Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:52])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:51])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:52])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:51])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(OCCC)ccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(OCCC)ccc[n+]4[O-])cc2)CCN3)cc1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (330 mg) in ethanol (20 ml) was added sodium borohydride (85 mg) at room temperature and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 14 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridine-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 113) (230.7 mg) as yellow crystals.
Reaction SMILES: O/[N:2]=[C:3](\[C:9](=O)[CH3:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[O:13]([C:15]#[N:16])[K]>CCO.O.[Pd]>[CH3:10][C:9]1[NH:16][C:15](=[O:13])[NH:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N#CO[K]
Reactant: CCOC(=O)/C(=N/O)C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.7 %

Procedure:
A mixture of ethyl (2E)-2-(hydroxyimino)-3-oxobutanoate (8.50 g, 53.41 mmol) and 10% Pd/C (0.42 g) in EtOH (25 mL) and a 1.5 M solution of HCl (40 mL) were stirred under hydrogen (50 psig) for 4 h. The vessel was carefully vented then the mixture was filtered through Celite which was subsequently washed with EtOH. The filtrate was concentrated slightly to remove some of the EtOH but the water bath was kept below 40° C. A 5M solution of aqueous HCl (5 mL) was added to the yellow solution and this was added dropwise to a solution of KOCN (6.50 g, 80.12 mmol) in water (25 mL) at RT. The reaction mixture was stirred at RT for 3 days then cooled to 0° C. After 2 h, the precipitate was filtered and washed with a cold 1:1 mixture of MeOH/water (20 mL) and dried under vacuum to afford 1.70 g (19%) of the title compound as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br. s., 1H), 10.14 (br. s., 1H), 4.16 (d, 2H), 2.20 (br. s., 3H), 1.23 (t, 3H). LCMS m/z 171.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].Cl[C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>O1CCCC1>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:24]
Reactant: COC(=O)CC(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1CCOC1
Product: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
2-Amino-5-methanesulfonylamino-benzenesulfonamide (prepared as described in Example 1d, 1.70 kg, 6.40 mol) was dissolved in tetrahydrofuran (35 L), and was then cooled to 0° C. Methyl 3-chloro-3-oxopropionate (792 mL, 7.40 mol) was added slowly, and the resulting mixture was then allowed to warm to 23° C. and stirred for 2 days. The solvent was removed in vacuo, and the residue was then diluted with water (4 L) and saturated aqueous sodium bicarbonate solution (2 L). The resulting solid was filtered, and was then washed with water (5 L). The solid was suspended in hot methanol (15 mL/g), and was then cooled to 23° C. and filtered to afford the desired product, N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (1.68 kg, 4.61 mol, 72%), as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.02 (3H, s), 3.60 (2H, s), 3.66 (3H, s), 7.38 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.53 (2H, bs), 7.73 (1H, d, J=2.4 Hz), 7.83 (1H, d, J=8.7 Hz), 9.43 (1H, s), 9.99 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2(F)[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9]2)=[N:6][CH:7]=1.[C:15]([O:19][C:20]([N:22]1[C@H:26]([CH2:27][F:28])[C@@H:25]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[O:24][C:23]1([CH3:45])[CH3:44])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[O:12]=[S:10]1(=[O:13])[CH:11]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([C@H:25]4[O:24][C:23]([CH3:44])([CH3:45])[N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[C@@H:26]4[CH2:27][F:28])=[CH:34][CH:33]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=S1(=O)CC(F)(c2ccc(Br)cn2)C1
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C4=CS(=O)(=O)C4)nc3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
The solution of the product of step 3, Example 18 (0.15 g, 0.538 mmol, 1 eq), (4S,5R)-4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (previously described in US2004082553, Example 20, intermediate 19, 0.234 g, 0.538 mmol, 1 eq) and sodium carbonate (0.171 g, 1.613 mmol, 3 eq) in mixture of Toluene/Ethanol/Water (1:1:0.5, 2.5 mL) is degassed with nitrogen for 30 minutes in sealed tube. To the resulting reaction mixture tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.054 mmol, 0.1 eq) is added. Resulting reaction mixture is heated at 80° C. for 6 hours. The reaction mixture is quenched with water (15 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer is dried over sodium sulphate and concentrated in vacuo. The crude compound is purified by column chromatography using (100-200 mesh silica). Desired compound is eluted with 30% ethyl acetate in hexane to afford title compound as yellow solid (0.16 g): 1H-NMR (400 MHz, DMSO) δ: 1.43 (bs, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 3.85-3.90 (m, 1H), 4.47-4.59 (m, 1H), 4.75-4.84 (m, 1H), 5.05 (s, 2H), 5.15 (d, 1H, J=7.16 Hz), 7.62 (d, 2H, J=8.12 Hz), 7.76 (s, 1H), 7.87 (d, 2H, J=8.2 Hz), 7.93 (d, 1H, J=8.12 Hz), 8.31-8.34 (dd, 1H, J1=8.24 Hz, J2=2.16 Hz). 9.07 (d, 1H, J=1.88 Hz). LC-MS (m/z): [M+H] 489.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[N:17]=[N:18][C:19](Br)=[CH:20][CH:21]=1>O1CCOCC1>[NH3:8].[Br:15][C:16]1[N:17]=[N:18][C:19]([N:11]2[CH2:10][C@@H:9]3[CH2:14][C@H:12]2[CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1ccc(Br)nn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Br)nn1
Product: N
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl-(1S,4S)-(+)-2,5-diazabicyclo-[2.2.1]-heptane-2-carboxylate (3.0 g, 15.1 mmol), 3,6-dibromopyridazine (3.6 g, 15.1 mmol) and dioxane (15 ml) was stirred for 3 days at 90° C. The crude product salt was filtered. Aqueous sodium hydroxide (50 ml, 1 M) was added to the solid material. The mixture was extracted with dichloromethane. Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as free base. Yield 1.71 g (32%).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH:10]([OH:18])[CH2:11]C2N3C2CCC3)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[BrH:19].[CH2:20](O)[CH3:21]>>[Br:19][C@@H:21]1[CH2:20][CH2:11][CH2:10][C@H:9]1[NH:5][CH2:11][CH:10]([OH:18])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: CCO
Reactant: O=[N+]([O-])c1nccn1CC(O)CC1C2CCCN21
Reactant: Br
Product: O=[N+]([O-])c1nccn1CC(O)CN[C@@H]1CCC[C@H]1Br

