Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:4](=[O:22])[C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.[Br:33]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:33][C:7]1[N:6]=[C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)=[O:9])[C:4](=[O:22])[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)nc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
5-Methyl-N-{[5-(methylsulfonyl)-pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.097 g, 0.21 mmol) was dissolved in DMF (2 ml) in a vial. To this mixture was added N-bromosuccinimide (0.055 g, 0.31 mmol), and the vial was sealed and the mixture was heated at 50° C. with stirring for 1 h. The crude mixture was added dropwise to water (40 ml) under magnetic stirring. The precipitate was isolated by filtration to give 0.105 g (92%) of 6-bromo-5-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([N:22](C(C)C)CC)(C)C.[OH-].[NH4+]>CN(C)C=O>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH2:22])=[O:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3oc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2c(=O)c3ccccc3oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of 9-oxo-9H-xanthene-4-carboxylic acid 5j (1.84 g, 7.66 mmol) in dimethylformamide (20 mL) was added N,N-diisopropyl-N-ethylamine (1.74 mmol, 9.96 mmol) and O(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (2.9 g, 7.66 mmol). The mixture was stirred for 30 min at rt, and ammonium hydroxide (2 mL) was added. The mixture was stirred for 3 h, poured onto ice, and the solid was collected via filtration. The solid was washed with water and air-dried to yield 1.78 g (97.2% of title compound 6j.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9](F)[CH:10]=1)[C:6]#[N:7].[F:14][C:15]([F:44])([F:43])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([OH:42])[C@@H:24]([C:28]2[CH:41]=[CH:40][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=1>>[F:14][C:15]([F:43])([F:44])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([O:42][C:9]2[CH:10]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=2)[C@@H:24]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:40][CH:41]=2)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
Using the procedure from EXAMPLE 75, 3-trifluoromethyl-5-fluorobenzonitrile and N-(4-{(1R)-1-[(R)-(4-trifluoromethoxyphenyl)(hydroxy)methyl]butyl}benzoyl)-β-alanine were converted to the title compound. LC3 4.01 min. (M+H)+ 609.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10]O)[CH2:7][C:6]=2[CH:12]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][Cl:21])[CH2:7][C:6]=2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1Cc2cc(Cl)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: ClCC1Cc2cc(Cl)ccc2O1
Temperature: 80 °C
Reaction time: 7 h
Yield: 46.2 %

Procedure:
To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (3 g, 16 mmol) in benzene (50 ml) was added pyridine (1.55 g, 19.6 mmol, 1.2 eq) and thionyl chloride (2.72 g, 23.0 mmol) dropwise with stirring at 0° C. for 7 hours at 80° C. in an oil bath. The reaction mixture was adjusted to ˜pH 8 with aqueous sodium bicarbonate and then extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran as an off-white solid (1.5 g, 46%); 1H NMR (300 MHz, CDCl3): δ 7.06-7.14 (m, 2H), 6.70 (d, J=8.4 Hz, 1H), 4.99-5.10 (m, 1H), 3.64-3.76 (m, 2H), 3.32-3.40 (dd, J=9.3 Hz, 16.2 Hz, 1H), 3.09-3.17 (dd, J=6.6 Hz, 16.2 Hz. 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:29]1([C:33]([Cl:35])=[O:34])[CH2:32][CH2:31][CH2:30]1>>[ClH:35].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:33]([CH:29]5[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCC4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 28.6 mg (0.24 mmol) of cyclobutanecarbonyl chloride are reacted together by general method F. 38 mg (61.3% of theory) of the title compound are obtained.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([Cl:21])=[CH:5][C:6]([Cl:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.S(=O)(=O)(O)[OH:24]>>[Cl:14][C:13]1[C:9]([C:7]2[CH:8]=[C:3]([CH:2]=[O:24])[C:4]([Cl:21])=[CH:5][C:6]=2[Cl:20])=[N:10][N:11]([CH3:19])[C:12]=1[O:15][CH:16]([F:18])[F:17]
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
Analogously to Example 12, 45.5 g (91 mmol) of 3-(5-dibromomethyl-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole were introduced into 65 ml of concentrated sulfuric acid. After working up, 20 g of the product were obtained. 1H-NMR (270 MHz, in CDCl3): δ [ppm]=10.41 (s,1H), 8.02 (s,1H), 7.65 (s,1H),6.77 (t,1H), 3.87 (s,3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:27])[CH3:26])[NH:20][C:19](=[O:28])[C@@H:18]([NH:29]C(OC(C)(C)C)=O)[CH2:17][C:16]2=[CH:37][CH:38]=[C:13]([CH:14]=[CH:15]2)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6]1)=[O:4].[ClH:39]>O1CCOCC1>[ClH:39].[CH3:1][O:2][C:3]([C@H:5]1[NH:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:27])[CH3:26])[NH:20][C:19](=[O:28])[C@@H:18]([NH2:29])[CH2:17][C:16]2=[CH:37][CH:38]=[C:13]([CH:14]=[CH:15]2)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSCCCCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CSCCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1

