Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([OH:20])=O)=[O:12].[NH:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])=[O:20])=[O:12]
Reactant: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1CO
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
3-(Indan-2-ylacetyl)-L-thioproline (4.40 g) and L-prolinol (1.53 g) were dissolved in 150 ml of methylene chloride, followed by addition of 2.90 g of WSC-HCl under agitation while cooling in ice and subsequent agitation for-another 30 minutes at room temperature. The reaction solution was washed sequentially in 5 HCl, saturated aqueous solution of sodium bicarbonate, saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography to obtain 2.40 g of 1-[3-(indan-2-yl-acetyl)-L-thioprolyl]-L-prolinol. Yield; 42%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:6]=[C:7]([C:12]([OH:14])=O)[S:8][C:9]=1[CH:10]=[O:11])[CH3:4].C([O:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[NH:31])[NH:29]O)=[CH:23][C:22]=1[CH2:32][CH3:33])C>CO>[CH2:32]([C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[C:12]([C:7]3[S:8][C:9]([CH:10]=[O:11])=[C:5]([CH2:3][CH3:4])[CH:6]=3)[O:14][N:31]=2)[CH:25]=[C:26]([CH3:27])[C:21]=1[CH2:20][CH2:19][C:18]([OH:34])=[O:17])[CH3:33]
Reactant: CCc1cc(C(=O)O)sc1C=O
Reactant: CCOC(=O)CCc1c(C)cc(C(=N)NO)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(CC)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method E followed by treating the corresponding propionic ester derivative for 1 h at rt with 1 N aq. NaOH in methanol starting from 4-ethyl-5-formyl-thiophene-2-carboxylic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid ethyl ester; LC-MS: tR=0.87 min; [M+1]+=399.20.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (83 mg, 0.37 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (109 mg, 0.37 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (127 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[NH:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26](Cl)Cl.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:26][N:19]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:17][N:16]=[C:15]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)[nH]1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: Cn1c(C(=O)CCCCCCc2ccccc2)nnc1-c1ccccn1
Yield: 23 %

Procedure:
A sample of 14b (3.0 mg, 0.009 mmol) was dissolved in a mixture of MeOH (0.1 mL): CH2Cl2 (0.1 mL). TMSCHN2 (7 μL, 0.013 mmol) was added dropwise causing gas to evolve, and after 0.5 h the reaction mixture was quenched with the dropwise addition of AcOH (50 μL). All volatiles were removed under reduced pressure to afford a residue that was purified by preparative thin layer chromatography (SiO2, 50% EtOAc-hexanes). The title compound (0.735 mg, 23%) was isolated along with the two other regioisomers (16; 1.01 mg, 32%; 17; 0.496 mg, 16%) as a colorless solid: 1H NMR (CDCl3, 500 MHz) δ 8.71 (dd, 1H, J=0.9, 4.9 Hz), 8.33 (d, 1H, J=8.0 Hz), 7.88 (dt, 1H, J=1.8, 7.8 Hz), 7.41 (ddd, 1H, J=1.1, 4.9, 7.6 Hz), 7.28 (m, 2H), 7.16 (m, 3H), 4.37 (s, 3H), 3.28 (t, 2H, J=7.4 Hz), 2.61 (t, 2H, J=7.7 Hz), 1.78 (m, 2H), 1.64 (m, 2H), 1.42 (m, 4H); HRMS-ESI-TOF m/z 349.2020 ([M+H]+, C21H24N4O requires 349.2023). Tetrazoles (15a-15e, 19a, 19b):
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 76.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,5-di-methoxyaniline (133 mg, 0.87 mmol) to provide 200 (114 mg, 76% yield) as a white solid. LC-MS (M+H=348, obsd.=348).
Reaction SMILES: Cl.[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][C:11](=[O:18])[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41]>CN(C=O)C.O>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[CH2:10][C:11](=[O:18])[N:12]2[CH2:13][CH2:14][N:15]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:42])[F:43])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
A solution of N-Biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) and K2CO3 (58 mg, 0.42 mmol) in DMF (2 mL) was stirred for 15 minutes at room temperature, then cooled to 0° C. and 1-bromomethyl-2-trifluoromethyl-benzene (50 mg, 0.21 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours then diluted with water. The resulting precipitate was filtered to afford 85 mg (85%) of N-biphenyl-4-yl-3-oxo-3-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-propionamide. LCMS: 482.2 (M+1)+, 98.8%, 1H NMR: (CDCl3): δ 10.0 (s, 1H), 7.76 (d, 1H), 7.66 (d, 3H), 7.58 (m, 5H), 7.44 (t, 2H), 7.34 (m, 2H), 3.7 (m, 4H), 3.6 (t, 2H), 3.48 (s, 2H).
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14]>O1CCCC1>[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([S:11][C:7]1[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: C=C(C)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(S)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Sc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixed solution of water (1.6 mL)-concentrated sulfuric acid (1.6 mL) was added 3-nitrothiophenol (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added a solution of α-methylstyrene (0.38 g) in tetrahydrofuran (1.6 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give 3-(1-methyl-1-phenylethylthio)nitrobenzene (0.88 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution were added methanol (10 mL), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give the title compound (0.69 g).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:27]1(O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccccc2)CC1

