg, 0.58 mmol) was added, followed by TEA (82 μL, 0.058 mmol). The resulting mixture was stirred at rt for 3 h. LC-MS indicated that the reaction was complete. Water (20 mL) was then added, the precipitates were collected by filtration and washed with cold water, dried in vacuum oven to give tert-butyl 4-(2-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenylcarbamoyl)pyridin-4-yloxy)piperidine-1-carboxylate (280 mg, 83%) as an off-white solid. LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16]C)=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:18]>>[C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([NH2:18])=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2ccccc2)CC1
Product: NC(=O)[C@H]1CC[C@@H](Nc2ccccc2)CC1
Temperature: 100 °C

Procedure:
cis-Methyl 4-(phenylamino)cyclohexanecarboxylate (0.50 g, 2.14 mmol) was dissolved in methanolic ammonia (15 ml) in a pressure bomb and heated at 100° C. for three days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude compound which was washed with n-pentane and dried in vacuo to afford 300 mg (63%) of cis-4-(phenylamino)cyclohexanecarboxamide as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([C:34]=4[F:35])=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:38].[ClH:40].CCOCC>>[ClH:38].[ClH:40].[ClH:38].[F:35][C:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26][C:25]=1[C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:18]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ncc5ccccc5c4F)c3)cn2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1ncc2ccccc2c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[6-amino-5-(4-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (16.0 mg, 0.0327 mmol) in DCM (0.60 mL, 9.4 mmol) was added 1.0 M of HCl in Et2O (0.90 mL, 0.90 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately a pale yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight, yielding the title compound as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.38 (s, 1H), 9.08-8.99 (brm, 1H), 8.91-8.80 (brm, 1H), 8.53 (brs, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.24 (dd, J=8.2, 0.8 Hz, 1H), 8.06 (d, J=0.4 Hz, 1H), 8.03 (ddd, J=0.8, 7.0, 8.2 Hz, 1H), 7.92 (ddd, J=1.0, 7.0, 8.2 Hz, 1H), 7.88 (brs, 1H), 4.54-4.45 (mc, 1H), 3.38 (brd, J=13.2 Hz, 2H), 3.09 (brq, J=11.6 Hz, 2H), 2.27-2.08 (m, 4H). MS(ES+): m/z=389.18 (18) [MH+], 306.13 (100) [MH+-piperidine]. HPLC: tR=1.69 min (polar—5 min, ZQ2).
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.[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>O1CCOCC1.O>[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:30]2[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]2)[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in dioxane (2 mL) was added with N-isopropylpiperazine (4 mmol). The resulting mixture was heated at reflux for 10 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL) with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-(1H-indazol-6-yl)-2-(4-isopropyl-piperazin-1-yl)-5-nitro-benzamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20].[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[C:19]([C:18]([CH3:22])([CH3:21])[CH2:17][C:11]1[CH:12]=[C:13]([O:16][CH2:39][C:35]2[CH:34]=[C:33]([CH:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][CH:36]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])#[N:20]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C#N)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)-2,2-dimethylpropanenitrile (136 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (136 mg) and tributylphosphine (0.22 mL) in toluene (5.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (225 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:13][CH3:14])[C:3]([OH:12])([C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)[C:4]#[CH:5].I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(#N)C>[OH:12][C:3]([C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)([C:2]([CH3:15])([CH3:1])[CH2:13][CH3:14])[C:4]#[C:5][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CC(O)(c1cncnc1)C(C)(C)CC
Reactant: Ic1cccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(O)(C#Cc1cccnc1)c1cncnc1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 128 %