Procedure:
Methyl ester 33 (0.300 g, 0.544 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL). The resultant solution was stirred at rt for 18 h before being concentrated in vacuo to yield an off white solid; 0.265 g, 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.CCN(C(C)C)C(C)C.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH:24]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=3[CH:14]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(=O)c2ccc(NC(=O)CCC3CCCC3)cc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 7-amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one (1.93 g, 10.0 mmol) and DIEA (1.55 g, 12.00 mmol) in DCM (50 mL) was added drop-wise a solution of 3-cyclopentylpropionyl chloride (Aldrich, 1.93 g, 12.0 mmol) in DCM. The reaction was stirred at 0° C. for 1 hr, then at rt for 3 hrs. The reaction mixture was washed with an aqueous solution of HCl (1N). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (30/70)) gave 3.05 g (96%) of the title compound as a pale yellow oil. HPLC, Rt: 4.26 min (purity: 99.6%). LC/MS, M+(ESI): 318.2, M−(ESI): 316.2. 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.05 (dd, J=1.9 Hz, J=8.4 Hz, 1H), 2.41 (t, J=7.6 Hz, 2H), 1.80-1.45 (m, 15H), 1.17-1.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[CH:20]([NH2:22])=O>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]3=[N:1][CH:20]=[N:22][C:15](=[O:17])[CH:3]3[CH:4]=[N:5]2)=[CH:12][CH:11]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1N
Product: COc1ccc(N2N=CC3C(=O)N=CN=C32)cc1
Temperature: 180 °C

Procedure:
A mixture of compound 44A (7 g, 26.8 mmol) and formamide (64.1 mL, 1607 mmol) was heated at 180° C. overnight and cooled. The precipitate was collected, washed with water and dried to provide the desired product: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.35 (1H, s), 8.28 (1H, s), 8.15 (1H, s), 7.85-7.93 (2H, m), 7.09-7.14 (2H, m), 3.82 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:13][CH2:14][C:15]#[N:16].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:37])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:13][CH2:14][C:15]#[N:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of the compound from Example 47 with a purity of 85% (0.21 mmol) were introduced into 14 ml of dichloromethane at 0° C., 59.1 mg (0.24 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 62 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:24]CCl>CN(C)C=O>[CH2:1]([NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCCc2ccccc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a suspension of 3-(3-phenethylsulfamoyl-phenyl)-acrylic acid (5h) (0.15 g, 0.45 mmol) in dichloromethane (2.0 ml) oxalyl chloride (0.14 ml, 1.57 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.16 g).
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:26](Br)[C:27]#[CH:28]>>[CH2:28]([O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4])=[CH:25][CH:24]=1)[C:27]#[CH:26]
Reactant: C#CCBr
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCOc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC=C(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-farnesyloxybenzoic acid with propargyl bromide, there is obtained p-farnesyloxybenzoic acid propargyl ester; B.P. 245°-250° C./0.1 mmHg.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(#N)C.C(N(C(C)C)CC)(C)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:24][CH:25]=2)=[O:31])=[CH:19][CH:18]=1)[CH3:17]
Reactant: CCOC(=O)CCNC(=O)c1ccc(CN)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCNC(=O)c1ccc(CNC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
Ethyl 3-(4-Aminomethylbenzoylamino)propanoate hydrochloride (0.25 g, 0.87 mmol) in acetonitrile (5 mL) and diisopropylethylamine (0.15 mL) was allowed to react with 4-trifluoromethoxyphenylisocyanate (0.37 g, 1.74 mmol) at 50° C. overnight. Upon cooling to 25° C. the product precipitated and was collected by filtration.
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([O:11][C:12]2[C:17]3[N:18]=[C:19]([NH2:21])[S:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:6]=1.[CH2:34]([CH2:38][CH:39]=O)[CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:32][C:2]([N:1]1[CH2:39][CH2:38][CH2:34][CH2:35][CH2:36]1)([CH3:33])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([O:11][C:12]2[C:17]3[N:18]=[C:19]([NH2:21])[S:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[N:6]=1
Reactant: O=CCCCC=O
Reactant: CC(C)(N)CNc1nc(Oc2cccc3sc(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(CNc1nc(Oc2cccc3sc(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-(2-amino-2-methylpropylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine (47 mg, 1.0 mmol, Example 80) and 50% aqueous solution of glutaric dialdehyde (40 mg, 0.2 mmol, Aldrich) in 1,2-dichloroethane (2 mL) was added sodium triacetoxyborohydride (212 mg, 1.0 mmol, Aldrich) and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was treated with sat. aqueous solution of NaHCO3 (5 mL), and extracted with EtOAc (2×20 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (10% MeOH/DCM) to afford the title compound as a white amorphous solid. MS (ESI, pos. ion.) m/z: 543 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[Cl-].[Cl:18][C:19]1[S:20][S+:21]=[C:22](Cl)[C:23]=1[Cl:24]>C(Cl)Cl>[Cl:24][C:23]1[C:22](=[N:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=2)[S:21][S:20][C:19]=1[Cl:18]
Reactant: Clc1s[s+]c(Cl)c1Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc(Cl)cc(N=c2ssc(Cl)c2Cl)c1

