Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1.[Cl:29]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>C(#N)C>[Cl:29][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8]([CH3:23])=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)cc1=O
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 70 °C

Procedure:
To a suspension of 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (1.0 g, 2.6 mmol) in anhydrous acetonitrile (15 mL) was added N-chlorosuccinimide (0.38 g, 2.9 mmol) and dichloroacetic acid (0.2 mL, 2.6 mmol). The reaction was heated in oil bath (70° C.) overnight under nitrogen. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. The resulting residue was washed with water for 30 min, filtered, and rinsed with water. The white solid (830 mg, 82%) was dried in vacuo. 1H-NMR (CD3OD, 400 MHz) δ 8.09 (dd, 1H, J=1.6 Hz), 7.88 (d, 1H, J=2 Hz), 7.56 (m, 2H), 7.01 (m, 2H), 5.57 (s, 2H), 2.16 (s, 3H), 2.13 (s, 3H); ES-HRMS m/z 421.0753 (M+H C20H16ClF2N2O4 requires 421.0761).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([I:1])[CH:7]=2)=[N:9]1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: Ic1cncc(-c2nn[nH]n2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cncc(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridine (273 mg, 1 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.31 mL, 1.3 eq), potassium carbonate (207 mg, 1.5 eq) in anhydrous DMF (4 mL) under nitrogen atmosphere was stirred and heated at 80° C. for 5 hours. The mixture was then diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated under reduced pressure, and the resulting brown oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:50 to 1:4) giving 3-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-5-iodopyridine as a soft white solid in the amount of 395 mg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:5]=[C:4]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:3]=3)[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1c(Cl)nc(NCc2ccccn2)nc1NCc1ccccn1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCc2ccccn2)nc(NCc2ccccn2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-[(pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in the presence of N-ethyl-diisopropylamine in dioxane at 90° C. during 18 hours to yield 4-(4-phenyl-piperazin-1-yl)-2,6-bis-[(pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, yellowish solid; MS: [M+H]+=478.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:27]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:27])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCOC(=O)CCCCCCCBr
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Product: COCCOCCOC(=O)CCCCCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 25 %

Procedure:
4,5-Diphenylimidazole (2.85 g) was treated with 2-(2-methoxy-ethoxy)ethyl 8-bromooctanoate (8.63 g) as described in Example 20 to give 2-(2-methoxyethoxy)ethyl 8-(4,5-diphenylimidazole-1-yl)octanoate as a colourless oil (1.5 g, 25%). Found: C, 72.28; H, 7.91; N, 6.35% C28H36N2O4 requires: C, 72.38; H, 7.81; N, 6.03%
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(c2ccccc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.155 g, 0.5 mmol) from Example UU, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.2 g, 0.55 mmol), K2CO3 (0.27 g, 1.95 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature, concentrated and the residue partitioned between 1N HC1 and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CHCl3 :hexane (5:90:10 to 10:90:10) gave the title compound, m.p. 132°-135° C. 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.76 (s, 3 H), 2.08-2.24 (m, 3 H), 2.48 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s , 1 H), 6.17 (s, 1 H), 6.46-6.55 (m, 3 H), 7.02 (t, 1 H), 7.22 (s, 1 H), 7.35-7.46 (m, 5 H), 9.23 (s, 1 H) 12.15 (bs, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[CH2:14]([NH2:16])[CH3:15]>C(Cl)Cl>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([NH:16][CH2:14][CH3:15])=[O:7]
Reactant: CCN
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C)c(N)c1
Reaction time: 0.08 h

Procedure:
4-methyl-3-nitro-benzoyl chloride (1.0 g, 5.0 mmol) was dissolved in DCM, and the solution was cooled to 0EC. Ethyl amine (2.0M in THF, 5.0 mL, 10 mmol) was added dropwise to the acid chloride, and the reaction stirred at 0EC for 5 min. The ice bath was removed and reaction continued to stir for 3. The solution was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting aniline (0.75 g) was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>C(Cl)Cl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Reactant: CN(C)CCN
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 79.9 %