Procedure:
α-[(Nitro-1H-imidazol-1-yl)methyl]azabicyclo[3.1.0]hexane-6-ethanol from Example 4 was ring-opened by the action of 2-3 equivalents of hydrogen bromide in ethanol to produce the title compound as the hydrobromide salt, mp 204°-205° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[C:23]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>>[O:20]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:35]2[CH2:36][CH2:37][N:32]([C:23]3[C:22]([CH3:21])=[CH:27][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:25][N:24]=3)[CH2:33][CH2:34]2)=[O:13])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 82.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (245 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Example 87, the title compound (449 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[Cl:21].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][C:13]2[C:3]([CH2:2][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[C:4]([Cl:21])[CH:5]=[CH:6][C:7]=2[CH2:8][CH2:9]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CBr)c2CC1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(Cc3cccnc3)c2CC1
Temperature: 60 °C
Yield: 58.2 %

Procedure:
Combine 6-bromomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (700 mg, 1.89 mmol), pyridine-3-boronic acid (273 mg, 2.22 mmol), tetrakis(triphenylphospine)palladium(0) (1.1 g, 0.95 mmol), and sodium carbonate (600 mg, 5.66 mmol) in a mixture of toluene (14 mL), ethanol (3.5 mL) and water (0.7 mL). Heat the mixture to 60° C. for 12 h under nitrogen. Cool the reaction and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane and hexane/EtOAc (10:1, 5:1 and 1:1) to obtain 3-tert-butoxycarbonyl-7-chloro-6-pyridin-3-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (410 mg, 59%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)(Cl)Cl>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 85 mg, 0.29 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (49 mg, 0.29 mmol) and molecular sieves 3 Å in dry methanol/chloroform (1:1, 10 mL) was heated to 70° C. for 3 hours. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (190 mg, 0.88 mmol) was added. After 30 minutes, the reaction was filtered through celite, the filtrate was concentrated to dryness, taken up in 15% methanol/chloroform, and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 70 mg (54%) of the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N:8]([CH:11]([CH3:26])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=CC(O)=[CH:21][CH:20]=3)=[N+:9]=[N-:10].N1C=CC=CC=1.O>ClCCl>[N:8]([CH:11]([CH3:26])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:21][CH:20]=3)=[N+:9]=[N-:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)-c1c(ccn1CC(C)N=[N+]=[N-])C2
Reaction time: 16 h
Yield: 85 %

Procedure:
0.7 ml of acetic anhydride was added while stirring to a solution of 1.05 g of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrol and 0.6 ml of pyridine in 30 ml of dichloromethane and the mixture was stirred for an additional 16 hours. Subsequently, the reaction mixture was treated with 50 ml of dichloromethane and 40 ml of water. The organic phase was separated and this was washed once with 50 ml of saturated sodium chloride solution. After drying over magnesium sulfate, the solution was concentrated in a vacuum and the crude product was purified by column chromatography on silica gel (ethyl acetate/hexane 1:2). 0.9 g (85%) of (RS)-1-(2-azido-propyl)-7-acetoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1>ClCCl>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[O:25])[CH:19]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cc(O)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 4-amino-m-cresol (Fluka, 4.17 g, 33.9 mmol) and triethylamine (23.6 mL, 0.170 mol) in dry dichloromethane (100 mL) was treated with 6-chloropyrimidine-4-carbonyl chloride, obtained as described above for Intermediate 7, step 1 (6.0 g, 34 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were dried on magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as yellow solid.
Reaction SMILES: C(=O)([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH:9]=1)OC(C)(C)C.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:10]3[CH:9]=[C:8]([OH:7])[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[N:11]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2ccc(-c3cc(OC(=O)OC(C)(C)C)n(-c4ccccn4)n3)cc2)cc1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: COc1ccc(-c2ccc(-c3cc(O)n(-c4ccccn4)n3)cc2)cc1
Yield: 62 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 43 of Example C-17 was used in place of Compound 27 of Example C-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]CC)=O)[CH:5]([N+:13]([O-])=O)[CH:4]([N:16]([CH2:25][C:26]([O:28]CC)=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:3]=1.ClC1N=C(C(OCC)=O)C([N+]([O-])=O)=C(Cl)[N:33]=1.C[O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1NCC(OCC)=O.C(N(C(C)C)CC)(C)C>>[OH:48][C:49]1[CH:50]=[C:51]([C:2]2[N:7]=[C:6]([C:8]([NH2:33])=[O:10])[C:5]3[NH:13][C:26](=[O:28])[CH2:25][N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[C:4]=3[N:3]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)CNc1ccccc1OC
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CCOC(=O)CN(c1ccccc1OC)C1N=C(Cl)N=C(C(=O)OCC)C1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CC(=O)Nc2c(C(N)=O)nc(-c3cccc(O)c3)nc21

