Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([NH:33][CH2:34][CH2:35]Br)=[O:32])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.BrCCN=C=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([NH:33][CH2:34][CH2:35][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:32])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC(=O)NCCBr)C1
Reactant: C1COCCN1
Agent: O=C=NCCBr
Solvent: CCO
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC(=O)NCCN2CCOCC2)C1

Procedure:
To a solution of 41 mg (0.075 mmol) of trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-bromo-ethyl)-urea, which is prepared as described in Example 26 using 2-bromoethyl isocyanate (Aldrich, Buchs, Switzerland), in 5 ml of ethanol is added 33 μl (0.375 mmol) of morpholine. The mixture is refluxed for 3 h and the crude mixture is purified by medium-pressure liquid chromatography to provide trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-morpholin-4-yl-ethyl)-urea. Analytical HPLC: tR=6.12 min (Grad 2); ES-MS: m/eo=555.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1.C(N(CC)CC)C.[CH3:45][C:46](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:47]>C(Cl)Cl>[C:46]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1)(=[O:47])[CH3:45]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Yield: 78 %

Procedure:
A solution of 0.02 g (0.04 mmol) of 1-(N-(3-aminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine, 0.025 mL (0.18 mmol) of triethylamine and 0.015 mL (0.16 mmol) of acetic anydride in 2 mL of CH2Cl2 was stirred for 12 h at rt. The reaction mixture was partitioned between EtOAc and water. The organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:1) to give 17 mg of the title compound. Mass Spectrum (EI) m/e 545 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:21](=[O:27])[CH:22]=[CH:23][C:24]2=[O:26])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C\C(=O)NCCCCCCOc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccc(OCCCCCCN2C(=O)C=CC2=O)cc1

Procedure:
The compound can be prepared from N-[6-(4-benzoylphenoxy)-hexyl]-maleamic acid from Example 11 by reacting with acetic acid and sodium acetate according to the method described in Example 2. The desired maleimide was isolated as its monohydrate by flash column chromatography. Mp 84--6° C. (Found: C, 72.78; H, 6.28; N, 3.58%. C23H23NO3, H2O requires C, 73.19; H, 6.65; N, 3.69%). H.p.l.c. 100%. FAB ms 378 (MH+). 1H-n.m.r. (CDCl3) δ 6.9 (2H, m, aromatic), 6.6 (2H, d, CH=CH), 3.9 (2H, m, CH2), 3.5 (2H, m, CH2), 1.8 (2H, m, CH2), 1.6 (2H, m, CH2), 1.5 (2H, m, CH2), 1.3 (2H, m, CH2). λmax (CH2Cl2) 286 nm, ε 16590.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: CC(Oc1ccncc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccncc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A mixture of 4-(1-(pyridin-4-yloxy)ethyl)benzoic acid (127 mg, 0.5 mmol), N-hydroxybenzotriazole (101.25 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. The mixture was washed with water (10 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyridin-4-yloxy)ethyl)benzamide (57 mg, 30%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, CD3OD): δ 8.23 (d, J=5.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.93-6.91 (m, 2H), 6.08 (s, 1H), 5.62 (q, J=6.3 Hz, 1H), 4.47 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.64 (d, J=6.3 Hz, 3H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)O

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate is added at a temperature in the region of 20° C. to 1.21 g (4.54 mmol) of 3-methoxycarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 22 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 mL of water and then triturated with 15 mL of 1N hydrochloric acid. After filtering off and drying the solid residue at ambient pressure at a temperature in the region of 50° C., 1.05 g of 3-carboxy-4-methyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a whitish solid. Mass spectrum (EI): EI: m/e 252 (M+.) m/e 207.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13](Cl)(=[O:15])=[O:14].CN.[CH2:19]([N:21](CC)CC)C>O1CCCC1.C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH:21][CH3:19])(=[O:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: Nc1cc(Cl)c(S(=O)(=O)Cl)cc1S(=O)(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNS(=O)(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1N
Reaction time: 0.75 h