Procedure:
To a suspension of Intermediate 12b (1 g, 3.87 mmol) in DCM (20 ml) was added COMU (1.891 g, 4.26 mmol) and DIPEA (0.812 ml, 4.65 mmol). The yellow solution was stirred for 2 min at rt and turned red. 2-Dimethylaminoethylamine (0.518 ml, 4.65 mmol) was added and the reaction mixture was stirred at reflux for 1 hr. After cooling to rt, the mixture was washed with water, saturated aqueous NH4Cl and extrated with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (ISCO CombiFlash Rf, 120 g silicagel; A=dichloromethane, B=DCM:7N NH3 in MeOH (9:1), 2% hold for 5 min, gradient to 50% B over 15 min). Fractions containing the product where combined to yield 1.355 g. The final product (1.015 g) was obtained after crystallisation from heptane as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].O[C:13]1[C:21]2[N:20]=N[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[NH2:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:21]=1[NH:20][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Nc1ccccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
4-Cyanobenzoic acid (294 mg, 2 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (768 mg, 4 mmol), hydroxybenzotriazole (324 mg, 2.4 mmol), triethylamine (808 mg, 8 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give N-(2-aminophenyl)-4-cyanobenzamide (364 mg, 77%) as a grey solid. LC-MS (m/z) 238 (M+1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:41])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O>C(O)(=O)C>[CH2:3]([NH:10][C:11](=[O:41])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCN2CCOCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 2.4 %

Procedure:
630 mg (1.56 mmol, 2 eq) of sodium hydroxide are added to a solution of 420 mg (0.78 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(2-morpholin-4-ylethoxy)biphenyl-4-yl]propanoate in 8 ml of 8/1/1 tetrahydrofuran/methanol/water. The reaction mixture is stirred for 4 hours at room temperature. The reaction medium is hydrolyzed with water and acetic acid and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (40/60 heptane/ethyl acetate) and then on preparative HPLC. 10 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(2-morpholin-4-ylethoxy)biphenyl-4-yl]propanoic acid are obtained in oil form. Yield=2%
Reaction SMILES: [CH:1]1(/[CH:8]=[C:9](\[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)/[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:32]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:32][C:15]1[S:14][C:13]([NH:12][C:10](=[O:11])/[C:9](/[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)=[CH:8]/[CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:17][CH:16]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2ncc(Br)s2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A suspension of (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 17, 63 mg, 0.133 mmol) and N-bromosuccinimide (26 mg, 0.146 mmol) in carbon tetrachloride (2 mL) at 25° C. was treated with benzoyl peroxide (2 mg, 0.006 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL). The organic phase was then washed with water (1×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 hexanes/ethyl acetate) afforded the (E)-N-(5-bromo-thiazol-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (35.5 mg, 48%) as an amorphous white solid.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.ClCCCC(OC(=O)C)(C)CCCCC.C([O:33][C:34](C)([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[C:39]#[N:40])(=O)C>>[OH:33][C@H:34]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:35]#[C:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:39]#[N:40].[OH:33][C@H:34]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:35]#[C:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:39]([NH2:40])=[O:11]
Reactant: CCCCCC(C)(CCCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: CCCCCC(C)(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-4-methylnonane (Example R). The product of Step A is thus ethyl 7-[N-(4-acetoxy-4-methylnonyl)-cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-4-methylnonyl)cyanamido]heptanoic acid (B) and 7-[1-(4-hydroxy-4-methylnonyl)ureido]heptanoic acid (C).
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH:9](O)[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[CH2:5][CH2:4]1.[OH-:40].[Na+]>C(O)C>[OH:1][C:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:26])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[OH:40])[CH2:7][CH2:8]1
Reactant: [OH-]
Reactant: CCOC(=O)C(C)(C)c1ccc(CCCC(O)N2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
According to the described procedure of Carr et al., U.S. Pat. No. 4,254,129, to a solution of 0.6 g of ethyl 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-hydroxybutyl]-α,α-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3 ½ hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanolbutanone to give 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, M.P. 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH2:5][CH:6]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8][C:7]=12.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH2:5][CH:6]2[C:11]([CH3:12])([CH3:13])[O:10][C:9](=[O:14])[NH:8][C:7]2=[C:2]([F:1])[CH:3]=1
Reactant: CC1(C)OC(=O)NC2=C(F)C=CCC21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)OC(=O)NC2=C(F)C=C(Br)CC21
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one (0. 15 g, 0.77 mmol) in acetic acid (5 mL) was added dropwise a solution of bromine (0.37 g, 2.31 mmol) in acetic acid (5 mL) under nitrogen at rt. After stirring for 10 minutes, the mixture was concentrated and the residue obtained was purified by a silica gel column (hexane:ethyl acetate/4:1) to afford 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one as an off-white solid (0.176 g, 84%) which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1.[CH:15]1([C:18]2[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=2)[CH2:17][CH2:16]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][C:20]2[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[NH:22][N:21]=2)[C:5]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl
Solvent: CCO
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A mixture of 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine (1.0 g, 4.1 mmol, 1.0 eq) and 5-cyclopropyl-1H-pyrazol-3-amine (756 mg, 6.2 mmol, 1.5 eq) in EtOH (4 ml) was stirred at room temperature for 2 h. The mixture was purified by silica gel column chromatography (PE/EtOAc=5:1 to 2:1) to afford 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (900 mg, 66%).
Reaction SMILES: C(Cl)CCl.[C:5]([OH:9])(=O)[CH:6]=[CH2:7].[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH2:20][NH:21][CH3:22].[CH:23]1[CH:24]=[CH:25]C2N(O)N=[N:29][C:27]=2[CH:28]=1.O>CN(C=O)C>[CH3:22][N:21]([CH2:20][C:12]1[N:11]([CH3:10])[C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5](=[O:9])/[CH:6]=[CH:7]/[C:28]1[CH:27]=[N:29][CH:25]=[CH:24][CH:23]=1
Reactant: On1nnc2ccccc21
Reactant: C=CC(=O)O
Reactant: CNCc1cc2ccccc2n1C
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cccnc1
Reaction time: 8 h
Yield: 40 %

