Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>CO>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:25]2[C:26]([C:27]([F:30])([F:29])[F:28])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:38])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:23]=[N:24]2)=[CH:32][CH:33]=1
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cnn(-c4ccc(Cl)cc4)c3C(F)(F)F)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc2cc(CNC(=O)c3cnn(-c4ccc(Cl)cc4)c3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
1 N NaOH (563 μL, 0.563 mmol) was added under nitrogen to [6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (243 mg, 0.469 mmol), prepared in the previous step, in 100 mL of MeOH plus 25 mL of water at room temperature. After the addition the reaction was stirred at room temperature overnight. The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the MeOH. The solid present was collected by filtration and dried under reduced pressure to give the title compound (210 mg, 89%) as a pink solid, mp 189-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 67.3 %

Procedure:
A mixture of 1-(4-nitrophenyl)-4-piperidone (0.6 g, 2.7 mmol), ethylene glycol (0.3 mL, 5.4 mmol) and p-toluenesulfonic acid (0.1 g in toluene (20 mL) was heated at reflux in a Dean-Stark apparatus until no more water accumulation occurred. The reaction was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with water then brine and dried over sodium sulfate. Concentration under reduced pressure afforded 8-(4-nitrophenyl)-1,4-dioxa-8-aza-spiro[4,5]decane (0.48 g, 66%).
Reaction SMILES: CC([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH:21]1[CH:22]=[CH:23][C:24]2[NH:14][C:15]([OH:16])=[C:17]([C:6]3[C:5](=[O:4])[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=3)[C:19]=2[CH:20]=1
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
Argon gas was blown into a suspension of indoxyl acetate (1.75 g, 10 mmol) and isatin (1.47 g, 10 mmol) in anhydrous methanol (20 mL) for 5 minutes. Sodium carbonate (2.12 g, 20 mmol) was added to the reaction liquid and stirred at room temperature for 18 hours. The reaction liquid was then poured into water (1 L). The precipitated crude crystals were collected by suction filtration. The resulting crude crystals were recrystallized from 1,4-dioxane/hexane to give purple needle-shaped crystals of indirubin (1.81 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(Cl)Cl.C(O)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[C:28]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1.81 6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was added decanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. The mixture was stirred for 20 minutes, then concentrated down to a crude solid. The solid was extracted into EtOAc (20 ml), and the insoluble salts were filtered. The EtOAc was removed. The crude oil was purified by flash choursomatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM). The oil thus obtained (254 g, 90%) was converted to a fumarate salt with fumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g, m.p.=100-102° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].Cl.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:25]([C:41]([OH:43])=O)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].NCC(N)=O>CN(C=O)C>[NH:24]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:25]([C:41]([NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: NCC(N)=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Reaction time: 8 h
Yield: 71 %

