Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[O-]P([O-])([O-])=O.[Na+].[Na+].[Na+].[CH3:36][NH:37][C:38](=[O:41])[CH2:39]Cl>CN1C(=O)CCC1>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:39][C:38]([NH:37][CH3:36])=[O:41])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CNC(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CNC(=O)CN1CC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C1
Yield: 28.5 %

Procedure:
A solution of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride from Example 65 (70 mg, 0.2 mmol) in NMP (2 mL) was treated with sodium phosphate tribasic (85 mg, 0.6 mmol) then N-methyl-2-chloro acetamide (24 mg, 0.22 mmol) in NMP (0.2 mL) and the mixture stirred at RT for 18 h. The mixture was loaded onto an Isolute® SCX-2 cartridge eluting with MeOH then 2M NH3 in MeOH. Appropriate fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 212 (24 mg, 29%). 1H NMR δ (ppm)(CDCl3): 8.50 (1 H, d, J=8.29 Hz), 7.89 (1 H, s), 7.68 (1 H, s), 7.22 (1 H, s), 7.10 (1 H, dd, J=8.33, 1.81 Hz), 6.99-6.96 (1H, m), 6.03-5.94 (1 H, m), 4.53-4.49 (2 H, m), 4.48-4.44 (2 H, m), 3.96 (2 H, t, J=7.77 Hz), 3.81 (1 H, t, J=7.74 Hz), 3.54 (2 H, t, J=7.43 Hz), 3.35 (2 H, s), 2.86 (3 H, d, J=4.93 Hz), 1.60 (6 H, d, J=6.63 Hz). LCMS: RT=2.53 min, M+H+=422
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][NH:10][C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[N:13]=1.[C:18]([Cl:27])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21]>>[ClH:27].[C:18]([N:10]1[C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[NH:9]1)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21]
Reactant: c1ccc(C2=Nc3cnccc3NN2)nc1
Reactant: O=C(Cl)c1ccccc1O
Agent: Cl
Product: O=C(c1ccccc1O)N1NC(c2ccccn2)=Nc2cnccc21
Yield: 78 %

Procedure:
2.46 g (0.01 moles) of 3-(2-pyridyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with salicyloyl chloride as described in Example 2 to obtain 1-salicyloyl-3-(2-pyridyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 78%; m.p.: 219°-220° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)=[O:26])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25](=[O:26])[C:27]3[CH:34]=[CH:33][C:30]([C:31]4[NH:1][C:4]5[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=5[N:10]=4)=[CH:29][CH:28]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Product: COc1ccc2nc(-c3ccc(C(=O)Nc4ccc5[nH]ccc5c4)cc3)[nH]c2c1

Procedure:
Compound 654 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitroanisole and 4-(5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C23H18N4O2: 383.14; found: 383.01.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C1COCC1>C(OCC)(=O)C>[CH2:14]([N:18]=[CH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[Cl:1])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=Cc1ccc2nccc(Cl)c2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a suspension of 4-chloro-quinoline-6-carbaldehyde (3.59 g, 18.73 mmol) in heptanes (36 mL) was added n-butylamine(1.51 g, 20.60 mmol, 1.1 equiv.) at room temperature. The reaction mixture was stirred for 5 h at room temperature by this time all solids were dissolved and gave a light brown solution containing a little oily stuff on the wall of flask. Then, 4 mL of THF was added and the clear solution was stirred for another 15 h. This solution was diluted with ethyl acetate (50 mL) and washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvents were removed under the vacuum and the remaining residue was dried under high vacuum to afford 4.62 g (˜100% yield) of butyl (4-chloro-quinolin-6-ylmethylene)-amine as a brown oil which was used directly for the next substitution reaction. LRMS(+) m/e calcd for C14H15ClN2 (M+H)+247.7, found 247.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[CH2:13][CH2:14][O:15][CH3:16])=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>CCOCC>[CH:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:3][C:2]([C:36]4[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14][O:15][CH3:16])[CH2:18][CH2:19]1)([CH3:25])[CH3:24]
Reactant: COCCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C(C)C)CC1
Reactant: Nc1ncc(B(O)O)cn1
Solvent: CCOCC
Product: COCCN(Cc1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1)C1CCN(C(C)C)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isopropyl-piperidin-4-yl)-(2-methoxy-ethyl)-amine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Acid/base work-up and trituration with ether yielded 334. 400 MHz, 1H NMR CDCl3: 9.30 (s, 2H), 7.26 (s, 1H), 5.22 (br s, 2H, NH2), 4.06 (s, 2H), 4.05 (t, 4H, J 4.4), 3.90 (t, 4H, J4.6), 3.50 (t, 2H, J6.0), 3.32 (s, 3H), 2.94 (d, 2H, J 11.2), 2.85 (t, 2H, J 6.1), 2.75-2.68 (m, 1H), 2.61-2.55 (m, 1H), 2.10 (t, 2H, J 11.4), 1.85 (d, 2H, J12.0), 1.65-1.53 (m, 2H), 1.03 (d, 6H, J 6.4). LC-MS (m+1)=527.41
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(NCc2ccccc2)c2[nH]ncc2n1

