Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C.O>CN(C)C(=O)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)c1ccccc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 38.9 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (330 mg, 0.86 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and benzoyl chloride (264 mg, 1.87 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 14 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:3, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (125 mg, 39%) as white crystals.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na].[Cl:7][C:8]1[CH:9]=[C:10]([C:19]2[N:20]=[C:21]([NH:24][C:25](=[O:41])[CH2:26][C:27]3[C:35]4[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]([CH3:39])[C:30]=4[O:29][C:28]=3[CH3:40])[S:22][CH:23]=2)[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16].[P:42]([O:54][CH2:55]Cl)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].[I-].[Na+]>CC(C)=O>[P:42]([O:54][CH2:55][N:20]1[C:19]([C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15]([F:18])([F:16])[F:17])=[C:8]([Cl:7])[CH:9]=2)=[CH:23][S:22][C:21]1=[N:24][C:25](=[O:41])[CH2:26][C:27]1[C:35]2[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]([CH3:39])[C:30]=2[O:29][C:28]=1[CH3:40])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:43]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: Cc1oc2c(c1CC(=O)Nc1nc(-c3ccc(OC(F)(F)F)c(Cl)c3)cs1)c(=O)n(C)c(=O)n2C
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1oc2c(c1CC(=O)N=c1scc(-c3ccc(OC(F)(F)F)c(Cl)c3)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in method C for the preparation of phosphate derivatives by the reaction of sodium salt of N-{4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide (50 g, 0.09 mol) with di-tert-butyl chloromethyl phosphate (Intermediate 1) (58.6 g, 0.23 mol) in presence of sodium iodide (10.8 g, 0.072 mol) in dry acetone (1250 ml) to obtain 50g of a product as a pale yellow solid. Alternatively the title compound was also prepared according to the general procedure as described in step 2 of method B for the preparation of phosphate derivatives by coupling N-{4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide (500 mg, 0.945 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.16 g, 3.307 mmol) using sodium hydride (57 mg, 1.418 mmol) in dry DMF (5 ml) to yield 197 mg of product as an off-white solid; 1H NMR (300 MHz, CDCl3): δ 1.49 (br s, 18H), 2.36 (s, 3H), 3.32 (s, 3H), 3.53 (s, 3H), 4.18 (s, 2H), 6.43 (d, J=6.3 Hz, 2H), 7.22-7.29 (m, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.7 Hz, 1H), 8.05 (s, 1H); ESI (m/z): 751 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-:11].[Cs+]>C(OCC)(=O)C.CCCCCCC>[OH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Br
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)c1ccccc1O
Yield: 83 %

Procedure:
Following general operating mode A, 2′-bromoacetophenone (199 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of an oil with a yield of 83% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[S:10]1(=[O:18])=[O:19]
Reactant: BrCCOCCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Yield: 54.4 %

Procedure:
In an analogous manner to general procedure IV, 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (2.07 g, 7.3 mmol) was treated with 1-bromo-2-(2-bromoethoxy)ethane (3.2 mL, 25.7 mmol) and cesium carbonate (2.4 g, 7.3 mmol) to give 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (1.72 g, 53%) as a white amorphous solid. MS (ES) m/z 368.7 [M+H—SO2]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[CH3:10])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:20]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:20])=[O:12])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: C1COCCO1
Reactant: COC(=O)c1sc(C=O)cc1C
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 5-formyl-3-methyl-thiophene-2-carboxylic acid methyl ester (3.2 g, 17.4 mmol) in dioxane (20 ml) was added 2-methyl-2-butene (15 ml) and a solution of Na2ClO2 (4.71 g, 52.1 mmol) and NaH2PO4 (4.71 g, 39.2 mmol) in water (15 ml). The mixture was stirred at rt for 1 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc and dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (3.13 g, 90% yield)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7]>ClCC(N(C)C)=O.COCCOC>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:5][C:6]([N:8]([CH3:24])[CH3:9])=[O:7])[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: CN(C)C(=O)CCl
Solvent: COCCOC
Product: CN(C)C(=O)CN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chlor-N,N-dimethyacetamide in 1,2-dimethoxyethane as solvent.
Reaction SMILES: F[C:2]1([F:16])[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH2:3]1.[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:16][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])=[CH:12][CH:13]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(C1=CCC(F)(F)C=C1)c1ccccc1
Reactant: O=C(O)c1cccc(O)c1
Product: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1

