Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH:20][C:21]1[CH:31]=[CH:30][C:24]2[C:25](=[O:29])[CH2:26][CH2:27][O:28][C:23]=2[C:22]=1[CH2:32][CH2:33][CH3:34]>>[O:29]=[C:25]1[C:24]2[CH:30]=[CH:31][C:21]([O:20][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:19])=[C:22]([CH2:32][CH2:33][CH3:34])[C:23]=2[O:28][CH2:27][CH2:26]1
Reactant: COC(=O)/C=C/c1ccccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccccc2/C=C/C(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, and starting with 0.5 g (1.5 mmol) of (E)-3-[2-[(5-bromopentyl)oxy]phenyl]-2-propenoic acid methyl ester and 0.3 g (1.45 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, (E)-3-[2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]phenyl]-2-propenoic acid was obtained in 24% overall yield after purification by flash chromatography (silica gel, chloroform-methanol-acetic acid) and recrystallization from acetonitrile as a colorless solid, mp 123°-126° C.
Reaction SMILES: [CH3:1][CH:2]([CH:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C(OC=C)(=O)CCCCCCCCCCC>>[CH3:1][CH:2]([C@@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(O)C(C)C(=O)OC
Agent: C=COC(=O)CCCCCCCCCCC
Product: CC[C@H](O)C(C)C(=O)OC
Temperature: 35 °C
Reaction time: 120 h
Yield: 77.8 %

Procedure:
A mixture of 7.2 g of methyl 2-methyl-3-hydroxypentanoate, 11.1 g of vinyl laurate, and 4.0 g of Lipase P (trade name, Amano Pharmaceutical Co., Ltd.) was stirred at 35° C. for 5 days. After stopping the reaction, the enzyme was removed by filtration and washed with n-heptane on a filter paper. n-Heptane was distilled away from the filtrate and the residue was subject to vacuum distillation to give 5.6 g of methyl (3S)-2-methyl-3-hydroxypentanoate of the following formula, [α]D20 =+3.8°(C=1.26, CHCl3). ##STR83## In addition, 3.6 g of methyl (3R)-2-methyl-3-dodecanoyloxypentanoate was obtained. αD =0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc(-c2cccc(Cl)c2)on1
Temperature: 0 °C

Procedure:
In a screw cap vial equipped with stir bar was added 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (110 mg, 0.49 mmol), dichloromethane (3 ml) and triethylamine (0.34 ml, 2.46 mmol). Cooled the mixture down to 0° C. and to it added methane sulfonyl chloride (0.08 ml, 0.98 mmol). Left the reaction mixture stirring at room temperature for 30 min. Reaction was quenched with saturated sodium bicarbonate (aqueous, 40 ml) and extracted with dichloromethane (3×30 ml). Combined organic phase was washed with brine (40 ml), dried (sodium sulfate), filtered and concentrated, in-vacuo to isolate the desired compound as brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[CH:15])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[O:25]1[C:2]([CH3:16])([CH3:1])[CH:3]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]#[CH:15])=[CH:10][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCOc1ccc(OCC=C(C)C)cc1
Solvent: ClCCl
Product: C#CCOc1ccc(OCC2OC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.4 g of 1-[(3-methyl-2-butenyl)oxy]-4-propargyloxy-benzene is dissolved in 80 ml of methylenechloride and cooled to 0°C. (ice-bath cooling). 7.15 g of 80% by weight m-chloroperbenzoic acid is added portionwise to this mixture and the solution is thereafter stirred at 0°C. for 2 hours. The mixture is worked up as follows: diluted with 350 ml of methylene chloride; washed with ice-cold 1-N caustic soda; washed with saturated aqueous sodium chloride solution; dried over sodium sulfate; and evaporated. By chromatography on Kieselgel, there is obtained 1-[(2,3-epoxy-3-methylbutyl)oxy]-4-propargyloxy-benzene; M.P. 72°-73°C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3nccc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=488.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([N:16]2[CH2:21][CH2:20][N:19]3[S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][CH:18]3[CH2:17]2)[C:9]=1[Cl:27])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[C:12]([CH:11]=[C:10]([N:16]2[CH2:21][CH2:20][N:19]3[S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][CH:18]3[CH2:17]2)[C:9]=1[Cl:27])[C:14]#[N:15]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN3C(CCS3(=O)=O)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCN3C(CCS3(=O)=O)C2)c1
Yield: 69 %

