Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].C(OC([NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=O)(C)(C)C.O.Cl>C(OCC)(=O)C>[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:26])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) and 4-(t-butoxycarbonylamino)piperidine (38.9 mg) was stirred at 140° C. for 5 hours. To the remaining product, water was added and the mixture was extracted with ethyl acetate, followed by drying on anhydrous sodium sulfate. The solvent was then removed to obtain a residue. To this residue, a 3 mol/L ethyl acetate solution of hydrogen chloride (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was again removed to obtain a residue. To this residue, ethyl acetate was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, followed by drying on anhydrous sodium sulfate. The solvent was then removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:methanol=3:1) to obtain 9-(4-aminopiperidine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (35.0 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])(=O)=O.Cl>C1(C)C=CC=CC=1.C(NCC(C)C)C(C)C.S(Cl)(Cl)(=O)=O>[Cl:22][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:10][CH2:11][C:12]=2[C:2]=1[OH:1]
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Temperature: 24 °C
Reaction time: 0.83 h
Yield: 88.8 %

Procedure:
Heat a mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 g, 0.4629 mol) and toluene (14.4 L) to 70° C. for 45 min until most of the starting material is dissolved. Add diisobutylamine (1.197 g, 1.62 mL, 9.26 mmol) followed by addition of sulfuryl chloride (62.48 g, 37.19 mL, 0.463 mol) in toluene (360 mL) over 20 min. Stir the reaction mixture for 50 min and then add additional sulfuryl chloride (4.536 g, 2.70 mL, 0.0336 mol) neat and stir the reaction mixture for 15 min at 70° C. Cool the reaction mixture to 24° C. over 30 min and then add 1N hydrochloric acid (2 L). Separate, wash the organic layer with saturated aqueous NaHCO3 (2 L), brine (2 L) and then dry over Na2SO4. Filter and remove the solvent with a rotary evaporator at 70° C. until about 672.5 g remains using the minimum effective vacuum in order to maintain a vapor phase sufficient to prevent drying above the solvent line and self-seeding, thus preventing crystallization under these conditions. Using toluene heated to 70° C., transfer the light-yellow solution to a preheated (70° C.) 3-neck flask equipped with a mechanical stirrer. Lower the temperature to 58° C. over 1 h. If available, seed the solution with crystals of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine from a prior synthesis to enhance crystallization. After 30 min, reduce the temperature further to 55° C. and observe the initiation of the crystallization process. Hold the temperature at 55° C. for 2 h followed by 4 h at 45° C., then turn off the heat allowing the mixture to slowly reach 24° C. (ambient temperature). After stirring for 8 h with the heat off, cool the mixture to 0° C. for 2 h followed by 2 h at −10° C. Collect the resulting dense, white, granular crystals by vacuum filtration at −10° C. Rinse the crystals twice with cold (−10° C.) toluene and vacuum dry at 50° C., 5 Torr, for 12 h., to obtain the desired intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp 133-134° C. MS (ES+) m/z 294 (M+H)+. Anal. Calc'd for C12H11ClF3NO2: C, 49.08; H, 3.78; N, 4.77; Cl, 12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[N:10]1[CH2:15][CH2:14][C:13]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1.[I:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(N(CC)CC)C>CCO>[I:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[CH2:8][CH2:9][CH:4]([OH:3])[CH:5]([N:10]2[CH2:15][CH2:14][C:13]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:11]2)[CH2:6]1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Reactant: BrCc1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC1CCN(Cc2cccc(I)c2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of 21c and 22c derived from a mixture of 19c and 20c as described above (676 mg, 1.81 mmol), 3-iodobenzylbromide (2.17 mmol, 645 mg), and triethylamine (10 mL) in absolute EtOH (20 mL) was refluxed for 18 h. Volatiles were removed under reduced pressure and the red residue was treated with water. After extraction in dichloromethane (3×30 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a dark red semi-solid residue. Chromatographic purification (silica gel, 50% ethyl acetate-hexanes) afforded 276 mg (30%) of the crude product as a yellow oil. The two regioisomers were separated by HPLC (Silica gel, Hexane/Isopropanol/Triethylamine: 98/2/0.02) and 13d was obtained as a white crystalline solid (166 mg, 18%). Only a trace of the other isomer was recovered. The hydrochloride of 13d was prepared in said methanolic saturated HCl and subsequently recrystallized from 50% i-PrOH-hexanes to provide a white powder; mp 245° C. 1H NMR ((CDCl3) δ1.59-2.06 (m, 8, 2 N--C H2 --C H2), 2.41-2.48 (m, 2, Ar--C H2 --CH2), 2.52-2.62 (m, 2, C H2 --CHOH), 2.75-2.78 (m, 4, Ar--CH2 --C H2 --C H2), 2.83-2.92 (m, 2, C H2 --CH2 --CHOH), 3.01-3.06 (d, 2, N--C H2 --CHN, J=10.0 Hz), 3.38-3.56 (m, 3, Ar--CH2 --N+CH--N), 3.85 (s, 1, C H--OH), 7.02-7.31 (m, 5, arom.), 7.44-7.48 (d, 1, arom., J=7.8 Hz), 7.58-7.62 (d, 1, arom., J=7.9 Hz), 7.68 (s, 1, arom.).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.[Cl:29]N1C(=O)CCC1=O>ClCCl>[Cl:29][C:6]1[S:5][C:4]([C@H:3]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:11])[CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1cccs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1ccc(Cl)s1
Yield: 36.3 %

