Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1.[CH:25](=O)[CH2:26][CH3:27].[BH4-].[Na+]>CO>[CH2:25]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1)[CH2:26][CH3:27]
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCN1CCCC(c2ccc(-c3nc4cccc(C(N)=O)c4o3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 19.8 %

Procedure:
A mixture of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (80 mg, 0.25 mmol) and propionaldehyde (72 mg, 1.25 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (45 mg, 0.75 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 2-(4-(1-propylpiperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide as a light yellow solid (18 mg, yield 23%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.94 (t, 3H), 1.58-1.64 (m, 3H), 1.81-2.01 (m, 3H), 2.11-2.20 (m, 2H), 2.43 (m, 2H), 2.97 (m, 1H), 3.08 (t, 2H), 7.50-7.54 (m, 3H), 7.91-7.94 (m, 2H), 8.29 (d, 1H); LC-MS (ESI) m/z: 364 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)(=O)=[O:9])=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)Cc1ccc(CCCS(=O)c2ccc(Cl)cc2)cc1
Reaction time: 0.67 h

Procedure:
To a 0° C. solution of Example 8 Part A sulfide (500 mg, 1.11 mmol) in acetone (6 ml) was added, dropwise, freshly prepared Jones reagent (2.67M, ca. 1.2 ml). After stirring for 40 minutes, the reaction was quenched with 2-propanol and then concentrated in vacuo. The residue was then stirred with water (50 ml) for 30 minutes at which time a yellow solid had formed. The solid was collected by filtration, washed with water and air dried. Chromatography (flash, silica, 25 mm dia., ethyl acetate then 20% methanol/chloroform) provided a white solid. The solid was then triturated with 2 portions of hot ethyl acetate (ca. 10 ml each) leaving the desired sulfoxide as white amorphous solid: 1H NMR (tetradeuteriomethanol, 270 MHz) δ 7.53-7.62 (m, 4H), 7.02-7.19 (m, 4H), 3.46 (s, 2H), 2.55-2.95 (m, 4H), 1.75-2.00 (m, 2H); 13C NMR (tetradeuteriomethanol), 67.88 MHz, complete decoupling) δ 178.3, 142.4, 139.9, 138.3, 134.9, 130.6, 130.5, 129.4, 127.0, 56.4, 43.1.
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].[O:19]1[C:24]2[CH:25]=[CH:26][C:27](N)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:19]1[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[C:27]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCCO5)c3c2s1
Yield: 33 %

Procedure:
Prepared from VII and 1,4-benzodioxan-6-amine. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 33%; yellow solid; mp 180-190° C.; IR (KBr) νmax/cm−1 3055, 2978, 2932, 2875, 2230, 1709, 1638, 1609, 1578, 1496, 1460, 1376, 1299, 1281, 1239, 1200, 1151, 1063, 916, 885, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.37 (d, 1H, J=8.4 Hz), 7.85 (m, 1H), 7.76 (m, 1H), 6.88 (d, 1H, J=8.4 Hz), 6.56 (m, 2H), 4.25 (s, 4H); HRMS calcd for C18H12N5O2S (M+H+): 362.0712, found 362.0696.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH3:29][CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH2:22][CH2:21][C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([C:11]3[N:12]4[C:4](=[CH:3][CH:2]=[N:1]4)[N:5]=[C:6]4[C:10]=3[CH2:9][CH2:8][CH2:7]4)=[CH:28][C:17]=2[CH:18]=1
Reactant: CC1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) was dissolved in acetonitrile (2 ml) followed by addition of 2-methylpyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:22]#[C:23]Br>CN(C)C=O>[C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1)#[N:22]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: N#CBr
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 10.0 g. (0.033 mole) of 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline, prepared as described in U.S. Pat. No. 3,511,836, 3.54 g. (0.033 mole) of cyanogen bromide and 33 ml. of N,N-dimethylformamide was stirred under nitrogen at room temperature (20°-25° C.) for 6 hours. The precipitated solid was recovered by filtration, washed with ether and air dried to afford 11.6 g. (85%) of the hydrobromide salt of the title compound. The salt was partitioned between 250 ml. of aqueous saturated sodium bicarbonate solution and 500 ml. of chloroform. The layers were separated and the chloroform layer concentrated in vacuo to afford the free base as a dry foam, 8.3 g. (80%); M.P. 215° C. The mass spectrum reveals a molecular ion peak at M/e 314. Infrared spectrum (CHCl3): peak at 4.5 μ (CN).
Reaction SMILES: [F:1][C:2]([F:43])([CH:40]([F:42])[F:41])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:7][N:6]=1.[OH-].[Na+:45]>>[F:43][C:2]([F:1])([CH:40]([F:41])[F:42])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=3)[C:25]([O-:27])=[O:26])=[CH:21][CH:22]=2)=[O:12])=[CH:7][N:6]=1.[Na+:45]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(OCC(F)(F)C(F)F)nc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(OCC(F)(F)C(F)F)nc3)cc2)C(=O)[O-])cc1

