Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.O[CH:18]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:19]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20]([OH:22])=[O:21].B(F)(F)F>C(Cl)Cl>[CH3:30][C:19]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:18][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(Oc1ccccc1)(C(=O)O)C(O)c1cccs1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Cc1cccs1)(Oc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of triethylsilane (56.4 g, 77.4 mL, 485 mmol) in 100 mL of CH2Cl2 at −20° C., boron trifluoride diethyl etherate (68.8 g, 61.5 mL, 485 mmol) was added. A solution of 3-hydroxy-2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid (45.0 g, 162 mmol) in CH2Cl2 (600 mL) was then added dropwise to the BF3 solution over 1 h, keeping the temperature at −15° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with 1 N NaOH (approx. 360 mL) diluted with 180 mL of water and the pH was adjusted to pH=4.0 using 1 N HCl and 1 N NaOH. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×300 mL). The combined organic layers were then washed with 0.1 N HCl (300 mL) and water (2×300 mL). Xylene (150 mL) and NaCl were added and the organics were concentrated to dryness to yield 40.0 g of crude product. The product was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 6.86-7.29 (m, 8 H), 3.53 (d, 2 H), 3.37 (d, 2 H), 1.44 (s, 3 H); MS (EI) 263.1 (M+H)+.
Reaction SMILES: C[C:2]1[C:10]2[S:9][C:8]3=[N:11][CH:12]=[N:13][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.F[C:15]1C2SC3=NC=NN3C=2C=C[CH:16]=1.N1N2C(S[C:32]3C=CC=C[C:33]=32)=NC=1.ClC1C2SC3=NC=NN3C=2C=CC=1.COC1C2SC3=NC=NN3C=2C=CC=1.CC1N=C2SC3C(C)=CC=CC=3N2N=1>>[CH2:15]([C:12]1[N:11]=[C:8]2[S:9][C:10]3[CH:2]=[C:3]([CH2:32][CH3:33])[CH:4]=[CH:5][C:6]=3[N:7]2[N:13]=1)[CH3:16]
Reactant: c1ccc2c(c1)sc1ncnn12
Reactant: Cc1cccc2c1sc1ncnn12
Reactant: Fc1cccc2c1sc1ncnn12
Agent: COc1cccc2c1sc1ncnn12
Agent: Cc1nc2sc3c(C)cccc3n2n1
Agent: Clc1cccc2c1sc1ncnn12
Product: CCc1ccc2c(c1)sc1nc(CC)nn12

Procedure:
The preferred compounds of this invention are 5-methyl-s-triazolo[5,1-b]benzothiazole, 5-fluoro-s-triazolo[5,1-b]benzothiazole, s-triazolo[5,1-b]benzothiazole, 5-chloro-s-triazolo[5,1-b]benzothiazole, 5-methoxy-s-triazolo[5,1-b]benzothiazole, and 2,5-dimethyl-s-triazolo[5,1-b]benzothiazole.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][C:21]1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38](N)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]C>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][CH2:21][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38])=[O:19])(=[O:15])=[O:16])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N-dodecylamine, mp 83°-85° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][S+]2CCCC2)[CH:9]=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[C:29]([CH:34]=[O:35])=[CH:30][CH:31]=[CH:32]C=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[OH-].[K+].CC#[N:40]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[C:29]([CH:34]3[CH:14]([C:10]4[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=4)[O:35]3)=[CH:30][CH:31]=[CH:32][N:40]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: O=Cc1ccccc1-c1cc(Cl)cc(Cl)c1
Reactant: CC#N
