Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]([CH3:24])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[OH:1][C@@:2]([CH3:24])([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:4]
Reactant: COc1ccc(NC(=O)[C@@](C)(O)COc2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@](O)(COc1ccc(O)cc1)C(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
(S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide (6d) (0.20 g, 0.60 mmol) was dissolved in dry CH2Cl2 (30 mL). BBr3 (4 mL of 1.0 M CH2Cl2 solution) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in a ice bath and hydrolyzed by adding water (25 mL). EtOAc (50 mL) was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc (2×10mL). The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with hexanes/EtOAc (3/7 v/v) to afford a white solid product, (S)-2-hydroxy-3-(4-hydroxyphenoxy)-N-(4-hydroxyphenyl)-2-methylpropanamide (6f), 0.13 g, 67.2% yield.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:14]([N:6]1[C:5]2=[CH:4][N:3]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:2]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(Cn2cc3c(c2Nc2ccccc2)c(=O)n(C)c(=O)n3CC(C)C)cc1
Temperature: 180 °C
Yield: 120.2 %

Procedure:
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (14 mg, 0.025 mmol) is placed in a Biotage microwave tube, and then aniline (0.5 mL, 5.4 mmol) is added. The mixture was heated at 180° C. for 4 h. The mixture is purified by a semi-preparative HPLC to give 13 mg of pure product (yield: 81%). MS (ESI) m/z 433.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.C(N(CC)CC)C.[CH2:32](Br)[CH:33]=[CH2:34]>CN(C)C=O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:34][CH:33]=[CH2:32])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Reactant: C=CCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
To a stirred solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.5 g; 1.37 mmol), prepared as in Example 10, and triethylamine (0.3 g; 3.0 mmol) in N,N-dimethylformamide (10 mL), was added allyl bromide (0.17 g; 1.4 mmol) in N,N-dimethylformamide (approximately 2 mL). The reaction mixture was stirred for 1.5 hours and the solvent removed. The residue was stirred with ammonium hydroxide and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2×50 mL) and purification of the combined methylene chloride layers by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2,3-dihydro-2-(1-prop-2-enylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.1 g; 0.27 mmol), m.p. 279°-281° C.
Reaction SMILES: Br.[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:51][CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55]>CN(C=O)C.CC(C)=O>[CH2:57]([O:56][C:54](=[O:55])[CH2:53][CH2:52][CH2:51][O:18][C:16]1[CH:15]=[CH:14][C:13]2[CH:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:2])[CH3:23])[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[CH2:10][CH2:11][C:12]=2[CH:17]=1)[CH3:58]
Reactant: CCOC(=O)CCCBr
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(O)ccc21
Agent: Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)CCc1ccccc1C2CCCN(C)C
Temperature: 90 °C
Yield: 82.6 %

Procedure:
To 500 mg (1.32 mmol) of 6 was added 10 ml of freshly distilled acetone (distilled over anhydrous K2CO3) and 10 ml of anhydrous DMF. To this reaction mixture was added 450 mg (3.0 mmol) of sodium iodide, 2 g of 4° A molecular sieves, 2 g (6.13 mmol) of cesium carbonate and a catalytic amount of 18-crown-6. To this reaction mixture was added 500 μl (3.38 mmol) of ethyl 4-bromobutyrate and the reaction mixture was heated on an preheated oil bath (90° C.) under argon atmosphere for 18 hours. The mixture was cooled to room temperature and filtered. The residue was washed with 30 ml of chloroform. The combined filtrate was concentrated under reduced pressure and redissolved in 100 ml of dichloromethane. This was washed with 2×100 ml of 5% NaOH followed by 2×100ml of water, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using 10% methanol in dichloromethane to give 450 mg (1.09 mmol, 83%) of 7 as a brownish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:12]=O)[C:8]=1[C:9]([OH:11])=[O:10].[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:11])=[O:10]
Reactant: COc1cccc(C=O)c1C(=O)O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(C=C2SC(=S)NC2=O)c1C(=O)O
Temperature: 0 °C

Procedure:
To a stirred hot solution of 2.10 g. (11.65 mM) of 6-methoxyphthalaldehydic acid and 1.57 g. (11.75 mM) of rhodanine in 8 ml. of acetic acid is added 3.12 g. (38.1 mM) of sodium acetate. The resulting solution is refluxed 0.5 hour and then poured into ice water to give a tan precipitate. The solid is collected and partially air-dried to give 5-(2-carboxy-3-methoxybenzylidene)rhodanine as a tan solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:40][CH3:41])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc21
Yield: 47.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.05 g (0.18 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic layers were washed with brine, dried, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.040 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-159).
Reaction SMILES: CN(CCCC(C#N)C1C=CC=CC=1C1C=CC=CC=1)C.S(=O)(=O)(O)O.[OH-].[Na+].[Cl-].[CH3:30][NH+:31]([CH2:33][CH2:34][CH2:35][CH:36]([C:49]([OH:51])=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH3:32]>>[CH3:30][N:31]([CH2:33][CH2:34][CH2:35][CH:36]([C:49]([OH:51])=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH3:32]
Reactant: C[NH+](C)CCCC(C(=O)O)c1ccccc1-c1ccccc1
Agent: CN(C)CCCC(C#N)c1ccccc1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Product: CN(C)CCCC(C(=O)O)c1ccccc1-c1ccccc1
Temperature: 5 °C