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-[2-(2,2,3,3-tetrafluoropropoxy)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)propionate (73 mg), which is the product of Example 102, was reacted with aqueous sodium hydroxide solution (1N, 0.13 ml) and the reaction mixture was treated to give the title compound (51 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][C@@H:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:23]([C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[C:3]([O:14][C@@H:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][C:39]1[CH:38]=[CH:37][C:36]([C:33]2[N:32]=[CH:31][C:30]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][N:34]=2)=[CH:41][CH:40]=1)=[O:8]
Reactant: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(C(=O)O)cc1N
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCc1cnc(-c2ccc(OC(=O)c3cc(N)c(O[C@H](C)CCCCCC)cc3[N+](=O)[O-])cc2)nc1
Yield: 82.7 %

Procedure:
5-Amino-2-nitro-4-[(R)-2-octyloxy]benzoic acid (0.06 g), 0.1 g of 4-(5-heptyl-2-pyrimidinyl)phenol and 0.04 g of 4-(dimethylamino)pyridine were dissolved in 10 ml of dichloromethane and the solution was treated portionwise within 10 minutes with 0.07 g of N,N'-dicyclohexylcarbodiimide while stirring. The mixture was stirred at room temperature for 40 hours, filtered and concentrated. Chromatography of the residue on silica gel with ethyl acetate/dichloromethane (vol. 1:8) and recrystallization from diethyl ether/hexane (vol. 1:1), gave 0.09 g of 4-(5-heptyl-2-pyrimidinyl)phenyl 5-amino-2-nitro-4-[(R)-2-octyloxy]benzoate of melting point 105° C.
Reaction SMILES: CO.[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=2[N+:20]([O-])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O=[Pt]=O.CC(O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=2[NH2:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CC(C)O
Solvent: CO
Product: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reaction time: 8 h