Procedure:
EDC (0.22 g, 1.14 mmole) was added to a solution of trans-3-3-pyridyl)acrylic acid (0.17 g, 1.14 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF (10 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (0.14 g, 40%) as a white solid: 1H NMR (360 MHz, CDCl3) indicated an approximately 8:1 mixture of amide rotamers; for the major rotamer: δ 8.79 (s, 1 H), 8.59 (d, J=3.9 Hz, 1 H), 7.84 (d, J=7.6 Hz, 1 H), 7.76 (d, J=15.5 Hz, 1 H), 7.59 (d, J=7.8 Hz, 1 H), 7.38-7.48 (m, 2 H), 7.19-7.27 (m, 1 H), 7.08-7.17 (m, 1 H), 6.98 (d, J=15.5 Hz, 1 H), 6.51 (s, 1 H), 4.94 (s, 2 H), 3.73 (s, 3 H), 3.09 (s, 3 H); MS (ES) m/e 306 (M+H)+. Anal. Calcd for C19H19N3O.0.20H2O: C, 73.86; H, 6.33; N, 13.60. Found: C, 73.52; H, 6.32; N, 13.43.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].Cl.C(OCC)(=O)C>C1COCC1.O.[Cl-].[Na+].O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:23])=[O:2])=[O:22]
Reactant: COC(=O)c1ccccc1NC(=O)COc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1ccccc1C(=O)O
Yield: 89 %

Procedure:
2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester (94.6 mg, 0.27 mmol) in THF/H2O (3:1, 25 mL) was treated with LiOHH2O (22.7 mg, 0.54 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and added ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=6:1) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid as a white solid (81.7 mg, 88.9% yield).
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.Cl[Si:11]([CH2:19][Cl:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[Cl:20][CH2:19][Si:11]([O:2][CH3:1])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO
Reactant: C[Si](Cl)(CCl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CO[Si](C)(CCl)c1ccccc1
Yield: 79.7 %

Procedure:
A solution of 1.6 ml (1.3 g, 0.040 mol) of methanol and 3.0 ml (2.2 g, 0.022 mol) of triethylamine in 100 ml of ether was stirred while a solution of 4.1 g (0.020 mol) of chloro(chloromethyl)methyl(phenyl)silane in 10 ml of ether was added dropwise. The resulting slurry was refluxed for 2 hours, cooled, washed with water, 0.1N aqueous HCl, saturated aqueous NaHCO3, water, and brine, dried over magnesium sulfate, and evaporated to leave 3.2 g of a pale yellow liquid. Distillation provided 1.7 g (42%) of the title compound as a colorless liquid: bp 46°-49° (0.05 mm); nD22 1.5207; nmr (CDCl3): 0.5 (3H, s), 3.0 (2H, s), 3.5 (3H, s) and 7.3-7.8 (5H, m).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([N:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH:17]1C(O)=O)=O.[C:26]([O:34][CH3:35])(=[O:33])[C:27]#[C:28][C:29]([O:31][CH3:32])=[O:30]>CC(OC(C)=O)=O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:16]2[C:17](=[C:27]([C:26]([O:34][CH3:35])=[O:33])[C:28]=1[C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20]2
Reactant: CC1(C)CC(C(=O)O)N(C(=O)CCN2C(=O)c3ccccc3C2=O)C1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c2n(c1CCN1C(=O)c3ccccc3C1=O)CC(C)(C)C2
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of 137i (crude, 72.5 mmol) and Ac2O (100 mL) was stirred at 90° C. for 0.5 h. Then dimethyl but-2-ynedioate 137j (20.6 g, 145 mmol) was added. See FIG. 2. The mixture was stirred at 110° C. for 2 h. Upon reaction completion, the mixture was concentrated under reduced pressure. The crude was purified by silica gel chromatography (PE/EA=50/1 to 1/1) to give dimethyl 5-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2,2-dimethyl-2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate 137k (15 g, 48%).