Procedure:
A solution of 6.0 g. of N,N-dimethyl-4-cyano-4-(1,1'-biphenyl-2-yl)butylamine in 65 ml. of 90% sulfuric acid was heated on a steam bath for eight hours. After cooling the reaction mixture to 5° C. and making it alkaline by the addition of 10% sodium hydroxide, the product was extracted therefrom intodiethyl ether. The ethereal extracts were washed with water and dried. Excess hydrogen chloride was bubbled into the ethereal solution, whereupona precipitate formed and was collected by filtration. Crystallization of the precipitate from ethanol afforded 2.9 g. of N,N-dimethyl-4-hydroxycarbonyl-4-(1,1'-biphenyl-2-yl)butylaminium chloride. M.P. 192°-194° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:24][CH:23]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: COc1ccc(CCN)cc1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccc(OC)cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(4-methoxy-phenyl)-ethyl-amine to afford the title compound. MS: m/e=392 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][C@@H:36]1[CH2:40][OH:41]>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:39][CH2:38][CH2:37][C@@H:36]4[CH2:40][OH:41])[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: OC[C@H]1CCCN1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCC[C@@H]4CO)c23)ccc1OCc1cccc(F)c1
Yield: 14 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and (R)-2-pyrrolidinemethanol to give the title compound in 14% yield; NMR Spectrum: 1.51 (m, 1H), 1.66 (m, 2H), 1.80 (m, 1H), 2.23 (s, 3H), 2.32 (q, 1H), 2.57 (m, 1H), 2.75 (dt, 1H), 3.14 (td, 1H), 3.24 (m, 1H), 3.40 (m, 2H), 4.39 (t, 2H), 4.44 (s, 1H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.31 (m, 2H), 7.48 (m, 3H), 8.16 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 493 (MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCNCC2)C3)CC1
Product: CCc1cnc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.91 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:14][C:13]=3[OH:26])[NH:11][C:7]=2[CH:6]=1)=O.[NH2:29][NH2:30]>CCO>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([NH:29][NH2:30])=[O:2])[CH:28]=[CH:27][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Reactant: NN
Solvent: CCO
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)NN)cc3[nH]2)c1
Temperature: 90 °C
Yield: 66.6 %

Procedure:
To a suspension of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid methyl ester (37.5 mg, 0.1 mmol) in EtOH (1 mL) was added anhydrous hydrazine (32 mg, 1 mmol). The reaction mixture was heated at 90° C. for 18 h, cooled to the room temperature, filtered to get the solid precipitate that was dried under reduced pressure to afford the title compound (25 mg, 33%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 4.51 (br s, 2H, NH), 7.11-7.17 (2H), 7.63 (d, J=9 Hz, 1H), 7.71 (d, J=9 Hz, 1H), 7.79-7.85 (2H), 8.10-8.21 (2H), 8.29 (s, 1H), 9.87 (br, 1H, NH). ESI-MS m/z 376.3 (MH+).
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:22][C:23]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26]>C(Cl)Cl>[CH2:1]([N:54]1[CH2:53][CH2:52][CH:51]([C:48]2[CH:49]=[CH:50][C:23]([OH:22])=[C:24]([CH:47]=2)[C:25]([NH:27][C:28]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][C:29]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[CH2:56][CH2:55]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetaldehyde (0.016 mL), acetic acid (0.024 mL), and sodium triacetoxyborohydride (0.11 g) were sequentially added to a methylene chloride (1.0 mL) suspension of tert-butyl 2-(2-hydroxy-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 1 hour. Acetaldehyde (0.016 mL) and sodium triacetoxyborohydride (0.11 g) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. After removal of the insoluble substance by filtration, a saturated aqueous solution of sodium bicarbonate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.045 g of tert-butyl 2-(5-(1-ethylpiperidin-4-yl)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: Br.[Br-].[NH2:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C([Li])CCC.[Cl:36][C:37]1[CH:51]=[CH:50][C:40]2[CH:41]=[CH:42][N:43]3[CH:49]=[CH:48][CH:47]=[C:44]3[C:45](=O)[C:39]=2[CH:38]=1>CCCCCCC.O>[Cl:36][C:37]1[CH:51]=[CH:50][C:40]2[CH:41]=[CH:42][N:43]3[CH:49]=[CH:48][CH:47]=[C:44]3[C:45](=[CH:6][CH2:5][CH2:4][NH2:3])[C:39]=2[CH:38]=1
Reactant: O=c1c2cc(Cl)ccc2ccn2cccc12
Reactant: NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: NCCC=C1c2cc(Cl)ccc2C=Cn2cccc21
Reaction time: 0.5 h

