Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=O)=[CH:3][CH:2]=1.[NH2:24][NH2:25].Cl>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12](=[N:24][NH2:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(Cc1ccnc2ccccc12)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: NN=C(Cc1ccnc2ccccc12)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-quinolin-4-yl-1-(3-trifluoromethyl-phenyl)-ethanone (1.0 g, 3.2 mmol) in ethanol (13 mL) is cooled to 0° C. and treated with hydrazine (0.6 g, 19 mmol) and concentrated hydrochloric acid (0.13 mL, 1.6 mmol). The mixture is refluxed for 2 h and concentrated in vacuo. The residue is taken up in dichloromethane and washed with saturated sodium bicarbonate (30 mL), water (2×30 mL), and brine (30 mL). The solution is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to yield the title compound, 1.0 g (97%), as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(C)(=O)=O)n3)ccc21

Procedure:
Title compound was prepared from 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (63 mg, 58%). LCMS: 501.11 (M+H), HPLC purity 99%, MP 105-109, 1H-NMR (CDCl3, 400 MHz) δ 12.01 (s, 1H), 10.27 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 8.05 (s, 1H), 7.57-7.44 (m, 4H), 7.15 (d, J=8.6 Hz, 1H), 3.35 (s, 3H), 3.14 (s, 3H), 2.34 (t, J=7.0 Hz, 2H), 2.07-2.03 (m, 2H), 1.24 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[N:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[N:19][C:18]([NH:22][CH:23]=O)=[CH:17]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[N+:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][N:19]=1)[C:12]([N:3]1[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]1=[O:11])=[N:13][CH:14]=[CH:15]2)#[C-:23]
Reactant: O=CNc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]c1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
4-8 (90.0 mg, 0.280 mmol) was suspended in CH2Cl2 (10 mL) and cooled to 0° C. To the mixture were added triphosgene (252 mg, 0.85 mmol) followed by Et3N (0.240 mL, 1.69 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine, and dried over Na2SO4. The residue was purified by silica gel chromatography (0-5% EtOAc in CH2Cl2) to give 73.3 mg (41%) of 4-9 as a pale white solid: 1H NMR (300 MHz, CDCl3) δ 9.18 (1H, br s), 8.86 (1H, d, J=5.7 Hz), 8.06 (2H, m), 7.90 (2H, m), 7.85 (1H, br s), 7.84 (1H, d, J=5.7 Hz); ESI-MS m/z 301 [C17H8N4O2+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1.[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([NH:23][CH3:24])[CH:14]=1.Cl>CCCCCC.O1CCCC1.O>[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:18])[CH2:6][C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[C:15]([NH:23][CH3:24])[CH:14]=1
Reactant: Cc1nnn[nH]1
Reactant: CNc1cc(F)ccc1C(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CNc1cc(F)ccc1C(=O)Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 53 ml) was added to a stirred suspension of 5-methyltetrazole (6.0 g) in dry tetrahydrofuran (250 ml) at 0° under nitrogen. A solution of methyl 4-fluoro-2-methylaminobenzoate (4.36 g) in dry tetrahydrofuran (20 ml) was added during 10 minutes. The mixture was stirred for 17 hours at room temperature and then for 3 hours at 40° to 70°. The mixture was cooled to room temperature and water (200 ml) was added. The mixture was neutralised with dilute aqueous hydrochloric acid and extracted with dichloromethane (3×100 ml). The combined extracts were dried and evaporated under reduced pressure. The residue was crystallised from industrial methylated spirit to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(1H-tetrazol-5-yl)ethanone, m.p. 214°-6°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:15])[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]1=[O:30])[CH2:6]2
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCCN1C(=O)c3ccccc3C1=O)C2
Yield: 96.4 %