Procedure:
18.5 g of 3,5-dichloro-aniline were dissolved in 300 ml of methylene chloride and 50 ml of triethylamine and 31.0 g of 3,4,5-trichloro-1,2-dithiolium chloride were introduced at 10°-15° C. The mixture was stirred for about 12 hours, until a test for aromatic amine, by diazotizing and coupling, proved negative. The resulting dark solution was then washed three times with 200 ml of water, dried over potassium carbonate and filtered over a column of aluminum oxide, to remove impurities that imparted a color. The filtrate was reduced to dryness in vacuo and the residue was recrystallized from petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][C:31]1[N:36]=[N:35][CH:34]=[C:33]([C:37]([OH:39])=O)[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37]([C:33]2[CH:32]=[C:31]([CH3:30])[N:36]=[N:35][CH:34]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C(=O)O)cnn1
Product: Cc1cc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cnn1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 6-methyl-pyridazine-4-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 6-methyl-pyridazine-4-carboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 557.9 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[BH4-].[Na+].C(O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([OH:17])[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(=O)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2C(O)c3ccc(OC)cc3C3CCCCC32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (58.0 mg, 0.17 mmol), sodium borohydride (52.0 mg, 1.40 mmol), ethanol (3.0 mL), tetrahydrofuran (3.0 mL), stir, and reflux under a nitrogen atmosphere. After 2 hours, cool to ambient temperature, and concentrate in vacuo. Add ethyl acetate to reaction mixture, wash with sat ammonium chloride solution(aq), Brine, and dry over sodium sulfate. Concentrate to yield the titled compound (57.0 mg, 99%) as a white solid. TLC Rf=0.12 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.50 (d, 1H, J=8.8 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.93 (d, 2H, J=8.4 Hz), 6.80 (dd, 1H, J=8.6, 2.4 Hz), 6.66 (m, 1H), 4.77 (d, 1H, J=9.7 Hz), 3.82 (m, 6H), 3.05 (m, 1H), 2.85 (m, 1H), 2.35 (m, 1H), 1.75 (m, 4H), 1.40 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]=[O:15])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: Cc1nnc(N=C=O)s1
Reactant: CNCCC=O
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CCC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-methylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reactions vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-ureido]propionaldehyde.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][N:13]([C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH2:12]2)[CH2:6][CH2:5]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCN(c3nccc(C(F)(F)F)n3)C2)C(=O)O1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2-chloro-4-(trifluoromethyl)pyrimidine following a procedure analogous to that described in
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:18][CH3:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CN
Product: CNC(=O)C1(c2ccc(F)cc2)CCCCC1
Yield: 86 %

Procedure:
The title compound was synthesized from 1-(4-fluorophenyl)cyclohexane-carboxylic acid (222 mg, 1 mmol) and methylamine (1 mL, 1M in THF, 1 eq) according to General Procedure G. The crude product was purified by silica gel column chromatography to give the amide (202.6 mg, 86%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH:22]=O)[C:19]([C:24](OC)=[O:25])=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[CH2:44][NH2:45].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[CH2:44][N:45]1[C:24](=[O:25])[C:19]2[C:18]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:21][C:20]=2[CH2:22]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1c(C=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Reaction time: 1 h
Yield: 3 %

Procedure:
Methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.175 g, 0.382 mmol) was dissolved in DCM (2 mL) and MeOH (1 mL). To this mixture was added (2,4-dimethoxyphenyl)methanamine (0.057 mL, 0.382 mmol) and sodium acetate (0.094 g, 1.145 mmol). The mixture was stirred in a capped 20 mL vial for 1 h, after which sodium cyanoborohydride (0.060 g, 0.954 mmol) was added. The reaction mixture was stirred at RT overnight. After the solvent was removed under reduced pressure, the residue was dissolved in DMSO/MeOH (1/1) solution. An off-white solid precipitate was initially formed, which was isolated by vacuum filtration, rinsed with MeOH, and air dried to give a first batch of the title compound (6.7 mg). The mother liquor was purified via preparative HPLC. The fractions were concentrated under reduced pressure until an off-white solid precipitate was formed, which was collected by vacuum filtration and air dried to give a second batch (46 mg) of the title compound (total 62.5 mg, 28%). [M+H] calc'd for C30H39N7O5, 578. found, 578.