Procedure:
GlyNH2.HCl (2.65 g, 0.024 mol) is dispersed in DMF and to this is added Et3N (3.35 ml, 0.024 mol) and HOBT (3.7 g, 0.024 mol). 9.0 g (0.024 mol) of BOC-D-Lys(Z) in a large volume of DMF is added and the GlyNH2 goes into solution. The total volume of DMF is 400 ml. The reaction is stirred overnight and then filtered. The solvent is evaporated off and the residue dissolved in CH2Cl2. This is washed with citric acid solution, Na2CO3 solution and then NaCl solution, and dried with MgSO4. The mixture is filtered, the filtrate evaporated down and the residue is taken up in ethyl acetate and cooled. The solid is filtered and washed with pet ether. More solid is obtained from the filtrate. Both crops are combined and triturated with ether. 7.5 g of a tan, solid is obtained in a 71% yield:
Reaction SMILES: [H][H].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([NH:37][C:38](=[O:40])[NH2:39])=[C:32]([C:34](=[O:36])[NH2:35])[CH:33]=2)=[CH:25][CH:24]=1)[C:12]([O:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CC(O)C.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:12]([O:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:30][C:31]([NH:37][C:38](=[O:40])[NH2:39])=[C:32]([C:34](=[O:36])[NH2:35])[CH:33]=2)=[CH:27][CH:28]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Hydrogen gas was bubbled through a suspension of Wilkinson's catalyst (767 mg, 0.829 mmol) in IPA (10 ml) and toluene (5 ml). After 5 minutes, a solution of cyclopentyl(2S,4E)-2-[(tert-butoxycarbonyl)amino]-5-{4-[4-carbamoyl-5-(carbamoylamino)-2-thienyl]phenyl}pent-4-enoate (300 mg, 0.553 mmol) in IPA (10 ml) was added. The mixture was kept under an atmosphere of hydrogen and placed in a preheated oil bath at 80° C. After 4 hrs the reaction was judged to be complete by LC-MS. The mixture was filtered whilst still hot and the filtrate evaporated in vacuo. The residue was subjected to column chromatography eluting with 4% MeOH in DCM. Yield=120 mg, 0.198 mmol, 36% yield. LCMS purity 90%: m/z 543 [M−H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6].[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:5]([C:9]1[CH:14]=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Aluminum chloride (44.4 g, 333 mmol) was cooled to −45° C., and toluene (1.25 L) was added followed by 2-tert-Butylphenol (50.0 g, 333 mmol). The sample was then stirred for 2 hours. In addition, acetyl chloride (26.1 g, 333 mmol) was added dropwise, followed by 2.5 hours of stirring. The reaction solution was added dropwise to ice-cold water (250 mL), and then this was stirred at room temperature. Crystals were collected by filtration and dried under reduced pressure (50° C.) to give 48.7 g of the subject compound as white crystals (yield: 76.1%, HPLC purity: 99.8%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:16]=3[N:17]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[N:21]=3)[N:19]=2)[CH2:10]1)(C)(C)C>C(OCC)C>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:16]=3[N:17]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[N:21]=3)[N:19]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Agent: Cl
Solvent: CCOCC
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CCC(N)C3)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.71 ml of a 2N solution of hydrogen chloride in diethyl ether was added to 81 mg (0.24 mmol) of tert.-butyl-(1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrrolidin-3-yl)carbamate (racemate, example 61A) and it was stirred for 4 h at room temperature. The reaction solution was concentrated and was purified by preparative HPLC (acetonitrile/water (+0.1% trifluoroacetic acid) gradient). The concentrated fractions were dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated by evaporation. 37 mg (55% of theor.) of the target compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
4-Ethoxycarbonylpiperidine (1.572 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); triethylamine (2.79 ml, 20.0 mmol) and benzyl chlorocarbonate (1.71 ml, 12.0 mmol) were added dropwise while cooled with an ice water bath; and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:3) to yield the title compound (2.315 g, 7.95 mmol, 79.5%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[O:21]>C(OCC)(=O)C>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:19]=1[C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1C#N
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylarnino)-5-nitrobenzonitrile (Example 96, step 1) and 2-bromo-3′-methylacetophenone. tlc: Rf=0.6 (33% ethyl acetate in hexanes)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Reactant: Cn1ccc(I)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 23 Step 9. LC-MS Method 2 tR=1.58 min, m/z=501, 479, 421.
Reaction SMILES: B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=[O:34].[Na+].[Na+].[CH2:51]([O:58][CH2:59]/[CH:60]=[CH:61]/[CH2:62][C@@H:63]([CH3:67])[C:64]([OH:66])=[O:65])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.COCOC.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[CH2:51]([O:58][CH2:59][C@H:60]([C@H:61]1[O:65][C:64](=[O:66])[C@H:63]([CH3:67])[CH2:62]1)[OH:34])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](C/C=C/COCc1ccccc1)C(=O)O
Reactant: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: COCOC
Solvent: O
Product: C[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reaction time: 0.17 h
Yield: 72 %

Procedure:
400 ml of a solution of a sodium tetraborate buffer solution (0.05 M) in a 0.4 mM disodium ethylenediaminetetraacetate aqueous solution, 0.648 g of tetrabutylammoniumbisulfate (1.91 mmol) and 11.1 g of 1,2:4,5-di-O-isopropylidene-β-D-erythro-2,3-hexodiuro-2,6-pyranose (43.0 mmol) were added to 10.1 g of (2R,4E)-6-benzyloxy-2-methylhex-4-enoic acid obtained in Example (76b) (43.2 mmol) in a mixed solvent of acetonitrile (167 ml) and dimethoxymethane (333 ml) at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was cooled in an ice bath. Then, a solution of 36.7 g of Oxone(trade mark) (59.6 mmol) in a 0.4 mM disodium ethylenediaminetetraacetate aqueous solution (200 ml) and a solution of 34.3 g of potassium carbonate (247 mmol) in water (200 ml) were separately added dropwise over eight hours. The mixture was stirred at the same temperature for one hour and then diluted with 100 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1-1/1) to obtain 7.82 g of the title compound (total yield over two steps: 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Product: Fc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1C(F)(F)F
Yield: 63.3 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl -acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 63%). MS (ISP) 427.0 [(M+H)+]; mp 162° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=2[C:12](O)=[O:13])[CH2:7]1.Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:11]=2[C:12]([NH:28][C:29]2([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:31][CH2:30]2)=[O:13])[CH2:7]1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)c(F)c4)C3)CC2)cc1
Yield: 54.7 %