Procedure:
tert-butyl-(2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)carbamate (70 mg, 0.164 mmol) in DCM (1 mL) was treated with TFA (0.240 mL, 3.12 mmol) at room temperature for 2 h. Solvent was evaporated and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0-5% methanol/dichloromethane). 3-amino-4-chloro-5-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)benzonitrile (37 mg) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.Br[CH2:14][CH2:15][OH:16]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:14][CH2:15][OH:16])[N:11]=[C:4]2[N:3]=1
Reactant: OCCBr
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: Cc1cc(C)n2nc(SCCO)nc2n1
Yield: 84 %

Procedure:
The compound of the first step was prepared according to the experimentals described for Example 1 above from of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 2-bromoethanol in 84% yield; EM (calc.): 224.1; MS (ESI) m/e: 225.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.09 (s, 1H), 5.05 (s, 1H), 3.70 (t, 2H), 3.30 (t, 2H), 2.66 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.O.[OH-].[Na+].FC(F)(F)[C:32](O)=[O:33]>>[C:1]([O:4][C:5]1[C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:8]([OH:12])=[C:9]([C:10]=1[CH3:11])[CH:32]=[O:33])(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1c(C)cc(O)cc1C(C)(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C
Temperature: 0 °C

Procedure:
0.33 g of 4-acetoxy-3-t-butyl-5-methylphenol and 0.33 g of hexamethylenetetramine were dissolved in 2 ml of trifluoroacetic acid and the solution was heated under reflux for 15 minutes. After cooling to 0° C., the reaction solution was combined with water, neutralized with a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layers were washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was dissolved in 5 ml of methanol and heated with 3.9 ml of 1N hydrochloric acid under reflux for one hour. The reaction solution was returned to room temperature and then combined with water, and the precipitated crystal was filtered off. After drying, 0.35 g of 5-acetoxy-4-t-butyl-2-hydroxy-6-methylbenzaldehyde was obtained as a white solid (72%).
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[N:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>C1COCC1.C(Cl)Cl>[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: N#CCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a stirred solution of (4,4-diphenylpiperidin-1-yl)acetonitrile (3.90 g, 14.1 mmol, 1.0 equiv) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0M, 50 mL, 50 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6N, 50 mL) was added cautiously and stirring was continued for 2 hours at 50° C. The mixture was cooled to room temperature, basified to pH 10 by addition of 6N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (30 mL) was added HCl in ether (1.0M, 16 mL, 1.1 equiv). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and this solution was added dropwise into ether (100 mL) with swirling. The resulting solid was filtered and washed with ether (3×50 mL). This solid was taken up in water (20 mL), which was basified to pH 10 by addition of 1M aqueous NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 3.70 g (94%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][C@H:2]1[CH2:7][N:6]([CH3:21])[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of phenylmethyl trans-2,5-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.35 g, 5.43 mmol) in dichloromethane (40 mL) at 0° C. was added formaldehyde (0.817 mL, 37% water solution, 10.87 mmol) followed by sodium triacetoxyborohydride (1.726 g, 8.14 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl trans-2,4,5-trimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.42 g, 100%). Phenylmethyl trans-2,4,5-trimethyl-1-piperazinecarboxylate (enantiomer 1) (480 mg) and phenylmethyl trans-2,4,5-trimethyl-1-piperazinecarboxylate (enantiomer 2) (400 mg) were separated by chiral chromatography. LCMS: (M+H)+: 263.3.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:8]([CH2:19][CH3:20])[C:9]([O:11][C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=[S:10])[CH3:7].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].Cl>C1COCC1.O>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[C:12]1([O:11][C:9](=[S:10])[N:8]([CH2:6][CH3:7])[CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[N:14][CH:13]1[F:18])[CH3:22]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCN(CC)C(=S)Oc1cccnc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)C1(OC(=S)N(CC)CC)C=CC=NC1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
250 ml (400 mmol) of n-BuLi (1.6M in hexane) are added to a solution of 57.9 g (410 mmol) of TMP in 750 ml of THF at -10° C. After the mixture has been stirred for 1 hour at -10° C., a solution of 64 g (280 mmol) of 3-diethylthiocarbamoyloxy-2-fluoropyridine in 200 ml of THF is added dropwise at -78° C. in the course of 30 minutes. After the mixture has been stirred for 1 hour at -78° C., 81.4 g (600 mmol) of diethylcarbamoyl chloride are added in the course of 1 minute, the mixture is stirred at -78° C. for 2 hours and heated to -20° C., 130 ml of 3N HCl are added, and the mixture is diluted with 1 l of water and brought to pH 7. The organic phase is washed 3 times with water. The combined aqueous phases are extracted twice using Et2O, and the combined organic phases are washed twice with water, dried over Na2SO4 and concentrated in vacuo at 60° C.: 116 g of a brown oil. Chromatography (ethyl acetate/hexane 1:1) gives 60 g (65% ) of beige crystals of m.p. 87°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)#[N:19]>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=372.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]2[CH2:4][O:22]2)=[CH:23][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(C3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60%, 0.5 g, 23.6 mmol) was diluted in DMSO (50 mL) and stirred for 30 min at rt under nitrogen. Trimethylsulfoxonium iodide (7.8 g, 35.37 mmol) was added in portions at 0° C. The reaction mixture was stirred for 1 h. Then a solution of 4-benzyloxybenzaldehyde (5 g, 23.58 mmol) in THF (15 mL) was added. The reaction solution was stirred at rt for 3 h. The reaction mixture was poured into ice-water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated to give 2-(4-(benzyloxy)phenyl)oxirane, which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[S:11][C:10]=1[CH2:18][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2sc(C(F)(F)F)cc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2sc(C(F)(F)F)cc2OCc2ccccc2)cc1
Reaction time: 6.75 h
Yield: 51.3 %