Reactant: c1cncc(C[S+]2CCCC2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: Clc1cc(Cl)cc(-c2ncccc2C2OC2c2cccnc2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 1-(pyridin-3-ylmethyl)tetrahydrothiophenium hexafluorophosphate (4.97 g, prepared according to JACS, 1997 (119), 12376) and 3′,5′-dichlorobiphenyl-2-carbaldehyde (3.07 g) in 80 mL of MeCN was added aqueous KOH (2 M, 12.18 mL). The reaction was stirred at room temperature for 21 h, then partitioned between water and dichloromethane. The aqueous solution was extracted with dichloromethane (4×). The combined organic solutions were dried over Na2SO4 and concentrated. Flash chromatography (10% to 80% EA in hexanes) provided 2.86 g of 2-(3,5-dichlorophenyl)-3-(3-pyridin-3-yloxiran-2-yl)pyridine 1-1 as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH:24][C:14](=[O:16])[C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A solution of N-benzyl-L-pyroglutamic acid (J. Am. Chem. Soc. 106:4539 (1984), 10.00 g, 45.62 mmol), L-tyrosine tert-butyl ester (11.91 g, 50.17 mmol) and BOP (22.19 g, 50.17 mmol) in DMF (250.0 mL) was charged to a 500 mL round bottom flask equipped with a stir bar and nitrogen inlet. Triethylamine (7.00 mL, 50.17 mmol) was added dropwise and the resulting solution was stirred at 25° C. for 16 h. The solution was transferred to a 1.0 L separatory funnel with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (300 mL×2), brine (300 mL×2), dried (MgSO4) and the solvent removed to give 18.63 g (93%) of N-(benzyl)-L-pyroglutamyl-L-tyrosine tert-butyl ester as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:25][CH3:26])=[C:7]([CH:12]=[C:13]([NH:15][C:16]([NH:18][C:19](=[O:24])/[CH:20]=[CH:21]/[O:22][CH3:23])=[O:17])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CO.O>[C:1]([C:5]1[C:6]([O:25][CH3:26])=[C:7]([CH:12]=[C:13]([N:15]2[CH:21]([O:22][CH3:23])[CH:20]([F:28])[C:19](=[O:24])[NH:18][C:16]2=[O:17])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO/C=C/C(=O)NC(=O)Nc1cc(C(=O)OC)c(OC)c(C(C)(C)C)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cc(N2C(=O)NC(=O)C(F)C2OC)cc(C(C)(C)C)c1OC
Temperature: 90 °C
Yield: 29 %

Procedure:
The fluorination procedure was performed as described in Lal, G S, et al. J. Org. Chem., 60:7340-7342 (1995). The product from Example 41A, Part B (0.42 g, 1.26 mmol) and Selectfluor™ (0.672 g, 1.9 mmol) were combined in a mixture of acetonitrile (8 mL) and methanol (1 mL) and heated at 90° C. under N2 for 5 h. The solution was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, concentrated and purified by column chromatography on silica gel to give the title compound (0.138 g, 29%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:37][CH2:36][C:24]4([CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH2:23][CH2:22]3)[C:18]([C:38]#[N:39])=[CH:17][N:16]=2)[CH:9]=1>C(Cl)Cl>[C:8]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][C:24]4([CH2:28][NH:27][CH2:26][CH2:25]4)[CH2:36][CH2:37]3)[C:18]([C:38]#[N:39])=[CH:17][N:16]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3nc(Nc4cccc(-c5ccccc5)c4)ncc3C#N)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cccc(-c3ccccc3)c2)nc1N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 mL) was added to a solution of the tert-butyl 8-[2-(biphenyl-3-ylamino)-5-cyanopyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (24 mg, 0.047 mmol) in CH2Cl2 (1 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford 2-(biphenyl-3-ylamino)-4-(2,8-diazaspiro[4.5]dec-8-yl)pyrimidine-5-carbonitrile as a white solid. MS ESI calcd. for C25H27N6 [M+H]+ 411, found 411. 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 7.87 (d, 7.9 Hz, 2H), 7.85 (s, 1H), 7.74 (t, J=7.6 Hz, 2H), 7.69-7.59 (m, 2H), 7.57 (d, J=7.8 Hz, 1H), 4.31-4.14 (m, 2H), 4.14-4.04 (m, 2H), 3.65-3.43 (m, 2H), 3.32 (t, J=5.6 Hz, 2H), 2.13 (t, J=7.4 Hz, 2H), 1.94-1.92 (br m, 4H).
