Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(C)=O)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>O>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1.[C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
With stirring, 424.5 g (2.0 moles) of benzoin are added to 650 ml of methyl ethyl ketone in a 2.5 liter sulfonating flask. The resultant beige suspension is stirred for 5 minutes, then 400.4 g (2.1 moles) of pulverised p-toluenesulfonyl chloride are added. No chemical reaction takes place as yet. The temperature falls from room temperature to c. +5° C. When the addition is complete, the suspension is stirred for a further 5 minutes and then 50 ml of deionised water are added. Then 293.3 g of 30% aqueous sodium hydroxide solution (corresponding to 2.2 moles of NaOH) are added dropwise over 30 minutes, while keeping the temperature at 10°-15° C. by cooling with an ice bath. The beige suspension is efficiently stirred at this temperature for 6 hours, then cooled to -10° to -15° C. and vigorously further stirred for a further hour at this temperature. The beige crystal slurry, which is readily stirrable up to the end, is isolated by filtration, washed with 1 to 3×200 ml of deionised water and thereafter once with 150 ml of aqueous ice-cold methyl ethyl ketone, and dried under vacuum at room temperature, to give 674 g (92% of theory) of benzoin p-toluenesulfonate in the form of white crystals which melt at 99°-101° C. The purity of the product is at least 98% according to analysis by thin-layer chromatography and NMR spectroscopy. A sample stirred in water shows no acid reaction to litmus paper.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:6]([C:26]([O:28][CH3:29])=[O:27])[CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:6]([C:26]([O:28][CH3:29])=[O:27])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CN(C(C)=O)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(C)=O)c2ccccc2CN1S(=O)(=O)c1ccc(O)cc1
Yield: 33.8 %

Procedure:
To a 0° C. solution of methyl 1-acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (9.8 g, 23.42 mmol) in methylene chloride (50 ml) was added, dropwise, a 1.0 molar solution of boron tribromide (51.52 ml, 51.52 mmol) in methylene chloride and the mixture was stirred overnight at room temperature. Ice and water were added to the reaction mixture and the insolubles filtered off. The filtrate was diluted with methylene chloride and water. The organic layer was separated, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by chromatography on silica gel (hexane:ethyl acetate (I:1)) to give 3.2 g of product as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:28]1(C(=O)CC=C)[C:32]2C=C[CH:35]=[CH:36][C:31]=2N=[N:29]1.O.NN>C1COCC1.CCO>[CH2:31]([C:32]1[NH:28][N:29]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:36]=[CH2:35]
Reactant: C=CCC(=O)n1nnc2ccccc21
Reactant: Cc1ccc(C(=O)Cc2ccccc2)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NN
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1[nH]nc(-c2ccc(C)cc2F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 1-(2-fluoro-4-methylphenyl)-2-phenylethanone (1.0 g, 4.38 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (8.76 mL, 8.76 mmol) slowly via syringe at 0° C. After stirring for 10 min, 1-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-one (0.984 g, 5.26 mmol) was added in one portion. The reaction was stirred at 0° C. for 30 min before quenched with AcOH (2 mL). To the reaction were added EtOH (30 mL), hydrazine hydrate (0.658 g, 13.14 mmol), and heated to reflux for 1 h. After cooled to room temperature, the reaction was concentrated and extracted with EtOAc/H2O, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (0.50 g). LCMS m/z=293.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.40 (d, J=5.94 Hz, 2H), 4.94-5.08 (m, 2H), 5.88-6.00 (m, 1H), 6.92-7.31 (m, 8H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([NH:20][C@H:21]([C:26](O)=O)[C:22]([OH:25])([CH3:24])[CH3:23])(OC(C)(C)C)=O.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCOCC1.CCOC(C)=O>[NH2:20][C@H:21]([C:26]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[N:12]=1)[C:22]([CH3:24])([OH:25])[CH3:23]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc2[nH]c([C@@H](N)C(C)(C)O)nc2c1
Reaction time: 0.5 h
Yield: 1.6 %