Procedure:
To a solution of 1-[(1R)-2-hydroxy-1-(2-thienyl)ethyl]-3-[4-(4-pyridinyl)phenyl]urea (700 mg) and acetic acid (734 mg) in dichloromethane (10 mL) were added N-chlorosuccinimide (303 mg) and the mixture was refluxed for 3 hours. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform/methanol (9:1) and crystallized from ethanol to afford 1-[(1R)-1-(5-chloro-2-thienyl)-2-hydroxyethyl]-3-[4-(4-pyridinyl)phenyl]urea (280 mg) as a crystal.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([I:21])[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].IC1C=CC=C2C=1N=C(SC)N(C[CH2:36][O:37][CH2:38]COC)C2=O>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:36][O:37][CH3:38])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([I:21])[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: COCCOCCn1c(SC)nc2c(I)cccc2c1=O
Product: COCCOCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O

Procedure:
This compound (0.33 g, 0.74 mmol) was prepared according to the procedures described for Intermediate 715, starting from 8-iodo-3-(2-(2-methoxyethoxyl)ethyl)-2-(methylthio)quinazolin-4(3H)-one (716b; 0.79 g, 1.87 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (ddd, J=14.43, 7.68, 1.56 Hz, 2H), 6.84 (t, J=7.73 Hz, 1H), 6.20 (s, 1H), 4.19-4.25 (m, 2H), 3.81-3.86 (m, 2H), 3.60-3.65 (m, 2H), 3.51-3.56 (m, 2H), 3.35 (s, 3H), 1.61 (s, 9H). m/z (ESI, +ve ion) 446.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:34])([F:33])[F:32])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:33])([F:32])[F:34])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([N:22]([CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)[C:36](=[O:37])[O:38][CH3:39])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C1CCCO1
Yield: 23.7 %

Procedure:
In a suspension of 0.07 g of 55% oily sodium hydride in 10 mL of tetrahydrofuran, a solution of 0.49 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(2-tetrahydrofuranyl)benzoic acid amide in 5 mL of tetrahydrofuran was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was stirred at at room temperature for 10 minutes. Then, 0.15 g of methyl chloroformate was added, and continued to stir at the same temperature further for 15 hours. After the completion of the reaction, the reaction was poured in 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.13 g of the aimed product as colorless resinous substance.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C[O-].[Na+]>C(O)C>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Sc1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Sc1ncc[nH]1
Yield: 75 %