Procedure:
A stirred mixture of 4,4-dimethyl-3-hydroxy-3-pyrimidin-5-ylhex-1-yne (412 mg, 2 mmol), 3-iodopyridine (412 mg, 2 mmol), triethylamine (300 μl, 2.2 mmol), copper-I-iodide (20 mg), and bis(triphenylphosphine) palladium-II-chloride (20 mg) in dry acetonitrile (5 ml) under nitrogen was heated at 65° C. After 40 minutes, the reaction was cooled and quenched with dilute aqueous hydrochloric acid. The mixture was neutralised with ammonia, extracted with ethyl acetate (3×20 ml), and the organic extracts were combined. Washing with ammonia, water, and brine, drying over magnesium sulphate and concentration under reduced pressure gave yellow crystals (720 mg). Recrystallisation from ethyl acetate gave the desired product of melting point 170.5°-171.5° C.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:20][CH:19]=1>O>[Br:1][C:29]1[CH:28]=[C:27]([CH:30]=[O:31])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=1
Reactant: COc1cc(-c2ccc(F)cc2)ccc1C=O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(F)cc2)c(Br)cc1C=O
Reaction time: 0.67 h
Yield: 180.3 %

Procedure:
Dibromoisocyanuric acid (10.6 g) was added at 15° C. to 30° C. to a DMF (90 mL) solution of 4′-fluoro-3-methoxybiphenyl-4-carbaldehyde (16.0 g), and the mixture was stirred for 40 minutes. Then, water (30 mL) was added thereto, and the mixture was further stirred for 1 hour. The deposited solid was collected by filtration and washed with a mixed solution of DMF (15 mL) and water (15 mL) and water (30 mL) in this order to obtain the title compound (20.6 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH2:25][CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+]>O1CCCC1.CO>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[CH2:25][CH3:26])=[O:31]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cc3c(c2n1Cc1ccccc1)CCC3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCC3
Temperature: 40 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A solution 2-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-benzyl-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (10 mg, 0.023 mmol) in 1:1 tetrahydrofuran/methanol (3 mL) was treated with 1 M aqueous lithium hydroxide solution (1.5 mL) The resulting mixture was warmed to 40° C. and stirred for 2 h. The mixture was concentrated in vacuo and treated with dilute hydrochloric acid. The resulting precipitate was collected via vacuum filtration. The solid was slurried with methanol, and the resulting solid collected via vacuum filtration to provide 5 mg (52%) of the title product as a white solid. 1H NMR (CDCl3) δ 7.25 (m, 3H), 7.03 (bs, 1H, —NH), 6.90 (d, J=6 Hz, 2H), 6.57 (s, 1H), 6.45 (bs, 1H, —NH), 5.50 (s, 2H), 4.77 (s, 2H), 2.90 (m, 6H), 2.04 (quintet, J=7 Hz, 2H), 1.18 (t, J=7 Hz, 3H); TOS MS ES+ exact mass calculated for C24H25N2O5 (p+1): m/z=421.1763. Found: 421.1767.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH:24]3[CH2:28][CH2:27][N:26]([CH:33]4[CH2:34][O:31][CH2:32]4)[CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCNC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCN(C4COC4)C3)c2c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine (21 mg, 0.05 mmol, prepared in analogy to Example 21-4) and oxetan-3-one (7.2 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added acetic acid (8.6 μL, 0.15 mmol). After the mixture being stirred at 55° C. for 1 hour, sodium triacetoxyborohydride (21 mg, 0.10 mmol) was added to the mixture. After being stirred for 2 hours at 65° C., the reaction mixture was concentrated in vacuo. The residue was portioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The separated organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 10 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 8.30 (d, J=1.9 Hz, 1 H), 7.84 (d, J=1.8 Hz, 1 H), 7.78 (s, 1 H), 7.68-7.64 (t, J=3.7 Hz, 1 H), 7.53-7.49 (t, J=3.7 Hz, 2 H), 7.39 (d, J=1.7 Hz, 1 H), 5.98 (s, 1 H), 5.20 (s, 2 H), 4.83-4.78 (m, J=4.7 Hz, 2 H), 4.69-4.60 (m, J=8.4 Hz, 2 H), 4.55 (brs, 2 H), 4.37 (s, 1 H), 3.80-3.74 (m, J=4.1 Hz, 1 H), 3.65-3.61 (m, J=4.2 Hz, 2 H), 2.96-2.89 (m, J=6.6 Hz, 2 H), 2.75-2.72 (m, J=3.3 Hz, 1 H), 2.63-2.47 (m, J=15.9 Hz, 2 H), 2.45 (s, 3 H), 1.95 (m, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[K+].Cl>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([O-:3])=[O:2]
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1CS(=O)(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Adapting the procedure of Makosza, et al, Liebigs Ann. Chem., 1984, 8-14, a stirred mixture of 4-nitro-pyridine-N-oxide (1.40 g, 10.0 mmol) and chloromethylphenylsulfone (1.92 g, 10.0 mmol) in DMSO (25 mL) in a cold water bath is treated with a solution of KOH (4.0 g, 71 mmol) in DMSO, stirred for 45 min, poured into 1.0 M hydrochloric acid and water and extracted with CH2Cl2. The aqueous phase is filtered and the filtercake is dried in vacuo to afford the title compound, 1.20 g (41% yield). The organic extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant wet solid is heated in boiling ethanol:water (4:1) and filtered. The filtrate is cooled, concentrated and filtered. This filtercake is dried in vacuo to afford an additional portion of the title compound, 0.967 g (74% total yield), mp 219-220° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][N:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)c1ccnc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1ccnc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 33 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinic acid as described in example 8 step 6 (65 mg, yield 33%). 1H NMR (400 MHz, CDCl3) δ 8.94-8.92 (dd, J=5.0 Hz, 0.8 Hz, 1H), 8.50 (m, 1H), 8.39-8.36 (t, J=5.6 Hz, 1H), 7.88-7.86 (dd, J=5.0 Hz, 1.5 Hz, 1H), 7.79-7.77 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.35-7.33 (d, J=8.5 Hz, 2H), 3.83-3.82 (d, J=5.8 Hz, 2H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C22H17ClF3N6O2S: 507.07. found: 508.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][S:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[CH3:18][S:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CSc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: CSc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3-(methylmercapto)aniline (18 μl, 0.144 mmol) similar to Example 92 and isolated as a yellow solid (21 mg, 58%). 1H NMR (CDCl3): 8.87-8.85 (m, 1H), 8.58 (d, J=7.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.61 (s, 1H), 7.48-7.44 (m, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.17-7.14 (m, 1H), 7.10-7.06 (m, 1H), 7.01 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:4]=2[CH2:3]1.C(OC([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=O)C>C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:4]2[CH2:3][CH:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:8]3[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:16]=1
Reactant: CC(C)c1ccc2c(c1)C(Cl)Cc1ccc(F)cc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)C(N1CCNCC1)Cc1ccc(F)cc1S2