Procedure:
7-Chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (1 g) and benzylamine (30 ml) were heated under reflux for 6 h. The benzylamine was removed in vacuo to yield an oily solid which was digested with 20% hydrochloric acid. The digest was basified with 10% sodium carbonate solution to yield two phases. The solid in the aqueous phase was filtered off to yield the product (0.71 g). The remaining oily phase was extracted with boiling chloroform (3×20 ml) and the extract dried (MgSO4) and evaporated to yield a second crop of product (0.54 g). The combined solids (1.25 g, 91%) were recrystallised from ethanol/petroleum ether to yield the 7-benzylamino-compound as white crystals m.p. 205°-206°.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11]([OH:22])=[N:10][C:8]=2[N:9]=1.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[N:10]([CH2:23][CH3:24])[C:8]=2[N:9]=1
Reactant: CCI
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 55.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidin-7(8H)-one (172 mg, .56 mmol) from Example 11. The mixture was heated at 50° C. for 1 hour resulting in a clear solution. Ethyl iodine (60 μL, 0.75 mmol) was added, and the solution was stirred at 50° C. for 3.5 hours, cooled to room temperature, and poured into 30 mL of ice water. The resulting precipitate was removed by filtration and partitioned between ethyl acetate and water. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography, eluting with ethyl acetate, provided 104 mg (55%) of 2-amino-6-(2,6-dichlorophenyl)-8-ethyl-pyrido[2,3-d]-pyrimidin-7(8H)-one, mp 207°-209° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH:2]([C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CC(C)C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(C(C)C)n1
Yield: 86.4 %

Procedure:
A solution of 2.35 g (23 mmol) of 2-methylpropane-thioamide and 2.89 ml (23 mmol) of ethyl bromopyruvate in 75 ml of acetone was treated with excess MgSO4 and heated at reflux for 2.5 h. The resulting mixture was allowed to cool, filtered, and concentrated in vacuo to an oil, which was taken up in chloroform, washed sequentially with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica gel using chloroform as an eluent to provide 3.96 g (86%) of the desired compound, Rf 0.21 (chloroform) as an oil. 1H NMR (CDCl3) δ 1.41 (t, J=8 Hz, 3H), 1.42 (d, J=7 Hz, 6H), 3.43 (heptet, J=7 Hz, 1H), 4.41 (q, J=8 Hz, 2H), 8.05 (s, 1H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:3]=1>[Pd].C1COCC1.CO>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCOc1nc(N)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1nc(N)c(N)cc1C(=O)OC