Procedure:
5.3 g (25.5 mmoles) of 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methyl-methanamine and 6.8 g (25.5 mmoles) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione are dissolved in 230 mL of acetone. 13 g (95 mmoles, 3.7 eq.) of potassium carbonate are added to the resulting solution. The mixture is then heated at reflux for 24 hours. After returning to ambient temperature, the potassium carbonate is filtered off and the filtrate is evaporated to dryness. The residue is taken up in water and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated to dryness. 9.7 g of expected product are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:49])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:49][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a solution of the acid (27) (75 mg, 0.36 mmol) and HOBt (54 mg, 0.40 mmol) in DMF (6 mL), was added amine 9 (135 mg, 0.40 mmol). After stirring for 5 min, EDC (84 mg, 0.42 mmol) was added and the reaction mixture was stirred for additional 4 hrs at room temperature. The reaction mixture was poured into NaHCO3 solution, extracted with EtOAc; the organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (Aquasil C-18 column, gradient MeOH/water from 60:40 to 95:5) to afford 28a (105 mg, 55% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.80 (s, 1H), 9.62 (s, 1H), 8.66 (d, 1H), 8.33 (s, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.54-7.49 (m, 2H), 7.06 (m, 2H), 6.89 (m, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 3.66 (s, 2H). MS (m/z): 532.0 (M+H).
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([C:30]4[CH:29]=[C:28]([C:31](=[O:33])C)[CH:27]=[CH:26][C:25]=4[C:24]4[C:19]3=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:8]=2[CH:7]=1)(=[O:5])C.[OH-:34].[Na+].S([O-])(O)=[O:37].[Na+]>O.O1CCOCC1>[CH:29]1[C:30]2[C:9]3([C:8]4[CH:7]=[C:6]([C:3]([OH:5])=[O:34])[CH:18]=[CH:17][C:16]=4[C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][C:28]=1[C:31]([OH:33])=[O:37]
Reactant: CC(=O)c1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C(C)=O)cc21
Reactant: [OH-]
Reactant: O=S([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: 25 °C