Procedure:
As shown by reaction (1), 4,-4-difluorobenzophenone is reacted with 3-hydroxybenzoic acid to obtain 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid. The reaction is carried out in a suitable aprotic solvent, such as dimethylsulfoxide or N,N-dimethylformamide, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. The 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (A) is then reacted with 3-aminophenol, as shown by reaction (2) to obtain 3-[4-(3-aminophenoxybenzoyl)phenoxy]benzoic acid (B). This reaction is carried out in a suitable aprotic solvent, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. At the end of the reaction period, the reaction mixture is cooled, then poured into water, which is then neutralized to precipitate the monomer (B). If desired, the crude monomer can be purified by recrystallization or by dissolving it in a suitable solvent and precipitating it from solution into a suitable non-solvent.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.Br[C:27]1[CH:48]=[CH:47][C:30]2[N:31]3[C:44]4[C:43]([C:29]=2[CH:28]=1)=[CH:42][CH:41]=[CH:40][C:39]=4[C:38]([CH3:46])([CH3:45])[C:37]1[C:32]3=[CH:33][CH:34]=[N:35][CH:36]=1>>[CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20]([C:27]5[CH:48]=[CH:47][C:30]6[N:31]7[C:44]8[C:43]([C:29]=6[CH:28]=5)=[CH:42][CH:41]=[CH:40][C:39]=8[C:38]([CH3:45])([CH3:46])[C:37]5[C:32]7=[CH:33][CH:34]=[N:35][CH:36]=5)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3
Reactant: CC1(C)c2cnccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc5c(c4)c4cccc6c4n5-c4ccncc4C6(C)C)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 7 by reaction of 36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid with (110 mmol) of 3-bromo-8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 50 g (88 mmol), 80% of theory, purity according to HPLC 99.9%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:27]1[S:31][CH:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=1)[CH3:26].[O:35]1[C:40]2([CH2:45][CH2:44][N:43]([CH2:46][C:47]3[CH:48]=[C:49]([CH2:53][CH2:54][OH:55])[CH:50]=[CH:51][CH:52]=3)[CH2:42][CH2:41]2)[CH2:39][NH:38][CH2:37][CH2:36]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([C:27]1[S:31][CH:30]=[C:29]([C:32]([N:38]2[CH2:39][C:40]3([CH2:41][CH2:42][N:43]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][OH:55])[CH:48]=4)[CH2:44][CH2:45]3)[O:35][CH2:36][CH2:37]2)=[O:34])[CH:28]=1)[CH3:26]
Reactant: CCc1cc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
HATU (0.209 g) was added to a stirred solution of 5-ethylthiophene-3-carboxylic acid (0.086 g), 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.160 g), and triethylamine (0.3 mL) in DMF (2 mL). After 1 h, the reaction mixture was diluted with ethyl acetate (25 mL) and washed with brine (2×25 mL). The ethyl acetate layer was evaporated in vacuo. Purification by silica gel chromatography eluting with 10:1, ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.18 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:17])=[C:10]2[O:14][CH:13]([O:15][CH3:16])[CH2:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[Cl:17][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]([O:15][CH3:16])[CH2:12]2
Reactant: CCOC(=O)c1ccc(Cl)c2c1CC(OC)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1Cc2c(C(=O)O)ccc(Cl)c2O1
Temperature: 55 °C

