Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28][CH2:27]1)=O.C(OC(NCCCN1CCN(CCCC(OC)=O)CC1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][CH2:23][CH2:24][N:26]1[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:31]1
Reactant: O=C(O)CCCN1CCN(C(=O)CCNc2ccccn2)CC1
Agent: COC(=O)CCCN1CCN(CCCNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCN1CCN(CCCNc2ccccn2)CC1

Procedure:
Prepared in an analogous manner to 4-[4-(N-pyridin-2-yl-beta-alanyl)-piperazin-1-yl]butanoic acid bis(trifluoroacetate) using methyl 4-(4-{3-[(tertbutoxycarbonyl)amino]propyl}piperazin-1-yl)butanoate in the place of methyl 4-{4-[N-(tert-butoxycarbonyl)-beta-alanyl]piperazin-1-yl}butanoate. 1H NMR (400 MHz, CD3CN) δ 7.91 (dt, 1H), 7.82 (d, 1H), 6.97 (d, 1H), 6.86 (m, 1H), 3.60-3.42 (m, 8H), 3.19-3.03 (m, 6H), 2.44 (t, 2H), 2.08 (t, 2H), 1.95 (d, 2H); MS (ESI+) for m/z 307 (M+H)+.
Reaction SMILES: [CH3:1][P:2](Cl)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13](=[O:27])[C@@H:14]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.CN1CCOCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][O:12][C:13](=[O:27])[C@@H:14]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:15]([P:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CP(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](CC(C)C)NCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](CC(C)C)N(Cc1cccnc1)P(C)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methylphenylphosphinic chloride (12.23 g, 70 mmol) is taken up in dichloromethane (100 mL) and cooled to 0° C. To this is added a solution of N-(3-picolyl) D-leucine methyl ester (15.5 g, 65.6 mmol) and N-methyl morpholine (19.24 mL, 175 mmol) in dichloromethane (100 mL). A catalytic amount of 4-dimethylaminopyridine is added and the reaction stirs for 16 hours at room temperature. More methylphenylphosphinic chloride is added (2 g, 11.46 mmol). The reaction continues to stir for 24 hours until complete. By TLC, the diastereomers do not separate. The product is purified by silica gel flash chromatography (5:95 ethanol:ethyl acetate) to give N-((R/S)-methylphenyl-phosphinyl)-N-(3-picolyl) D-leucine methyl ester as an oil. To this ester is added a solution of NH2OK (250 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (10:90 ethanol:ethyl acetate) to give 8.6 g of N-hydroxy-2(R)-[[(R/S)-methylphenylphosphinyl]3-picolylamino]-4-methylpentanamide as a 60 (R)/40 (S) mixture of diastereomers: MS-IS m/z 376 [M+H]+, 398[M+Na]+. (R1 =3-pyridyl methyl, R2 =isobutyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=O)OC.O.[NH2:29][NH2:30]>>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:30][N:29]=1
Reactant: COP(=O)(CC(=O)CCC(C)(C)C)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: CC(C)(C)CCc1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
light yellow viscous oil MS (ESI): 273.2 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (5,5-dimethyl-2-oxo-hexyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].N1C=CC=CC=1.[O:22]=[C:23](Cl)[O:24][C:25](Cl)(Cl)Cl.[CH3:30][O:31][C:32]1[C:37]2[O:38][CH2:39][O:40][C:36]=2[CH:35]=[C:34](CO)[CH:33]=1>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:23]([O:24][CH2:25][C:34]2[CH:33]=[C:32]([O:31][CH3:30])[C:37]3[O:38][CH2:39][O:40][C:36]=3[CH:35]=2)=[O:22])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: COc1cc(CO)cc2c1OCO2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cc(COC(=O)n2ccnc2[C@@H](C)c2cccc(C)c2C)cc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the compound of Example 1 (180 mg, 0.90 mmol) and pyridine (146 μl, 1.80 mmol) in anhydrous acetonitrile (3 ml), at 0° C. and under nitrogen, was added diphosgene (54 μl, 89 mg, 0.45 mmol). The mixture was allowed to warm to room temperature and stirred for 10 min, before addition of (7-methoxy-1,3-benzodioxol-5-yl)methanol (137 mg, 0.75 mmol) in acetonitrile (1 ml), via syringe. The reaction mixture was stirred at room temperature for 30 min and then filtered.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[S:23][C:22]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[OH:16][CH:15]([CH2:17][NH:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]2[C:29]3[C:21]([CH3:20])=[C:22]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:23][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:31][CH2:32]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(N)CC3)c12
Product: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(NCC(O)COc4ccc(O)cc4)CC3)c12
Yield: 17 %

Procedure:
Synthesis followed SP6 (3 h), using 150 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 17% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 14% yield.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH2:36]([NH2:38])[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:36]([NH:38][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH3:37]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNC[C@@H]1CNC[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reaction time: 8 h

