Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.O[Li].O>O>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (11 mg, 0.017 mmol, 1 equiv) in 9:1 MeOH:water (1.1 mL) was added LiOH.H2O (28 mg, 0.671 mmol, 40 equiv). The reaction was heated to 70° C. for 1 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Product isolated (7.2 mg, 77%). 1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=7.6 Hz, 1H), 7.76 (d, J=6.1 Hz, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.06 (s, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.89 (d, J=11.6 Hz, 1H), 6.62 (t, J=8.1 Hz, 1H), 5.90-5.80 (m, 1H), 5.68 (br. s., 1H), 5.54 (d, J=15.6 Hz, 1H), 4.44 (br. s., 1H), 3.80-3.65 (m, 3H), 3.39 (d, J=11.3 Hz, 1H), 2.87 (d, J=8.5 Hz, 1H), 2.37 (d, J=8.2 Hz, 1H), 2.33-2.29 (m, 1H), 2.28 (br. s., 3H), 2.08-1.98 (m, 1H), 1.76-1.58 (m, 2H), 1.52-1.40 (m, 2H), 1.01 (s, 3H), 0.94 (s, 9H), 0.83 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 642.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15]Cl)=[O:8].[C-:25]#[N:26].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:25]#[N:26])=[O:8]
Reactant: [C-]#N
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCCl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCC#N
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(3,5-dichlorophenoxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide (3.91) in dry N,N-dimethylformamide (35 ml) containing potassium cyanide (0.78 g) was heated to 95° C. for 6 hours, cooled to ambient temperature then stored for 18 hours. The mixture was poured into water, extracted with diethyl ether (three times) and the extracts were combined, washed with water (three times), dried over magnesium sulphate then evaporated under reduced pressure to give the required product as a yellow oil, 3.42 g. A portion of this material was fractionated by chromatography (silica; hexane/ethyl acetate 3:1 by volume) to give a pure sample of 2-(3,5-dichlorophenoxy)-N-(1-cyano-6-methylhept-4-yn-6-yl) butyramide as a yellow gum, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.58(3H, s); 1.60(3H, s); 1.82-1.88(2H, m); 1.92-1.98(2H, m); 2.36-2.40(2H, t); 2.48-2.56(2H, m); 4.38-4.42(1H, t); 6.26(1H, s); 6.84(2H, s); 7.04(1H, s).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([Cl:18])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1ccc(C(F)(F)F)cc1

Procedure:
A stirred solution of 3-(4-(trifluoromethyl)phenyl)propanoic acid (500 mg, 2.292 mmol) in thionyl chloride was allowed to reflux for 2 hours and concentrated under reduced pressure to afford the crude title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:30][CH2:29][C:26]3[CH:25]=[C:24]([CH3:23])[O:28][N:27]=3)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: Cc1cc(CN)no1
Product: Cc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-methyl-3-isoxazolemethanamine (CAS registry No. 154016-48-5) as starting materials; LC-MS (UV peak area/ESI) 100%, 426.0822 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])[CH:16]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2Cl)c1
Yield: 70.8 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.051 g (70%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:47]3[CH2:46][CH2:45][C:44]([C:40]4[CH:41]=[CH:42][CH:43]=[C:38]([O:37][CH3:36])[CH:39]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: COc1cccc(C2(C(N)=O)CCNCC2)c1
Agent: Cl
Product: COc1cccc(C2(C(N)=O)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)c1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.75 g, 1.4 mmol) and 4-(3-methoxy-phenyl)-piperidine-4-carboxylic acid amide hydrochloride (0.5 g, 1.85 mmol) to give the title compound: Rf =0.43 (silica gel, 10% methanol/chloroform).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.[OH-].[K+]>C(O)C>[CH3:26][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10]
Reactant: O=C1CCCc2ccccc21
Reactant: CN(C)CCCOc1ccccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=C1CCc2ccccc2C1=O
Yield: 110.9 %