Procedure:
To a solution of (3-benzyloxy-5-trifluoromethylthiophen-2-yl)-(4-methoxy-phenyl)methanone (220.2 mg, 0.56 mmol) as synthesized by the method described in International Publication No. WO04/007517 and triethylsilane (1.34 mL, 8.41 mmol) in dichloromethane (1.1 mL), trifluoroacetic acid (3 mL) was added at 0° C. in a nitrogen stream over five minutes. The reaction mixture was stirred at the same temperature for 6.75 hours, and then triethylsilane (0.9 mL, 5.61 mmol) was added thereto. The reaction mixture was stirred at the same temperature for 16.75 hours, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (108.8 mg, 51%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[S:26][C:27]([CH3:30])=[N:28][N:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1nnc(N)s1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)s1
Yield: 62.1 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-methyl-1,3,4-thiadiazole (39.2 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(5-methyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (40.4 mg).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=C(C)C=2N=1.Cl.[CH3:33][N:34]([CH3:64])[C:35]1[N:40]=[CH:39][C:38]([C:41]2[N:42]=[C:43]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)[C:44]3[S:49][C:48]([CH2:50][N:51]4[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]4)=[C:47]([CH3:57])[C:45]=3[N:46]=2)=[CH:37][N:36]=1.[C:65](O)(=[O:69])[C@H:66]([CH3:68])[OH:67]>>[CH3:64][N:34]([CH3:33])[C:35]1[N:40]=[CH:39][C:38]([C:41]2[N:42]=[C:43]([N:58]3[CH2:59][CH2:60][O:61][CH2:62][CH2:63]3)[C:44]3[S:49][C:48]([CH2:50][N:51]4[CH2:56][CH2:55][N:54]([C:65](=[O:69])[C@@H:66]([OH:67])[CH3:68])[CH2:53][CH2:52]4)=[C:47]([CH3:57])[C:45]=3[N:46]=2)=[CH:37][N:36]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N(C)C)nc3)nc12
Reactant: C[C@H](O)C(=O)O
Agent: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N(C)C)nc3)nc12