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]#[N:27])[CH:23]=2)[CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].CCO.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]#[N:27])[CH:23]=2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCN(CC1Cc2ccc(C#N)cc2C1)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CC(CN1CCNCC1=O)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{(chloroacetyl)[(5-cyano-2,3-dihydro-1H-inden-2-yl)methyl]amino}ethyl)carbamate (350 mg, 0.9 mmol) in HCl/dioxane (20 mL) was stirred at RT for 12 hours and then concentrated to dryness. To the residue was added 20 mL EtOH and K2CO3 (500 mg, 3.7 mmol). The resulting mixture was heated to reflux for 4 hrs before cooled to RT and filtered. The filtrate was concentrate and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give 2-[(2-Oxopiperazin-1-yl)methyl]indane-5-carbonitrile. MS m/z: 256 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)=[O:29]
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CN(C(=O)CCl)CCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
In a 100-mL round-bottom flask, the benzyl morpholine-2-carboxylate (50%, 1.00 g, 2.3 mmol) as the crude tfa salt was taken up in dichloromethane (8 mL), resulting in a white suspension. N-Ethyl-N-isopropylpropan-2-amine (1.4 ml, 7.9 mmol) was added, and the solid dissolved. The solution was cooled to 0 deg, and 2-chloroacetyl chloride (0.20 ml, 2.5 mmol) was added. The reaction mixture was allowed to warm naturally to ambient temperature where it was stirred for 14 h. The reaction mixture was diluted with DCM (75 mL), and the organic layer was extracted with dilute sodium bicarbonate (2×7 mL) then with half-saturated brine (7 mL), then was dried over sodium sulfate. The residue was purified through silica gel (100 mL) which had been deactivated with TEA (10 mL) using 90% EtOAc-hexane, affording the title compound (474 mg, 1.6 mmol). MS m/z 298 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[CH2:11]([O:18][C:19]1[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:46]=[C:45]([O:47][CH2:9][CH2:8][Br:7])[CH:44]=[CH:43][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1OCc1ccccc1
Reactant: BrCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OCCBr)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
Potassium carbonate (1.6 g) and 1,2-dibromoethane (2.6 mL) were added to a N,N-dimethylformamide (5.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamido)-4-phenylbenzoate (0.29 g), followed by stirring at 120° C. for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-91% hexane/ethyl acetate] to obtain 0.19 g of tert-butyl 2-(2-(benzyloxy)-4-(2-bromoethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH3:31]
Reactant: CCCBr
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 91.1 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.475 ml (5.181 mmol) of propyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 202 mg (0.4720 mmol, 91%) of 2-propoxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.94 (3H, t, CH3), 1.6-2.2 (6H, m, 3CH2), 2.36 (4H, t, 2CH2), 2.65 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 3.99 (2H, t, CH2), 6.60 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 427 (M-H)-
Reaction SMILES: C(O[C:4]([C:6]1([C:28](OCC)=[O:29])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[N:22]=[CH:21]3)=[CH:15][CH:16]=1)=[O:5])C.C(OC(=O)C(NC1C=[N:46][C:47]([O:50]C2C=C3C(=CC=2)N(C)N=C3)=CC=1)C(OCC)=O)C.BrCCCBr.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:74](C)C=O>>[CH3:27][N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][C:14]3[N:13]=[CH:12][C:11]([N:7]4[C:6]5([C:28](=[O:29])[NH:74][C:47](=[O:50])[NH:46][C:4]5=[O:5])[CH2:10][CH2:9][CH2:8]4)=[CH:16][CH:15]=3)=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3C)c2)nc1
Reactant: CCOC(=O)C(Nc1ccc(Oc2ccc3c(cnn3C)c2)nc1)C(=O)OCC
Reactant: CN(C)C=O
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cn1ncc2cc(Oc3ccc(N4CCCC45C(=O)NC(=O)NC5=O)cn3)ccc21
Temperature: 55 °C

Procedure:
1-[6-(1-Methyl-1H-indazol-5-yloxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester can be prepared by dissolving 2-[6-(Methyl-1H-indazol-5-yloxy)-pyridin-3-ylamino]-malonic acid diethyl ester (9.25 mmol) in dimethylformamide (90 mL), followed by addition of 1,3 dibromopropane (938 μL, 9.25 mmol) and cesium carbonate (6 grams, 18.5 mmol). The reaction mixture is stirred for approximately 24 hours to 48 hours. The mixture is filtered through celite, and then concentrated under vacuum while heating to 55° C. to remove the dimethylformamide (azeotroping with toluene). The crude product obtained is chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40m column) to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:22].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (25 g), methylboronic acid (8.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (1:1)(2.9 g) and potassium fluoride (16 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g). 4-(3,5-Dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g) was dissolved in chloroform (100 mL), 4N hydrogen chloride/ethyl acetate (50 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, and the mixture was filtered to give the title compound (10 g).