Procedure:
α-Tetralone (26.4 g) and 40 g of 2-[3-(dimethylamino)propoxy]benzaldehyde are reacted in 180 ml of ethanol in the presence of 1.2 g of potassium hydroxide following the procedure in Example 1A. The product is extracted with ether and the solvent is evaporated to give a viscous residue (67.2 g), which begins to solidify on standing. It is crystallized from a mixture of 120 ml of warm diisopropylether and 120 ml of hexane to give 45.7 g of crystals, melting point 67-69° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([NH2:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][N:13]([CH3:12])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(NC(=O)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of 4-cyanobenzoyl chloride (2.5 g) in dichloromethane (50 ml) was added dropwise with stirring over 45 minutes to an ice-cold solution of t-butyl 2-methylcarbazate (2.0 g) in dichloromethane (50 ml) containing triethylamine (1.9 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then washed with water, dilute aqueous sodium bicarbonate solution and brine, dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate to give t-butyl 3-(4-cyanobenzoyl)-2-methylcarbazate (2.5 g) as a white solid; m.p. 179°-181° C.; NMR Spectrum (DMSO-d6) 1.27-1.55 (9H, br s), 3.10 (3H, br s), 8.00 (4H, s), 10.90 (1H, s); Mass Spectrum m/Z 276 (M+H)+ ; Elemental Analysis: calculated for C14H17N3O3 : C, 61.1%; H, 6.2%; N, 15.3%; found: C, 61.6%; H, 6.2%; N, 15.5%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](O)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][N:1]1[CH2:2][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[N:6]2)[CH2:4]1
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cn1ccnc1CN1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00017 mol), 1-methyl-1H-2-imidazolecarboxylic acid (0.056 g, 0.0005 mol), and acetic acid (0.03 g, 0.0005 mol) in dichloroethane (2.5 mL) was stirred at room temperature under an atmosphere of nitrogen for one and a half hours. Sodium triacetoxyborohydride (0.072 g, 0.00034 mol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for two hours. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-3-azetanyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.000044 mol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[C:25]([CH3:30])([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1

Procedure:
Intermediate 1 was coupled with 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[N:12](=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])\[NH2:13].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:13]/[N:12]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: N/N=C/c1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Cc1cccc(Cl)c1)N/N=C/c1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A flask is charged with (3-chlorophenyl)acetic acid (0.34 mmol), 4-dimethylaminopyridine (0.66 mmol), a solution of N-{2-[(E)-hydrazonomethyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide (0.33 mmol) in N,N-dimethylacetamide (1 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 mmol). The reaction is stirred at room temperature for 18 hours. The reaction is worked up either by adding water and obtaining a solid precipitate, or by evaporating the reaction mixture. The product is purified on silica gel with ethyl acetate-methylene chloride mixtures. Obtained a 60% yield of N-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl]-4-(trifluoromethyl)benzenesulfonamide. 1H NMR (400 MHz, CDCl3)(mixture of geometric isomers) d 3.73&4.17(2s, 2H); 7.16 (m); 7.36 (m); 7.47 (s); 7.60m; 7.66 (m); 7.75 (m); 7.89 (s); 7.96 (m); 8.06 (m); 9.62 (bs); 10.80 (bs). ESI− for C22H17ClF3N3O3S: m/z =494 (M−H)−.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][C:16](=O)[CH2:15][CH2:14][O:13]1)=O)C.C1C[O:22]CC1>>[OH:9][CH2:10][C:12]1([OH:22])[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CCOC(=O)C1CC(=O)CCO1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1(O)CCCCO1
Temperature: 0 °C
Yield: 61 %

Procedure:
To a cooled (0° C.), stirred suspension of LiAlH4 (3.42 g, 90.0 mmol) in anhydrous THF (50 mL) was added dropwise a solution of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (5.17 g, 30.0 mmol). After stirring for 1 hour, the reaction was quenched by the slow, sequential addition of water (3.4 mL), 15% NaOH (3.4 mL), and water (10.0 mL). The inorganic salt was filtered off and extracted with EtOAc repeatedly since the product was absorbed on the solid. Solvent removal afforded 2.42 g (61%) of yellow oil. The crude mixture was carried to the next step without purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([O:3][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])[C:17]([CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[N:15]=1
Reactant: Cc1cc(O)cc(C#N)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
At 0° C., NaH (60%, 125 mg, 3.06 mmol, 1.0 eq.) was added to 3-hydroxy-5-methyl-benzonitrile (408 mg, 3.06 mmol) in 10 mL of DMF solution. The reaction mixture was stirred at 0° C. for 5 minutes. 2,4,6-Trichloro-5-isopropyl-pyrimidine (691 mg, 3.06 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAc/hexane) to give a white solid (868 mg, 88%). LC-MS shows 322.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 3.60 (m, 1H), 2.42 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:3]([CH3:7])[C:4]([OH:6])=O.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH3:7][C@@:3]12[C:4](=[O:6])[CH2:11][C@@H:10]1[CH2:9][CH:8]=[CH:2]2
Reactant: C=CCCC(O)C(C)C(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: C[C@]12C=CC[C@H]1CC2=O
Reaction time: 3 h
Yield: 19.2 %