Procedure:
First 7.2 g of bromine and then a solution of 3.0 g of 2,2'-diacetyl-9,9'-spirobifluorene in a little dioxane are added dropwise at 0° C. while stirring to a solution of 6.0 g of sodium hydroxide in 30 ml of water. After stirring for a further hour at room temperature, the clear yellow solution is admixed with 1 g of sodium hydrogen sulfite dissolved in 20 ml of water. After acidification with concentrated hydrochloric acid, the precipitated colorless product is filtered off and washed with a little water. Recrystallization with ethanol gives 9,9'-spirobifluorene-2,2'-dicarboxylic acid as clear prisms (m.p. 352° C.).
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC(=O)OCC.O>[CH3:22][N:6]1[C:5]2[S:23][C:2]([O:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:36])[F:37])[CH:30]=3)=[C:3]([CH:24]=[O:25])[C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(OC(F)(F)F)c3)sc21
Temperature: 80 °C
Yield: 40.8 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2, 3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (See Compound 2, Step 4, 100 mg, 0.232 mmol) in DMSO (2 mL) was added 3-(trifluoromethoxy)phenol (82.6 mg, 0.464 mmol) and K2CO3 (96.1 mg, 0.696 mmol). The reaction was heated to 80° C. for 18 h, cooled to RT then diluted with EA (10 mL) and water (10 mL). The organic layer was washed with aq. 1N LiCl (3×5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 3:1) to give 1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (50 mg, 40.8% yield) as a solid. LCMS: [MH+-THP] 445 and TR=1.834 min.
Reaction SMILES: [OH:1][C:2]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:24]/[OH:25])/[NH2:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([O:12]CC)=[O:11])[CH2:5]1.[C:26]1([C:32]2[C:36]([C:37]([F:40])([F:39])[F:38])=[C:35]([C:41](F)=O)[O:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[OH:1][C:2]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:41]([C:35]3[O:34][N:33]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:36]=3[C:37]([F:40])([F:38])[F:39])[O:25][N:24]=2)=[CH:20][CH:21]=1)([CH3:15])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([OH:12])=[O:11])[CH2:5]1
Reactant: CCOC(=O)[C@H]1CCCN(CC(C)(O)c2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CN1CCC[C@H](C(=O)O)C1)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
To a mixture of (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)propyl)piperidine-3-carboxylate (72 mg, 0.206 mmol) and 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (53.4 mg, 0.206 mmol) in acetonitrile (5 mL) was added DIEA (0.072 mL, 0.412 mmol). After 2 hr, TBAF in THF (0.206 mL, 0.206 mmol) was added and the reaction was stirred overnight at RT. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass and concentrated in vacuo. The residue was treated with 6N HCl with MeCN as a co-solvent and heated at 50° C. for 4 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 12 mg of (35)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.10-8.19 (2H, m), 7.68-7.80 (2H, m), 7.59 (2H, d, J=6.59 Hz), 7.44-7.56 (3H, m), 3.59-3.81 (2H, m), 3.31-3.53 (2H, m), 3.01-3.19 (1H, m), 2.73-3.00 (2H, m), 1.73-2.12 (2H, m), 1.60 (3H, d, J=15.82 Hz), 0.68-1.45 (3H, m). HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:13]C(OCC1C=CC=CC=1)=O)[CH3:3].CO.[H][H]>[Pd].O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH2:13])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
A solution of 8.7 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline N-ethylamide hydrochloride in 100 ml. of methanol is stirred with 500 mg. of 20% palladium on carbon under one inch water pressure of hydrogen for three hours. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure and at 35°-40° C. The residual foam is used without further purification.
Reaction SMILES: C(N(CC)CC)C.S(O/[N:19]=[C:20](\[C:27]#[N:28])/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CO>[NH2:28][C:27]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:19][S:29][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)O/N=C(\C#N)c2ccccc2)cc1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1snc(-c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Triethylamine (5.39 g, 53.3 mmol) was added dropwise to a stirred solution of (Z)—N-(tosyloxy)benzimidoyl cyanide (Preparation 103B, 8 g, 26.6 mmol) and methyl 2-mercaptoacetate (2.86 mL, 32.0 mmol) in MeOH (70 mL) at room temperature. After stirring at room temperature for 3 h, the reaction was cooled and treated with 100 mL ice/water. The resultant solid was filtered and washed with water. The solid was vacuum dried to yield 6 g brown colored solid. Recrystallization from hexane/ethyl acetate yielded the titled compound (3 g) as a beige colored needles. The compound had an LC/MS M+1=235.2.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:9][O:10][C:11]2[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.[F:22][C:23]([F:34])([F:33])[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[CH3:3][C:4]1([CH2:9][O:10][C:11]2[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][N:6]([C:30]([C@H:27]2[CH2:26][CH2:25][C@H:24]([C:23]([F:22])([F:33])[F:34])[CH2:29][CH2:28]2)=[O:31])[CH2:5]1
Reactant: CCOC(=O)c1ncccc1OCC1(C)CCNC1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OCC1(C)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-((3-methylpyrrolidin-3-yl)methoxy)picolinate dihydrochloride (EXAMPLE 86, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.O.Cl.[O:13]=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:17]1[CH2:18][CH2:19][C:14](=[O:13])[CH2:15][CH2:16]1
Reactant: O=C1CCNCC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of 3,4-dichlorobenzyl chloride (2.8 ml), 4-ketopiperidine hydrochloride monohydrate and triethylamine (8 ml) in dimethylformamide (30 ml) was stirred at room temperature for 20 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate/isohexane. Yield 2.1 g.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:15](Cl)(=[O:17])=[O:16].C([O:23][C:24](=[O:30])[C@H:25]([CH:27]([CH3:29])[CH3:28])[NH2:26])(C)(C)C.C(N(CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH3:28][CH:27]([CH3:29])[C@H:25]([NH:26][S:15]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[CH:1]=1)(=[O:17])=[O:16])[C:24]([OH:30])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1S2)C(=O)O
Reaction time: 2 h
Yield: 17.4 %

Procedure:
The crude thianthrene-2-sulfonyl chloride (1.19 g, 3.77 mmol) was mixed with 0.79 g (3.77 mmol) of (L)-valine-t-butyl ester and triethyl amine (1.58 mL, 11.3 mmol) in 50 mL of dichloromethane. After 2 hours, the reaction was partitioned between 1 M HCl and dichloromethane. The organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, and concentrated to give an oily green solid. This compound (0.46 g, 1.0 mmol) was stirred in 5 mL of trifluoroacetic acid for 1 hour and then concentrated in vacuo. The residue was triturated with diethyl ether to give 0.26 g of the title compound as a fluffy white solid.
Reaction SMILES: [ClH:1].FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(NC[C@H]3CCNC3)=O)SC=12.[F:41][C:42]1[CH:76]=[C:75]([NH:77][C:78]([NH:80][C:81](=[O:89])[CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[S:79])[CH:74]=[CH:73][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]3[CH:59]=[CH:58][C:57]([N:60]4[CH2:65][CH2:64][N:63](C(OC(C)(C)C)=O)[CH2:62][CH2:61]4)=[CH:56][CH:55]=3)[S:53][C:46]=12>>[ClH:1].[ClH:1].[F:41][C:42]1[CH:76]=[C:75]([NH:77][C:78]([NH:80][C:81](=[O:89])[CH2:82][C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)=[S:79])[CH:74]=[CH:73][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]3[CH:55]=[CH:56][C:57]([N:60]4[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]4)=[CH:58][CH:59]=3)[S:53][C:46]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)CC1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)NC[C@H]4CCNC4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(N5CCNCC5)cc4)sc23)c(F)c1
Yield: 21 %