Procedure:
The title compound was prepared in analogy to example 162 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155) and phenol. White solid (71%). MS (EI): 477.1 (M+H)+.
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8](N)=[CH:7][CH:6]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:9]([O:11][CH3:12])=[N:10][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:6][CH:7]=2)[N:20]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1nc(P(C)(C)=O)ccc1N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(P(C)(C)=O)ccc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1

Procedure:
Add 20% palladium hydroxide on carbon (Pearlman's catalyst) (232 mg) to a solution of 5-(R)-[1-(S)-benzyloxy-2-(S)-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(S)-(2-cyclohexylethyl)-morpholine-4-carboxylic acid tert-butyl ester (232 mg, 0.31 mmol) in methanol (5 mL). Stir under 1 atmosphere of hydrogen gas at room temperature overnight, filter through a pad of Celite® and concentrate to give the desired compound as a colorless oil which is used directly without further purification (138 mg, 93%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (10 g, 102.52 mmol) and ethyl chlorooxoacetate (13.77 ml, 123.02 mmol) in dichloromethane (163 ml) at 0° C. was added triethylamine (28.6 ml, 205.04 mmol) drop wise. The reaction was stirred at room temperature for 1.5 hrs. The reaction was quenched with 20 ml of methanol, and then concentrated. The resulting solid was triturated with THF and filtered away. The filtrate was concentrated. The residue was vacuum distilled bulb to bulb. At approximately 85° C. impurities were collected and then discarded. The title compound was collected at approximately 120° C. as a neat oil (11.6 g, 72.0 mmol, 70.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][C:34]2[C:39]([CH3:40])=[CH:38][C:37]([Cl:41])=[CH:36][N:35]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([N:32]([CH2:33][C:34]2[C:39]([CH3:40])=[CH:38][C:37]([Cl:41])=[CH:36][N:35]=2)[CH2:17][C:12]2[C:11]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([CH3:9])[CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reacting of 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde, 4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave 4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 1.22 (br, 2H), 1.44 (s, 9H), 1.59 (br, 2H), 1.60 (s, 6H), 2.27 (s, 3H), 2.47 (m, 3H), 3.34 (s, 2H), 3.65 (s, 2H), 4.03 (br, 2H), 6.87 (m, 4H), 7.18 (m, 1H), 7.36 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 8.21 (s, 1H), 8.48 (d, 1H, J=3.9 Hz). Deprotection with TFA using General Procedure F gave (5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-piperidine-4-yl-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br-:10].[Br-:11].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:10][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([Br:11])[C:6]=1[OH:9]
Reactant: COc1ccc(O)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)c(O)c(Br)c1
Yield: 101.2 %