Procedure:
The title compound (D179) (80 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(3,4-difluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D128) (100 mg, 0.267 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (60.83 mg, 0.267 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: Cc1cccc(C=O)c1
Reactant: NC1CC1
Product: Cc1cccc(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 3-methylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]CC3C=CC=CC=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cn1ccc2cc(O)ccc21
Reaction time: 16 h

Procedure:
Compound 72A (18.9 g, 64 mmol) was dissolved in 100 ml 1:1 ethyl acetate/ethanol. 200 mg 10% Pd/C was added followed by purging with hydrogen. The reaction was stirred vigorously under balloon pressure for 16 h. The reaction was filtered through Celite® and concentrated to an oil which was filtered through 0.45 uM filter to give a pale yellow oil which crystallized on standing. MS m/z 206 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:25][C:26]([F:29])([F:28])[F:27]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1ccc(Br)c(OCC(F)(F)F)c1
Temperature: 150 °C
Yield: 35.4 %

Procedure:
To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (2.5 g) in acetonitrile (0.5 mL) and DMF (10 mL) in a microwave tube was added potassium carbonate (2.93 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.79 g). The mixture was heated to 150° C. in a microwave oven for 30 minutes. The solvent was removed in vacuum, ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Recrystallization of the residue from ethanol gave 1.2 g of the title compound. The mother liquor was concentrated in vacuum and purified by aminophase-silica-gel chromatography followed by recrystallized from methanol and water to give further 0.64 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11](=O)([O:13]CC)[NH2:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[NH:12][CH:1]=1
Reactant: CCOC(N)=O
Reactant: CC(=O)Nc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1[nH]cnc2ccccc12

Procedure:
From acetanilide. Acetanilide reacts with ethyl carbamate in the presence of phosphorous pentoxide to produce 4-quinazolone. For unsymmetrical 4-quinazolones this reaction produces a mixture of regioisomers, thereby complicating the isolation and lowering the yield. ##STR7##
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:12]Br)[CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:14]Br)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S:28]([O-])([O-])(=O)=O.[Na+].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][S:28][CH2:12][C:7]3[C:6]=2[C:11]=1[CH:10]=[CH:9][CH:8]=3
Reactant: O=S(=O)([O-])[O-]
Reactant: BrCc1cccc2c(Br)ccc(CBr)c12
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c3c(cccc13)CSC2

Procedure:
A mixture of 1-bromo-4,5-bis(bromomethyl)-naphthalene (0.38 g, 0.97 mmol) and sodium sulfide nonahydrate (0.25 g, 1.04 mmol) in dimethylformamide (13 mL) was stirred at room temperature for 5 h, in the presence of sodium sulfate as scavenger for the water. The reaction mixture was poured into water and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated to dryness, to yield 6-bromo-1H,3H-naphtho[1,8-cd]thiopyran as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]2[C:29]([O:31][C:32](=O)[C:20]=12)=[O:30]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[C:32](=[O:31])[C:20]3[CH:19]=[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[CH:22][C:21]=3[C:29]2=[O:30])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccccc2N2C(=O)c3cc4ccccc4cc3C2=O)cc1
Temperature: 110 °C
Yield: 54.4 %

Procedure:
A pressure tube was charged with N-(4-methoxyphenyl)-2-aminobenzamide (500 mg, 2.07 mmol), 2,3-napthalenedicarboxylic anhydride (409 mg, 2.07 mmol), and tetrahydrofuran (10 mL). The resultant slurry was then placed in a bath heated to 110° C. for 16 h. After cooling to ambient temperature and concentration to ½ of the solution volume, the product was triturated with 50% hexanes/50% ethyl acetate and the resulting solid collected by filtration. Recrystallization from hexanes/ethyl acetate yielded 476 mg (55%) of the title compound.