Procedure:
A solution of 4-tert-butyl-1,2-diaminobenzene (1 g, 6 mmol), N-boc-3-hydroxy-L-valine (1.4 g, 6 mmol) and triethylamine (1.5 mL, 15.1 mmol) in dioxane (50 mL) was stirred at 0° C. for 15 minutes. T3P (50% w/w in EtOAc, 4.6 mL, 7.3 mmol) was added dropwise and the reaction continued stirring at this temperature for 30 minutes. The reaction was then heated to reflux for 5 hours before cooling and diluting with EtOAc. The solution was washed with saturated aqueous sodium carbonate solution twice, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-50% EtOAc in heptanes. The residue was dissolved in dioxane (10 mL) at 0° C. and treated with 4M HCl in dioxane (10 mL). The reaction was stirred at room temperature for 2 hours before concentrating in vacuo. The residue was washed with EtOAc and pentane before basifying with saturated aqueous NaOH solution and extracting into EtOAc. The organic layer was collected, dried over Na2SO4, concentrated in vacuo and triturated with 10% EtOH in pentane (5 mL) to afford the title compound (25 mg, 2%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CO[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([N:16]1[CH2:15][CH2:3][CH:2]([C:1]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A solution of 10.0 g (61.6 mmol) of benzyl acrylate and 19 mL (74.2 mmol) of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 75 mL of CH2Cl2 at 0° C. was treated with 0.5 mL (6.5 mmol) of TFA while maintaining the internal temperature at less than 3° C. The reaction was warmed to rt and stirred for 2.5 h. The reaction mixture was washed with 250 mL of 1N NaHCO3 and 250 mL of sat'd NaCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a 40L Biotage column using 19:1 v/v hexane/acetone as the eluant to afford 18 g (99%) of the title compound as a light yellow oil: RF: 0.28 (9:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 2.15-2.20 (m, 2H), 2.60 (m, 1H), 2.73-2.77 (m, 2H), 3.02 (m, 1H), 3.13 (m, 1H), 3.66-3.73 (m, 2H), 5.17 (s, 2H), 7.28-7.42 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: O=Cc1ccc2c(n1)COC2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C1OCc2nc(C3OCCO3)ccc21
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (100 mg, 0.61 mmol) in anhydrous benzene (5 mL) is added ethylene glycol (0.1 mL, 1.77 mmol), a catalytic amount p-toluenesulfonic acid monohydrate and 4 Å mole sieves. The reaction mixture is heated at a reflux temperature for 20 h. The reaction mixture is allowed to cool to room temperature and saturated aqueous NaHCO3 solution is added. The resulting mixture is filtered through celite, washed with saturated aqueous NaHCO3 and EtOAc. The isolated organic layer is washed with brine (1×), dried with anhydrous Na2SO4, and concentrated. The residue is treated with EtOAc-Hexane (1:4) and the light brown solid which forms is collected by filtration and dried to give the title compound (42 mg, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([C:49]3[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=3)[C:10]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc(Cn2nc(-c3cnn(C)c3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 50.9 %

Procedure:
A 100 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (50.0 mg, 0.0708 mmol, prepared in Example 63, step A), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44.2 mg, 0.212 mmol), Pd(OAc)2 (3.18 mg, 0.0142 mmol), tricyclohexylphosphine (5.95 mg, 0.0212 mmol), cesium fluoride (96.8 mg, 0.637 mmol) and CH3CN (10 mL). The reaction mixture was stirred at 100° C. 1 hour. The reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (23.8 mg, 50.9%). LRMS (APCI pos): >95% purity, 254 nm, m/e 661 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:27][C:26]=2[C:36]([OH:38])=[O:37])[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:15]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:25]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:27][C:26]=1[C:36]([OH:38])=[O:37])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(Cl)cc2Cl)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CCNCC1
Reaction time: 4 h
Yield: 107.2 %

Procedure:
A solution of 4-[(2-Carboxy-5-phenyl-thiophen-3-yl)-(2,4-dichloro-benzoyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.42 mmol) in dioxane (4 ml) at 21° C. under nitrogen was treated with anhydrous 4M HCl (3 ml, 12.6 mmol, 30 eq). After 4 h the reaction was stripped off solvent and the residue triturated with ether to give 3-[(2,4-Dichloro-benzoyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid as a pale yellow powder (214 mg, 100%) 1H NMR (Acetone, 400 MHz) 7.76-7.73 (m, 2H), 7.64 (s, 1H), 7.45-7.38 (m, 3H), 7.30 (bs, 1H), 7.28-7.24 (m, 1H), 4.93-4.84 (m, 1H), 3.56-3.49 (m, 2H), 3.25-3.14 (m, 2H), 3.05-2.55 (bs, 1H), 2.50-2.37 (m, 2H), 2.13-1.83 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:24]([C:22]3[O:23][C:19]([C:16]4[CH:17]=[CH:18][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=4)=[CH:20][CH:21]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Product: O=[N+]([O-])c1ccc(-c2ccc(-c3nc4cc(Br)cnc4[nH]3)o2)cc1

Procedure:
By a procedure similar to Example 274 but starting from 5-bromopyridine-2,3-diamine and 5-(4-nitrophenyl)-2-furaldehyde, the title compound was obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:31]4[S:32][C:28]([CH3:27])=[CH:29][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cncs1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 5-methylthiazole
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[CH:13]=2)[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:7]4[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]4)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[CH:13]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1cccnc1N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1cccnc1N1CCN(c2cc(NC3CC3)n3ncc(C=C4NC(=O)NC4=O)c3n2)CC1
Temperature: 80 °C
Yield: 10.6 %