Procedure:
A mechanically stirred MeOH (3.8 L) suspension containing 1-[4-phenylmethoxy-3-nitrophenyl]ethanone (76.5 g, 282 mmol) was degassed with argon for 40 minutes at ~10° C. prior to addition of PtO2 (2.34 g, 10 mmol). Hydrogen was sparged into the reaction mixture at 8° C. to 10° C. via a subsurface gas inlet. After 8 hours, the completed reaction was degassed with Ar while being warmed to ~15° C., diluted with CHCl3 (250 mL) and filtered. The filtrate was stripped to give 70 g crude product which, after trituration for ten minutes with i-PrOH (450 mL) at 60° C., yielded 57.4 (84%) of the title compound.
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1O>CCCCCC.C(OCC)(=O)C>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:17]3[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([CH3:22])[C:18]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c2c1OC(=O)C2c1ccc(C(C)C)cc1
Yield: 20 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid and 2,5-dimethylphenol synthesized in Reference Example 1, the title compound was synthesized in the same manner as in Reference Example 2. Yield 20%. Melting point: 107-109° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[S:21]1[C:25]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:24][N:23]=[CH:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:25]3[S:21][CH:22]=[N:23][CH:24]=3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cncs2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2cncs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(thiazol-5-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 423.08 g/mol.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].C[O:32][CH2:33][CH2:34][O:35][CH3:36]>>[O:35]1[C:36]2([CH2:8][CH2:13][N:12]([CH2:2][CH2:3][O:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([NH:17][C:18]5[CH:26]=[C:25]6[C:21]([CH:22]=[N:23][NH:24]6)=[CH:20][CH:19]=5)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]4)=[CH:7][C:6]=3[O:27][CH3:28])[CH2:11][CH2:10]2)[O:32][CH2:33][CH2:34]1
Reactant: COCCOC
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCC2(CC1)OCCO2
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 716.0 mg (5.0 mmol) of 1,4-dioxa-8-azapiro[4,5]decane and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 16 hr. The work up gave 173.1 mg (69.2%) of the product as aoff white solid, m.p. 245° C. (dec.), mass (electrospray, m/e): M+H 501.0.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C[O:5][C:6](=O)[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@H:13]1[C@@H:17]([OH:18])[CH2:16][C@@H:15]([OH:19])[C@@H:14]1[CH:20]=[CH:21][C@H:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH3:2][CH2:1][NH:3][C:6]([CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:14](/[CH:20]=[CH:21]/[C@@H:22]([OH:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:15]([OH:19])[CH2:16][C@@H:17]1[OH:18])=[O:5]
Reactant: CCN
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Solvent: O
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 23 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
56 g of ethylamine (MW=45.08; 47.9 equivalents) in 24 mL of water were added to 8.08 g of crude (Z)-7 [(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclo-pentyl]hept-5-enoic acid methylester (MW=402.54; 1 equivalents) and the resulting solution was stirred for 48 h at 23° C. The excess of ethylamine was removed by distillation in vacuo (25°, 100 mbar) after complete conversion. To the residue were added 400 mL of methylenechloride and 100 mL of water and the pH was adjusted to 1.5 by addition of 1M aqueous hydrochloric acid. After separation of the layers the organic layers were washed with 100 mL of saturated aqueous sodium bicarbonate, 100 mL of water, and 100 mL of brine. The solution was filtered and concentrated in vacuo yielding 8.33 g of oily bimatoprost crude. To the residue were added 25 mL of acetonitrile. After adding seeds the mixture was stirred for 30 minutes at ambient temperature, cooled to 0° C. and stirred for two hours at this temperature.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:8])[CH:7]=1.[CH3:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C.C(OCC)(=O)C>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][O:31][CH:26]([CH3:25])[CH2:27]3)[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=1
Reactant: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Reactant: CC1CNCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nn2c(O)cc(N3CCOC(C)C3)nc2c1Cc1cccc(C(F)(F)F)c1C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg, 0.17 mmol), prepared as described in Example 1, step d, in ethanol (1.5 mL) was added 2-methylmorpholine (85 mg, 0.84 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 145° C. for one hour. The reaction mixture was diluted with ethyl acetate (15 mL), washed with 5% HCl solution (3 mL). Organic layer was dried, filtered, and concentrated to dryness. The crude was purified by reverse-phase HPLC to provide the titled compound. (28 mg, 39%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, MeOD) δ ppm 1.17 (br. s., 2H) 1.19 (d, J=1.26 Hz, 1H) 2.13 (br. s., 3H) 2.47 (br. s., 3H) 2.66 (t, J=11.62 Hz, 1H) 2.68 (br. s., 1H) 2.94-3.06 (m, 1H) 3.63 (br. s., 3H) 4.01 (br. s., 2H) 7.11 (br. s., 1H) 7.23 (br. s., 1H) 7.51 (br. s., 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][CH:13]([CH3:15])[CH3:14].[CH3:19][Si](Cl)(C)C>CO>[CH3:19][O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:10]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.50 g of L-leucine-L-leucine, under argon, is added, via a syringe, 10 ml of methyl alcohol and 0.610 ml of trimethylsilyl chloride. The reaction is stirred overnight at room temperature. The mixture is concentrated in vacuo to give 0.554 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:18]1([O:17][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([OH:25])=[O:14])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A rapidly stirred solution of 4-benzyloxy-3-cyclopentyloxybenzaldehyde (10.5 g; that is prepared as described in Reference Example 37) in glacial acetic acid (100 mL) is treated with sulfamic acid (4.85 g) and stirred at room temperature for 10 minutes. The solution is then cooled in an ice bath and treated with a solution of sodium chlorite (4.2 g) in water (100 mL) during 15 minutes at 13°-15° C. During the addition a white precipitate forms and, because stirring becomes difficult, a further quantity of glacial acetic acid (60 mL) is added. After warming to room temperature, the solution is stirred for a further 6 hours and further quantities of sodium chlorite (1.6 g) and sulfamic acid (1.7 g) are added. The mixture is poured onto water and the resulting solid is filtered off and dried, to give 3-cyclopentyloxy-4-benzyloxybenzoic acid (10g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=2)[C:31](O)=[O:32])[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:28]2[CH:29]=[C:30]([C:31]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:17]([CH2:16][O:15][C:14]4[C:4]5[C:3]([NH2:2])=[N:8][S:7](=[O:9])(=[O:10])[NH:6][C:5]=5[CH:11]=[CH:12][CH:13]=4)[CH2:18]3)=[O:32])[CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)c4ccnc(-n5ccnc5)c4)C3)c21