Procedure:
Prepared analogously to example 154d by hydrogenation of the product obtained in (800d) using palladium on charcoal in THF and methanol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:13])[CH3:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of 4-fluorobenzaldehyde (5 mL, 45.2 mmol), propan-2-one (9.13 mL, 124 mmol), and water (9.5 mL) was added 12 mL of a 1% solution of NaOH in water. The reaction mixture was heated at 65° C. for 2 h. The mixture was then partitioned between EtOAc and ice water, the organic layer separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under vacuum. The product was obtained as a yellow oil and was used in the next step without further purification (7.93 g, 48.3 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.54-7.51 (m, 2H), 7.47 (d, 1H), 7.08 (t, 2H), 6.64 (d, 1H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:47][CH2:48][O:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][O:51]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)[C:22]([CH2:40][O:41][CH2:47][CH2:48][O:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COCCOC3CCCCO3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (300 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto is added sodium hydride (28 mg) under ice-cooling, and the mixture is stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (0.15 ml) is added to the reaction solution, and the mixture is stirred at room temperature for 2 hours and 30 minutes. After addition of sodium hydride (28 mg) and 2-(2-bromoethoxy)-tetrahydropyran (0.15 ml), the mixture is stirred at 50° C. for 2 hours and 30 minutes. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R*,4S*)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{2-[(tetrahydropyran-2-yl)oxy]ethoxymethyl}pyrimidin-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (201 mg). MS (m/z): 742 [M+H]+
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][CH2:12][CH3:13].ClCCl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCNC1Cc2ccccc2C1
Solvent: ClCCl
Product: CCCN(C(=O)c1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a stirred solution of Indan-2-yl-propyl-amine (20.0 g, 114 mmol) in dichloro methane (200 mL) triethyl amine (17.4 mL, 125 mmol) was added. To this solution was then dropwise added benzoyl chloride (17.6 g, 125 mmol), followed by stirring at ambient temperature for 2 hours. The reaction was finally quenched by addition of dilute hydrochloric acid (50 mL, 10% HCl). The organic layer was separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent yielded 31.5 g (99%) of the title compound as a dark oil.:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].C([O-])(O)=O.[Na+].C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([NH:15][CH2:14][CH2:12][OH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Benzylchloroformate (44.95 kg, 263.5 mol, 1.0 eq.) was added over a 2 hour period at room temperature to a solution of ethanolamine (16.1 kg, 263.5 mol, 1.0 eq.) in water (34 gal). After stirring for 30 minutes, this was added to a cold (5-10° C.) solution of NaHCO3 (33.2 kg, 395.25 mol, 1.5 eq) in H2O (330 L) over a 30 min period and then allowed to stir at room temperature overnight. Ethyl acetate (22 gal) was added, the layers separated, and the aqueous layer extracted again with 22 gal. ethyl acetate. The combined organic extracts were concentrated under vacuum to a volume of 10 gal, and the remainder displaced with isopropyl ether. The resulting slurry was stirred and cooled to +10° C. for 2 hours, then filtered. The solids were washed with isopropyl ether and vacuum dried to give the title compound(39.1 kg, 71.1%). mp 61-63° C. NMR (300 MHz, d6 -DMSO): δ=7.50-7.37 (m, 5H), 7.37-7.16 (m, 1H), 5.05 (s, 2H), 4.70-4.63 (m, 1H), 3.46-3.37 (m, 2H), 3.13-3.03 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)C(OCC)=O>CS(C)=O.[Cl-].[Na+].O.O>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:2](=[O:1])[CH2:3][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:15]=1
Reactant: CCOC(=O)C(C(=O)c1cccnc1)c1ccsc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1ccsc1)c1cccnc1
Temperature: 160 °C
Yield: 67.8 %

Procedure:
To a solution of ethyl 3-oxo-3-(pyridin-3-yl)-2-(thiophen-3-yl)propanoate (2 g, 7.26 mmol) in DMSO (20 mL) was added catalytic amount of brine (0.2 mL). The reaction mixture was heated at 160° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was concentrated in vacuo and purified by column chromatography to afford Intermediate 56 (1 g, yield 68%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[CH:41]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:41]1([NH:47][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Reactant: NC1CCCCC1
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NC3CCCCC3)cc2OC)cc1O