Procedure:
A mixture of 20 g of 10-chloro-3-fluoro-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin, 21 g of 1-(ethoxycarbonyl)piperazine and 30 ml of chloroform is refluxed for 5 hours. After cooling, it is diluted with chloroform, the solution thoroughly washed with water, dried with potassium carbonate and after filtration evaporated under reduced pressure. The residue (27 g, 96%) is a crude glassy 10-(ethoxycarbonylpiperazino)-3-fluoro-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin which is used for hydrolysis in this state without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:19][C@H:18](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:19][C@@H:18]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 15.0 g of 1-[(phenylmethoxy)carbonyl]-trans-4-tosyloxy-L-proline, methyl ester (J.A.C.S., 79, 191 (1957)) and 75 ml of piperidine is stirred at room temperature for 24 hours. The excess piperidine is removed under reduced pressure and the residue is dissolved in 50 ml of chloroform. The latter solution is extracted twice with 10 ml portions of water, dried (MgSO4), filtered and the solvent evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33][OH:34]>O.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([O:34][CH2:33][CH2:32][O:31][CH3:30])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: COCCO
Reactant: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(Cl)nc32)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(OCCOC)nc32)cc1)OCC
Temperature: 120 °C

Procedure:
To a solution of diethyl 4-((6-amino-2-chloro-9H-purin-9-yl)methyl)benzylphosphonate (1 equiv.) in 2-methoxyethanol (0.10 M) was added sodium hydride (1.3 equiv.). The reaction mixture was then heated to 120° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature. The mixture was then diluted with water and EtOAc. This mixture was transferred to a separatory funnel and washed with water three times. The organic layer was then separated, dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound in quantitative yield as a solid.