Procedure:
Following the procedure described above for the synthesis of compound 137a (scheme 25, example 97) but substituting compound 135b for the compound 158, title compound 159 was obtained in 21% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.48(s, 1H), 11.84(s, 1H), 9.26(bs, 1H), 8.62(d, J=5.6 Hz, 1H), 8.05(d, J=12.0 Hz, 1H), 7.94(s, 1H), 7.81(d, J=8.8 Hz, 2H), 7.62-7.55(m, 2H), 7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 7.10(d, J=8.8 Hz, 2H), 6.85(d, J=5.6 Hz, 1H), 3.83(s, 2H), 3.58-3.51(m, 4H), 3.26-3.18(m, 4H). LRMS (M+1) 597.2 (100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][CH:17]([C:20]([O:22]C)=[O:21])[CH2:18][CH2:19][C:13]=3[O:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].O>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][CH:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19][C:13]=3[O:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCc2onc(-c3ccc(C(C)C)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(-c2noc3c2CCC(C(=O)O)CC3)cc1
Temperature: 20 °C
Reaction time: 68 h
Yield: 73.4 %

Procedure:
0.286 g (0.00091 mol) of methyl 5,6,7,8-tetrahydro-3-(4-isopropylphenyl)-4H-cyclohept[d]isoxazole-6-carboxylate was dissolved in 15 ml of methanol, 0.15 g (0.0027 mol) of potassium hydroxide and 2 ml of water were added and the mixture was stirred at 20° C. for 68 hours. The methanol was removed by evaporation. Water was added and the mixture was extracted once with diethyl ether. The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with sodium chloride solution and dried over magnesium sulfate. Evaporation gave a residue which was crystallized from methylcyclohexane to give 200 mg of 5,6,7,8-tetrahydro-3-(4-isopropylphenyl)-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 109°-111° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[N:3]=1.[CH3:26][NH2:27].C1[CH2:32][O:31]CC1>>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][CH:22]([CH3:25])[CH2:23][O:24][C:32](=[O:31])[NH:27][CH3:26])[N:3]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N[C@H](C)CO)nc2N)cc1Cl
Reactant: CN
Reactant: C1CCOC1
Product: CNC(=O)OCC(C)Nc1ncc(Oc2cc(Cl)c(OC)cc2C(C)C)c(N)n1
Reaction time: 2 h

Procedure:
1,1-Carbonyldiimidazole (0.97 g, 6 mmol) was added to a solution of 2-[4-Amino-5-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-ylamino]-(R)-propan-1-ol from Example 4 (0.22 g, 0.6 mmol) in 20 mL of THF at room temperature. The mixture was stirred for 2 hours and methylamine (3 mL, 2M/THF, 0.6 mmol) was added. The reaction mixture was stirred overnight and concentrated under reduced pressure, diluted with water (75 mL), and extracted with EtOAc (2×75 mL). The organic phase was washed with Brine and dried with MgSO4. The solution was filtered and concentrated. The residue was purified on two Silica preparative TLC plates (20×40 cm) eluting with 5% MeOH/dichloromethane affording 143 mg of methyl-carbamic acid 2-[4-amino-5-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-ylamino]-propyl ester: MS (M+H); 424: MP; 63.5-69.4° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:17]O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: O=C(O)CCCc1nc2ccccc2s1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCc1nc2ccccc2s1
Yield: 73 %

Procedure:
A solution of 4-(2-benzothiazolyl)butanoic acid (3.75 g, 16.1 mmol, prepared according to the procedure of Example 11 in JP, A, 8-208631 (1996)) in hydrochloric acid-methanol (80 ml) was stirred at room temperature overnight, and evaporated. The residue was dissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and purified through flash column chromatography to give methyl 4-(2-benzothiazolyl)butanoate (2.75 g, 73%).