Procedure:
Cool a solution of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride (32.3 g) in tetrahydrofuran (THF, 150 ml) to -78° C. under a nitrogen atmosphere. Add a solution of 1.45 Molar methylamine in benzene (100 ml) containing triethylamine (10.1 g) dropwise with stirring over 45 minutes. After the addition is complete, stir at room temperature for 3 hours. Vacuum evaporate the solvent and partition the residue between ethyl acetate (EtOAc) (500 ml) and 10% aqueous citric acid (50 ml). Separate the organic layer and wash with saturated aqueous NaHCO3 (100 ml) followed by brine (100 ml). Dry the solution over Na2SO4, filter and vacuum evaporate the solvent. Triturate the residue with ether (100 ml) and collect the product by filtration. Vacuum dry at room temperature to give the title compound, m.p. 153°-155° C. Rf (silica gel; CH2Cl2 :EtOAc,97:3)=0.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:36])([F:38])[F:37]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 4-fluoro-3-(trifluoromethyl)benzaldehyde in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as an off-white solid. MS (m/e)=548.1 [M+H+].
Reaction SMILES: [OH:1][C:2]1([CH3:8])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:9][CH2:10][C:11](Cl)=[O:12].C(N(CC)CC)C.C(O)C>CN(C1C=CN=CC=1)C.O.C(Cl)Cl>[Cl:9][CH2:10][C:11]([O:1][C:2]1([CH3:8])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)=[O:12]
Reactant: CC1(O)CCOCC1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(OC(=O)CCl)CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
A four-necked flask having an inner volume of 100 mL, which was equipped with a dropping funnel, a thermometer and a nitrogen introducing pipe, was charged with 4.64 g (40.0 mmoles) of 4-hydroxy-4-methyltetrahydropyran and 20.0 g of methylene chloride and further charged with 0.24 g (2.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 6.78 g (60.0 mmoles) of 2-chloroacetyl chloride. Subsequently, 6.37 g (63.0 mmoles) of triethylamine was added dropwise at room temperature over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours. To this reaction mixed solution, 1.11 g (24.0 mmoles) of ethanol was added dropwise, and subsequently, 20.0 g of water was added dropwise; and the mixture was stirred for 20 minutes. This reaction mixed solution was separated into an aqueous layer and an organic layer. The aqueous layer was extracted twice with 20 mL of methylene chloride; the extract was combined with the foregoing organic layer; the mixture was washed once with 10 mL of water and concentrated in vacuo, thereby obtaining 6.09 g (31.6 mmoles) of 4-chloroacetoxy-4-methyltetrahydropyran (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[N:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[C:6]([CH3:13])([CH3:14])[N:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]=2[N:3]=1
Reactant: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1(C)C
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCN1c2nc(Cl)ncc2N(c2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a stirred solution of 2-chloro-7,7-dimethyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (707 mg, 2.5 mmol) in dichloromethane (50 mL) was added triethylamine (25.0 mmol), cupric acetate (908 mg, 5.0 mmol) and phenylboronic acid (610 mg, 5.0 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 48 h at room temperature with an air balloon. Then the reaction mixture was filtered over celite. The filtrate was washed with aqueous saturated sodium bicarbonate (2×30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (Eluent: 2% methanol in dichloromethane) to give titled product (yield; 46%). 1HNMR (300 MHz, CDCl3): δ 1.0 (s, 3H), 1.02 (s, 3H), 1.61-1.65 (m, 9H), 3.64 (q, J=5.1 Hz, 2H), 7.06 (s, 1H), 7.18-7.21 (m, 2H) and 7.48-7.57 (m, 3H).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]1([CH3:46])[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1OBO>COCCOC.O.CCO>[C:37]1([CH3:46])[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccccc1OBO
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 28.9 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(PPh3)Cl2 (˜1 mol %), and Cs2CO3 (17.8 mg, 0.0547 mmol) in DME/H2O/EtOH (7/3/2, 0.5 mL). O-tolyl boronic acid (6.3 mg, 0.046 mmol) was added and the solution was heated in the microwave for 5 minutes at 160° C., filtered, and was purified by Prep HPLC to give 6 mg (23%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 451 (M−H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.78-1.86 (m, 2H), 2.19 (br d, 2H), 2.22 (s, 3H), 3.13-3.19 (m, 2H), 3.58 (br d, 2H), 3.81-3.92 (m, 3H), 5.43 (s, 1H), 6.34-6.40 (m, 1H), 6.88 (d, 1H), 7.23-7.43 (m. 10H), 7.54 (m, 2H), 8.14 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19]O>>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(CC(=O)O)cc(C(C)(C)C)c(O)c1C
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C
Temperature: 68 °C

Procedure:
11.8 grams of 5-tert.-butyl-2,3-dimethyl-4-hydroxyphenylacetic acid was added at 20° C. to 200 ml of methanol previously saturated with hydrogen chloride gas. The slightly pinkish solution was heated at reflux (68° C.) for 3 hours after which about one-half of the solvent was removed at reduced pressures and the reaction mixture then poured into about 500 ml of an ice-water mixture with stirring until all the ice had melted. The precipitated crystals were filtered, washed with water and dissolved in benzene. The benzene solution was successively washed with water, saturated sodium bicarbonate solution and finally with water to pH 7, the benzene solution being dried over anhydrous sodium sulfate. The clear benzene solution, freed of drying agent by filtration, was concentrated at reduced pressure. The resulting solid residue was triturated with hexane to remove color bodies. After recrystallization from methanol, the desired product was obtained as white crystals melting at 117° to 119° C. (Compound 14).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[OH-].[K+]>C(O)C.O>[OH:4][CH2:3][CH2:2][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ccc(OCCO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-ethanol (5.0 g, 0.04 mol) and 4-(trans-4-propylcyclohexyl)phenol (4.4 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, separating the solids from liquid, dissolving them in toluene (100 ml), filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene and recrystallizing the resulting crystals from n-heptane to obtain the objective 1-(2-hydroxyethoxy)-4-(trans-4-propylcyclohexyl)benzene. Yield: 1.8 g (34%). C-S: 71.5° C. S-I: 81.4° C.
Reaction SMILES: [C:1]([C:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])([O:3]C)=[O:2].[OH-].[K+]>CO.O1CCCC1.O>[C:1]([C:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])([OH:3])=[O:2]
Reactant: COCOC1=C(C(=O)OC)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCOC1=C(C(=O)O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Yield: 53.7 %