Procedure:
The corresponding enantiomer N-((3S,4R)-4-Ethylaminomethyl-pyrrolidin-3-ylmethyl)-N-isopropyl-4-methoxy-3-(3-methoxy-propoxy)-benzamide is obtained as follows: A solution of (3S,4R)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.27 g, 2.58 mmol) and gaseous ethylamine (0.704 g, 15.5 mmol; Fluka 02940) in 1,2-dichloroethane (10 mL) is stirred at room temperature for 30 min, then sodium triacetoxyborohydride (1.37 g, 6.45 mmol) is added in one portion and the mixture is stirred overnight. The organic phase is washed with saturated aqueous NaHCO3 solution, the water layers are re-extracted with CH2Cl2, and the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound. MS: 522.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])[OH:4].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:44](O)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([O:4][CH:3]([CH2:2][Cl:1])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(=[O:46])[CH3:45]
Reactant: CC(=O)O
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(S(N)(=O)=O)cc1C(CCl)OC(C)=O

Procedure:
2.64 g (9.9 mmol) of α-chloromethyl-2-methoxy-5-sulphamoylbenzenemethanol and 100 ml of dichloromethane are introduced into a 250-ml round-bottomed flask. 10 ml of dimethylformamide are then added with stirring, followed by 852 μl of acetic acid, 2.56 g of dicyclohexylcarbodiimide and 121 mg of dimethylaminopyridine. The mixture is allowed to react for 1 hour at room temperature, and is then filtered and rinsed with 50 ml of 5% sodium hydrogen carbonate solution and then with 50 ml of water. The rinsing liquors are extracted with 2 times 20 ml of acetic acid, and the organic phases are then combined, dried and concentrated. On chromatographing the residue on a silica column with a 25:75 mixture of ethyl acetate and cyclohexane, 1.9 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].[N:32]1[CH:37]=[CH:36]C=[CH:34][CH:33]=1>>[CH2:33]([NH+:32]([CH2:24][CH3:3])[CH2:37][CH3:36])[CH3:34].[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([O:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)CCCO
Reactant: c1ccncc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC[NH+](CC)CC
Product: COc1ccc(C(OCCCC(=O)[O-])(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
A solution of 4,4′-dimethoxytrityl chloride (695 mg, 2.05 mmol) and 4-hydroxybutyric acid (208 mg, 2.0 mmol) in anhydrous Pyridine (20 mL) was stirred overnight and concentrated to an oil in vacuo. The residue was dissolved in a mixture of MeOH and CH2Cl2 (95:5, v/v; 200 mL) and washed with 2M aqueous triethylammonium acetate (5×20 mL). The organic solution was evaporated, re-dissolved in CH2Cl2, dried over Na2SO4, and evaporated to give the crude title compound in a quantitative yield (1016 mg).
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(O)(C)C>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C:9]3[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=3)[N:3]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(Cl)nc2c1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a suspension of methyl 2-chloro-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.23 mmol) in isopropyl alcohol (2.5 mL) was added N,N-diisopropylethylamine (84 μL, 0.48 mmol) and p-chlorobenzylamine (70 μL, 0.57 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (46 mg, 44%). LC-MS: (FA) ES+ 456.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13]N=[CH:11][CH:10]=1.[CH3:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.[C:21]([O-])(=O)C.[K+]>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.CN(C)C(=O)C>[CH3:15][C:16]1[O:17][C:18]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=2[C:9]2[CH:10]=[CH:11][CH:21]=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccco1
Reactant: Nc1cnc(-c2ccncc2)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2nc(N)cnc2-c2ccccc2)o1
Reaction time: 40 h
Yield: 12.4 %

Procedure:
An oven dried resealable Schlenk tube was charged with 6-chloro-5-pyridin-4-ylpyrazin-2-amine (Preparation 7, 300 mg, 1.45 mmol), 2-methylfuran (1.31 mL, 14.5 mmol), potassium acetate (213 mg, 2.17 mmol) and N,N-dimethylacetamide (6 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (117 mg, 0.10 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 150° C. oil bath. After 40 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted with ethyl acetate (×3), the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (dichloromethane/methanol 98:2 to dichloromethane/methanol 90:10) furnished the title compound as a brown solid (45 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].O=[C:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH:10]2[CH2:11][CH2:12]2)[N:1]=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1C1CC1
Product: CCOC(=O)c1c(C)nc2cccc(C3CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-cyclopropylbenzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (80%). MS 271 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4].Cl.[CH3:34][O:35][C:36](=[O:40])[CH2:37][NH:38][CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:32])[CH:10]=1
Reactant: CNCC(=O)OC
Reactant: CN(C)C(=O)c1cc(C=O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CNCCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-formylphenyl)amide (137 mg) and N-methylglycine methyl ester hydrochloride (45 mg) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (97 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1, v/v) to give the title compound (120 mg).
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)c1nsc(=O)o1
Product: CCOC(=O)c1nsc(-c2ccccc2)n1
Yield: 32.6 %