Procedure:
A mixture of 5.0 g (0.05 mole) of 2-mercaptoimidazole. 7.9 g (0.05 mole) of 2-chloronitrobenzene, 6.5 g (0.12 mole) of sodium methoxide and 150 ml of ethanol was stirred and refluxed for 5 hours. An additional 0.8 g of 2-chloronitrobenzene, was added and refluxing continued for 5 more hours. The mixture was filtered hot and the filtrates concentrated. The residue was partitioned with water and dichloromethane. The undissolved solid was collected by filtration to give 8.3 g of product. The dichloromethane was dried and concentrated. The residue was recrystallized from dichloromethane to give an additional 1.2 g of product. The total yield was 87% and the product was obtained as yellow rods, mp 178°-181° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[I-].[CH3:11][S+](C)C.[OH-].[K+]>CC#N.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[CH2:11][O:9]2)[N:7]=1
Reactant: O=Cc1cccc(F)n1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1cccc(C2CO2)n1
Temperature: 67.5 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of 6-fluoro-pyridine-2-carbaldehyde (1.88 g, 15 mmol), trimethylsulfonium iodide (3.3 g, 16.2 mmol) and KOH (crashed, 3.46 g, 61.9 mmol) in CH3CN (190 mL, containing 0.2 mL of water) was stirred at 65-70° C. under N2 for overnight. The mixture was cooled to rt and diluted with EtOAc (100 mL). After filtration, the filtrate was concentrated. The residue was portioned between H2O (100 mL) and EtOAc (80 mL), the aqueous layer was further extracted with EtOAc (4×80 mL). the combined EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (530 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:39])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[C:32](=[O:37])[C:31]2=[O:38])[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:39])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[C:32](=[O:37])[C:31]2=[O:38])[CH:25]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C(=O)C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)NS(=O)(=O)C5CC5)cc4CC3(C)C)c2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (192 mg, 4.8 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (593 mg, 4.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (200 mg, 1.2 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (51 mg, 20%) as a white solid: LC/MS m/e calcd for C26H30N4O5S (M+H)+: 511.62, observed: 511.2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][S:11](Cl)(=[O:13])=[O:12].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:10][S:11]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
Quinuclidin-3-ol (10.0 g, 0.0787 mol) was dissolved under N2 in dry dichloromethane (200 ml) and cooled in an ice bath to 0° C. Methanesulphonyl chloride (7.3 ml, 10.8 g, 0.094 mol, 1.2 eq) and dry pyridine (7.64 ml, 7.46 g, 0.094 mol, 1.2 eq) were added and the mixture stirred at 0° C. for 20 min. The solution was then warmed to r.t. and stirred under N2 for 1 h. Saturated aqueous potassium carbonate solution (150 ml) was added, and the organic layer extracted and collected. The aqueous layer was re-extracted with EtOAc (3×200 ml), the organic solutions dried (Na2SO4), filtered, and evaporated to dryness under reduced pressure to yield a pale yellow oil which was pumped under high vacuum to remove any last traces of pyridine to yield the title compound (D8) (15.8 g, 98%).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:6]=1[C:21](=[O:23])[CH3:22].[CH:24](OCC)=O.Cl>O>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]2[C:6]([C:21](=[O:23])[CH:22]=[CH:24][NH:4]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of sodium methylate (270 mmol, 14.75 g, favorable prepared from sodium metal and methanol before use), 1,2-dimeythoxyethane (122 ml) and 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (6.68 g 24 mmol) was stirred at 0° C. for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132 mmol) was added to the reaction mixture, that was allowed to come to room temperature and stirred for further 4 hours. The mixture was diluted with water (50 ml) and acidified to pH 1 by adding hydrochloric acid (1N, 185 ml). The precipitate was filtered, washed with water and dried to give 6.51 g of product [D]. Yield: 94%.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4F)c3c2s1
Yield: 68 %