Procedure:
A mixed solution of 3-hydroxy-2-methylhept-6-enoic acid (5.45 g, 34.5 mmol), potassium acetate (7.0 g, 71.3 mmol), and acetic anhydride (30 mL) was stirred at room temperature for 1.5 hours and then stirred for 3 hours under conditions of heating to reflux. The reaction solution was left overnight, then diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil (810 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:39])[NH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:32])[CH3:31])[CH:23]=1.[C:40](Cl)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([NH:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:39])[NH:29][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])[CH:23]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(N)c12
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(NC(C)=O)c12
Reaction time: 2 h
Yield: 34 %

Procedure:
4-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) was diluted in pyridine (1 mL) and treated with excess acetyl chloride (10 μL). The reaction was allowed to stir for 2 hours. The mixture was concentrated and diluted with MeOH (1 mL). The product began to crash out, it was sonicated and filtered and washed with MeOH to afford the titled compound (8 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.41 (1H, s), 8.43 (1H, s), 8.31-8.38 (1H, m), 7.88-7.92 (1H, m), 7.82-7.87 (2H, m), 7.80 (1H, d, J=7.63 Hz), 7.71 (1H, d, J=8.55 Hz), 7.54-7.60 (1H, m), 7.43-7.49 (2H, m), 7.36-7.43 (5H, m), 7.28 (2H, t, J=7.78 Hz), 7.17 (1H, t, J=7.32 Hz), 2.76 (3H, d), 1.79 (3H, s), 1.69 (6H, s). LC-MS retention time 1.42 min; m/z 564 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.00 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=11.26 min, purity=95%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.[C:13](OC(C)=C)(=[O:15])[CH3:14]>C(OCC)(=O)C>[C:13]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([NH2:1])[C:3]([Cl:12])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:15])[CH3:14]
Reactant: Nc1c(Cl)ccc2c1CNCC2
Reactant: C=C(C)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(Cl)c(N)c2C1

Procedure:
8-Amino-7-chloro-1,2,3,4-tetrahydroisoquinoline, prepared as in Example 12, is treated with one molar equivalent of isopropenyl acetate in refluxing ethyl acetate for 16 hours. The solvent is evaporated and the residue crystallized from benzene to yield 2-acetyl-8-amino-7-chloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])=[CH:3][C:2]=1[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
3-Amino-4-benzyloxy-N-(3-cyclohexylphenyl)phenylacetamide (the compound of Example 33) (200 mg) is dissolved in pyridine (5 ml), and thereto is added dropwise methanesulfonyl chloride (111 mg), and the mixture is stirred for 0.5 hour. Water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried under sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-methanesulfonylaminophenyl-acetamide (200 mg). This product is dissolved in ethanol (10 ml), and thereto is added 10% palladium on carbon (20 mg). The mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 10% chloroform/methanol) to give the desired compound (120 mg).
Reaction SMILES: ClC1C=CC(OCC2C=CC=CC=2)=C(C2C=CC=CC=2[B:14]([OH:16])[OH:15])C=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1>>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][O:42][C:33]2[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:32]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[B:14]([OH:16])[OH:15])=[CH:45][CH:46]=1
Reactant: Fc1ccc(COc2ccc(C(F)(F)F)cc2-c2ccccc2Br)cc1
Reactant: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Product: OB(O)c1ccccc1-c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1

Procedure:
Prepared as for {5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid but using 2′-bromo-2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)biphenyl instead of 2′-bromo-5-chloro-2-[(phenylmethyl)oxy]biphenyl. LC/MS t=3.63, [MH−] 389.0