Procedure:
Ethyl 2-chloro-6-((2-ethoxy-2-oxoethyl)(2-methoxyphenyl)amino)-5-nitro-5,6-dihydro-pyrimidine-4-carboxylate. Ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (3.0 g, 11.27 mmol), ethyl 2-(2-methoxyphenylamino)acetate (2.35 g, 11.27 mmol) and diisopropylethylamine (4.36 g, 33.81 mmol) were reacted according to General Procedure C and partitioned between water and ethyl acetate (3×) to afford the title compound without purification (2.05 g, 41%). MS (ESI) m/z 439.2 [M+1]+, 441.4 [M+2]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])([O-])=O.[K+].[K+].Cl>C1COCC1.O>[C:11]([CH:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
A mixture of 1-(bromomethyl)-2,3-dichlorobenzene (82 g, 0.34 mol), ethyl 2-cyanoacetate (82 g, 0.34 mol) and K2CO3 (187.7 g, 1.36 mol) in THF (1.5 L), was stirred at 60° C. for 16 h. The reaction mixture was cooled and adjusted pH to 2-3 with 4N aq. HCl. The mixture was diluted with water (1 L) and extracted with ethyl acetate (400 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography eluted with PE:EA=15:1 to provide the titled compound (45 g, 48%), as a white solid; 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (t, J=7.2 Hz, 3H), 3.23 (dd, J=9.6, 13.8 Hz, 1H), 3.56 (dd, J=6.0, 13.8 Hz, 1H), 3.91 (dd, J=6.0, 9.6 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 7.21 (t, J=7.8 Hz, 1H), 7.28 (dd, J=1.8, 7.5 Hz, 1H), 7.45 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1csc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1csc(C2CCN(CCCC(O)c3ccc(F)cc3)CC2)n1
Reaction time: 26 h

Procedure:
A 0.35 g. portion of 3,6-dihydro-α-(p-fluorophenyl)- 4-(4-methyl-2-thiazolyl)-1(2H)-pyridinebutanol, prepared as described in Example 12, is dissolved in 10 ml. of ethanol and 0.1 g. of palladium on carbon catalyst is added. The mixture is reduced to room temperature and pressure for about 26 hours. The mixture is filtered and the filtrate evaporated yielding a white solid which is recrystallized from acetonitrile giving a white crystalline solid, m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:8]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>CO>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:8]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:7]=1)[CH3:24]
Reactant: COC(=O)Cc1ccc(OCC2CO2)cc1OCC(F)(F)F
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CC(O)COc1ccc(CC(=O)OC)c(OCC(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of methyl 4-(glycidyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate (0.25 g, 0.81 mmol) from Step 1 of Example 34 in MeOH (3 mL) was added diethylamine (0.5 mL). The solution was kept at ambient temperature for 12 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 4-(3-diethylamino-2-hydroxypropyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate as a pale yellow oil (HPLC retention time=6.9 min (method A); TLC Rf =0.23 (95:5 CH2Cl2 :MeOH)).
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:23]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(c1ccccc1)c1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(c1ccccc1)c1ccccc1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Cumylphenyl benzoate is prepared in accordance with the following procedure: one mole of cumylphenol was dissolved in 600 ml of benzene containing 1.2 moles of triethylamine in a 2-liter stirred glass reactor equipped with external heating and cooling devices. The reaction mass was cooled to and maintained at 15°-20° C. during the addition of 1.1 moles of benzoyl chloride over a period of 1.5 hours. After completion of addition, the resulting slurry was heated to and maintained at 40°-45° C. for 1 hour, and thereafter cooled to ambient temperature and filtered. The filter cake was washed with 200 ml of toluene and the combined washings and filtrate distilled to give 214.9 g (68 mole %) of a pale yellow oil having a boiling point at 0.5 mm Hg of 261°-265° C., a specific gravity at 55° C. of 1.082, and a viscosity at 55° C. of 215 cps. On standing, the oil solidified to form a white solid having a melting point of 43°-46.5° C.