Procedure:
Anhydrous 3-aminopropyltriphenylphosphonium bromide hydrobromide, 9.0 g., is suspended in 30 ml. dry tetrahydrofuran and 0.038 moles of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 3.44 g. of 9-chloro-11H-pyrrolo[2,1-b][3]benzazepin-11-one is added to the deep red solution and the reaction is maintained at reflux for 10 hours. Water, 500 ml., is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 100 ml. benzene is added. After stirring, the benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution and is extracted with 3 × 50 ml. portions of benzene. The benzene extracts are washed, then dried with anhydrous sodium sulfate and concentrated in a vacuum leaving a residue of 9-chloro-11-(3-aminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4](O)[CH:3]1[NH:9][C:10]([C@@H:12]([NH:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:15])=[O:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[C:3]([NH:9][C:10]([C@@H:12]([NH:24][C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:15])=[O:16])=[O:11])=[CH:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NC1C(O)CCCC1O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCCC=C1NC(=O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
A solution of morpholine-4-carboxylic acid [(R)-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide (90 mg, 0.19 mmol) in methylene chloride (6 ml) was treated with Dess-Martin periodinane (162 mg, 0.38 mmol). After stirring at room temperature for 2 hours the reaction mixture was washed with a solution of Na2S2O3 in water (0.26M), then with saturated aqueous bicarbonate solution then with water, then dried over Na2SO4 and then evaporated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane to give morpholine4-carboxylic acid [(R)-1-(6-oxo-cyclohex-1-enylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide (8 mg). 1H NMR (CDCl3): 9.00 (s, 1H), 7.82 (t, J=5 Hz, 1H), 7.53–7.38 (m, 5H), 6.06 (d, J=6 Hz, 1H), 5.00 (m, 1H), 4.47–4.27 (m, 2H), 3.85 (m, 1H), 3.77–3.62 (m, 4H), 3.48–3.36 (m, 4H), 3.27 (m, 1H), 2.58–2.46 (m, 4H), 2.08–1.97 (m, 2H). MS: 450 (MH+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.Cl[C:34]1[O:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1>>[O:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[N:6]([CH2:5][C:4]1[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:3]=1[C:2]([F:32])([F:1])[F:31])[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:19])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
Similarly prepared from methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorobenzoxazole.
Reaction SMILES: [CH3:1][C:2]([C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH2:6])([CH3:4])[CH3:3].CN(C=O)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:4][C:2]([C:5]([C:7]1[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=1[C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[F:30])=[CH2:6])([CH3:1])[CH3:3]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: C=C(c1cc(C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Temperature: 90 °C
Reaction time: 17 h
Yield: 19.5 %

Procedure:
To a stirred solution of 66.18E (0.550 g, 1.5 mmol) in DMF (3.0 mL, 1.5 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.38 g, 2.3 mmol) (commercially available from Aldrich), potassium carbonate (0.62 g, 4.5 mmol) and then tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol). The mixture was heated to 90° C. and stirred for 17 hours. The resulting mixture was then cooled to room temperature, diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.18F as a colorless oil (0.100 g, 19% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[N:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[CH:18]1([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:7]=[C:2]([N:25]3[CH:26]=[C:22]([I:21])[N:23]=[CH:24]3)[N:3]=2)[CH2:20][CH2:19]1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nc(C3CC3)c2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)nc(-n3cnc(I)c3)c2)cc1

Procedure:
The title compound was prepared 2-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.33) (1.0 g, 3 mmol) and commercially available 4-iodo-imidazole (0.782 g, 4 mmol) according to the general procedure IVa. Obtained as a yellow solid (1.44 g, 93%). MS (ISP) 456.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([C:21]4[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=4)[OH:20])[CH:17]=3)[N:12]=[C:11]([O:34]C)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=4)[CH:17]=3)[NH:12][C:11](=[O:34])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1cc(-c2cc(Cl)cc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cc(Cl)cc(Cl)c3)c2c1

Procedure:
Following the same procedure as described in example 1F, [4-(3,5-dichloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (886 mg, 1.68 mmol) was treated with HCl in aqueous THF to yield the title compound of 16D. It was directly used for the next reaction without further purification.