Procedure:
A mixture of 7-chloro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (1.17 mmol) and sodium hydroxide (1.75 mmol) in MeOH (1.3 mL) and water (1.3 mL) is heated to 55° C. for 90 min. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H-NMR (DMSO-d6): δ=13.1 (bs, 1H); 7.45 (d, J=8.3 Hz, 1H); 7.38 (d, J=8.5 Hz, 1H); 5.87 (d, J=6.3 Hz, 1H); 3.67 (dd, J=18.1 Hz, J=6.0 Hz, 1H); 3.47 (s, 3H); 3.30 (d, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>C(O)C>[CH2:19]([O:18][C:14](=[O:17])[NH:15][N:16]=[CH:12][C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]=1)[CH3:20]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=Cc1c[nH]c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Penyl-4-imidazolecarboxaldehyde (8.16 g) is dissolved in hot ethanol (200 ml). A hot solution of ethyl carbazate (5.52 g) in ethanol (50 ml) is added. A precipitate forms immediately and the mixture is heated and stirred for about 10 minutes. The mixture is then cooled to 0° C and the precipitate collected by filtration to yield the title product, m.p. 196°-200° C.
Reaction SMILES: [I-:1].[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][N+](C)(C)C.[C:12]1([P:18]([C:25]2C=CC=CC=2)[C:19]2C=CC=CC=2)C=CC=CC=1>C(#N)C>[I-:1].[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][P+:18]([CH3:25])([CH3:19])[CH3:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[N+](C)(C)Cc1ccc[nH]1
Agent: [I-]
Solvent: CC#N
Product: C[P+](C)(C)Cc1ccc[nH]1
Yield: 152.7 %

Procedure:
Subsequently, to a suspension of (pyrrol-2-yl)methyl trimethylammonium iodide (7.59 g, 28.52 mmol) obtained above in acetonitrile (60 ml) was added triphenylphosphine (8.98 g, 34.2 mmol) with stirring, and the resulting mixture was stirred at 80° C. for 6 hours. After cooling, the reaction mixture was concentrated to about one-half of its initial volume, to which was added ethyl acetate (100 ml). The crystals precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo to afford (pyrrol-2-yl)methyl trimethylphosphonium iodide (12.33 g, yield: 92%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[N:33]=[C:34]([CH3:38])[N:35]([CH3:37])[CH:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[N:33]=[C:34]([CH3:38])[N:35]([CH3:37])[CH:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Cc1nc(Br)cn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)cn1C
Temperature: 100 °C
Yield: 17.8 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 4-bromo-1,2-dimethyl-1H-imidazole (102.1 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give white solids, 19.7 mg (yield 17.8%). 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.45 (d, J=1.1 Hz, 1H), 7.20 (m, 1H), 4.73 (p, J=5.9 Hz, 1H), 3.71-3.61 (m, 1H), 3.56 (s, 3H), 3.45-3.36 (m, 1H), 3.23-3.14 (m, 1H), 2.91-2.67 (m, 1H), 2.31 (s, 3H), 2.42-2.19 (m, 2H), 1.30 (d, J=6.0 Hz, 3H), 1.14-1.04 (m, 2H), 1.04-0.93 (m, 2H) ppm; MS (ESI+) m/z 380.12 (M+H).
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=O)=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C1(C(NO)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:26][OH:25])=[O:24])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: ONC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Yield: 66.1 %

Procedure:
To a solution of 260 mg (0.81 mmol) of 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in 50 mL of anhydrous dimethylformamide 111 mg of N-hydroxybenzotriazole (0.81 mmol), 0.16 mL of N-methylmorpholine, 205 mg (1.07 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 585 mg (2.13 mmol) of triphenylmethylhydroxylamine were added consecutively. After 48 hours at room temperature the solvent was removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was then dried over sodium sulfate and evaporated. The crude was treated with 10 mL of a mixture dichloromethane-trifluoroacetic acid and after 4 hours the volatiles were removed in vacuo. The residue was redissolved with dichloromethane and washed with aqueous NaHCO3 and the product purified by chromatography on a silica gel column, eluted with CH2Cl2—CH3COCH3 4/1, to give 180 mg (66% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@H:8]([NH:12][C:13](=[O:22])[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:25]([CH2:24][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@H:8]([NH:12][C:13](=[O:22])[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)[C@H](O)c1ccccc1)CC2
Reaction time: 5 h
Yield: 57 %