Procedure:
Prepared from VII and 2,4-difluoroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 68%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2228, 1645, 1611, 1583, 1557, 1488, 1460, 1378, 1357, 1311, 1276, 1260, 1172, 1138, 1091, 962, 854, 831, 818; 19F NMR (282 MHz, DMSO-d6) δ −117.6, −118.7; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.22 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.35-7.24 (m, 2H), 7.06 (t, 1H, J=7.8 Hz); HRMS calcd for C16H8N5SF2 (M+H+): 340.0468, found 340.0458.
Reaction SMILES: [Na].[C:2](OCC)(=O)[CH2:3][C:4](OCC)=O.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:4][CH2:3][CH3:2])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na]
Solvent: O
Product: CCCc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Sodium metal (6.9 g, 300 mmol) was added in small pieces to a refluxing solution of diethyl malonate (90 ml, 480 mmol). When the sodium was completely dissolved, 2-chloro-5-nitropyridine (45 g, 285 mmol) was added in small portions. Reflux was continued for 20 hours. Water (500 ml) was added and the organic material was extracted into 4×200 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude malonate intermediate was then dissolved in 100 ml of water and 100 ml of concentrated sulphuric acid, and the mixture was refluxed at 110° C. for 18 hours. The mixture was then poured into 1200 ml of concentrated sodium hydroxide solution, and the organic material was extracted into 5×350 ml of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was evaporated. This gave 42.60 g (90%) of 5-nitro-2-n-propylpyridine as an orange oil. 1H-NMR (MeOD, 200 MHz) δ: 0.98 (t, 3H); 1.79 (sext, 2H); 2.89 (t, 2H); 7.51 (d, 1H); 8.48 (dd, 1H); 9.25 (d, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO.[Rh]>[ClH:1].[NH2:2][C@@H:3]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CC1CCCCC1

Procedure:
L-Phenylalanine, methyl ester, hydrochloride, 292 g (1.35 mol) in about 4 L of methanol is exposed to hydrogen gas in the presence of 10% Rhodium on carbon catalyst. After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure to a volume of about 500 ml. Diethyl ether, about 1 liter, is added to the thick slurry of crystals and the mixture filtered and washed with diethyl ether to afford 288.9 g of (S)-α-aminocyclohexanepropanoic acid, methyl ester, hydrochloride; mp 157°-159° C.; [α]D23 =+21.6° (c=1.09% methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([CH2:13][C:14]([O:16]CC)=O)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH3:21][CH:22]([CH3:37])[CH2:23][CH2:24][N:25]1[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28](=O)[O:27]C1=O.[H-].[Na+].C(O)(=O)C>C1COCC1>[OH:27][C:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:25]([CH2:24][CH2:23][CH:22]([CH3:37])[CH3:21])[C:14](=[O:16])[C:13]=1[C:8]1[NH:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:10](=[O:11])(=[O:12])[N:9]=1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OC)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 0 °C
Yield: 79.9 %

Procedure:
To a solution of the product of Example 183B (0.5 g, 1.6 mmol) and the product of Example 12A (0.375 g, 1.6 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. was added sodium hydride (95%, 0.162 g, 6.4 mmol). The reaction was heated at reflux for 4 hours, cooled to 0° C., and treated dropwise with glacial acetic acid (3 mL). The resulting mixture was heated at reflux for 2 hours, cooled to 25°, and diluted with ice water (150 mL). The resulting precipitate was collected by filtration, washed with water and recrystallized from dioxane/water to give the title compound (566 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 441 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.62 Hz, 6 H) 1.48 (m, 2 H) 1.64 (m, 1 H) 3.82 (s, 3 H) 4.29 (m, 2 H) 7.16 (m, 4 H) 8.36 (dd, J=7.54, 2.02 Hz, 1 H) 8.52 (dd, J=4.60, 2.02 Hz, 1 H) 15.86 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc(F)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(2,6-dichlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 12—Step A–B, (replacing methyl 2-fluorophenoxyacetate with methyl 2,6-dichlorophenoxyacetate) 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1–2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.131 g of the hydrochloride salt (Mass spec. M+1=430, MP=248.2–249.1° C.).