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=C([CH:12]=[CH:13][CH:14]=1)C=C.[OH2:15]>>[Cl:6][C:7]1[CH:8]=[C:2]([C@H:1]([OH:5])[CH2:3][OH:15])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)O
Reactant: C=Cc1cccc(Cl)c1
Reactant: O
Product: OC[C@@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
AD mix alpha (86.0 g) was added to a stirred mixture of tert-BuOH (300 ml) and H2O (300 ml), mixture was stirred for 15 min at RT, than cooled to 0° C. 3-Chlorostyrene (8.51 g, 0.061 mol) was added over 15 min. The mixture was stirred at 0° C. for 48 h. The reaction was quenched by adding 10% aq. sodium sulfite (120 ml) followed by addition of EtOAc (200 ml). The layers were separated and the aqueous layer was extracted with EtOAc (200 ml). The combined organic layers were washed with 0.4 M H2SO4 in saturated Na2SO4 (100 ml), followed by drying over Na2SO4. The solvent was evaporated, the residue was separated on SiO2 (70 g) (CHCl3-MeOH 0 to 10%). Colorless oil, 9.83 g (0.057 mol, 93%). 1H NMR (300 MHz, DMSO) δ 7.20-7.40 (m, 4H), 5.39 (d, J=4.6 Hz, 1H), 4.76 (t, J=5.8 Hz, 1H), 4.54 (q, 4.9=Hz, 1H), 3.43 (m, 2H)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NCC(O)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(O)C(F)(F)F)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 3-amino-1,1,1-trifluoropropan-2-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=487.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30][CH3:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30][CH3:31])[CH:4]=1)#[N:2]
Reactant: CSc1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (95.0 mg, 0.213 mmol) was dissolved in THF (4 ml), and methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 101 mg, 0.426 mmol) was added. After 30 min of stirring at room temperature, HPLC showed complete conversion. The mixture was diluted with ethyl acetate (4 ml), and water (1 ml) was added. The mixture was then applied to a Merck Extrelut® NT3 column and the filtrate was purified by preparative HPLC. Concentration of the product fractions gave 96.0 mg (quant.) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[NH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-])=O.[H][H]>[Pd]>[CH2:8]([CH:7]([NH:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[NH2:1])[CH2:10][CH3:11])[CH3:9]
Reactant: [H][H]
Reactant: CCC(CC)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: CCC(CC)Nc1ccccc1N
Yield: 100 %

Procedure:
In a 2 liter Paar hydrogenator is placed 2.5 grams of 10% palladium on carbon catalyst, 800 milliliters of absolute alcohol and 250 grams of o-nitro-N-(1-ethylpropyl)aniline. Hydrogen is introduced and the reduction takes about 21/2 hrs. The reaction is exothermic and the temperature subsides as the reaction goes to completion. The catalyst is removed by filtration and the ethanol evaporated to yield a nearly quantitative yield (214 grams) of product as a dark oil. A pure sample is obtained by vacuum distillation b.p. 2.0 mm Hg=125°-126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C25H25FN6O3, 476.2