Procedure:
Prepared as in Example 2 from (S)-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide hydrochloride (Example 2a) and 2-(1H-imidazol-1-yl)isonicotinic acid (Example 52a) (42% yield). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 1.42-1.60 (m, 2H), 1.71 (m, 1H), 1.93 (m, 1H), 2.22 (m, 1H), 3.11 (m, 1H), 3.34-3.75 (m, 1H), 3.92-4.42 (m, 2H), 6.63 (m, 1H), 6.74 (br s, 1H), 7.11 (s, 1H), 7.29 (m, 1H), 7.42 (m, 1H), 7.52-8.28 (br s, 2H), 7.76 (m, 1H), 7.93 (m, 1H), 8.52 (m, 2H), 10.71 (br s, 1H). MS 482 (MH+).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].[O-]CC.[Na+].C(O)(=O)C>C(O)C>[CH3:12][CH:11]1[NH:14][C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:13]1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=NC(C)NC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of ethyl acetoacetate (0.8 g, 6.14 mmol) in ethanol (8 mL) was added acetamidine hydrochloride (0.6 g, 6.3 mmol) and stirred at r.t. for 10 min. A solution of sodium ethoxide [prepared from sodium (0.28 g, 12.3 mmol) and ethanol (3 mL)] was added dropwise and the whole mixture refluxed for 6 h. The reaction mass was cooled, acidified with acetic acid and concentrated under reduced pressure to give a residue which was washed twice with ethyl acetate to afford 2,6-dimethyl-2,5-dihydro-3H-pyrimidin-4-one (460 mg, 60%) as a solid.
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].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[C:25]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:22][CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4cccc(Cl)c4)c3c2s1
Yield: 74 %

Procedure:
Prepared from VII and 3-chloroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 74%; pale yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2849, 2226, 1643, 1611, 1577, 1461, 1377, 1354, 1306, 1218, 1161, 1128, 1070, 974, 875, 833; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.40-7.35 (m, 2H), 7.19-7.11 (m, 2H); HRMS calcd for C16H9N5SCl (M+H+): 338.0267, found 338.0259.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1F)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)cc1F)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 55 %

Procedure:
3-[(2,4-Difluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 60-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (55% yield); mp 141–149° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.1 (3H, s, NCH3), 3.77 (3H, s, OCH3), 4.14 (2H, s, NCH2), 4.92 (2H, s, NCH2), 6.8–6.9 (2H, m, aromatics), 7.35–7.41 (1H, m, aromatic).