Procedure:
To 4-methoxyphenol (10.00 g, 80.6 mmol) in CH2Cl2 (70 mL), add a stirred solution of benzyltrimethylammonium tribromide (69.10 g, 177.2 mmol) in CH2Cl2 (500 mL) and MeOH (200 mL). Stir the reaction for 12 hours and remove the solvent in vacuo. Add methyl tert-butyl ether (MTBE) (600 mL) and collect the precipitate (benzyltrimethylammonium bromide) by filtration and wash with MTBE (200 mL). Filter the organics through Celite® and concentrate to provide the subtitled product (23.0 g, >95%) as an orange solid that may be used without purification. 1H NMR (DMSO-d6) δ 3.69 (s, 3H), 7.14 (s, 2H), 9.32 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[CH:6][CH:5]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-(difluoromethoxy)benzaldehyde (10 g, 58 mmol) and (S)-2-methylpropane-2-sulfinamide (13 g, 105 mmol) in THF (50 mL) was added Ti(OEt)4 (43 mL, 209 mmol) and the reaction was stirred at RT overnight. The mixture was poured into brine (400 mL) and stirred for 10 min, filtered, and the filtered solids rinsed with additional THF/EtOAc. The organic layer was separated, and the aqueous layer extracted with additional EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was dry loaded and passed through a SiO2 plug eluting with a EtOAc/hexane gradient (10 to 15% EtOAc) to afford 16 g (100%) of (S,E)-N-(4-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (378) as pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC=CC=1>CC(O)=O.[Fe]>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])cc(N)c1F
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of methyl 2-fluoro-3,5-dinitrobenzoate (D137) (24.4 g, 0.1 mol, 1 equiv) in AcOH (1 l) was added iron (27.5 g, 0.5 mol, 5 equiv) and the resulting suspension was vigorously stirred for 1 h. The temperature was kept below 35° C. by small amount of cooling using an ice bath during that period. Toluene (200 ml) was added and the suspension filtered through a pad of celite. The remaining solution was concentrated in vacuo and the residue partitioned between AcOEt and a saturated aqueous NaHCO3 solution. The two layers were separated and the aqueous phase was extracted twice with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (17 g, 79%) as a yellow solid which was used in the next step without further purification. [M−H]−=212.9, RT=2.68 min.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: CCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-E1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and propionyl chloride were converted to l-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6Hpyrazolo[3,4-c]pyridin-6-yl)propan-1-one as a white solid (35 mg, 63%): mp 182-187° C.; 1H NMR (500 MHz, DMSO-d6) δ13.15-13.10 (m, 0.25H), 12.87 (br s, 0.75H), 7.76-7.72 (m, 1H), 7.51-7.49 (m, 1H), 4.85-4.83 (m, 1H), 4.68-4.57 (m, 3H), 3.69 (s, 0.5H), 3.63 (s, 1.5H), 3.15-3.13 (m, 2H), 2.79-2.77 (m, 1H), 2.68-2.55 (m, 2H, partially merged with DMSO peak), 2.46-2.38 (m, 2H), 1.76-1.71 (m, 4H), 1.02 (t, J=7.5 Hz, 3H); ESI MS m/z 471 [M+H]+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.[CH3:19][C:20]1(C)[C:24](C)(C)OB(C(C)=C)O1>O1CCOCC1.O.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>[CH2:19]=[C:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH3:24]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 100 °C
Yield: 96.7 %

Procedure:
118-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (750 mg, 2.12 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (712 mg, 4.24 mmol) Cs2CO3 (1.72 g, 5.29 mmol) and Pd(PPh3)4 (122 mg, 0.11 mmol) in dioxane/H2O (9:1, mL) was heated to 100° C. for 2 h in a microwave reactor. The mixture was then concentrated in vacuo and the residue purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) to give the title compound (550 mg). UPLC-MS: MS 269.2 (M+H+); UPLC rt 0.83 min.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH3:28][N:29]=[C:30]=[S:31]>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:30]([NH:29][CH3:28])=[S:31])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: CN=C=S
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 31.4 mg (0.429 mmol) of methyl isothiocyanate and 5 ml of THF is stirred at 20° C. for 15 hours. Concentration to a volume of about 1 ml, addition of 5 ml of diethyl ether to the concentrate and filtration yield 4-(3-chloro-phenylamino)-3-[4-(methylamino-thiocarbonylamino-methyl)phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 1.22%; m.p. 216-218° C. (decomp.), ESI-MS: (M−H)−=437.