Procedure:
A solution of 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.5 g, 1.25 mmol) and potassium hydroxide (0.21 g, 3.75 mmol) in methanol (13 mL), tetrahydrofuran (5 mL) and water (7.5 mL) under an argon atmosphere was heated at 65° C. for 3 h. The mixture was partitioned between methylene chloride and acidic water, was extracted twice, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 5% methanol/chloroform, provided an oil (0.26 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10](N)=[O:11])=[N:8][S:9][C:5]=2[CH:4]=1.[OH-:15].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10]([OH:15])=[O:11])=[N:8][S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(N)=O)nsc2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(C(=O)O)nsc2c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of the amide (5.46 mmol) in methanol (100 mL) was added 10 N sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h, cooled to rt, and was acidified to pH <2 by the slow addition of conc. hydrochloric acid. The organic layer was extracted with dichloromethane (2×) and was dried over sodium sulfate. The crude product was purified by chromatography (300/50/1 dichloromethane/methanol/formic acid) to provide 6-methoxy-1,2-benzisothiazole-3-carboxylic acid (89%) as a pink solid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=[O:7].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:24]=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][N:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[CH:4]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Under inert atmosphere, a mixture of 2-Trifluoromethyl-isonicotinic acid (1.0 equiv.), BOP (1.2 equiv.), DIPEA (1.5 equiv.) in DCM (C=0.1 molL−1) and MeOH (C=0.1 molL−1) was stirred at RT for 16 h. The reaction mixture was evaporated to dryness. The resulting residue was hydrolysed with HCl 1N and extracted twice with Et2O. The organic layers were combined, washed with a saturated solution of NaHCO3, brine, dried over MgSO4, concentrated to afford the product as transparent oil in a 66% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[CH:25][C:24]=1[O:31][CH:32]([CH2:35][F:36])[CH2:33][F:34]>>[Cl:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[O:31][CH:32]([CH2:35][F:36])[CH2:33][F:34])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: FCC(CF)Oc1ccc(CCl)cc1Cl
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(OC(CF)CF)c(Cl)c3)ccc12

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 2-chloro-4-(chloromethyl)-1-(1,3-difluoropropan-2-yloxy)benzene, the title compound was prepared using a similar method to the one described in Example 1.48, Step B. LCMS m/z=450.1 [M+H]+; 114 NMR (400 MHz, CDCl3) δ ppm 2.27-2.36 (m, 1H), 2.67 (dd, J=16.4, 8.4 Hz, 1H), 2.87-2.97 (m, 2H), 3.75 (quintet, J=7.4 Hz, 1H), 3.98-4.05 (m, 1H), 4.15 (ddd, J=9.9, 8.6, 4.1 Hz, 1H), 4.56-4.69 (m, 3H), 4.75-4.78 (m, 2H), 5.00 (s, 2H), 6.12 (s, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.06-7.09 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.31 (dd, J=8.4, 2.1 Hz, 1H), 7.51 (d, dr=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Product: O=C(c1ccc(F)cc1)c1ccc(F)c(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 74 step (i) but instead using 3-chloro-4-fluorobenzoyl chloride and fluorobenzene.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(O)C>O.[OH-].[Na+]>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:2][OH:3])=[CH:7][CH:6]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Cl)cc1
Yield: 75.7 %

Procedure:
To a solution of 50 g of hydroxylamine hydrochloride in 300 ml of water was added a suspension of 20 g of 4-chlorobenzaldehyde in 200 ml of 10% aqueous sodium hydroxide solution. Ethanol was then added until the mixture was clear. The solution was heated on a steam bath for 25 minutes, then cooled in an ice bath. The solid which separated was collected by filtration and dried in a vacuum desiccator. A second fraction was obtained by adding water just to the cloud point. This solid was collected and dried and the two products combined to give 16.75 g of 4-chlorobenzaldoxime, m.p. 108°-109°.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)c1ccc(Cl)c(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-amino-4-chlorobenzotrifluoride by Procedure A. The product was isolated upon basic work-up and purified by preparative LCMS to give the title compound as the free base. 1NMR (CDCl3) δ 6.40 (br s, 2H), 7.11-7.15 (d, 1H), 7.18-7.25 (m, 2H), 7.35-7.41 (d, 1H), 7.42-7.46 (m, 2H), 8.57 (s, 1H). MS(ES+) m/z 312 ([M+1]+, 100).