Procedure:
Hydantoin (4 mg, 0.04 mmol) and 2-(4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (16 mg, 0.04 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (4 uL, 0.04 mmol). The reaction was heated at 80° C. for 12 hours. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was further purified by recrystallization from ethyl acetate/hexanes and dried in vacuo to give 2-(4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (2 mg, 21% yield). LCMS (M+1=471)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11](=[S:31])[CH2:10][N:9]=1
Reactant: Cc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7,8-dimethyl-2H-1,4-benzodiazepin-2-thione (Iw) was prepared by reacting 0.0006 moles of 5-(2-chlorophenyl)-1,3-dihydro-7,8-dimethyl-2H-1,4-benzodiazepin-2-one (Iw) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][NH:16]C4CCNCC4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37]N[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:24]([N:8]1[C:9]2[C:14]([CH2:15][N:16]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:23]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:25]
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCNCC3)c21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1c(-c2nonc2N)nc2cncc(CN3CCN(c4ccc(F)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product of Example 191 Step 1 (0.10 g, 0.38 mmole) in 1,2-dichloroethane (5 ml) was treated with 1-(4-fluorophenyl)piperazine (0.10 g, 0.58 mmole) and stirred at ambient temperature for 15 minutes. Sodium triacetoxyborohydride (0.16 g, 0.76 mmole) was added and the reaction mixture stirred at ambient temperature for 18 hours. The mixture was diluted with dichloromethane, washed (×2) with saturated sodium hydrogen carbonate solution followed by saturated brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford the title compound; MS (ES+) m/e 357 [M+H]+. The following examples were prepared from the product of Example 191 Step 1 using the method described in Example 200.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid methyl ester (656 mg, 1.99 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (920 mg, 21.9 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid (570 mg, 91%) as a tan solid: mp 91-94° C.; EI-HRMS m/e calcd for C20H26O3 (M+) 314.1881, found 314.1872.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH2:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([NH:15][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)=[O:13])[CH:17]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Product: O=C(Nc1cnc2ccccc2c1)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), reacted with 3-aminoquinoline (Aldrich) to give the title compound as a green amorphous solid. MS (ESI, pos. ion.) m/z: 377 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[N:30]1([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:33][CH:32]([OH:34])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([N:30]5[CH2:33][CH:32]([OH:34])[CH2:31]5)[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: OC1CN(C2CNC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.38 mmol), [1,3′]biazetidinyl-3-ol (0.098 g, 0.77 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (0.162 g, 0.77 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80) to give 494 as an off-white solid (0.101 g, 53%). LCMS (Method I): RT=2.31 min, [M+H]+ 504.2. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.28-7.22 (m, 2 H); 5.26 (d, J=6.8 Hz, 1 H); 4.28-4.21 (m, 4 H); 4.19-4.15 (m, 3 H); 3.83 (s, 2 H); 3.79-3.75 (m, 7 H); 3.47-3.35 (m, 2 H); 3.20 (q, J=7.4 Hz, 2 H); 3.02 (t, J=6.8 Hz, 2 H); 2.82 (t, J=6.8 Hz, 3 H); 1.36-1.29 (q, J=7.4 Hz, 3 H)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[CH:34]=[C:35]([OH:41])[CH:36]=[C:37]([F:40])[C:38]=1[F:39].[CH2:42]([C@H:47]1[CH2:52][CH2:51][C@H:50]([CH2:53]O)[CH2:49][CH2:48]1)[CH2:43][CH2:44][CH2:45][CH3:46]>O1CCCC1>[CH2:42]([C@H:47]1[CH2:52][CH2:51][C@H:50]([CH2:53][O:41][C:35]2[CH:34]=[C:33]([F:32])[C:38]([F:39])=[C:37]([F:40])[CH:36]=2)[CH2:49][CH2:48]1)[CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CCCCC[C@H]1CC[C@H](CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](COc2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.31 g (7.5 mmol) of diethyl azodicarboxylate are added at 0° C. to 1.97 g (7.50 mmol) of triphenylphosphine in 30 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 0.5 hour. 1.11 g (7.50 mmol) of 3,4,5-trifluorophenol and 1.38 g (7.50 mmol) of trans-4-pentylcyclohexylmethanol are then added, and the mixture is stirred at room temperature for 18 hours. Evaporation of the solvent and chromatography on silica gel using hexane give 1.23 g of product. ##STR5## Phase sequence: X 14 (-26) I