Procedure:
A solution of 8.76 g (0.050 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate in 180 g (35 equiv., 1.75 mol) of redistilled benzonitrile was held at reflux for 72 hours. The solution, which contained the product in 62% yield (gc assay), was concentrated under vacuum to 90° C (0.5 torr). The residue was heated with 200 ml of hexane at reflux; the supernatant was decanted, treated with charcoal, filtered, and concentrated under vacuum to 6.1 g of oil and solid. The mixture was chromatographed on 200 g of silica gel (Woelm, for dry column chromatography) with benzene. The first 500 ml of eluate contained 0.8 g of product and impurities. The next 1200 ml of eluate gave 3.82 g (33%) of pure liquid product (gc assay), which crystallized after several months, mp 32°-35° C; nD25 = 1.5937; mass spectrum m/e (rel. intensity, fragment) 234 (18, M+ ), 206 (3, M+ -C2H4), 189 (10, M+ -OEt), 135 (100, M+ -EtO2CCN), 103 (14, C6H5CN+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1C1=CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ccccc2c(C2=CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 35 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)acetate (36 mg, 0.087 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 5 mL) was added lithium hydroxide (21 mg, 0.88 mmol) and the reaction was heated to 35° C. overnight. The reaction was then heated to 45° C. for 2 hours, and subsequently 5 equivalents of lithium hydroxide was added, and the reaction stirred at room temperature over 2 days. The reaction was then heated to 50° C. overnight. The crude reaction was purified by reverse phase HPLC (Gemini, 20-100% ACN/H2O+0.1% TFA). Product was lyophilized to give a white powder (8.6 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.39 (m, 2H), 5.66 (m, 2H), 2.66 (m, 1H), 2.58 (s, 3H), 2.13 (m, 3H), 1.64 (m, 2H), 1.23 (s, 9H), 1.16 (s, 3H), 1.14 (s, 3H). LCMS-ESI− (m/z): [M−H]− calcd for C25H31O3: 379.24. found: 379.27.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)[CH:17]=3)[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[S-:30][C:31]#[N:32].[K+].BrBr>>[NH2:32][C:31]1[S:30][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:14][C:15](=[O:27])[C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]5([C:25]#[N:26])[CH2:24][CH2:23]5)[CH:17]=4)[CH:10]=[CH:11][C:12]=3[CH3:13])[CH:28]=[CH:29][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Yield: 20 %

Procedure:
Using N-[3-(4-aminophenoxy)-4-methylphenyl]-3-(1-cyanocyclopropyl)benzamide (1.92 g, 5.0 mmol), potassium thiocyanate (1.94 g, 20.0 mmol) and bromine (1.20 g, 7.50 mmol), and in the same manner as in Example A25(v), the title compound (0.44 g, 20%) was obtained as a pale-yellow powder. 1H-NMR (CDCl3, 300 MHz) δ 1.50 (2H, dd, J=5.1, 7.8 Hz), 1.76 (2H, dd, J=5.1, 7.8 Hz), 2.25 (3H, s), 6.50 (2H, br s), 6.98-7.04 (2H, m), 7.21-7.25 (2H, m), 7.41-7.65 (4H, m), 7.71-7.85 (3H, m).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Br:48][C:49]1[CH:50]=[CH:51][C:52]([NH:58][CH3:59])=[C:53]([CH:57]=1)[C:54](O)=[O:55].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[C:49]([Br:48])[CH:50]=[CH:51][C:52]=3[NH:58][CH3:59])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CNc1ccc(Br)cc1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1ccc(Br)cc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 5-bromo-2-methylaminobenzoic acid (8.4 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19][NH:29][C:24]3[N:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[N:23]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Reactant: Nc1nc(F)cc(F)n1
Agent: Cl
Product: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nc(F)cc(F)n2)cc1
Yield: 45 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.42 g, 45% yield). M/e+ 390.2 for C18H11ClF3N5 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26])=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of compound 40 (4.00 g, 0.0110 mole) in 10 mL of ethyl acetate at room temperature was added 5N HCl in 5 ethyl acetate (50 mL, freshly prepared, 0.25 mole) in one portion. The solution was stirred for 3 hrs, solvent was evaporated, CH2Cl2 was added and the solvents were reevaporated. The residue was pumped at <1 mm Hg on a vacuum pump for 24 hours to afford 3.37 g (~Quantitative crude yield) of product 41 as a colorless foam. TLC (silica gel; CH2Cl2, methanol, conc. NH4OH: 27:3:1): Rf=0.32.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:3]=1.[NH2:23][NH2:24]>C(O)C.C1COCC1>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:4]1[N:3]=[C:2]2[NH:23][N:24]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[C:7]2=[CH:6][N:5]=1
Reactant: O=C(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1ccccc1Oc1ncc2c(-c3cccs3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
[4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanone (82 mg, 0.23 mmol) was dissolved in a mixture of 10 mL ethanol and 0.5 mL THF, and 15 mg of anhydrous hydrazine was added. The reaction mixture was stirred at room temperature for 10 minutes and then was heated to 80° C. for 20 minutes. Solvent was removed under reduced pressure, and the residue was purified by preparative scale TLCusing 1.8% MeOH in methylene chloride to yield 36 mg of 6-(2-Chloro-phenoxy)-3-thiophen-2-yl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=329. Mp=221.3-223.1° C.