Procedure:
Example 238 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and cyclohexylamine. Mass Spectrum: 617 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCC(Cn2ccnc2)OCc2ccc(Cl)cc2Cl)cc1
Solvent: ClCCl
Product: O=S(CC(Cn1ccnc1)OCc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To 6.1 g (0.0143 mole) 3-(4-chlorophenylthio)-2-(2,4-dichlorobenzyloxy)-1-(1-imidazolyl)propane in methylene chloride (25 ml) at 0° C., 2.8 g (0.0143 mole) 85% meta-chloroperoxybenzoic acid in methylene chloride (50 ml) were added dropwise over about 30 minutes. The reaction mixture was maintained at about 0° C. during the addition and for about 11/2 to 2 hours after the addition. The reaction mixture was washed with a sodium bicarbonate solution (5%), with a bisulfite solution, dried, filtered, and concentrated to give 6.1 g of the above-identified product as a yellow oil.
Reaction SMILES: [C:1](/[C:4](/[C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:5]\[NH:6][C:7]([NH2:9])=O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:18]>O>[Cl:18][C:7]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:4]([C:1](=[O:3])[CH3:2])=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)/C(=C\NC(N)=O)C(=O)C(F)(F)F
Solvent: O
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
A mixture of compound (E)-1-(2-acetyl-4,4,4-trifluoro-3-oxobut-1-en-1-yl)urea (55 g, 0.25 mol) and POCl3 (240.7 g, 1.57 mol) was stirred at 100° C. for 3 h. The mixture was added dropwise to water (1.5 L) at rt and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography eluting with PE/EtOAc 3/1 to give compound 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (23.5 g, 42.7% yield) as a pale-yellow oil. 1H NMR (CDCl3 300 MHz): δ 8.80 (s, 1H), 2.58 (s, 3H). 19F NMR (920-083-1A CDCl3 400 MHz): δ −65.5 ppm. 13C NMR (903-158-1A CDCl3 400 MHz): δ 195.9, 162.3, 160.1, 153.8 (dd, J=50 Hz), 130.9, 119.5 (dd, J=366 Hz), 30.7.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[SnH3][C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:13]3[O:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: [SnH3]c1cc2ncccc2o1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2ncc(-c3cc4ncccc4o3)n2n1
Yield: 57.3 %

Procedure:
In an inert atmosphere, 3.0 g (12.9 mmol) of 3-bromo-6-chloroimidazo[1,2-b]-pyridazine, 6.85 g (16.8 mmol) of the crude 2-stannylfuro[3,2-b]pyridine, 246 mg (1.29 mmol) copper (I) iodide and 453 mg (0.645 mmol) bis(triphenylphosphine) palladium(II)chloride in 100 mL of THF was stirred over night at 85° C. in a sealed pressure tube. The solvent was evaporated, the obtained solid was digested in dichloromethane/methanol and filtered off. The solid was washed with methanol and hexane to give 2 g of the title compound as solid material.
Reaction SMILES: [CH2:1]([C@@H:3]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]1([CH3:22])[CH:23]=[CH:24][C:18]([S:15]([O:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](CO)COCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H](COCc1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
1.34 g (0.0069 mol) of 2-(R)-ethyl-3-benzyloxypropan-1-ol (XVIId-1), 12 ml of dichloromethane, 1.31 g (0.0069 mol) of tosyl chloride and 0.084 g (0.0007 mol) of 4-dimethylaminopyridine are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is cooled to 0° C. and then 0.89 ml (0.011 mol) of pyridine is added dropwise. After leaving overnight in a refrigerator, the mixture is hydrolyzed using a 10% aqueous citric acid solution. The phases are separated and the aqueous phase is extracted with ethyl ether. The combined organic phases are washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/cyclohexane=750:25). 1.54 g (0.0044 mol) of the title compound (XVIIId-1) are obtained.