Procedure:
A mixture of 15.8 g of N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, obtained according to Example 3(b), 7.1 ml of ethyl bromoacetate, 22 g of anhydrous potassium carbonate and 1 g of potassium iodide in 600 ml of anhydrous acetone, is heated with reflux and with stirring for 5 hours and a half. The reaction mixture is filtered, evaporated to dryness and the oil which separates is left to crystallize. The solid so obtained is purified by flashchromatography (elution with a 1/1 mixture of ethyl acetate/cyclohexane). The solid on the column is taken up and treated with 20 ml of ethyl ether, filtered and crystallized from ethyl acetate to give 11.5 g of N-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, SR 58638; m.p. 115°-117° C.; [alpha]=-98.3° (methanol, c=1%). Yield: 57%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:14])[CH:8]=[CH:9][C:10]([O:12]C)=[O:11].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:14])[CH:8]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)C=CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C=CC(=O)c1ccccn1

Procedure:
A mixture of 15 g of 4-(2-pyridyl)-4-oxo-2-butenoic acid, methyl ester in chloroform (50 ml) is stirred with 3.14 g of sodium hydroxide in 50 ml of water for 5 hours at room temperature. The aqueous layer is separated, washed with chloroform and acidified with 4.71 g of acetic acid, yielding the title compound.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[CH:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.IC>C1COCC1.O>[CH3:2][C:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCCC1
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of nBuLi in hexanes (242 mL, 387 mmol) was added to a −78° C. solution of diisopropylamine (39.1 g, 387 mmol) in anhydrous THF (300 mL) and the resultant mixture was stirred for 30 min at −78° C. A solution of ethyl cyclopentanecarboxylate (50 g, 352 mmol) in anhydrous THF (150 mL) was added dropwise into the mixture and the reaction mixture was stirred at −78° C. for 1 h. Iodomethane (79.2 g, 558 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred overnight. The mixture was poured into water and extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 1-methylcyclopentanecarboxylate (47 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ 4.03 (q, J=7.2 Hz, 2 H), 1.37-2.03 (m, 8 H), 1.15-1.12 (m, 6 H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].Cl[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH:31]=[CH:32][C:33]([O:35]C)=[O:34])[CH:25]=1.[H-].[Na+].Cl>C1COCC1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])[CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20]
Reactant: COC(=O)C=Cc1cc(Cl)nc(C)n1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(C)n3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (606 mg) and methyl 3-(6-chloro-2-methylpyrimidin-4-yl)acrylate (424 mg) in THF (10 mL) was added 60% sodium hydride (120 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg) as a white solid.
Reaction SMILES: CP(C)C.O.[N:6]([CH2:9][C:10]1[C:11]([F:27])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:21]#[N:22])[C:13]([Br:16])=[CH:14][CH:15]=1)=[N+]=[N-]>C1COCC1>[NH2:6][CH2:9][C:10]1[C:11]([F:27])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:21]#[N:22])[C:13]([Br:16])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN=[N+]=[N-])c2F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Trimethylphosphine (1M in THF) (6.41 mL, 6.41 mmol) and water (0.384 mL, 21.36 mmol) were added to a solution of 3-{[3-(azidomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.630 g, 4.27 mmol) in THF (30 mL) at RT. The mixture was stirred at RT overnight. The solvent was evaporated. The residue was purified by chromatography with dichloromethane:methanol to give the title compound (1.21 g, 79%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (s, 1H), 7.60 (dd, 1H), 7.43-7.51 (m, 2H), 7.41 (t, 1H), 3.75 (s, 2H), 1.92 (br. s., 2H).