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (100 mg) was reacted with 70 mg 2-(dimethylamino)pyrimidin-5-yl-5-boronic pinacol ester via General Procedure A. This crude intermediate was subjected to General Procedure D in which 100 mg of the crude HCl salt of N,N-dimethyl-5-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with 60 mg L-lactic Acid via General Procedure B to give 25.5 mg of 407 after reverse phase HPLC purification. MS (Q1) 527.3 (M)+.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[CH:6]([O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[C:21](C(O)=O)[C:17]=3[NH:18][C:19]=2[CH:20]=1)=[O:11])([CH3:8])[CH3:7].C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>O>[C:4]([C:21]1[C:17]2[NH:18][C:19]3[CH:20]=[C:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[CH:13]=[CH:14][C:15]=3[C:16]=2[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1)(=[O:5])[NH2:2]
Reactant: CN(C)C=O
Reactant: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(-c3ccccc3)nc12
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Product: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12
Yield: 90 %

Procedure:
Dry DMF (10 mL) was added to a mixture of 7-(isopropoxycarbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylic acid (0.95 g, 2.54 mmol), NH4C1 (0.41 g, 7.6 mmol), EDC (1.46 g, 7.61 mmol), and 1-hydroxybenzotriazole hydrate (1.03 g, 7.61 mmol). After stirring for a few minutes, TEA (1.06 mL, 7.61 mmol) was added and the reaction left stirred overnight. It was diluted with water (200 ml) and the precipitate was collected by filtration, washed with water and dried to leave isopropyl 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylate (0.925 g, 2.28 mmol, 90% yield) as a yellow solid. MS (ESI) m/z 374.04 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89 (1H, s), 8.66 (1H, br. s.), 8.54 (1H, s), 8.46 (1H, s), 8.38 (1H, d, J=8.24 Hz), 8.33 (2H, d, J=7.32 Hz), 7.92-7.99 (1H, m), 7.88 (1H, dd, J=8.24, 1.22 Hz), 7.57 (2H, t, J=7.63 Hz), 7.46 (1H, t, J=7.32 Hz), 5.22 (1H, dt, J=12.51, 6.26 Hz), 1.39 (6H, d, J=6.41 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3C(=O)C4C=CC=CC=4C3=O)[CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NN>CCO>[NH2:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])/[CH:12]=[CH:11]/[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCCN3C(=O)c4ccccc4C3=O)c2)cc1
Agent: NN
Solvent: CCO
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCCN)c2)cc1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added Example 27, (2E)-3-[4-(tert-butyl)phenyl]-N-{3-[2-(1,3-dioxobenzo[c]azolin-2-yl)ethoxy]phenyl}prop-2-enamide, (856 mg, 1.83 mmol), EtOH (15 mL) and hydrazine (574 uL, 18.3 mmol, Aldrich). The reaction mixture was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (40 mL), washed with 10% K2CO3 (15 mL), water (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (step gradient, EtOAc followed by 1:1 EtOAc:EtOH) provided the title product as an oil. MS (ESI, pos. ion) m/z: 339 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6]1)(=O)C.[OH-].[Na+]>CCO>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C@@H:7]2[CH2:8][CH2:9][C@@H:5]([OH:4])[CH2:6]2)=[CH:15][CH:14]=1
Reactant: CC(=O)O[C@@H]1CC[C@@H](c2ccc(Br)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of (1R,3R)-3-(4-bromophenyl)cyclopentyl acetate (CARBOXYLIC ACID 8, Step B, 536 mg, 1.9 mmol) in 5.0 mL of EtOH was added sodium hydroxide (1.9 mL, 5.0 N). After stirring at rt for 30 min, solvent was removed and the residue was partitioned between sat'd NaHCO3 (50 mL) and CH2Cl2 (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×50 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 7:3 v/v hexanes/EtOAc as the eluant afforded 445 mg (97%) of the title compound: 1H NMR δ 1.49 (br. s, 1H), 1.56-1.81 (m, 2H), 2.05-2.27 (m, 4H), 3.35 (m, 1H), 4.52 (m, 1H), 7.09 (d, J=8.2, 2H), 7.40 (d, J=8.3, 2H).